Item
1. Business
Overview
We
are a clinical stage biotechnology company, focused on leveraging artificial intelligence (“A.I.”), machine learning
and genomic data to streamline the drug development process and to identify the patients that will benefit from our targeted oncology
therapies. Our portfolio of therapies consists of small molecules that others have tried, but failed, to develop into an approved
commercialized drug, as well as new compounds that we are developing with the assistance of our proprietary A.I. platform and
our biomarker driven approach. Our A.I. platform, known as RADR®, currently includes more than 1.2 billion data
points, and uses big data analytics (combining molecular data, drug efficacy data, data from historical studies, data from scientific
literature, phenotypic data from trials and publications, and mechanistic pathway data) and machine learning to rapidly uncover
biologically relevant genomic signatures correlated to drug response, and then identify the cancer patients that we believe may
benefit most from our compounds. This data-driven, genomically-targeted and biomarker-driven approach allows us to pursue a transformational
drug development strategy that identifies, rescues or develops, and advances potential small molecule drug candidates at what
we believe is a fraction of the time and cost associated with traditional cancer drug development.
Our
strategy is to both develop new drug candidates using our RADR® platform and other machine learning driven methodologies,
and to pursue the development of drug candidates that have undergone previous clinical trial testing or that may have been halted
in development or deprioritized because of insufficient clinical trial efficacy (i.e., a meaningful treatment benefit relevant
for the disease or condition under study as measured against the comparator treatment used in the relevant clinical testing) or
for strategic reasons by the owner or development team responsible for the compound. Importantly, these historical drug candidates
appear to have been well-tolerated in many instances, and often have considerable data from previous toxicity, tolerability and
ADME (absorption, distribution, metabolism, and excretion) studies that have been completed. Additionally, these drug candidates
may also have a body of existing data supporting the potential mechanism(s) by which they achieve their intended biologic effect,
but often require more targeted trials in a stratified group of patients to demonstrate statistically meaningful results. Our
dual approach to both develop de-novo, biomarker-guided drug candidates and “rescue” historical drug candidates by
leveraging A.I., recent advances in genomics, computational biology and cloud computing is emblematic of a new era in drug development
that is being driven by data-intensive approaches meant to de-risk development and accelerate the clinical trial process. In this
context, we intend to create a diverse portfolio of oncology drug candidates for further development towards regulatory and marketing
approval with the objective of establishing a leading A.I.-driven, methodology for treating the right patient with the right oncology
therapy.
A
key component of our strategy is to target specific cancer patient populations and treatment indications identified by leveraging
our RADR® platform, a proprietary A.I. enabled engine created and owned by us. We believe the combination of our
therapeutic area expertise, our A.I. expertise, and our ability to identify and develop promising drug candidates through our
collaborative relationships with research institutions in selected areas of oncology gives us a significant competitive advantage.
Our RADR® platform was developed and refined over the last four years and integrates millions of data points immediately
relevant for oncology drug development and patient response prediction using artificial intelligence and proprietary machine learning
algorithms. By identifying clinical candidates, together with relevant genomic and phenotypic data, we believe our approach will
help us design more efficient preclinical studies, and more targeted clinical trials, thereby accelerating our drug candidates’
time to approval and eventually to market. Although we have not yet applied for or received regulatory or marketing approval for
any of our drug candidates, we believe our RADR® platform has the ability to reduce the cost and time to bring
drug candidates to specifically targeted patient groups. We believe we have developed a sustainable and scalable biopharma business
model by combining a unique, oncology-focused big-data platform that leverages artificial intelligence along with active clinical
and preclinical programs that are being advanced in targeted cancer therapeutic areas to address today’s treatment needs.
Scientific
literature offers a definition for “drug rescue” as research involving abandoned small molecules and biologics that
have not been approved by the U.S. Food and Drug Administration (“FDA”). These rescued molecular compounds are often
abandoned by pharmaceutical companies in the drug discovery or preclinical testing phase, typically because they do not prove
effective for the specific use for which they were developed. Some of these compounds may be useful in treating other diseases
for which they have not been tested. See, Hemphill, Thomas A., “The NIH Promotes Drug Repurposing and Rescue,”
Research Technology Management, v. 5, no. 5, pp. 6-8 (2012). Our use of the term “rescue”, “drug rescue”,
or “drug rescuing” refers to, “…a system of developing new uses for chemical and biological entities
that previously were investigated in clinical studies but not further developed or submitted for regulatory approval, or had to
be removed from the market for safety reasons.”, which is a definition we believe is recognized in the drug discovery, drug
development and pharmaceutical and biotechnology industries. See, Naylor, S. and Schonfeld J., “Therapeutic Drug
Repurposing, Repositioning and Rescue,” DDW (Drug Discovery World) Winter 2014, and Mucke, HAM, A New Journal for the Drug
Repurposing Community. Drug Repurposing, Rescue & Repositioning 1, 3-4 (2014). The use of the term “drug rescue,”
“rescuing,” or words of similar meaning in this report should not be construed to mean that our RADR®
platform has resolved all issues of safety and/or efficacy for any of our drug candidates. Issues of safety and efficacy for any
drug candidate may only be determined by the U.S. FDA or other applicable regulatory authorities in jurisdictions outside the
United States.
Our current portfolio
consists of four compounds in active development: two drug candidates in clinical phases, one in preclinical studies, and one in
research optimization. All of these drug candidates are leveraging precision oncology, A.I. and genomic driven approaches to accelerate
and direct development efforts. We currently have two drug candidates in clinical development, LP-100 and LP-300, where we are
leveraging data from prior preclinical studies and clinical trials, along with insights generated from our A.I. platform, to target
the types of tumors and patient groups that would be most responsive to the drug. Both LP-100 and LP-300 showed promise in important
patient subgroups, but failed pivotal Phase III trials when the overall results did not meet the predefined clinical endpoints.
We believe that this was due to a lack of biomarker-driven patient stratification. Additionally, we have one new drug candidate,
LP-184, in preclinical development for two potentially distinct indications where we are leveraging machine learning and genomic
data to streamline the drug development process and to identify the patients and cancer subtypes that will best benefit from the
drug, if approved. As part of our antibody drug conjugate (ADC) program commenced in early 2021, we have initiated the optimization
and evaluation of an antibody drug conjugate aimed at leveraging our LP-184 molecule in combination with an antibody for select
solid tumors.
Our
development strategy is to pursue an increasing number of oncology focused, molecularly targeted therapies where artificial intelligence
and genomic data can help us provide biological insights, reduce the risk associated with development efforts and help clarify
potential patient response. We plan on strategically evaluating these on a program-by-program basis as they advance into clinical
development, either to be done entirely by us or with out-licensing partners to maximize the commercial opportunity and reduce
the time it takes to bring the right drug to the right patient.
We have out-licensed
our drug-candidate LP-100 to Allarity Therapeutics A/S (“Allarity Therapeutics”), a European biotechnology company.
LP-100 is in a Phase II clinical trial in metastatic, castration-resistant, prostate cancer (mCRPC) that is managed by Allarity
Therapeutics. Our second clinical-stage drug candidate in the rescue process is LP-300. LP-300 is a small molecule with cysteine
modifying activity on select proteins, which has an existing investigational new drug application (“IND”). We are in
the process of initiating discussions with the U.S. FDA to launch a future phase II clinical trial for LP-300 with a stratified
patient population of approximately 40 to 75 patients. Our new drug candidate, LP-184, is in a preclinical translational ex
vivo study using fresh human biopsies. LP-184 is a next generation alkylating agent with nanomolar potency that preferentially
damages DNA in cancer cells that overexpress certain biomarkers. LP-184 is in the fulvene class of compounds and has shown preliminary
preclinical indications of lower toxicity, longer half-life, and increased antitumor activity as compared to other compounds in
this drug class. Subject to regulatory clearance to move forward under a future IND application, we are planning a Phase I clinical
trial for LP-184 across multiple solid tumors that express a certain biomarker profile, and in glioblastoma to begin in late 2021
or early 2022. Our antibody drug conjugate (ADC) program is in early stage development and compound optimization for solid tumors.
LP-100
(Irofulven) is showing promise in solid tumors, primarily prostate cancer, where it is being advanced in an out-licensing transaction
with Allarity Therapeutics, after being in-licensed and developed by us. LP-100 has been well-tolerated, based on initial
observations from a phase II clinical trial in Europe in mCRPC. Continuing enrollment for this Phase II clinical trial has slowed
during the COVID-19 pandemic. Allarity Therapeutics has also stated that it is focusing its existing resources on other programs
that are currently higher priority for Allarity than LP-100. As of the date of this report, we are unable to forecast the timeline
for the completion of the Phase II clinical trial. Recently published data (also supported by prior publications on Irofulven)
indicates that tumors carrying mutations in ERCC2 and ERCC3 genes are likely to be sensitive to LP-100, and that the drug will
be synthetically lethal in these tumors, in a fashion similar to the activity of PARP inhibitors in BRCA deficient tumors. These
observations expand the potential treatment indications for LP-100 to include urothelial tumors, including bladder cancers, since
as many as 10% of bladder cancers carry ERCC2/ERCC3 mutations. These indications may represent a more rapid and efficient path
to potential approval of LP-100, and we are evaluating possibilities aimed at maximizing the value of these additional observations.
Most
patients with metastatic prostate cancer present with localized cancer, for which the standard of care may include active observation,
radiation, surgery, and androgen deprivation/suppression therapy. Responses to such therapy can be transient and many patients
will develop a castration resistant prostate cancer (CRPC) and develop, or are at risk to develop, mCRPC which accumulates genomic
alterations including DNA repair deficits. Chemotherapeutic agents play a critical role in the management of both metastatic castration
sensitive and mCRPC. The frequent use of the chemotherapy drug docetaxel in treating metastatic androgen sensitive prostate cancers
exemplifies this role. Historical observations of potential anticancer activity of LP-100 in clinical studies with prostate cancer,
and evidence of sensitivity to LP-184 in prostate cancer cell lines along with the development of computational methods that integrate
gene expression signatures, support LP-184 as a drug candidate with potential for use in combination with androgen deprivation
therapy for metastatic prostate cancer that is castration sensitive as well as metastatic prostate cancer that is castration resistant.
LP-184
is a new small molecule drug candidate that in preliminary preclinical studies has demonstrated increased plasma stability, reduced
total body clearance, significantly longer half-life, and potentially greater tumor regression than other studied fulvene based
compounds. We estimate that a substantial number of patients each year who suffer from metastatic prostate cancer globally could
be eligible for potential treatment with LP-184, if approved. In addition, the observed nanomolar potency of LP-184 suggests that
it may have anticancer properties in a wide range of solid tumors as an alkylating agent that works by causing DNA damage in tumor
cells. Other indications for LP-184 in solid tumors are emerging as a result of early developmental and biomarker studies, including
ovarian, breast, liver, kidney, pancreatic and thyroid cancers, as well as certain glioblastomas.
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Based on increased
sensitivity in cell-lines and PDx models exhibiting DNA repair deficient genetic backgrounds, we believe that LP-184 could
have potential for targeted treatment of DNA repair deficient hereditary breast and ovarian cancers, from which more than
2.3 million patients suffer globally according to the Global Cancer Observatory.
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Based on recent
observations, we also believe that LP-184 could have potential as treatment (alone or in combination with other treatments)
for glioblastoma, which is an aggressive type of cancer that accounts for more than half of all primary brain tumors. The
American Association of Neurological Surgeons estimates that glioblastoma has an incidence of two to three per 100,000 adults
per year and accounts for about 17% of all tumors of the brain (primary and metastatic).
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Our A.I. platform
RADR® helped uncover genomic biomarkers that we believe indicate certain patients could be more responsive
to therapy with LP-184.
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Further
work on these biomarkers both in-silico and in preclinical studies will help to establish a genomic signature that may
accelerate our time to a clinical trial and help guide patient selection. We believe that the market for LP-184 as a molecularly-targeted
drug candidate could be significant.
LP-300
(disodium 2,2’-dithio-bis-ethane sulfonate or dimesna) is a late-stage clinical drug candidate that was in-licensed by us
from BioNumerik Pharmaceuticals, Inc. (“BioNumerik”) in May 2016, and subsequently acquired by us in January of 2018.
Using our RADR®platform as part of the drug rescue process, we have identified LP-300 for use in a more targeted
set of cancer patients who exhibit a biomarker profile that we believe correlates with non-or never smoking status but still have
a form of non-small cell lung cancer (NSCLC). LP-300, originally branded as Tavocept®, is a molecular entity that
we believe may be capable of ameliorating the toxic side effects of chemotherapeutic drugs such as cisplatin, and it also appears
to act as a potential chemoenhancer. LP-300 has been studied in multiple randomized, controlled, multi-center non-small cell lung
cancer (NSCLC) trials that included administration of either paclitaxel and cisplatin and/or docetaxel and cisplatin. Since acquiring
LP-300 from BioNumerik, we have not yet conducted further clinical testing of LP-300. We are currently evaluating LP-300 for the
launch of a targeted phase II trial, in non or never smoking patients with NSCLC in combination with chemotherapy, under an existing
IND.
Prior
clinical trials conducted by BioNumerik for LP-300 did not meet their primary clinical endpoints and at least one or more future
clinical trials that meet their pre-specified primary endpoints with statistical significance will be required before we can obtain
a regulatory marketing approval, if any, to commercialize LP-300. Prior clinical trial observations are not necessarily predictive
of the outcome of any future clinical trials we may conduct.
Retrospective
analyses of the results of a multi-country phase III lung cancer trial conducted by BioNumerik in subgroups of NSCLC adenocarcinoma
patients receiving LP-300, paclitaxel and cisplatin demonstrated substantial improvement in overall survival, particularly among
female never smokers, where a 13.6 month improvement in overall survival (p-value 0.0167, hazard ratio 0.367) in favor of LP-300
was observed, as compared to placebo in the subgroup of paclitaxel/cisplatin-treated patients. Similar retrospective findings
of increased overall survival in the subgroup of LP-300/paclitaxel/cisplatin treated female Asian patients with adenocarcinoma
of the lung were observed in a randomized, double-blind, placebo-controlled trial in Japan. We plan on advancing this drug candidate
for the never or non-smoker population of patients due to the following important market and clinical need factors:
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As many as 40% of
lung cancers either do not carry currently known targetable proteins or will progress despite initial therapy resulting in
a dependence upon chemotherapeutic drug regimens in their treatment, and according to the Global Cancer Observatory, lung
cancer is the second most common cancer with over 2 million cases globally.
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Approximately 40%
of all lung cancers are adenocarcinomas, with more than half of such lung adenocarcinomas occurring in women.
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As many as 20% of
people who die from lung cancer in the United States every year have never smoked or used any other form of tobacco.
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With declining rates
of smoking, especially in North America and Europe, the relative proportion of lung cancer patients who are never-smokers
is increasing, and this does not appear to be confounded by passive smoking or misreported smoking status.
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Women who have never
smoked have a higher proportion of lung cancer than men who are lifelong never-smokers.
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In the clinical
research community, a greater focus is being placed on lung cancers that occur in the never-smoking population along with
the recognition that such lung cancers might be a genetically distinct type of cancer with a different molecular profile than
smoking-based lung cancers.
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Mechanistic studies
indicate that LP-300 may work by disruption at binding sites of oncoproteins such as ALK, MET, ROS1 and EGFR which are more
commonly altered in female non-smokers and Asian females than in any other groups.
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Never-smokers have
also been observed to be less responsive to therapies that stimulate or leverage the immune system such as checkpoint inhibitors
or PD-1 and PL-L1 inhibitors. In a meta-analysis research publication of 1,981 patients by Drs. Li, Huang and Fu published
in OncoTargets and Therapy, June 26, 2018 which spanned 3 Phase III randomized, controlled clinical trials the authors
observed that, “…PD-1 inhibitors were more efficacious in smoking NSCLC patients compared with chemotherapy.
No better survival of nonsmoking patients was observed in the treatment of PD-1 inhibitors than chemotherapy.”
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We
are focused on advancing the development of LP-300 as a combination therapy for non or never-smokers with NSCLC adenocarcinoma
and potentially among non or never-smokers with a genomic signature that correlates with a higher potential of response to this
drug compound. We selected NSCLC in non- or never smokers as our lead proposed indication because it is a cancer with a growing
patient population, without effective treatment options, and LP-300 has shown an improvement in overall survival in this targeted
sub-group population in prior clinical studies.
In
vitro studies indicate that the target-specific effects of LP-300 potentially correlate to the covalent modification of accessible
cysteine residues important in protein function/structure. These could be involved in disruption/ blocking of cofactor binding
sites resulting in blocking of oncoproteins such as ALK, MET, ROS1, and EGFR that are more commonly altered in female non-smokers
than in any other group. Other potential mechanisms of action of LP-300 could include impact on stress induced oxidoreductases
thereby allowing LP-300 to exert its potential chemo-enhancing effects in the presence of chemotherapeutic agents such as cisplatin.
LP-300 is postulated to potentiate antitumor cytotoxicity of standard of care chemotherapy agents such as cisplatin. We believe
a key LP-300 related mechanism is likely to occur through the increase of tumor cell sensitivity to oxidative stress. Additionally,
via induction of NRF2 (also known as NFE2L2), LP-300 has the potential to provide protection of healthy cells against chemotherapy-associated
toxicity, and such protection potential was observed with LP-300 combination therapy in both prior nonclinical studies and clinical
trials
A
differential gene expression analysis of whole transcriptome profiling data from LP-300 treated versus untreated NSCLC adenocarcinoma
cells has been performed. Using a threshold of fold change > 2 out of a set of 51 curated NRF2 (NFE2L2) target genes as well
as NRF2 itself, we observed the top significantly upregulated genes in response to LP-300 exposure. Based on our observations,
we believe these genes could include NFE2L2, NQO1, PHGDH, HMOX1, SLC7A11, SRXN1, SOX2, GPX2, GPX3, GPX4, GPX7, G6PD, SIRT1, ITGB2
and BCL2. Our analysis indicates that these genes preferentially map to the following biological signaling pathways: (i) detoxification
of reactive oxygen species; (ii) glutathione metabolism; and (iii) inflammatory response. We filed a patent application in March
of 2020 on this discovery.
The
interaction network of selected genes along with the associated biological pathways is shown in the figure below.
As
part of our overall growth strategy, we plan to grow our pipeline by identifying new drug candidates and pursuing potential indications
for both LP-184 and LP-300 while leveraging our RADR® platform. We are also pursuing the identification and design
of potential combination therapies in cancer for our compounds by leveraging our RADR® platform to analyze synergistic
genomic networks and biological pathways with other currently approved drugs. We intend to select our next clinical program in
the next twelve months.
We
have an extensive multi-national portfolio of intellectual property directed to our drug candidates, and to protect the targeted
use and development of our portfolio of compounds in specific patient populations and in specific therapeutic indications. In
addition, as our RADR® platform and other machine learning driven methodologies progress and mature, we will continue
to evaluate additional ways to further protect these assets.
As
of March 2021, we own or control over 70 active patents and patent applications across 14 patent families whose claims are directed
to our drug candidates and what we plan to do with our drug candidates. We have in-licensed or acquired patents from AF Chemicals,
and BioNumerik that are directed to the compounds, LP-100, LP-184 and LP-300. Additionally, we have also filed patent applications
to further enhance, and extend the use of these in-licensed compounds. Our 14 patent families are directed to our drug candidates,
their usage, manufacturing and other matters. These matters are essential to precision oncology and relate to: (a) uniquely powerful,
data-driven, biologically relevant biomarker signatures, (b) patient selection and stratification approaches that rely on prediction
of response derived from these signatures and, (c) the ability to develop novel, combination therapy approaches with existing
therapeutics.
Our
Drug Candidate Pipeline
One
of the ways we are building our drug candidate pipeline is by in-licensing clinical stage drug candidates that may have been discontinued
for development. We use our RADR® platform to assist in analyzing prior clinical research conducted by others to
identify small-molecule oncology drug candidates that have (i) a well-tolerated profile evidenced by completion of phase I clinical
trials, and (ii) demonstrated at least limited antitumor or anticancer activity in clinical trials. We intend to implement an
efficient and thorough workflow to advance the drug candidates in our pipeline as potential precision medicine treatments for
cancer. Our targeted development workflow includes preclinical studies where drug activity and associated gene signatures are
identified, in part through strategic collaborations with some of the top academic institutions and clinical translational centers
in the world. Using this collaborative approach, together with innovative observations from our RADR® platform,
we intend to develop and add drug candidates to our pipeline with the objective of treating the right patient populations with
the right oncology therapies.
We
use our RADR® platform to identify potential biomarkers for patient response to a drug candidate and we further
intend to validate the selected drug candidate and potential associated biomarkers by conducting small, focused early phase clinical
trials. We intend to create various exit opportunities between one to three years for each drug candidate that progresses successfully.
For each drug candidate that progresses, along with its newly identified biomarker diagnostic potential for drug response, we
intend to partner, out-license, or internally develop the drug.
Our
current pipeline of development programs involves three small molecule drug candidates: LP-100, LP-184 and LP-300.
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LP-100 (6-Hydroxymethylacylfulvene
or irofulven) LP-100 has been out-licensed to Allarity Therapeutics and is in a phase II clinical
trial in AR-targeted and Docetaxel-Pretreated mCRPC Patients.
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LP-300 (Sodium
2,2’-disulfanediyldiethanesulfonate) (Tavocept®) We are currently evaluating LP-300 for the launch
of a phase II clinical trial, in combination with chemotherapy in non-smokers or never-smokers with NSCLC adenocarcinoma that
have a unique biomarker profile.
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LP-184. (hydroxyureamethylacylfulvene) LP-184
is a next generation alkylating agent with nanomolar potency that preferentially damages DNA in cancer cells that overexpress
certain biomarkers. LP-184 is in preclinical development and is in the planning stages for a phase I clinical trial.
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LP-100
is currently being advanced by our licensee, Allarity Therapeutics. LP-184 and LP-300 are being advanced solely by us. There is
currently no active IND in the U.S. for LP-100 and LP-184. We currently have an existing IND in the U.S. for LP-300 that was transferred
to us as part of our in-licensing and agreement with BioNumerik to acquire the rights to the compound.
Additional
Portfolio Opportunities
Based
on the recognition of antibody drug conjugates (ADCs) as a promising therapeutic approach for cancer treatment, and one that has
growing interest due to the potential to increase targeted cancer cell death, we have started reviewing our portfolio of small
molecules for their potential to be used as part of an ADC approach. ADCs can increase selectivity and maximize tumor cell death
and also minimize collateral toxicity. Our compounds LP-100 and LP-184 have the potential to be linked to antibodies (or peptides)
and used in potential additional indications or alongside other small molecules or immuno-oncology agents. We believe that LP-300
can also play a role in developing ADC constructs and increasing the potential to deliver targeted therapies. We are actively
researching and reviewing potential development pathways and partnerships that would enable us to develop an ADC complement to
our portfolio.
The
last two years have seen five FDA approvals in the growing class of ADCs for therapeutic use. This has driven increased deal-making
and portfolio additions by large pharma companies. In addition to the acquisition of Immunomedics by Gilead, Merck acquired Velos
Bio in November of 2020 and NBE Therapeutics was acquired by Boehringer Ingelheim in December of 2020. It is notable that both
NBE and Velos, at the time of their acquisition, had just successfully completed Phase 1 trials using their ADC approach in specific
cancer subtypes.
On
December 30, 2020, we entered into an Evaluation and Limited Use Agreement (the “Evaluation Agreement”) with Califia
Pharma, Inc. (“Califia”). Califia’s founder, Michael J. Kelner, M.D., is a widely published researcher with
recognized expertise in the areas of illudofulvene chemistry and antibody drug conjugates. Califia has developed novel transcriptional-coupled
repair inhibitors that have demonstrated potential for an improved therapeutic index compared to traditional ADC payloads.
The
Evaluation Agreement provides for Lantern and Califia to collaborate on the in vitro and in vivo testing and evaluation of novel
Califia payloads conjugated to a Lantern targeting entity. The Evaluation Agreement also provides us with the right to negotiate
with Califia for exclusive license rights to use LP-184 and related analogs as the payload with an affinity drug conjugate or
small molecule drug conjugate targeting entity supplied by Lantern. We also have the right under the Evaluation Agreement to negotiate
for non-exclusive license rights to use a Lantern targeting entity with a payload and linker combination selected from novel specified
Califia payloads and linkers.
We
plan on increasing our focus on CNS (Central Nervous System) cancers based on the promising data that has been generated in experiments
conducted with LP-184. LP-184 has shown that it can cross the blood brain barrier (BBB) while leaving neuronal cells intact. This
unique profile has been validated in neuronal cell-plate assays, neuronal spheroids, and also in xenograft models and is now undergoing
further validation in a collaboration with an affiliate of the Johns
Hopkins School of Medicine. We have launched a program in GBM, and have uncovered several
additional CNS cancers we believe will be sensitive to LP-184 based on genomic profiling and biomarker analysis conducted with
our A.I. platform, RADR. We expect to focus additional resources on developing LP-184 as both monotherapy and combination therapy
in several rare and ultra-rate CNS and brain cancers.
Based
on the positive data regarding the blood brain barrier permeability for LP-184, we reviewed and analyzed a range of CNS cancers,
beyond GBM, that we believe to have the potential to be responsive to LP-184 and make an improvement in patient survival. One
of the CNS tumor types that was identified by RADR was ATRT, Atypical Teratoid Rhabdoid Tumor, which is a very rare, fast-growing
tumor of the brain and spinal cord. It usually occurs in children aged three years and younger, but can also occur in older children
and sometimes adults. However, the younger the patient the poorer the prognosis for survival. ATRT has no known approved targeted
therapies and there is no standard chemotherapy regimen. According to the NCI, approximately 90 percent of ATRTs are characterized
by a SMARCB1 mutation, which significantly reduces the ability of the surrounding cells to suppress the tumor. ATRT occurs in
about 50 to 60 children per year and less than 10 adults per year, although recent diagnosis has increased due to improved access
to cancer care and improved diagnostic methods. We believe that we can target this genetically defined subset of ultra-rare ATRT
cancers, and plan on pursuing this indication in collaborations with academic cancer centers and potentially pursuing orphan or
fast-track status if the additional data we obtain supports that this has the potential for changing the clinical outcome for
patients.
We
have obtained initial cell line data regarding LP-184 and ATRT that we believe supports the potential for LP-184 to qualify in
the future for possible grant of a Rare Pediatric Disease Designation for use of LP-184 for ATRT. Additionally, we believe that
subject to LP-184 successfully completing required clinical trials and regulatory requirements, LP-184 for the rare disease indication
of ATRT may also potentially qualify for grant of a Rare Pediatric Disease Priority Review Voucher ("PRV"). Under Section
529 of the Federal Food, Drug, and Cosmetic Act, FDA will award a PRV to sponsors of rare pediatric disease product applications
that meet certain criteria. Under this program, a sponsor that receives approval for a drug or biologic for a rare pediatric disease
may qualify for a PRV that can be redeemed to receive expedited review of a subsequent product marketing application. A PRV
may be redeemed by the company that initially receives it, or the PRV can be sold to another
company.
Our
Precision Cancer Therapy Development Using Our Innovative RADR® Platform
Historically,
cancer treatment protocols include surgery, chemotherapy and radiation therapy. Treatments have been selected based on histologic
type and disease spread, irrespective of genetic differences among patients. With the advent of precision therapies, cancer treatments
increasingly target specific genes or mechanisms of action for a more personalized approach to patient care. This trend represents
a substantial advance in cancer treatment because tumor growth is highly dependent on genetic changes and the genetic profile
of the individual and the progression of the disease is highly variable amongst patients.
Our
RADR® platform is core to our drug development approach for identifying the desired candidates to in-license and
develop. According to a recent article in JAMA (Estimated Research and Development Investment Needed to Bring a New Medicine
to Market, 2009-18, JAMA, March 3, 2020) oncology drug development is costly, risky, and highly competitive
with an average success rate of 4% to 8% and average developmental costs of over $1 billion per successful drug. There is a critical
need to rescue clinical research on drugs that have failed clinical trials in order to provide additional possible therapies for
patients while reducing the overall cost of therapeutic development. Many drug failures within oncology may be attributed to the
heterogeneity of the tested patient population, even though there may be a strongly positive therapeutic impact on certain patient
subgroups within that population.
As
data-centric and machine learning approaches begin to change the pace and scale of drug discovery and development, research and
development (“R&D”) we believe efforts in large biopharma companies will begin to shift away from traditional
approaches towards new data and A.I.-centric approaches. According to Deloitte Consulting, in Ten Years On | Measuring the
return from pharmaceutical innovation 2019, “decades of advances in science and technology have driven improvements
in health care outcomes and influenced stakeholder expectations of the role of the biopharmaceutical industry (biopharma). However,
the past decade has seen increasing pressures undermine the productivity of biopharma R&D, leading to a decade of decline
in the return on investment. At the same time, innovative new treatments are changing the face of disease management. New
treatment modalities and an increasing understanding of precision medicine have led to the need for new R&D models...”
The Deloitte Consulting report further describes that R&D costs will, “shift from traditional discovery and trial execution
to a process driven by large datasets, advanced computing power and cloud storage”.
Analysts
estimate that this shift from traditional screening, and trial-based studies to leveraging in silico, data and A.I. methodologies
will drive a significant increase in the spending on A.I. by the biopharma and drug discovery community to approximately $4 billion
by 2021, increasing by about 40% annually from $730 Million in 2019 according to PMLive and Global Market Insights. As a result
of these trends and changes in the R&D model in biopharma, we believe that we, and companies that are using data-centric and
A.I. centric approaches to drug discovery and development, are in an ideal position to benefit from this industry shift that has
the potential to help deliver drugs to the right patients faster, with a higher degree of personalization and a potentially lower
amount of average costs in the development cycle.
Our
drug rescue approach leverages substantial prior research and development investments in candidates that were withdrawn from development
prior to submission for FDA approval. The large volume of failed compounds, recent developments that permit increased access to
validated genomic and biomarker data, and the rapid evolution of AI technology creates an opportunity to efficiently capitalize
on these investments.
Our
RADR® platform is rapidly emerging as a robust and scalable platform for targeted cancer therapy development. Through
the use of AI and machine learning, RADR® is designed to quickly identify and guide the development of compounds
that we can develop as potential oncology agents through either a process of drug rescue, drug repositioning or de-novo development.
RADR® is being developed on a routine basis through an accumulation and curation of genomic and biomarker data
that is directly relevant to the measurement and classification drug-tumor interaction, and clinical datapoints related to patient
response and patient stratification.
Predicting
optimal drug responses in cancer patients requires the identification and validation of predictive biomarkers. Our RADR®
platform seeks to identify biomarkers to assist in selecting patients who have the highest likelihood to respond to our
drug candidates. For example, the targeted indications for our drug candidate LP-184 were chosen in part because they are known
to highly express the protein coding gene PTGR1. Our preclinical “PRostate cancer Artificial Intelligence Study using Ex
vivo models” or “PRAISE” trial and our planned clinical trial for LP-184 are intended to examine biomarkers
related to LP-184’s molecular and cellular targets to identify those that may correlate with clinical observed anticancer
activity. This method of using and validating targeted biomarkers during development and then using these biomarkers during clinical
trials can lead to shortening of the development timeline and compression of costs associated with oncology drug development.
Similarly,
we believe LP-300 targets molecular pathways that are more common in female non- or never smokers than in any other group and
also targets kinases involved in key signaling pathways involving enzymes critical for DNA synthesis and repair, such as Excision
Repair Cross-Complementation Group 1 (ERCC1), Ribonucleotide Reductase 1 (RNR1), Ribonucleotide Reductase 2 (RNR2), as well as
enzymes and proteins important in regulating cell redox status, such as Thioredoxin (TRX), Peroxiredoxin (PRX), Glutaredoxin (GRX),
and Protein Disulfide Isomerase (PDI). Our plan is to bring LP-300 into a targeted phase 2 clinical trial within the non- or never-smoker
sub-group that are identified with the adenocarcinoma sub-type of NSCLC.
Our
RADR® Platform
The
human genome consists of 19,000 to 20,000 protein coding genes. One input record derived from available data bases and analyzed
by our RADR® platform consists of datapoints (expression values) from approximately 20,000 genes, another input
record type is drug sensitivity data (IC20, IC50), and other sets include key clinical parameters from HIPAA compliant patient
data and clinical histories. Our RADR® platform uses a data-driven gene feature selection methodology that is a
combination of biology, informatics, and statistics – computational biology. The architecture and modules of our platform
are depicted in the image below.
RADR®
Platform Architecture and Modules
Our
platform uses AI and machine learning to identify genes and genomic signatures believed to be highly correlated with drug sensitivity.
These statistically significant genes are furthered filtered in the pathway network and interaction analysis to identify genes
believed to be biologically relevant. Genes that make up this layer are either related to the molecule’s mechanism of action
or heavily connected to each other in gene networks. Lastly, another inductive learning algorithm ranks these filtered genes based
on drug sensitivity by calculating the half maximal inhibiting concentration (IC50) of the correlated relationship.
In this way, our platform has the potential to predict drug sensitivity, classify a patient as responder or non-responder and
identify biomarkers for each drug-tumor combination.
We developed our platform
using primarily open-source third party supervised algorithms such as Neural Networks, Support Vector Machine, Random Forest, K-Nearest
Neighbors, Logistic Regression and Penalized Multivariate Regression. Each algorithm is trained with input data to predict drug
sensitivity (regressor models) and stratify patient response as responder or non-responder (classifier models). Model tuning and
optimization is then performed using a hyperparameter search algorithm in order to produce the predicted lowest cross validation
error. The models are then evaluated using traditional performance metrics such as accuracy, area under the curve, sensitivity,
specificity, precision, root mean square error and mean absolute error calculations.
A
feature reduction algorithm is then used to reduce the number of genes under analysis to a biomarker gene panel of less than approximately
50 genes. This set of genes is intended to carry the highest coefficient to predict drug sensitivity and the highest variable
importance in classifying a responder from a non-responder. Genes that do not help in predicting the output variable are eliminated
sequentially.
Our
RADR® Platform Workflow
Our
RADR® platform’s proprietary workflow involves preliminary statistical analysis on approximately 18,000 features
typically from whole transcriptomic datasets reducing the set to approximately 2,000 features. This is followed by gene filtering
via biological and statistical methodologies yielding approximately 200 significant genes. Feature selection ensures that genes
that do not contribute to response prediction are excluded from the output dataset. The prediction component subsequently applies
an A.I.-driven reduction algorithm to the previously filtered genes generating a targeted set of typically less than 50 candidate
biomarkers predictive of response to a particular molecule.
A
distinct and unique benefit of the RADR® platform is its ability to integrate biological knowledge and data-driven
feature selection to generate hypothesis-free biomarker signatures. This can then aid in identifying novel targets for predictive
screening and drug development.
Our RADR® platform is enabled through access
to, and analysis of, a number of key datasets: (i) publicly available databases (ii) data from commercial clinical studies and
trials and (iii) our proprietary data generated from ex vivo 3D tumor models specific to drug-tumor interactions. We incorporate
automated supervised machine learning strategies along with big data analytics, statistics and systems biology to facilitate identification
of new correlations of genetic biomarkers with drug activity. The value of the platform architecture is derived from its validation
through the analysis of over 1.2 billion oncology-specific clinical and preclinical data points, more than 140 drug-cancer interactions,
and over 55,000 patient records from five data bases, one of which is our internal data base. Our long-term objective is to collect
and analyze over ten billion oncology-specific clinical and preclinical data points to further enhance the prediction power of
our RADR® platform. We use cancer cell line gene expression profiles and drug sensitivity data (IC50) as one of
its input types. In a population of 10 case studies our platform was able to distinguish responders from non-responders with an
average historical accuracy of over 80%. We have also used our platform to generate genetic signatures that we believe to have
applicability for the majority of FDA approved drug-tumor indications. External validation, through retrospective data analysis,
of patient datasets from 10 independent clinical studies achieved an average response prediction accuracy greater than 80%, and
internal analysis of 120 drug-tumor interactions in cell lines achieved an accuracy of greater than 85%.
We
have developed our platform in a cloud environment that efficiently uses parallel processing to analyze patient stratification
and biomarker selection. Best software engineering practices are followed while designing and developing our platform’s
architecture. Each component of the platform’s architecture is unit tested and then integration tested to ensure functions
and programs are working as designed. In order to track modifications in the software, a version control system is in place. Detailed
documentation has been created to record the design and architecture of our platform.
Our
platform uses a simple user input and GUI based AI architecture that can be used in many pharmaceutical research areas such as
biomarker identification, patient stratification, drug rescue and reposition by bioinformaticians, clinicians and trained wet-lab
scientists.
Our
Strategy
Our
mission is to bring the right cancer drugs to the right patients by transforming the drug development process through the use
of artificial intelligence and data-driven development approaches. Our proprietary A.I.-enabled, and precision oncology approach,
which focuses on developing our own pipeline of compounds by rescuing drug candidates that have previously failed and developing
new compounds that are targeted to specific biological activity and genomic pathways, has the potential, we believe, to bring
drugs to market faster, with lower costs, and with reduced risk, thereby enabling a change in the cost and availability of precision
cancer therapy. We work with leading research laboratories, translational medicine and cancer centers to develop our studies and
clinical trials for our portfolio, and actively update and improve our RADR® platform to incorporate additional
biomarker data, patient outcome data, cancer drug efficacy studies and computational models that relate to oncology drug development
and prediction of patient response.
As
part of our growth strategy, we plan to:
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Pursue existing
indications for both LP-184 and LP-300, leveraging our RADR® platform to refine and optimize our trial design
and biomarker signatures that correlate to potential patient response.
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Expand our pipeline
by identifying new drug candidates that have either been abandoned or have failed in late stage clinical trials, and have
the potential to benefit from a precision medicine approach that leverages our expertise and A.I. platform.
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Identify and
design potential combination therapy approaches to use our compounds in conjunction with currently approved drugs by leveraging
our RADR® platform to analyze and uncover synergistic mechanisms and biological pathways using genomics and
machine learning.
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Increase the
number of data points powering our RADR® A.I. platform from more than the current 1.2 billion to approximately
three billion by the end of 2021.
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Advance the algorithms,
methodologies and models that underlie our computational and machine learning platform to improve the predictive power, and
to develop additional capabilities that are focused on accelerating or de-risking oncology drug development.
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Pursue collaborations
and partnerships with other biotech and pharma companies where our A.I. and precision oncology expertise can be used to de-risk
or accelerate development programs and where our stockholders can receive a significant economic benefit.
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Continue to develop
and patent intellectual property and advance our intellectual property portfolio associated with both fundamental patents
and patents associated with precision, patient stratified, targeted therapies and genomic or biomarker signatures.
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Select and launch
our next clinical development program in the coming twelve months.
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LP-300
General
Overview
LP-300
is a cysteine-modifying molecular entity that works to modulate multiple cellular pathways simultaneously and is a potential combination
agent for targeted indications in NSCLC. LP-300 is a small molecule (molecular weight 326.4 Da) that was in-licensed from BioNumerik
Pharmaceuticals, Inc. in May 2016, and subsequently acquired by us in 2018. We are focused on repositioning LP-300 as a potential
combination therapy for non-smoking (or never-smoker) NSCLC patients with histologically defined adenocarcinoma. Since obtaining
LP-300 rights from BioNumerik, we have not yet conducted further clinical testing of LP-300. We are currently evaluating LP-300
for the launch of a phase II trial, in combination with chemotherapy under an existing IND. Prior clinical trials conducted by
BioNumerik for LP-300 did not meet their primary clinical endpoints, and at least one or more future clinical trials that meet
their pre-specified primary endpoints with statistical significance will be required before we can obtain a regulatory marketing
approval, if any, to commercialize LP-300. Safety and efficacy determinations are solely within the authority of the FDA in the
U.S. or other regulatory agencies in other jurisdictions. Currently there is no approved therapy specifically for the growing
indication of non-smokers (or never-smokers) with NSCLC, and female non- or never smokers appear to be uniquely responsive to
LP-300. With both chemosensitizing and chemoprotective activity, LP-300 has potential as a combination agent or adjuvant in front
line, second line or salvage therapy in newly diagnosed, relapsed, metastatic or advanced NSCLC for overall survival enhancement
and toxicity alleviation from primary chemotherapy or standard of care. We are currently in the early stages of defining a specific
biomarker signature that correlates with heightened sensitivity to LP-300. We believe that this signature may help accelerate
the clinical development of LP-300 and has the potential to guide patient selection for targeted clinical trials.
LP-300
has been administered in multiple clinical trials to more than 1,000 patients and has been generally well-tolerated. Retrospective
analyses of the results of a multi-country phase III lung cancer trial (study ID DMS32212R) in subgroups of adenocarcinoma patients
receiving LP-300, paclitaxel and cisplatin demonstrated substantial improvement in overall survival, particularly among female
never smokers, where a 13.6 month improvement in overall survival (p-value 0.0167, hazard ratio 0.367) in favor of LP-300
was observed, as compared to placebo in the subgroup of paclitaxel/cisplatin-treated patients. Similar retrospective findings
of increased overall survival in the subgroup of LP-300/paclitaxel/cisplatin treated female Asian patients with adenocarcinoma
of the lung were observed in a randomized, double-blind, placebo-controlled trial in Japan. Prior historical clinical trial observations
are not necessarily predictive of the outcome of future trials. No assurances can be given that we will be successful in obtaining
marketing approval for LP-300. The chemical structure of LP-300 is depicted below.
LP-300
Chemical Structure
Based on the subgroup observations of increased overall survival
described above, we believe LP-300 has potential for an orphan indication designation in treating non- or never smokers with advanced
NSCLC adenocarcinoma. Although orphan status has not previously been granted for non-smoking associated NSCLC, we believe pursuit
of this designation is supported by the unique observations regarding LP-300 and the growing recognition that non-smoking associated
NSCLC is a distinct disease type as compared to smoking associated NSCLC. Summarized below are some key findings from LP-300’s
prior clinical trials:
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LP-300 targets molecular pathways that are more common in female non-smokers than in any other group. Key mechanisms have been elucidated to support LP-300’s role in the observed treatment benefits for females and never smokers noted in the Phase III NSCLC adenocarcinoma trial. The rationale for these observations includes the following: (1) Met/ALK & EGFR alterations are more common in non-smokers, who are most commonly female and present with advanced stage adenocarcinoma; (2) laboratory data indicate that LP-300 targets both EGFR WT/mut+ and Met/ALK; and (3) a high percentage of adenocarcinoma patients are either EGFR mutants or Met/ALK positive.
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There are several key pathways in NSCLC adenocarcinoma whose targets are often overexpressed in females, and LP-300 modulates these pathways. LP-300 targets the following key pathways: (1) kinases involved in key signaling pathways (ALK, ROS, MET); (2) enzymes critical for DNA synthesis and repair (ERCC1, RNR1, RNR2); and (3) enzymes and proteins important in regulating cell redox status (TRX, PRX, GRX, PDI). The alterations that are targeted and modulated by LP-300 are more likely in women with lung adenocarcinoma, especially non-smokers.
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LP-300 showed that females had a survival increase from 13 months to 25 months, based on a retrospective subgroup analysis of a Phase III NSCLC adenocarcinoma trial. Results from a Phase III NSCLC adenocarcinoma trial exhibited an overall survival of 25.0 months, with a 2-year survival of 51.4%, in the subgroup of females with advanced adenocarcinoma of the lung receiving paclitaxel/cisplatin and LP-300. The observed results were statistically significant (p-value = 0.0477; HR=0.579) and were observed in a subgroup of 114 patients in retrospective analyses. Consistent statistically significant retrospective subgroup analysis results were observed in female NSCLC adenocarcinoma patients receiving paclitaxel/cisplatin and LP-300 in a prior LP-300 double-blind, placebo-controlled phase III trial conducted in Japan.
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LP-300 exhibits potential to reduce anemia and protect against chemotherapy-induced kidney toxicity, both of which are conditions that disproportionately affect females. The LP-300 arm of the Phase III NSCLC adenocarcinoma trial also demonstrated the potential for LP-300 to protect against chemotherapy-induced kidney toxicity and anemia. These findings complement earlier clinical observations regarding LP-300’s potential to protect against neuropathy and other chemotherapy-induced toxicities.
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Background-Scope of Prior Phase III
NSCLC Adenocarcinoma Trial (LP-300)
LP-300 was studied
in a randomized, multi-center (trial locations in four US states and five European countries), double-blind and placebo-controlled
Phase III trial from 2010 to 2013 in patients with adenocarcinoma of the lung (the “Phase III NSCLC adenocarcinoma trial”).
The aim of the trial was to determine whether LP-300, combined with a standard combination of chemotherapy drugs, would increase
survival in patients with advanced NSCLC adenocarcinoma. The secondary aim of the trial was to determine if the chemoprotective
properties of LP-300 were effective in preventing or reducing common side-effects of cancer treatment, including kidney damage,
anemia, nausea and vomiting that can occur with these drug combinations. The trial enrolled NSCLC patients with newly diagnosed
or recurrent advanced (stage IIIB/IV) primary adenocarcinoma of the lung. Patients with confirmed histopathological diagnosis of
inoperable and measurable advanced primary adenocarcinoma (including bronchioalveolar cell carcinoma) of the lung, and no prior
systemic treatment for NSCLC including chemotherapy, immunotherapy, hormonal therapy, targeted therapies or investigational drugs,
were included in the trial. Overall survival was the primary outcome measure. Patients in the control arm received standard of
care (cisplatin and either paclitaxel or docetaxel) plus placebo, whereas patients in the treatment arm received standard of care
(cisplatin and either paclitaxel or docetaxel) plus LP-300. The primary results of the trial for patients receiving cisplatin and
paclitaxel are outlined in the table below. While the overall results of the Phase III NSCLC adenocarcinoma trial did not meet
the specified endpoint of the trial in increasing overall survival in all patients, when the data were retrospectively separated
by gender and smoking status, the trial data demonstrated that all never smokers, especially female never smokers, saw increased
survival with LP-300 combination treatment with paclitaxel and cisplatin. Furthermore, the LP-300 group in the phase III NSCLC
adenocarcinoma trial exhibited well-tolerated advantages relating to the potential to protect against chemotherapy-induced nephrotoxicity,
neuropathy and nausea along with reduced anemia.
The figure below depicts
the survival curves for cisplatin/paclitaxel subgroups for the Phase III NSCLC adenocarcinoma trial that ended in 2013, as summarized.
The Kaplan Meier curves maintain consistent separation between treatment arms for the never smokers, females, and female never
smokers.
Rationale Behind LP-300 Rescue
and Repositioning Efforts
Based on the results
from the prior Phase III NSCL adenocarcinoma trial, we are in the process of designing a new Phase II clinical trial to target
the population of non- or never smokers with adenocarcinoma that saw the greatest benefit in the previous Phase III trial. Although
the incidence of non-smokers with NSCLC is rising currently there is no approved therapy specifically for the growing indication
of non-smokers (or never-smokers) with NSCLC. Preclinical observations support that LP-300 preferentially modulates ALK and EGFR,
two commonly mutated genes in non-smokers with adenocarcinoma. Based on the findings from the previous Phase III NSCL adenocarcinoma
trial, it is possible that the benefits of combining LP-300 with standard of care chemotherapy could be further improved by identifying
additional molecular biomarkers in patients who respond well to LP-300 combination treatment. We continue to seek additional opportunities
for LP-300. Some of our considerations include a non- or never smoker population with a specific genetic signature that correlates
to increased LP-300 sensitivity. We believe that this may also qualify as an orphan (rare disease) designation being a defined
subset of NSCLC.
Clinical Translation Strategies
We have conducted discussions
with more than ten key opinion leaders (KOLs) in the US, UK and India who recognized non-smokers with NSCLC adenocarcinoma as a
unique population that could benefit from targeted precision oncology therapy. We intend to invite active participation and input
from clinical and regulatory experts including KOLs and FDA authorities to facilitate evaluation of parameters important for repositioning
our LP-300 program and conducting precision clinical trials.
Disease Background and Opportunity
Lung cancer remains
one of the most common and deadly cancers worldwide. Lung cancer accounts for 13% of all new cancer diagnoses but 24% of all cancer
deaths. Lung cancer kills more people annually than cancers of the breast, prostate, colon, liver, kidney, pancreatic, and melanoma
combined. The American Cancer Society’s estimates for lung cancer in the US for 2019 are:
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Approximately 228,150 new cases of lung cancer (116,440 in men and 111,710 in women)
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Approximately 142,670 deaths from lung cancer (76,650 in men and 66,020 in women)
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The most common type
of lung cancer is called non-small cell lung cancer (“NSCLC”), which represents about 85% of all lung cancer.
Lung adenocarcinoma,
a histological subtype of NSCLC that originates within the glands that line the lung, is the most common subtype of lung cancer
in the world inflicting approximately 50% to 65% of non-Asians and approximately 70% to 85% of Asians diagnosed with lung cancer.
According to the SEER Cancer Statistics Review (November 2018) published by the National Cancer Institute and other published literature,
60% to 65% of all new lung cancer diagnoses are among people who are former smokers or have never smoked, while 10-15% of new lung
cancer cases are among never-smokers.
Over one-half of the
patients diagnosed with NSCLC in any given year will present with inoperable advanced (stage IV) disease, for which there is no
cure. Patients with stage IV NSCLC exhibit a median overall survival time of 8 to 10 months; approximately one-third of patients
will survive for year, and only 10% to 21% of those patients will survive for two years.
Lung cancer is the
most common cause of global cancer-related mortality, leading to over a million deaths each year and adenocarcinoma is its most
common histological subtype. Worldwide, lung cancer occurred in approximately 2.1 million patients in 2018 and caused an estimated
1.8 million deaths. NSCLC is described as any type of epithelial lung cancer other than small cell lung cancer (“SCLC”).
The 5-year survival rate for NSCLC is 16%. Rapid advances in understanding the molecular pathogenesis of NSCLC have demonstrated
that NSCLC is a heterogeneous group of diseases. Although the initial treatment of localized disease is the same, the molecular
characterization of tumor tissue in patients with NSCLC serves as a guide to treatment both in those who present with metastatic
disease and in those who relapse after primary therapy. Molecularly targeted therapies have dramatically improved treatment for
patients whose tumors harbor somatically activated oncogenes such as mutant EGFR1 or translocated ALK, RET, or ROS1. Mutant BRAF
and ERBB2 are also investigational targets. Smoking is the major cause of lung adenocarcinoma but, as smoking rates decrease, proportionally
more cases occur in never-smokers (defined as less than 100 cigarettes in a lifetime). KRAS mutations in lung cancer cases are
nearly exclusive to smokers. KRAS, “Kristen rat sarcoma viral oncogene homolog,” is a protein involved in regulating
cell division. KRAS mutation is a gain-of-function mutation (i.e. somatic mutation turns RAS, a benign gene “proto-oncogene”
into KRAS, an oncogenic driver of many tumors). KRAS-mutated non-small cell lung cancer represents 20% to 25% of all NSCLC. There
are no current KRAS-mutated NSCLC-targeted therapies but there are targeted therapies for the indication by targeting downstream
pathways - for example mTOR inhibition. Tumor suppressor gene abnormalities, such as those in TP53, STK11, CDKN2A8, KEAP1, and
SMARCA4 are also common but are not currently clinically actionable.
In reviewing lung cancer
incidence and mortality rates among never-smokers in the Journal of Clinical Oncology, Wakelee, H.A. et al. have reported that
the age-adjusted incidence rates of lung cancer among never-smokers aged 40 to 79 years from large population-based cohorts ranged
from 14.4 to 20.8 per 100,000 person-years in women and 4.8 to 13.7 per 100,000 person-years in men, supporting earlier observations
that women are more likely than men to have never smoking-associated lung cancer. The biology of lung cancer in never-smokers is
apparent in differential responses to epidermal growth factor receptor inhibitors and an increased prevalence of adenocarcinoma
histology in never-smokers. Lung cancer in never-smokers is an important public health issue needing further exploration of its
incidence patterns, etiology, and biology. Due to the fact that there are no known therapy options for this group, we believe that
aggressive development of therapy options is needed and is a high unmet clinical need.
The table below illustrates
the growing concern of lung cancer in nonsmokers and never-smokers, and is a sample of the recent literature on the topic of never-smokers
that the Company has used in assessing the potential patient and unmet clinical needs in this cancer.
Source
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Date of Study / Publication
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Illustrative Quote
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American Cancer Society
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Oct. 31, 2019
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“As many as 20% of people who die from lung cancer in the United States every year have never smoked or used any other form of tobacco.”
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Journal of Royal Society of Medicine
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Aug. 25, 2019
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“Globally, there is wide variation in the proportion of lung cancers in never-smokers, in the range of 10% to 25%. With declining rates of smoking, the relative proportion of lung cancers in never-smokers are increasing and this does not appear to be confounded by passive smoking or misreported smoking status.”
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Roswell Park
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Apr. 3, 2019
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“…15% of lung cancers are found in people who have never smoked.”
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Cancer Research U.K.
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Nov. 16, 2018
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“Around 10-15% of the lung cancer patients I see have never smoked.”
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ASCO – The Asco Post
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Dec. 25, 2017
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“In the United States, about 20% of women with lung cancer are never-smokers, and about 7% of men with lung cancer are never-smokers.”
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Clinical Cancer Research
September 2009
Volume 15, Issue 18
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Sep. 15, 2009
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“The lung cancer death rates among never-smokers, although “rare” by conventional definitions (<40,000 US deaths per year), is similar to the death rates from leukemia, and endometrial cancer in women and cancers of the esophagus, kidney, and liver in men in the United States, and may be even more important in other populations, including Chinese women
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In 2019 in the US,
9,034 cases of NSCLC adenocarcinoma cases are estimated to be diagnosed in female non-smokers, accounting for approximately 3.9%
of all lung cancer cases. With an estimated 120,000 globally projected adenocarcinoma cases of NSCLC in non-smoking females in
2019, this specific indication may possibly be classified as a rare disease. When attempting to explain some gender susceptibility
differences, research has demonstrated that women with NSCLC tend to be:
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2-3 times more likely to be non-smokers;
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more likely to develop adenocarcinoma and;
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having metastatic disease.
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The high rate of adenocarcinomas in non-smoking
women suggests the possible existence of other etiological factors in addition to smoking. Some factors that have been considered
include gender-specific genetic alterations and predispositions, passive smoke effects, different nicotine metabolism in women,
occupational exposure, diet, and chronic obstructive pulmonary disease. Based upon 2018 estimates published by Global Cancer Observatory
and 2019 estimates published by the American Cancer Society, below is an overview of relevant potential patient population and
market sizes that we believe LP-300 could address, if approved:
Lung cancer
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Global
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US
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Total 2019 lung cancer estimated incidence (new cases)
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2,000,000
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228,150
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NSCLC adenocarcinoma incidence (~40% of all lung cancers)
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800,000
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91,260
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Never-smokers estimate (~15% of adenocarcinoma)
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120,000
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13,689
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Female never-smoker estimate (~66% of never-smokers with lung cancer are female)
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79,200
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9,034
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Total Patient Segment in New Lung Cancer
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4.0
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%
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4.0
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%
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Limitations on Current Treatment
Treatment of patients
with advanced NSCLC in the first-line setting usually includes chemotherapy (including taxanes, vinorelbine, or gemcitabine) in
combination with a platinum doublet (cisplatin or carboplatin). According to the clinical practice guidelines published by the
National Comprehensive Cancer Network, many of these combinations have reached a plateau in terms of overall response (≥ 25%
to 35%), time to progression (four to six months), median survival time (eight to ten months), one-year survival rate (30% to 40%),
and two-year survival rate (10% to 15%) in patients with good performance status. Treatment remains palliative and is limited due
to inherent toxicities that may affect the quality of life resulting from treatment. Toxicities can be life-threatening or cause
treatment delays, thereby limiting the intensity of treatment delivered and affecting its efficacy. Common and serious chemotherapy-induced
toxicities, such as anemia, emesis, and peripheral neurotoxicity resulting from treatment with platinum and taxanes, and nephrotoxicity
due to cisplatin can result in treatment delays, dose modifications, and in severe cases, discontinuation of treatment. We believe
it is important to pursue the development of novel therapies and combinations thereof that can substantially improve patient survival
and quality of life by potentiating the antitumor activity of chemotherapy treatment while protecting against chemotherapy-induced
toxicity.
Market Opportunity
Most non-smoker patients
with lung cancer are women, and adenocarcinoma is the most common type. Non-smoker patients with non-small-cell lung cancer (“NSCLC”)
generally have a better response to inhibitors of epidermal-growth-factor receptor (EGFR) tyrosine kinase, including without limitation
gefitinib and erlotinib, than do those with a history of tobacco smoking. Studies have identified differences in chromosomal aberrations,
genetic polymorphisms, gene mutations, and methylation status between lung cancer in non-smokers and tobacco-associated lung cancer.
These clinical and biological differences suggest that the two cancers have overlapping but unique pathways of carcinogenesis.
The EGFR mutation is one of the most important genetic change in lung cancer in people who have never smoked because it is more
common in lung cancer in never-smokers than in tobacco associated lung cancer and is associated with greater therapeutic benefit
from inhibitors of EGFR. Other alterations associated with never-smokers include mutations, fusions or amplifications in ALK, ROS1,
RET and MET genes. Based upon published articles in CA: Cancer Journal for Clinicians and Nature Review Cancer, incidence in never-smokers
is 10% to 15% of all lung cancers and globally, NSCLC in never-smokers comprises 15% to 20% of cases in men and greater than 50%
in women. In Asia, never-smokers with NSCLC are 60% to 80% women and 20% to 40% men.
We are focused on advancing
LP-300 as a potential combination therapy for non- or never smoking NSCLC patients with adenocarcinoma by leveraging our A.I. platform
to help uncover the genomic and biomarker networks that are associated with response in the never-smoker and non-smoker groups.
Additionally, through our early, preclinical work to define a gene signature that correlates with heightened sensitivity to LP-300,
we believe there is potential to further expand the indication to include all NSCLC patients that have this identified genetic
profile in their cancer. Currently there is no approved therapy specifically for the growing indication of non-smokers (or never-smokers)
with NSCLC, and female non- or never smokers appear to be uniquely responsive to LP-300. If successful, LP-300 could provide
improved patient benefit in terms of improved survival, and secondarily through the concurrent prevention and mitigation of common
and serious chemotherapy-induced toxicities.
LP-300 Summary of Preclinical and Clinical
Studies
Through partnerships
and third-party outsourcing arrangements, we are conducting, or have conducted, the following preclinical studies on LP-300.
Cell line work with third party CROs
A study was conducted
to assess whether LP-300 induces or suppresses specific biological pathways or functions that impact tumor cell proliferation,
survival or apoptosis. In this study, NSCLC cell lines were exposed to selected concentrations of LP-300 alone and in combination
with cisplatin, for defined duration. After exposure to the drugs in cell culture according to the chosen treatment conditions,
RNA was obtained and transcriptomic analysis was performed using a NovaSeq 6000 next-generation sequencing platform. Overall,
1.26 million data points were generated and analyzed from this study yielding differential gene expression profiles between LP-300
untreated versus treated samples. Key pathways that emerged as being regulated by LP-300 include redox homeostasis and NRF2/Antioxidant
Response Element signaling, among others.
We are working with
a preclinical and discovery focused CRO to generate supporting preclinical data on LP-300 anticancer activity profiles in various
molecular and demographic brackets of NSCLC cell line models. The goal of this study is to generate dose response curves
and associated IC50 values for LP-300 alone as well as in combination with Cisplatin (standard of care agent) and selected
targeted therapy agents on up to 20 different NSCLC cell lines. Genetic backgrounds of NSCLC drivers and related oncogenes
in these cell lines are known, and will help to establish correlations between LP-300 cytotoxicity and specific markers.
We intend to evaluate the status of LP-300 as a chemosensitizing agent, whether LP-300 triggers catastrophic oxidative stress,
and understand specific transcriptional characteristics of tumors that are sensitive or resistant to LP-300 alone and in combination
with other treatments. From this ongoing study, we hope to develop information to assist in further stratifying patients
that would be key targets for future clinical trials. LP-300 could potentially be positioned to treat advanced NSCLC adenocarcinoma
not just in never-smokers but also based upon genetic alterations.
Fox Chase Collaboration
We are engaged in discussions
with Fox Chase Cancer Center (“FCCC”) to identify opportunities for collaborative research, both preclinically and
clinically, for advancing LP-300. The objective is to develop studies to further elucidate the mechanism of action of LP-300, and
to pursue a Phase II clinical trial in never-smokers with NSCLC. Regarding preclinical studies, we intend to discuss appropriate
preclinical studies with cell lines, organoids or patient derived xenograft (PDX) models that are required to move forward to a
clinical trial. In pursuing the areas of LP-300 related cysteine modification of EGFR / FGFR and other drivers commonly altered
in never-smoking NSCLC, we plan on comparing LP-300 response in cell line models with EGFR exon 3 deletion, EGFR L858R/ T790M,
exon 19 or 21 deletions, and EGFR wild type among other genetic backgrounds. We are interested in prioritizing studies that will
progress towards a Phase II trial, including a PDX trial testing LP-300 in combination with selected tyrosine kinase inhibitors
(TKIs) in addition to cisplatin / paclitaxel as standard of care agents in relevant models and comparing never-smokers and nonsmokers
to smokers.
Prior Completed Trials of LP-300
Phase I. LP-300
has been evaluated in five Phase I studies (DMS10001, BioNumerik, 09/1997 through 04/2004; DMS10002, BioNumerik, 12/1997 through
08/2001; DMS12209, ASKA Pharmaceutical, 04/2000 through 12/2001; DMS10011, BioNumerik, 02/2006 through 07/2006; and DMS12307, Baxter,
07/2002 through 07/2005) to determine the maximum tolerated dose (“MTD”), and to evaluate the safety, tolerability,
pharmacokinetics, and potential efficacy of LP-300 (alone or in combination with cisplatin, cisplatin/paclitaxel, or carboplatin/paclitaxel).
An MTD for LP-300 was not reached in any of the Phase I studies at dose levels of up to 41 g/m2.
Phase II.
In a U.S. multi-center, randomized, open-label trial (n=160 patients) with advanced (Stage IIIB and IV) NSCLC treated with
LP-300 or no LP-300 (DMS22210/CALGB 30303, Cancer and Leukemia Group B, 08/2004 through 03/2007), although the overall population
did not meet the pre-specified primary endpoint, an analysis of a subgroup of patients with adenocarcinoma revealed that the difference
in the median overall survival period between the 2 treatment groups was statistically significant (LP-300 = 15.6 months, no LP-300
= 8.9 months; Log-rank p=0.0326), and the median overall survival for patients who received LP-300 was 6.7 months longer than that
of those who did not receive LP-300.
Phase III. LP-300
has been evaluated in five Phase III studies: two in patients with metastatic breast cancer, with a primary endpoint examining
the ability to reduce platinum/taxane induced peripheral neuropathy, and three in patients with NSCLC or advanced primary lung
adenocarcinoma. (DMS32205R, ASKA Pharmaceutical, 08/2005 through 02/2008; DMS30203R, BioNumerik, 09/2001 through 10/2006; DMS30204R,
ASKA Pharmaceutical, 04/2003 through 03/2006; DMS32206R, Baxter, 10/2002 through 04/2006; and DMS32212R, BioNumerik, 04/2010 through
06/2013) Although the overall population did not meet the pre-specified primary endpoints in any of the trials, analysis of subgroups
of patients in one multi-country lung adenocarcinoma trial and one Japanese NSCLC trial revealed differences in the median overall
survival between the two treatment arms (with or without LP-300 treatment). The results from the two key lung cancer trials obtained
from retrospective analyses are described below:
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Multi-country, double-blind, randomized, multi-center & placebo-controlled trial (n=540 patients) with advanced primary lung adenocarcinoma treated with LP-300 or Placebo & paclitaxel or docetaxel with cisplatin (DMS32212R). (the Phase III NSCLC adenocarcinoma trial)
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Treatment with LP-300 nearly doubled the Overall Survival in women receiving paclitaxel/cisplatin (25.0-month median OS in LP-300 arm vs. 13.2-month OS in control arm) and the results in this subgroup were statistically significant (P-value = 0.0477; HR = 0.579)
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For never smoking women with adenocarcinoma of the lung receiving paclitaxel/cisplatin, the Overall Survival in the LP-300 arm was more than double the control arm (27.0 months vs. 13.4 months, respectively) also being statistically significant in favor of LP-300 (P-value = 0.0167; HR = 0.367) and the 2-year survival was 72.4% in the LP-300 arm vs. 32.3% in the control arm.
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Statistically significant subgroup analyses and trends from this LP-300 Phase III NSCLC adenocarcinoma trial support repositioning LP-300 for non- or never smokers with adenocarcinoma of the lung.
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Randomized, double-blind, placebo-controlled and multi-center trial in patients with advanced NSCLC receiving paclitaxel & cisplatin (Japan Trial) (DMS32205R). The Japan Trial observations support and complement observations in the multi-country Phase III NSCLC adenocarcinoma trial. The observations for the female adenocarcinoma patient population in the LP-300 multi-country Phase III NSCLC adenocarcinoma trial are consistent with observations made for the subgroup of females with adenocarcinoma of the lung receiving paclitaxel/cisplatin and LP-300 or placebo in the Japan Trial. Although the overall population in the Japanese trial did not meet the pre-specified primary endpoint, a retrospective analysis of the subgroup consisting of female patients with adenocarcinoma revealed that the difference in the median overall survival period between the two treatment arms in this subgroup was significant (P-value = 0.0456, HR = 0.376).
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The LP-300 arm of the
multi-country Phase III NSCLC adenocarcinoma trial also demonstrated safety profile advantages in terms of the potential to protect
against chemotherapy-induced kidney toxicity and chemotherapy-induced anemia. These observations complemented earlier clinical
observations regarding LP-300’s potential to protect against neuropathy and other chemotherapy-induced toxicities. Results
from these trials indicate that treatment with LP-300 may, in further clinical testing, lead to improved survival in female and
non- or never smoking patients with primary adenocarcinoma of the lung receiving cisplatin/paclitaxel combination chemotherapy.
Phase II and III LP-300 Adverse Events
Summary
The following summarizes
adverse events reported from a total of 1,712 patients enrolled in five randomized multi-center phase II and phase III studies
with chemotherapy, with or without LP-300. A total of 1,712 patients were enrolled in these studies, of which 856 patients received
LP-300 with chemotherapy.
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All Adverse Events (AEs). The most frequently-occurring adverse events in patients receiving LP-300 with chemotherapy were generally similar to patients receiving placebo or chemotherapy alone. These events included blood and lymphatic system disorders (myelosuppression manifested as anemia, leukopenia, lymphopenia, neutropenia, and thrombocytopenia; also including decreased hematocrit, hemoglobin, lymphocyte count, neutrophil count, red blood cell count, platelet count, and white blood cell count), with an incidence ranging from 12% to 83%; gastrointestinal disorders including constipation, abdominal pain, diarrhea, nausea, stomatitis, and vomiting, with an incidence ranging from 22% to 83%; general disorders and administrative site conditions including fatigue (ranging from 17% to 85%); infusion/injection site pain/reactions (ranging from 12% to 18%); malaise (ranging from 16% to 28%); peripheral edema (ranging from 13% to 22%); pyrexia (ranging from 10% to 17%); infections and infestations disorders including nasopharyngitis (ranging from 11% to 16%); investigations including increased liver function tests including ALT, AST, and alkaline phosphatase (ranging from approximately 10% to 55%); increased blood lactate dehydrogenase (ranging from approximately 17% to 26%); increased blood urea or blood uric acid (ranging from approximately 11% to 32%); increased gamma-glutamyltransferase (ranging from approximately 23% to 33%); decreased total protein (ranging from approximately 12% to 21%); metabolic and nutritional disorders including weight decreased (ranging from 15% to 22%), anorexia (ranging from 14% to 82%), and hypomagnesemia (ranging from 22% to 30%); musculoskeletal and connective tissue disorders including arthralgia, back pain, and myalgia (ranging from 7% to 80%); nervous system disorders including dysgeusia (ranging from 12% to 22%), headache (ranging from 14% to 17%), and peripheral neuropathy (motor and sensory – ranging from 22% to 86%); psychiatric disorders including insomnia (ranging from 12% to 17%); respiratory, thoracic, and mediastinal disorders including dyspnea (ranging from 12% to 40%); skin and subcutaneous disorders including alopecia (ranging from 33% to 92%); rash (ranging from 22% to 29%); nail disorder/discoloration (10%); and vascular disorders including angiopathy (ranging from 64% to 69%) and flushing (ranging from 15% to 39%).
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Treatment-Related Adverse Events. Frequently occurring treatment-related AEs experienced by patients receiving LP-300 with chemotherapy included gastrointestinal disorders manifesting as nausea and vomiting (ranging from 12% to 67%, and 12% to 32%, respectively); fatigue (ranging from 22% to 82%); infusion/injection site pain/reactions (ranging from 11% to 18%); increased ALT (alanine aminotransferase) and gamma-glutamyltransferase (ranging from approximately 13% to 18%, and approximately 11% to 12%, respectively); peripheral neuropathy (motor and sensory – ranging from 14% to 54%); and vascular disorders including angiopathy (ranging from 60% to 69%), and flushing (ranging from 8% to 11%).
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Serious Adverse Events (SAEs). 11% to 49% of patients receiving LP-300 with chemotherapy,
and 7% to 42% of patients in control groups receiving chemotherapy alone experienced SAEs during randomized multicenter studies.
Frequently-occurring SAEs in patients receiving LP-300 with chemotherapy included pneumonia, hypersensitivity or drug hypersensitivity,
dyspnea, pyrexia and dehydration, diarrhea, anaphylactic shock or anaphylactic reactions, vomiting, disease progression, infection,
bronchospasm, pleural effusion, pulmonary embolism, thrombosis, hemolysis, nausea, chills, fatigue, sudden death, neutropenic
infection, sepsis, anorexia, neutropenia, febrile neutropenia, pneumonitis, rash, and hypotension. Multiple allergic reactions
have been reported in clinical trials of LP-300, and some of these reactions have been severe. It is possible that patients
could experience an allergic reaction that is life-threatening. Five reports of grade 3 or 4 hemolysis events with three
fatal outcomes were reported in patients receiving LP-300 with chemotherapy in a study involving the weekly drug administration
schedule. Two events of hemolysis were reported in a study involving drug administration every two weeks. No events
of hemolysis were reported in studies using the three weeks schedule of administration, which is the administration schedule
used for the multi-country Phase III NSCLC adenocarcinoma trial.
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Treatment-Related Serious Adverse Events. Approximately 7% of patients receiving LP-300 with chemotherapy experienced treatment-related SAEs during randomized multicenter studies. The most frequently-occurring treatment-related SAEs experienced by patients receiving LP-300 with chemotherapy were hypersensitivity or drug hypersensitivity (five and two patients, respectively) and neutropenia (six patients). Other treatment-related SAEs experienced by patients receiving LP-300 with chemotherapy included hemolysis, bronchospasm, febrile neutropenia, anemia, nausea, and pulmonary edema (three patients, each); chills, diarrhea, pyrexia, neutropenic infection, hyperglycemia, acute respiratory distress syndrome, pulmonary embolism, sudden death, infection, and rash (two patients, each); and angina pectoris, cardiac arrest, tachycardia, sudden hearing loss, abdominal pain, vomiting, adverse drug reaction, anaphylactic shock, C. difficile colitis, pneumonia, sepsis, chemical cystitis, thrombosis in device, dehydration, leukopenia, anorexia, atrial fibrillation, fatigue, weight decrease, muscle disorder, pain in extremity, dizziness, peripheral sensory neuropathy, dyspnea, hypotension, and thrombosis (one patient, each).
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Clinical Evidence of Toxicity Protection
by LP-300
The data from randomized
multicenter studies of LP-300 and chemotherapy demonstrates objective evidence of several instances where treatment with LP-300
appears to provide potential benefit in terms of preventing and mitigating chemotherapy-induced toxicities, particularly in studies
of LP-300 and chemotherapy in patients with advanced NSCLC. These data support that LP-300 has the potential to protect against
chemotherapy-induced toxicities, including gastrointestinal, renal, electrolyte disturbances, and anemia; and there is data supporting
the potential for LP-300 to protect against severe forms of these toxicities. In addition, treatment with LP-300 may protect against
severe platinum-induced hearing loss and dehydration.
LP-300 Mechanism of Action
LP-300 is a water-soluble
disulfide compound that lacks a free thiol or sulfate moiety. We postulate this unique structure of LP-300 may allow it to potentiate
antitumor activity of certain types of cytotoxic chemotherapy, and exert chemoprotective effects, through distinct and interrelated
mechanisms. In plasma, the lack of a free thiol prevents untoward reactivity and drug-drug interactions, and thereby may allow
chemotherapeutic agents to retain their efficacy. Once inside the tumor cell, LP-300 is metabolized and may then potentiate antitumor
activity of cytotoxic certain types of chemotherapy. A significant fraction of LP-300 is taken up by the kidneys, where LP-300’s
metabolites can interact with chemotherapy drugs, such as cisplatin, and potentially diminish the chemotherapy drug’s ability
to cause organ damage. We believe the postulated mechanisms that can enhance tumor directed chemosensitivity include restoration
of apoptotic sensitivity thereby countering drug resistance; oxidative stress enhancement; anti-angiogenesis; decreased DNA synthesis
and gene expression; and decreased glutathione and precursors (limiting glutathione tumor-mediated drug resistance). When LP-300
accumulates in the kidneys it appears to reduce the toxicity of certain drugs, such as cisplatin, that are excreted through the
renal system.
As depicted in the
model below, we believe LP-300 and its metabolites can modulate key components of the thioredoxin and glutaredoxin systems, which
are believed to be involved as major mechanisms of the potentially enhanced antitumor effects of LP-300 with chemotherapy. The
thioredoxin pathway is commonly upregulated in adenocarcinomas, and examination of primary lung tumors from non-smokers have shown
significantly increased gene expression of thioredoxin. Overexpression of thioredoxin in cancer cells has been postulated to lead
to resistance to apoptosis, increased cellular proliferation, increased gene expression, increased angiogenesis, increased conversion
of DNA into RNA, and resistance to oxidative stress induction. We believe the modulation of thioredoxin expression is important
for the observed increases in patient survival identified in retrospective analyses of certain subgroups of patients with primary
adenocarcinoma of the lung receiving LP-300 in conjunction with cisplatin and paclitaxel chemotherapy. Different glutaredoxin transcript
variants have been found to be elevated in transformed cells, and glutaredoxin isoforms (e.g., variants of glutaredoxin 2) have
been found to be elevated in NSCLC cell lines, lending evidence for potential roles of glutaredoxin in tumor progression.
We believe LP-300 and
its metabolites may potentiate the antitumor activity of chemotherapy by:
(1) shifting the redox
balance and concentrations of reduced forms of thioredoxin and glutaredoxin to inactive oxidized forms of thioredoxin and glutaredoxin,
thereby restoring apoptotic sensitivity, increasing sensitivity to oxidative stress, inhibiting cell growth and angiogenesis, RNA
to DNA synthesis, and growth signaling, and
(2) forming thioredoxin
or glutaredoxin adducts, which as inactive forms lead to thioredoxin- and glutaredoxin-mediated reduction of downstream targets
in the cell that are important for tumor resistance to chemotherapy, angiogenesis and cell growth.
We believe that LP-300
may potentiate antitumor activity of certain types of cytotoxic chemotherapy, and exert chemoprotective effects through several
distinct and interrelated mechanisms of action. LP-300 is a cysteine-modifying agent that appears to modulate multiple cellular
pathways simultaneously. Experimental data indicate that LP-300 modifies and/or modulates the following key pathways:
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Kinases involved in key signaling pathways (EGFR, ALK, ROS, MET)
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Enzymes critical for DNA synthesis and repair (ERCC1, RNR1, RNR2)
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Enzymes and proteins important in regulating cell redox status (TRX, PRX, GRX, PDI)
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The following key mechanisms
have been observed to support our belief that LP-300 has potential to play an important role in the treatment of females and non-
or never smokers with NSCLC adenocarcinoma. We believe these mechanisms help to explain the retrospective subgroup observations
for females and never smokers receiving LP-300 together with cisplatin and paclitaxel in the Phase III NSCLC adenocarcinoma trial:
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LP-300 targets cysteine residues. Computational and experimental data indicate that LP-300 demonstrates specificity towards cysteines. LP-300-mediated xenobiotic modulation of protein targets on cysteine results in distinct, (multi)target-specific effects correlated to the role of the cysteine residue(s) in the target.
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LP-300 alone inhibits human ALK and stimulates the inhibitory effect of crizotinib on human ALK. Alterations in ALK, along with MET, ROS1 & PDGFRA are thought to underlie nearly 10% of NSCLC adenocarcinoma cancers. Liquid Chromatography (LC), Mass Spectrometry (MS) and X-ray structural data demonstrate that LP-300 covalently modifies human ALK on Cys1156 and Cys1235. Enzyme assay data demonstrates that LP-300 inhibits human ALK’s kinase activity and stimulates the inhibitory effect of crizotinib on human ALK’s kinase activity.
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LP-300 inhibits human MET kinase activity and stimulates Staurosporine inhibition of human MET kinase activity. Mesenchymal Epithelial Transition Factor Kinase (MET) kinase mutations and amplification are an important, specific subset of NSCLC adenocarcinoma. Enzyme assays demonstrate that LP-300 inhibits human MET kinase activity and stimulates the inhibitory activity of staurosporine on human MET kinase.
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LP-300 inhibits EGFR kinase activity. EGFR mutations are an important, specific subset of NSCLC adenocarcinoma, particularly in non-smoker females. Enzyme assays demonstrate that LP-300 inhibits EGFR kinase activity and potentiates the inhibitory effect of eErlotinib on wild type as well as mutant EGFR kinase activity.
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LP-300 modestly inhibits retinal rod outer segment kinase (ROS1) activity. ROS1 chromosomal rearrangements are a recently identified class of mutations in NSCLC. Estimates of frequency of ROS1 rearrangements range from 1% to 2%. Experimental data are as follows:
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Enzyme activity data demonstrates that LP-300 has an effect on Human ROS1 activity when ROS1 is preincubated with LP-300. We hypothesize that pre-incubation allows slower reacting cysteine residues to be modulated by LP-300.
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Based on modeling studies, the cysteines on ROS1 appeared to be in less optimal orientations compared to cysteines in ALK.
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LP-300 appears not to impact ROS1 activity unless ROS1 and LP-300 are pre-incubated prior to kinase assays. Therefore, to see an effect in vivo, it may be necessary to administer LP-300 prior to LP-300’s effects on ROS1 through preincubation of ROS1 and LP-300, suggesting slower xenobiotic modulation reactions. However, there are several possible explanations for the LP-300 effect on ROS1 and in the absence of an X-ray structure this remains a hypothesis.
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LP-300 modifies Ribonucleotide Reductase 1 and 2 (RNR1 and RNR2). Selective, elevated expression of the RNR1 subunit is associated with gemcitabine resistance in NSCLC. RNR1/RNR2 are essential for DNA synthesis, DNA repair & cell proliferation. RNR1/2 catalyzes the formation of deoxyribonucleotides needed for DNA synthesis, from ribonucleotides.
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LP-300 targets proteins that may result in protection against chemotherapy-induced nephrotoxicity and neuropathy. The LP-300 derivative-cisplatin/paclitaxel conjugate is inactive and this conjugate is not a substrate for aminopeptidase/γ-Glutamyl-transpeptidase (APN/GGT). These LP-300 heteroconjugates appear to cause potent inhibition of APN/GGT leading to suppression/bypass of renal APN/GGT xenobiotic metabolism pathways promoting protection against chemotherapy-induced nephrotoxicity. In addition, binding of the LP-300 derivative with reactive cisplatin/paclitaxel species, appears to inactivate the platinum-catalyzed microtubule hyper-polymerization. This action may serve to protect against chemotherapy-induced peripheral neuropathy.
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LP-300 modulates protein function in a way that may promote chemosensitization. LP-300 appears to promote covalent oxidation of redox proteins Thioredoxin (TRX), Peroxiredoxin1 (PRX1) and Glutaredoxin (GRX). This action may keep these redox proteins in an inactive non-signaling state, which could enhance sensitivity to oxidative stress and apoptosis induced by concomitant chemotherapy.
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Using various in
vitro experimental approaches, LP-300 has been observed to form adducts on cysteines of various protein targets such as those
listed below. For several of these targets, studies evaluating enzyme activity associated with the targets have demonstrated inhibition,
modulation or impairment of such activity. In addition, X-ray crystallographic studies support LP-300 derived adducts at specific
cysteines on these proteins.
Targeted Proteins Modified by LP-300
Cellular Target of LP-300
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Cellular consequence of LP-300-modification and/or modulation
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Cellular thiol/disulfide balance
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LP-300 and LP-300-derived mesna disulfide heteroconjugates are pharmacological surrogate/modulators of physiological thiols and disulfides (e.g., glutathione, cysteine, and homocysteine).
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Gamma-Glutamyltranspeptidase Aminopeptidase N
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LP-300 and LP-300-derived mesna disulfide heteroconjugates can inhibit gamma-glutamyltranspeptidase and aminopeptidase N enzyme activity.
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Tubulin
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LP-300 exerts direct and indirect protective interactions with tubulin.
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Anaplastic Lymphoma Kinase (ALK)
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LP-300 disrupts/blocks ATP binding site resulting in inhibition of ALK kinase activity (vide infra).
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Mesenchymal Epithelial
Transition (MET) Factor Kinase
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Modification of non-active site cysteine(s) resulting in enzyme inhibition (MET).
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ROS1 kinase
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LP-300 xenobiotically modifies ROS1 kinase in a time dependent manner.
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Redox Balance
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LP-300 and LP-300-derived mesna disulfide heteroconjugates assist in the maintenance of cellular redox balance and support cellular defenses against oxidative insult.
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Thioredoxin (Trx) Glutaredoxin (Grx)
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LP-300 modifies non-catalytic cysteines important in redox protein function/structure (Grx and Trx).
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Thioredoxin (Trx) Glutaredoxin (Grx)
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LP-300 and/or LP-300-derived mesna disulfide heteroconjugates function as alternative substrates/inhibitors (Trx, Grx) resulting in impaired enzyme activity.
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Peroxiredoxin (Prx)
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LP-300 disrupts active site structure (Prx) resulting in impaired enzyme activity.
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Mechanistic evaluation
of LP-300 revealed that it has cysteine-modifying activity on select Receptor Tyrosine Kinases (RTKs) initiating proliferative
signaling such as ALK, EGFR, MET and ROS1. LP-300 may also serve as a potential chemosensitizer for certain combination chemotherapies
by inactivating proteins such as Thioredoxin (TRX), Glutaredoxin (GRX) and Peroxiredoxin (PRX) that are important in modulating
cellular redox status and in turn drug resistance. Higher levels of PRX gene expression have been shown to correlate significantly
with the absence of smoking history and with the female gender.
We believe well-tolerated
profile advantages of LP-300 are imparted through its chemoprotective action via production of inactive LP-300-chemotherapeutic
conjugates and preventing toxic taxane/platinum metabolites in the kidney, and targeting toxicity-inducing molecules and pathways
(e.g. APN, GGT, and Tubulin).
We plan to conduct
additional mechanism of action studies aimed at identifying and validating signaling molecules and pathways selectively triggered
by or responding to LP-300, as well as identifying additional potential drug combinations for clinical applications. Using female
non- or never smoker-derived lung adenocarcinoma cell lines that are sensitive to the combination of cisplatin, paclitaxel and
LP-300, we intend to analyze the induction of expressed genes in a time and concentration-dependent manner. Identification of a
pharmacodynamic biomarker that would be relevant at a lower dose of LP-300 could be a potentially valuable outcome of this investigation.
We intend to employ established cell lines with known genetic backgrounds as well as fresh patient tumor specimens as in vitro
or ex vivo model systems to perform drug response assays and genomic/ transcriptomic profiling. We believe these studies
may assist with determination of correlations between frequently occurring known driver mutations or resistance-related alterations
in ALK, EGFR, MET, ROS1 etc. and sensitivity to LP-300.
Planned Phase II Clinical Trial for
LP-300
We intend to conduct
a Phase II clinical trial of LP-300 in patients with adenocarcinoma NSCLC that are believed most likely to respond to treatment
based on the characteristics of the tumor being treated and other preclinical studies being conducted with CROs and key collaborators.
This proposed clinical trial will be subject to obtaining input from the FDA and other regulatory bodies, as well as approval by
investigators and Institutional Review Boards. We anticipate employing a combination therapy approach that includes a doublet
chemotherapy treatment. Our planned clinical trial of LP-300 may span over a two year period or more in either a single center
or in multi-center locations involving approximately 40 to 75 patients diagnosed with adenocarcinoma NSCLC with little to no history
of smoking and no prior chemotherapy treatment. We further anticipate that the primary objective of the study will be to investigate
the response to treatment with a recommended Phase II dose of LP-300 in combination with chemotherapy in non- or never smoking
patients with NSCLC. Secondary objectives may include (i) to assess the efficacy of LP-300 in combination with chemotherapy
in patients with NSCLC and non- or never smoking status, (ii) to assess the efficacy of LP-300 in combination with chemotherapy
in non-smoking females versus non-smoking males with NSCLC, (iii) to further investigate the safety and toxicity profile/tolerability
of the LP-300 and chemotherapy combination, and (iv) to investigate biomarkers correlated with potential efficacy of LP-300 in
paired tumor biopsies. We expect that the primary endpoint of the study will be overall survival with possible secondary
endpoints of (i) progression-free survival, (ii) objective response rate, (iii) identification of gene signatures correlated with
potential LP-300 efficacy from matched tumor tissue analysis, and (iv) protection against chemotherapy-induced nephrotoxicity.
We have contracted with Patheon API Services, Inc., a division of Thermo Fisher Scientific, Inc., to manufacture a sufficient quantity
of the active pharmaceutical ingredient for LP-300 to conduct a phase II trial.
Our RADR® Platform’s
Approach to LP-300 Repositioning
Our RADR®
platform is being implemented with the objective of uncovering insights from LP-300 rescued preclinical data as well as from
lung cancer clinical trial data regarding actionable bioinformatics, biomarkers, target population demographics and smoking history.
Differential expression analyses of RNAseq data on LP-300 pre- and post-exposure in selected NSCLC cell lines has revealed gene
sets that could be upregulated and downregulated in response to LP-300 treatments involving the mapping of genes performing cellular
redox functions, kinases involved in proliferating signaling, and apoptotic markers. We are currently in the early stages of defining
a specific biomarker signature that correlates with heightened sensitivity to LP-300. We believe that this signature may help accelerate
the clinical development of LP-300 and has the potential to guide patient selection for targeted clinical trials. We are also developing
a list of approved cancer drugs that, when used in combination with LP-300, may have potential to improve the overall benefit to
patients through either potentially greater anticancer properties or improved tolerability. We believe identifying such combinations
would be attractive to established pharmaceutical and biotech companies.
Acquisition of Tavocept® (LP-300) Rights from
BioNumerik
In January 2018, we
entered into an Assignment Agreement (the “Assignment Agreement”) with BioNumerik Pharmaceuticals, Inc. (“BioNumerik”),
pursuant to which we acquired rights to domestic and international patents, trademarks and related technology and data relating
to LP-300 for human therapeutic treatment indications. Mr. Margrave, our Chief Financial Officer and Secretary, formerly served
as the President, Chief Administrative Officer, General Counsel and Secretary of BioNumerik and has a minority ownership interest
in BioNumerik. The Assignment Agreement replaced a License Agreement that was entered into between us and BioNumerik in May 2016.
We made upfront payments totaling $25,000 in connection with entry into the Assignment Agreement.
If we commercialize
LP-300 internally, we will be required to pay to the BioNumerik-related payment recipients designated in the Assignment Agreement
a percentage royalty in the low double digits of cumulative net revenue up to $100 million, with incremental increases in the percentage
royalty for net cumulative revenue between $100 million and $250 million, $250 million and $500 million, and $500 million and $1
billion, with a percentage royalty payment that could exceed $200 million for net cumulative revenue in excess of $1 billion. In
addition, we have the right to first recover certain designated portions of patent costs and development and regulatory costs before
the payment of royalties described above. We are obligated to make royalty payments under the Assignment Agreement during the “Agreement
Term” that started on January 5, 2018 and continues (on a country-by-country and product-by-product basis) until the
later to occur of (i) five (5) years after the expiration of the last to expire Patent Rights, as defined in the Assignment Agreement,
in an applicable country in the Territory, as defined in the Assignment Agreement, and (ii) if no Patent Rights exist in such country,
fifteen (15) years after May 31, 2016.
If
we enter into a third party transaction for LP-300, we are required to pay the BioNumerik-related payment recipients a specified
percentage of any upfront, milestone, and royalty amounts received by us from the transaction, after first recovering specified
direct costs incurred by us for the development of LP-300 that are not otherwise reimbursed from such third party transaction.
In addition, the Assignment Agreement provides that we will use commercially diligent efforts to develop LP-300 and make specified
regulatory filings and pay specified development and regulatory costs related to LP-300. The Assignment Agreement also provides
that we will provide TriviumVet DAC (“TriviumVet”) with (i) specified data and information generated by us with respect
to LP-300, and (ii) an exclusive license to use specified LP-300-related patent rights, trademark rights and related intellectual
property to support LP-300 development in non-human (animal) treatment indications. Under the Assignment Agreement, we are required
to pay all patent costs on covered patents related to LP-300. Patent costs paid by us with respect to LP-300 related patents amounted
to approximately $59,000 and $74,000 for the years ended December 31, 2018 and December 31, 2019, respectively. These patent costs
are fully recoverable at the time of any net revenue from LP-300, with up to 50% of net revenue amounts to be applied towards repayment
of patent costs until such costs are fully recovered. In addition to the recovery of patent costs, we have the right to recover
the $25,000 upfront payments made in connection with entry into the Assignment Agreement, which payments are recoverable prior
to making any royalty or third-party transaction sharing payments. We also have the right to recover all previously incurred LP-300
development and regulatory costs, with up to a mid-single digit percentage of net revenue amounts to be applied towards repayment
of development and regulatory costs until such costs are fully recovered.
LP-184
General Overview
LP-184 (hydroxyureamethylacylfulvene)
is currently in preclinical development. LP-184 is a small molecule drug candidate that is a next generation alkylating agent that
preferentially damages DNA in cancer cells that overexpress certain biomarkers. It is from the fulvene class of compounds. LP-184
has nanomolar potency and it is a member of a new generation of acylfulvenes, a family of naturally-derived anticancer drug candidates.
Earlier generations of acylfulvenes showed great promise in preclinical studies, but were hampered in human clinical studies because
of the inability to deliver effective therapeutic doses due to unacceptable toxicities to normal cells. In preclinical studies,
LP-184 has shown significantly enhanced antitumor activity and substantially reduced toxicity as compared to earlier generation
acylfulvenes. In addition, we have used our RADR® platform, together with work of collaborators, to develop a patient-specific
biomarker test we believe will be predictive of LP-184’s anticancer activity in targeted patient populations. We plan on
using this test to facilitate patient selection in our planned Phase 1 clinical trial for LP-184. The chemical structure of LP-184
is depicted below.
LP-184 Chemical Structure
We have conducted LP-184
preclinical studies using fresh biopsy material from patients with advanced prostate cancer, which we see as a potential LP-184
indication. In addition, we are also evaluating LP-184 in a number of solid tumors that overexpress certain biomarkers that have
been identified as correlating with potential response to LP-184. Preliminary analysis suggests that LP-184 is also expected to
be a pro-drug likely activated by the enzyme Prostaglandin Reductase 1 (“PTGR1”). We believe LP-184’s mechanism
of action is to alkylate DNA and protein macromolecules, form adducts, and arrest cells in the S-phase of the cell cycle.
In preclinical studies,
LP-184 has demonstrated tumor regression in a xenograft mouse model of multi-drug resistant lung adenocarcinoma without dose-limiting
toxicities. In mouse model studies, LP-184 further demonstrated favorable in vivo pharmacokinetic properties including increased
half-life, plasma stability and bioavailability with reduced total body clearance. Further preliminary results from mouse studies
reveal a better in vivo hematological profile for LP-184 with decreased neutropenia and thrombocytopenia events.
Using our RADR®
platform, we have derived a 10-gene signature composed of candidate biomarkers determining sensitivity to LP-184. Genes from
this signature, such as PTGR1, were found to be implicated in the potential induction of bioactivation of LP-184. We believe LP-184
may be well positioned as a new drug candidate for individual patient genetic profiles identified as having DNA repair complex
deficiencies or other commonly prevalent gene signatures. LP-184 displayed less bone marrow toxicity in preclinical studies (dog
and mouse), had an improved pharmacokinetic profile (increased bioavailability as reflected by increased AUC), was stable in plasma,
and had an increased shelf life or stability in pharmaceutical grade material (sterile glass containers) for its class of compounds.
LP-184 retained selective cytotoxicity towards solid tumor derived cell lines in vitro. LP-184 can be synthesized from original
stock material (Illudin S) with additional steps.
We believe LP-184 is
a non-hormone, non-chemotherapy, next generation alkylating agent with nanomolar potency that preferentially damages DNA in cancer
cells that overexpress certain biomarkers indicated primarily in solid tumors such as those in prostate, pancreatic and ovarian
cancers. LP-184 was developed using combinatorial chemistry approaches. Based on screening against conventional therapies both
in vitro and in vivo, LP-184 cytotoxicity appears to be mediated through the Transcription Coupled Nucleotide Excision
Repair (TC-NER) pathway, via alkylation of DNA leading to cell cycle arrest in S phase. Additional cytotoxic effects on tumors
may include the generation of reactive oxygen species, chemical modification of various intracellular proteins, and induction of
the Mitogen Activated Protein Kinase (“MAPK”) pathway followed by apoptosis. A proposed model for the mechanism of
action of LP-184 is illustrated below.
We anticipate that
the results from ongoing preclinical cell line studies will inform the targets for broader indications for LP-184 in solid tumors.
Our RADR® platform has identified multiple solid tumor cancer indications that highly express PTGR1, including prostate,
ovarian, kidney, liver, lung, pancreatic and thyroid cancers. Our RADR® platform will be employed to correlate results
from ongoing preclinical studies with gene expression data to attempt to determine the likely anticancer activity of LP-184 in
these cancer indications. Based on these results, we intend to conduct follow-up studies in patient derived xenografts (PDX) models
to further elucidate precise targets and potential patient groups for future LP-184 clinical trials.
LP-184 Biomarker Background Using Our RADR®
platform
LP-184 biomarker studies
are being conducted by us to investigate the validity of relevant biomarkers. An NCI-60 cell line panel is being used to obtain
gene expression data and sensitivity data (GI50). Determination of potential biomarkers for LP-184 target indications
is performed by correlation analysis between normalized gene expression and GI50 values followed by biological and statistical
filtering. For further testing, we intend to acquire biopsy tissues (from prostate and ovarian cancer patients) to perform gene
expression analysis, predict potential drug response using Artificial Intelligence and machine learning and validate the results
experimentally by preclinical drug sensitivity testing.
Our RADR®
platform was used to analyze our dataset on preclinical LP-184 sensitivity to and baseline gene expression profiles of 57 cell
lines from the NCI-60 panel. Panel A in the figure below highlights the comparison of LP-184 sensitivity prediction accuracy across
a range of biomarker numbers. Starting from greater than 18,000 genes, our RADR® platform identified the 10 most
significant genes as predictive of response to LP-184 treatment. As depicted in panel B below, out of 18 cell lines included in
the blinded test set, our RADR® platform correctly predicted all 10 out of the actual 10 sensitive cell lines. Panels
C and D show model performance metrics such as area under curve (AUC) and confusion matrix representation, respectively. Model
training was performed using an initial set of 66 genes derived from 39 cell lines from the NCI-60 dataset. Model testing was conducted
on 18 cell line records isolated as the blinded hold-out set.
We believe that genes
from the 10 identified by our RADR® platform have been shown to be functionally involved in the postulated mechanism
of action of LP-184, thereby reaffirming our belief in the utility and value of our RADR® platform. We intend to
further extend and validate these cell line-derived preliminary biomarker analyses using LP-184 sensitivity and gene expression
data derived from fresh tumor biopsy samples. Our goal is to determine the molecular profiles of patient tumors that predict potential
drug response and to derive a diagnostic assay for stratifying patients. We believe that precision biomarker approaches increase
the likelihood that a treatment will be found to be effective in a relatively small phase II cohort by eliminating the most likely
non-responders and selecting the most likely responders. We anticipate that our RADR® platform driven determination
of molecular profiles of tumor tissues that are sensitive to LP-184 will greatly assist with stratification of patients in a future
phase II clinical trial.
As described above,
analysis of LP-184 using our RADR® platform yielded a 10-gene pan-cancer signature of candidate biomarkers associated
with LP-184 sensitivity. We intend to further validate these preliminary biomarker analyses using LP-184 sensitivity and pre-treatment
gene expression data derived from ex vivo models of fresh tumor biopsy samples from selected cancer indications. Furthermore,
gene weightage analysis was performed using Garson’s function to analyze the relative ranking of 10 genes in the LP-184 signature
associated with anticancer sensitivity. We believe that PTGR1 stands out as the gene with the highest relative importance for purposes
of determining LP-184 sensitivity.
The effect of gene
expression on the response variable was also studied across the identified LP-184 signature genes using the Lek’s profile
function as depicted below. We believe that the high expression of PTGR1 is significantly correlated to a possible positive anticancer
response to LP-184. The Lek’s profile method explores the relationship of the outcome variable and a predictor of interest,
while holding other predictors at constant values.
Numerous studies have
determined that PTGR1 expression is elevated in several tumor types, including prostate. Our RADR® platform analyses
indicate that tumor cells with high PTGR1 expression may be more sensitive to DNA damaging drugs like LP-184. Independent studies
suggest that PTGR1 may be responsible for converting LP-184 to its active form. These two results support our belief that PTGR1
is the most prominent biomarker for predicting LP-184’s potential anticancer activity in targeted tumor types. Clinical mapping
of PTGR1 expression profile was performed in independent historical datasets of unselected prostate cancer patients. Using our
RADR® platform, we analyzed historical data from a total of 2,204 prostate cancer patients from 14 different studies
and identified that on average 30% of the patient population showed high PTGR1 expression, and 39% of the patient population showed
intermediate PTGR1 expression, representing a group of patients that has the potential to be at least partial responders to LP-184.
Disease Background for Prostate,
Ovarian and Liver Cancer
Initial target patient
populations for LP-184 include advanced cancers of the prostate and ovary. Based on computational analysis of in vitro cell
line sensitivity data, we believe additional cancer types, including liver, kidney and thyroid, deserve further consideration as
target indications in which LP-184 is predicted to have potential anticancer activity.
Prostate Cancer
Prostate cancer is
the most commonly diagnosed cancer in men in the US and the second leading cause of cancer-related death in men in the US. The
American Cancer Society’s estimates for prostate cancer in the United States for 2019 are:
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Approximately 174,650 new cases of prostate cancer
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●
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Approximately 31,620 deaths from prostate cancer
|
Approximately
50% of patients who die from prostate cancer have metastases at diagnosis. The survival gains over the last decade have been modest
with acceleration in life-extending drug development occurring in the last three years. Hormonal therapy works to reduce testosterone
levels in the body to a level equal to that seen if physical castration were to occur. However, hormonal therapy can become refractory
after one to three years and tumor growth may resume. This is referred to as Castration-Resistant Prostate Cancer (“CRPC”).
About 10 - 20 % of prostate cancer patients develop CRPC within five years. According to JP Morgan, in 2011, approximately 136,000
men were treated for CRPC. Typically, standard hormonal therapy involving Androgen Deprivation Therapy (ADT) was prescribed in
the past for all comer patients. Current prescribed regimens involve intensified therapy for most patients (docetaxel for high
volume disease, and Zytiga for low and high volume disease) whereas upcoming molecularly selected agents in addition to hormonal
therapy are used in an individualized approach to metastasis-directed or local therapy. Standard of care agents for prostate cancer
include without limitation (i) Androgen production suppressors, such as Leuprolide (Lupron, Eligard), Goserelin (Zoladex), Triptorelin
(Trelstar), Histrelin (Vantas), Abiraterone (Zytiga), (ii) Androgen signaling blockers, such as Flutamide (Eulexin), Bicalutamide
(Casodex), Nilutamide (Nilandron), and Enzalutamide (Xtandi), and (iii) chemotherapeutics such as docetaxel and cabazitaxel. Drug
classes of new small molecules in development include PARP inhibitors, PI3K inhibitors and DNA Damage Repair (DDR) inhibitors.
The PARP inhibitor rucaparib (Rubraca) has recently been approved by the FDA. The identification and characterization of new molecular
targets, agents exploiting new or non-parallel mechanisms of action, and the discovery of predictive biomarkers for mCRPC, are
three of the major unmet needs in the prostate cancer space in the era of precision medicine that we believe LP-184 may address.
Ovarian Cancer
According
to the American Cancer Society and other published sources, ovarian cancer is the second most common gynecologic cancer in the
US. Ovarian cancer ranks fifth in cancer deaths among women, accounting for more deaths than any other cancer of the female reproductive
system. Ovarian cancer is the second most common gynecologic malignancy in developed countries, with an incidence of 9.4 per 100,000
women and a mortality rate of 5.1 per 100,000. In developing countries, it is the third most common gynecologic malignancy, with
an incidence of 5.0 per 100,000 and a mortality rate of 3.1 per 100,000. About 85% of ovarian cancer patients stop responding to
or relapse within two years after first line therapy. The American Cancer Society estimates for ovarian cancer in the US for 2019
are:
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Approximately 22,530 women will receive a new diagnosis of ovarian cancer.
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Approximately 13,980 women will die from ovarian cancer.
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A
woman’s lifetime risk of developing ovarian cancer is 1 in 75, and her chance of dying of the disease is 1 in 1004. The disease
typically presents at late stage when the 5-year relative survival rate is only 29%. Few cases (15%) are diagnosed with localized
tumor (stage 1) when the five-year survival rate is 92%. The overall five-year relative survival rate generally ranges between
30%–40% across the globe and has seen only modest increases (2%–4%) since 1995.
Carboplatin
in combination with paclitaxel has been the standard of care in the adjuvant and first-line settings for ovarian cancer, and, despite
all relevant efforts, improving upon this standard in clinical practice has proven extremely hard. Attempts to improve survival
and response rates using a triplet rather than the traditional doublet have failed to demonstrate any effective advantage. Prolonging
antineoplastic therapy after the conventional 5 to 6 cycles also was not reported to provide significantly better outcomes. Intraperitoneal
or dose-dense chemotherapy, and alternative platinum doublets, have been tested alongside targeted therapies such as bevacizumab,
pazopanib, nintedanib and PARP inhibitors (olaparib/ rucaparib) with limited success to date. At present, alternatives to standard
therapy do exist, but none has proven to be superior to conventional treatments, with the notable exception of carboplatin-paclitaxel
plus bevacizumab. In light of available data, none of the other options can be considered a “new standard” that fits
all. We believe that LP-184 has the potential to serve patient subgroups from multiple cancer types based on their gene signature
status in a tissue-agnostic manner.
Liver Cancer
According
to estimates published by the American Cancer Society and other published sources, liver cancer incidence has more than tripled
since 1980. Liver cancer develops approximately three times more often in men than in women. Liver cancer death rates have increased
over 2% per year since 2007. The American Cancer Society’s estimates for primary liver cancer (hepatocellular carcinoma)
and intrahepatic bile duct cancer (cholangiocarcinoma) in the US for 2019 are:
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Approximately 42,030 new cases (29,480 in men and 12,550 in women) will be diagnosed
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Approximately 31,780 people (21,600 men and 10,180 women) will die of these cancers
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Market Opportunity for LP-184
We are targeting a
set of indications for LP-184 based on combining the factors of predicted response, unmet clinical need and market opportunity.
These include prostate, ovarian and liver cancers. Below is an overview of relevant patient numbers and market sizes that we believe
LP-184 may potentially address, if approved, based upon published estimates by the Global Cancer Observatory and other published
sources:
Prostate cancer
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|
Global
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|
|
US
|
|
Total 2019 prostate cancer estimated incidence (new cases)
|
|
|
1,300,000
|
|
|
|
174,650
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CRPC incidence, ~20% of all prostate cancer
|
|
|
260,000
|
|
|
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34,930
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|
Metastatic CRPC incidence, ~80% of newly diagnosed CRPC
|
|
|
208,000
|
|
|
|
27,944
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|
Patient fraction in target segment
|
|
|
16
|
%
|
|
|
16
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%
|
Ovarian cancer
|
|
Global
|
|
|
US
|
|
Total 2019 ovarian cancer estimated incidence (new cases)
|
|
|
300,000
|
|
|
|
22,530
|
|
Estimated patients not responding to or relapsing within 2 years after first line therapy (85% of all ovarian cancers)
|
|
|
255,000
|
|
|
|
19,150
|
|
Patient fraction in target segment
|
|
|
85
|
%
|
|
|
85
|
%
|
Liver cancer
|
|
Global
|
|
|
US
|
|
Total 2019 liver cancer estimated incidence (new cases)
|
|
|
841,000
|
|
|
|
42,030
|
|
Estimated patients with hepatocellular carcinoma (75% of all liver cancers)
|
|
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630,750
|
|
|
|
31,522
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Patient fraction in target segment
|
|
|
75
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%
|
|
|
75
|
%
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Summary of LP-184 Preclinical Studies
Below is a summary
of preclinical studies conducted on LP-184:
LP-184 screening studies using MV522
lung cancer line.
In cell line screening
studies, LP-184 retained toxicity against the MV522 lung cancer line but displayed reduced toxicity against the normal 8392 B cell
and CHRF 288-11 megakaryocyte lines (platelet precursors). From the NCI-60 cell line panel, LP-184 demonstrated increased tumor-killing
activities against a variety of cancer cell lines, notably prostate, ovarian, lung and renal cancers. These observations are summarized
below.
Cell Line
|
|
LP-184
IC50 (nM)
|
|
8392 Normal B Cells
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|
|
>100,000
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|
CHRF 288-11 Megakaryocytic Cells
|
|
|
8,800
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|
PC3 Prostate
|
|
|
140
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|
DU145 Prostate
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|
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14
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|
OVCAR3 Ovarian
|
|
|
100
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|
OVCAR5 Ovarian
|
|
|
45
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|
A549 Lung
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|
70
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A498 Renal
|
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25
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MV522 Lung (multi-drug resistant)
|
|
|
210
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|
In hematotoxicity studies,
animals were treated 3 times per week for 3 weeks with control (sterile saline), or LP-100 at 10 mg/kg (MTD), or LP-184 at 10 mg/kg
(80% MTD). N=6, mean + SD. LP-184 neutrophil and platelet results vs LP-100; p <0.02. Based on these studies, we believe LP-184
shows potential for an enhanced in vivo hematological safety profile. LP-184 appears less toxic to normal blood cells than
LP-100. Studies in mice showing WBC differentials data indicated that LP-184 induces less thrombocytopenia and neutropenia than
LP-100. The tables and figure below summarize these observations.
Groups of 6 mice treated 3X per week for 3 weeks with 10
mg/kg drug
Analyte
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|
Control
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|
|
LP-100
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|
|
LP-184
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|
White blood cell count*
|
|
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4.57±0.82
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|
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|
1.97±0.44
|
|
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3.02±0.67
|
|
Neutrophil count*
|
|
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1.61±0.19
|
|
|
|
0.51±0.03
|
|
|
|
1.03±0.11
|
|
Hemoglobin (g/dL)
|
|
|
9.9
|
|
|
|
8.2
|
|
|
|
10.6
|
|
Platelet count*
|
|
|
574±127
|
|
|
|
384±64
|
|
|
|
587±149
|
|
In both human plasma
and in mice, LP-184 demonstrated a superior pharmacokinetic property profile compared to LP-100.
Pharmacokinetic property
|
|
LP-100
|
|
|
LP-184
|
|
Half life (h)
|
|
|
0.1
|
|
|
|
2.4
|
|
AUC (ng*h)
|
|
|
695
|
|
|
|
2200
|
|
Cmax (ng/ml)
|
|
|
5650
|
|
|
|
9730
|
|
Xenograft studies by Staake, et al.
2016
In a preclinical animal
study by Staake MD, et al. of Hydroxyurea derivatives of irofulven with improved antitumor efficacy reported in Bioort Med Chem
Lett. 2016: 26(7): 1836-1838, LP-184 treatment indicated a greater tumor regression in a mouse model with human cancer than LP-100.
LP-184 was tested in
a variety of xenograft models including MV522 lung adenocarcinoma and was found to be superior to LP-100 in its ability to induce
tumor regression or complete tumor remission. As described in the following figure, treatment with LP-184 demonstrated substantial
regression of lung cancer tumors in mice treated with the 10 mg/kg and 20 mg/kg doses.
Glioblastoma
Glioblastoma is a fast-growing,
aggressive type of CNS (Central Nervous System) tumor that forms on the supportive tissue of the brain. Glioblastoma is the most
common grade IV brain cancer. The American Cancer Society estimates that approximately 23,890
brain and other nervous system cancers (13,590 men and 10,300 women) will occur in the U.S. in 2020. It also estimates that in
2020, approximately 18,020 deaths will occur from brain and other nervous system cancers. Approximately 240,000 new glioblastoma
cases are estimated to occur each year worldwide, with approximately 11,000 to 13,000 new glioblastoma cases estimated to occur
each year in the U.S. Glioblastomas usually affect adults. Treating glioblastoma is very difficult due to the brain-blood
barrier and treatment often focuses primarily on relieving symptoms. The standard treatment
for glioblastoma includes radiation and chemotherapy with temozolomide. Based on an article in the journal Genes and Diseases (Temozolomide
resistance in glioblastoma multiforme, Genes Dis., 2016 May 11;3(3):198-210) and other publications, at least fifty percent
of temozolomide treated patients do not respond to this treatment, and others often form resistance to temozolomide based regimens.
Based on recent observations
and a preclinical study, we believe that LP-184 could have potential as treatment (alone or in combination with other treatments)
for glioblastoma, which is an aggressive type of cancer that begins in the brain and accounts for more than half of all brain cancers.
Our A.I. platform has helped to uncover biomarkers that may make a patient more responsive to LP-184 for the treatment of glioblastoma
as well as LP-184 in combination with other approved therapies. We have filed a patent application on this discovery.
Ongoing and Planned Preclinical Studies
for LP-184
For LP-184, we have
conducted and planned the following preclinical studies:
Cell line sensitivity
studies. We have partnered with a CRO to generate key preclinical data on LP-184 anticancer activity profiles in various cancer
types. The goal of this study is to generate dose response curves and associated IC50 values for LP-184 as monotherapy
on 41 different cancer cell lines representing prostate, NSCLC, ovarian, liver, kidney and thyroid cancer indications. PTGR1 transcript
levels in these cell lines are generally known, and will help to determine correlations between LP-184 cytotoxicity and PTGR1 gene
expression. LP-184 sensitivity profiles in cell lines from various cancer types, including liver, NSCLC and ovarian, were compared
with publicly available data for standard of care chemotherapy agents cisplatin and pemetrexed that are commonly prescribed in
NSCLC. In this cell line panel, LP-184 showed nanomolar potency whereas cisplatin and pemetrexed were less effective. A representative
chart demonstrating the superior potency of LP-184 is depicted in the graph below. From this ongoing study, we hope to identify
tumor types in addition to prostate that would be key potential targets for future clinical trials. LP-184 could potentially be
positioned to treat tumors not just based upon tissue of origin or histology, but upon the PTGR1 expression status of the tumors.
We have now demonstrated
LP184 activity in a panel of NSCLC cell lines. The data we have obtained support LP-184’s potential as a candidate for lung
cancers that carry mutations in genes such as KEAP, which otherwise make such tumors refractory to alkylating agents.
By utilizing wet lab
generated IC50 values across several tumor cell lines, including prostate, NSCLC, ovarian, liver, kidney and thyroid cancer, we
reaffirmed and validated our RADR generated signature as a robust predictive tool to assess sensitivity in tumors.
We have now confirmed
that the racemically pure negative isomer of LP-184 is several orders of magnitude superior to the positive enantiomer, while retaining
differential toxicity between tumor cells and normal cells.
We are in the process
of translating the leads generated by our A.I. based in silico analysis to confirm the most optimal drug combinations that would
best enhance the efficacy of LP-184 and broaden potential indications of its utility.
The strong antitumor
response of LP-184 observed in glioblastoma cell lines, prompted our further assessment of LP-184 as a candidate for glioblastoma
and other CNS tumors. Since CNS tumor effective agents require the ability to cross the blood brain barrier (BBB), we used in silico
analysis to determine the potential of LP-184 to penetrate BBB. Positive results from such analysis led us to partner with a CRO
to validate the ability of LP-184 to cross the BBB in a multicellular in vitro model. Based on this research, we believe
LP-184 is as efficacious as the standard of care Temozolomide in penetrating the BBB. These data have now led to a strategic collaboration
with investigators at The Kennedy Krieger Institute, an affiliate of the Johns Hopkins
School of Medicine.
Strategic Academic Collaborations
for LP-184
We are or have been
involved in the following academic collaborations for LP-184:
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Georgetown University. We have entered into the second phase of our collaboration with Georgetown University. In the first phase, we confirmed the efficacy of LP-184 in a panel of prostate cancer organoid models. In the second phase, we will focus on wet lab validation of the leads generated by our A.I. models of the gene dependency of most sensitive prostate cancers. This project is intended to provide necessary experimental data for use of LP-184 in a personalized medicine approach to treating prostate cancer. Our gene correlation data has highlighted the deficiency of several pathways that hypothetically would allow LP-184 to be synthetically lethal in tumors with such disruptions. Our RADR analysis also indicates that as many as 20% of prostate cancers carry markers that will make these tumors highly sensitive to LP1-84. In Phase 2 or our collaboration with Georgetown, we are focusing on the development of gene specific isogenic engineered prostate cancer cell lines to dissect the pathways as well as extend the 2D and 3D prostate cancer studies to in vivo genomically defined prostate cancer PDXs. In addition, we have designed studies that will test LP-184 in combination with several other drugs that are known to inhibit pathways needed to repair damage to DNA caused by LP-184. The advantage of combining our DNA damaging agent along with a DNA damage repair inhibitor is that it is expected to substantially extend the tumor specific efficacy of LP-184, including prostate cancers that might otherwise not carry deficiencies in the DNA repair pathway. We expect that the drug sensitivity data and genomic data from these studies will further guide optimal positioning of LP-184.
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●
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Memorial Sloan Kettering Cancer Center. We collaborated with the Memorial Sloan Kettering Cancer Center to evaluate LP-184 efficacy in preclinical models of cancer with defective DNA damage repair backgrounds, specifically ERCC3 mutations that are relatively common in hereditary breast and ovarian cancers. This study helped us in our efforts to (i) identify biomarkers (genomic, transcriptomic and/ or proteomic) associated with transcription-coupled nucleotide excision repair (TC-NER), the DNA repair pathway that acylfulvenes are known to target, and (ii) develop strategies for targeting vulnerabilities in this pathway during tumor growth (i.e. identify additional genetic backgrounds in this DNA repair pathway that can act with LP-184 in a synthetically lethal manner to inhibit tumor growth). Evidence from in vitro cell line work provided independent support for our belief in LP-184 anticancer activity in an engineered ERCC3 mutant breast cancer cell line model. The observed growth inhibition in this model fit well with the previously reported sensitivity range for LP-184 in the NCI-60 breast cancer cell line panel. This project provides a foundation to explore hereditary cancers with certain DNA damage repair deficiencies as potential indications for future LP-184 studies. An extrapolation of the results from this collaboration, when linked in the context of recent data and publications and other observations regarding acylfulvene mechanism of action, supports the potential for LP-184 to act as a synthetic lethal agent in tumors that carry mutations in ERCC3.
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●
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The Research Institute of Fox Chase Cancer Center (“FCCC”). Our ongoing collaboration with FCCC has yielded results that strongly link LP-184 efficacy to the expression of PTGR1. PTGR1 was identified by our RADR analysis as the lead gene candidate, the expression of which is essential to LP-184 mediated cytotoxicity. Using CRISPR engineered cells, we have now demonstrated a total lack of activity in tumor cell lines where PTGR1 expression is artificially knocked out. These data continue to support our RADR based predictions and the strategies of using LP-184 for tumor indications based upon PTGR1 expression. Our RADR analysis has identified a multitude of tumors with a higher than required threshold of PTGR1 expression. We have further validated the activity of LP-184 in a panel of pancreatic cancer cell lines. Studies to evaluate the efficacy of LP-184 in pancreatic cancer PDX models and in xenografts are ongoing. Our intent is to use the results from these studies to support our filing for orphan drug designation for LP-184 for use in pancreatic cancers.
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●
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Kennedy Krieger Institute and the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center. We have initiated a new collaboration with Kennedy Krieger Institute and investigators at the Johns Hopkins School of Medicine. We sought this collaboration following multiple unique findings regarding LP-184, including: the efficacy of LP-184 in glioblastoma (GBM); a positive result suggesting the ability of LP-184 to penetrate the Blood Brain Barrier, in amounts similar to the GBM standard of care agent Temozolomide (TMZ); and LP-184’s special ability to kill GBM cells irrespective of the methylation status of MGMT promoter. We believe there is an urgent unmet need for an effective therapy to treat GBM with unmethylated MGMT. Both wet lab data and RADR based gene correlations highlighted sensitivity of tumor cells that carry unmethylated MGMT to LP-184. We will seek to obtain additional data in an expanded panel of GBM tumor cell lines, neurospheres obtained from patient biopsies and evaluation of LP-184 in GBM xenografts in order to support an orphan drug designation for LP-184 for GBM. Early results from this collaboration continue to support the cytotoxicity of LP-184 in both GBM cell lines and neurospheres. Additional GBM in vivo studies involving animal xenografts are expected to be completed in the first quarter of 2021.
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●
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Clinical Trials and Research Innovation Center in Northern Ireland. In 2019, we initiated a new collaboration with the Clinical Trials and Research Innovation Center in Northern Ireland (“C-TRIC”) on a novel preclinical ex-vivo study focused on determining gene signatures correlated with LP-184 anticancer activity in human fresh prostate tumor tissue biopsies. This study was paused due to the COVID-19 pandemic, including the impracticality of international travel and the reprioritization of projects due to the pandemic. We are collaborating with other studies in the U.S. and will evaluating recommencing the study with C-TRIC as more is learned following the end of the COVID-19 pandemic.
|
Ongoing pre-IND Enabling and Planned
IND Enabling Animal Studies
We intend to obtain
toxicity data on fully synthetically produced (-) and (+) or R and S enantiomeric forms of LP-184 from cell line efficacy studies
as well as non-GLP dose range finding studies in rats. We expect to select the enantiomer with the most favorable safety and antitumor
profiles for continued analyses and further studies. Enantiomers are molecules that are non-superimposable mirror images of each
other. We have planned an animal study to determine the selection of the desired LP-184 enantiomer involving non-GLP dose range
finding in rats to compare toxicity of the enantiomers. Pursuant to the planned study, Sprague-Dawley rats will be given intravenous
(over 30 min) doses of the two compounds in sterile saline on Days 1 and 8, using a syringe pump or infusion pump. We anticipate
that the high dose will cause detectable toxicity to permit comparison between the two (+S) and (-R) enantiomers. Once an enantiomer
selection decision is made, we intend to conduct further IND-enabling animal studies involving some or all of the following: (i)
non-GLP dose range finding in rats, (ii) GLP analysis of toxicity in rats, (iii) non-GLP dose range finding in dogs, (iv) GLP analysis
of toxicity in dogs, (v) LC-MS/MS Method development for the determination of LP-184 levels in Rat and Dog Plasma, (vi) HPLC Method
development, (vii) Compatibility study of dose formulations and infusion systems (GLP), and (viii) Hemolytic potential (GLP).
Planned Phase I Clinical Trial for
LP-184
Once regulatory clearance
has been obtained to move forward under a future IND and subject to any changes or modifications in the IND in response to comments
from the FDA, we intend to conduct a Phase I clinical trial to study LP-184 versus placebo in combination with neoadjuvant chemotherapy
for the treatment of late stage solid tumors expected to include ovarian, prostate and liver cancer with high expression of the
protein coding gene PTGR1 (Prostaglandin Reductase 1). We anticipate that the study will have a duration of 6 to 18 months and
be located in a single center or multiple centers. We intend to conduct the study in two phases. In Phase 1A, we intend to perform
a dose escalation using a standard 3 + 3 escalation strategy with a primary objective to assess the safety and toxicity profile
of LP-184 in patients with solid tumors using the NCI CTCAE v.4.03 and to determine the maximum tolerated dose (MTD). In Phase
IB we intend to perform a dose expansion involving treatment with LP-184 at the MTD in patients with metastatic solid tumors, with
a primary objective to assess the safety and toxicity profile of LP-184 at the targeted MTD in patients with advanced solid tumors.
Further planning and development of secondary objectives and primary and secondary endpoints are in process and will be subject
to FDA review and comment.
LP-100
General Overview
LP-100 or
6-Hydroxymethylacylfulvene (or irofulven) exploits cancer cells’ deficiency in DNA repair mechanisms. We have
out-licensed LP-100 to Allarity Therapeutics. LP-100 is in a phase II clinical trial in androgen receptor (AR)-targeted and
Docetaxel-pretreated metastatic castration-resistant prostate cancer (mCRPC) patients. We hold an exclusive license for the
development and commercialization of LP-100.
LP-100 shows multiple
cytotoxic effects on tumor cell biology such as DNA adduct formation, RNA polymerase stalling and redox protein modification. It
demonstrates enhanced sensitivity in DNA repair deficient (e.g. ERCC3 mutant or knockout) in vitro and in vivo models.
In historical testing, clinical antitumor activity for LP-100 was observed in approximately 10-12% of patients with multidrug resistant
advanced prostate cancer with notable resolution of bone metastases.
History of LP-100
LP-100 belongs to the
family of compounds and small molecular entities (molecular weight <330) that represent a class of anticancer agents derived
from fungal toxins called Illudins. Acylfulvenes were originally synthesized and developed by Drs. Michael J. Kelner and Trevor
C. McMorris at University of California at San Diego (“UCSD”). In 1987, Professor McMorris published the first preclinical
evaluation of the Illudins as anticancer agents and a library of hundreds of acylfulvene derivatives was created, many with significant
in vitro and in vivo antitumor activity and potentially improved selectivity for tumor cells versus normal cells.
The compound Illudin S was found to be highly cytotoxic against cancer cells, but demonstrated a poor therapeutic index. Better
understanding of the mechanism of action led to the development of a novel family of semisynthetic antitumor agents, or next-generation
acylfulvenes such as 6-hydroxymethylacylfulvene, now designated as LP-100. LP-100 is a semisynthetic derivative of Illudin S, one
of a series of sesquiterpene natural products (Illudins) isolated from the Lantern mushroom Omphalotus illudens. LP-100
was selected for further study based on its potential to demonstrate promising antitumor activity while maintaining a more favorable
therapeutic index, compared to previously studied Illudins. The chemical structure of LP-100 is depicted below.
LP-100 Chemical Structure
Mechanism of Action
LP-100 leads to rapid
inhibition of DNA synthesis and induction of DNA damage. LP-100 is a monofunctional covalent DNA binder that inhibits DNA synthesis
and replication, affects cell cycle and induces apoptosis. DNA repair of LP-100-induced lesions is mediated by components of the
transcription-coupled nucleotide excision repair (TC-NER) pathway. LP-100 produces damage to DNA that can only be repaired by the
TC-NER pathway. The DNA damage is unique, as two enzymes, RNA Polymerase III and Topoisomerase I (Topo 1), associated with the
TC-NER are displaced leading to irreversible inactivation of the repair pathway. Other conventional DNA damaging chemotherapeutic
agents, such as cisplatin, etoposide, doxorubicin and others, produce general damage that can be repaired by the Global Genome
Nucleotide Excision Repair (GG-NER) pathway. Tumor cells often develop multidrug resistance (MDR) making them impossible to kill
using conventional drugs. LP-100 appears to retain activity against MDR tumor cells regardless of the mechanism of resistance and
tumor cells appear less likely to become resistant to LP-100. Killing of MDR tumor cells by LP-100 reflects its unique mechanism
of disrupting the TC-NER pathway. Cell-based studies have demonstrated selective cytotoxicity of LP-100 towards a variety of solid
tumor cell lines. The tumor cells cannot recover from this damage, undergo S-phase arrest, and then irreversibly initiate both
caspase-dependent and –independent apoptosis pathways. LP-100 produces DNA damage and induces apoptotic DNA fragmentation
in several tumor cell lines. Normal diploid cells, in contrast, do not normally need repair by the TC-NER pathway unless exposed
to UV light. Treatment of mouse xenografts of human tumors with LP-100 results in tumor shrinkage. Synergistic or additive activity
is observed when LP-100 is combined with various traditional anticancer agents.
LP-100 acts as a DNA
damaging agent by causing alkylation of DNA and adduct formation. It modulates the TC-NER DNA repair pathway further activating
the MAPK signaling cascade followed by apoptosis of target cells. Also, LP-100 induces RNA Polymerase II stalling in actively transcribed
regions, triggering cell death possibly due to collisions between transcriptional machinery and the replication fork. LP-100 is
not a substrate for drug efflux pumps, which helps to counteract chemoresistance to LP-100. Sensitivity to LP-100 is unlikely to
be influenced by common resistance-inducing phenomena observed for other DNA damaging agents like cisplatin. Antitumor activity
of LP-100 is independent of cellular p53 and p21 tumor suppressor gene status (such as loss of p53 or p21). LP-100 also produces
redox protein modifications by targeting key redox-controlling proteins TrxR/ GrxR. Distortion of the redox status of cellular
proteins serves as a pro-apoptotic stimulus in cancer cells.
LP-100 Clinical Profile
Clinical studies of
LP-100 have been conducted in multiple solid tumor indications including prostate, ovarian, colorectal, pancreatic, thyroid, lung,
breast and gastric cancers. More than 38 Phase I or Phase II trials involving > 1,300 patients have been conducted with LP-100.
In prior clinical trials, LP-100 showed activity and produced regression in a variety of cancers, but failed to meet required endpoints
for clinical trial success. Objective responses were reported for LP-100 single agent therapy in drug-resistant prostate (hormone
and taxotere refractory), ovarian (platinum resistant), pancreatic, sarcoma, kidney, endometrial, and lung cancers. LP-100 also
showed cancer treating potential when administered in combination with a variety of conventional chemotherapeutics including Camptosar,
GemZar, Taxotere, Xeloda, Cisplatin, and Oxaliplatin. In a study of patients who failed prior conventional therapies, two rounds
of LP-100 therapy led to rapid resolution of ovarian cancer metastasis. In a randomized Phase IIb study of patients with metastatic
hormone refractory taxotere-resistant prostate cancer, LP-100 was compared to mitoxantrone. A total of 138 patients were enrolled
and specified endpoints included overall survival, response rate, and safety assessment. The median one-year survival increased
from 22% in the mitoxantrone-treated control group to 41% in the LP-100-treated group. Median overall survival was 10.1 months
for treatment arm (LP-100 + Prednisone) and 7.4 months for control arm (Mitoxantrone + Prednisone), i.e. a 37% increase over standard
of care. Treatment was well-tolerated in all arms. The most frequent Grade 3–4 toxicities (as % of patients in treatment/control
arms) were asthenia (8%/0%), and vomiting (4%/0%). Grade 3–4 hematological events included neutropenia (22%/61%) and thrombocytopenia
(23%/4%).
In 2001, LP-100 received
FDA’s fast track status and a Phase III international clinical trial for LP-100 in refractory pancreatic patients was started.
Clinical trials looked promising in shrinking tumors of drug-resistant pancreatic cancer. However, MGI Pharma stopped the Phase
III clinical trial because it was unlikely for the trial to reach its objective due to a greater than expected survival benefit
associated with the comparator agent (5-FU). In 2005, Phase II clinical trial results of LP-100 in women with recurrent and heavily
pre-treated ovarian cancer revealed retinal toxicity. This retinal damage was associated with dose and administration of drug.
LP-100 has been well-tolerated,
based on initial observations from the phase II clinical trial in Europe that is being managed by Allarity Therapeutics in patients
with metastatic, castration-resistant, prostate cancer. This Phase II trial is aimed at evaluating the antitumor effect of LP-100
treatment in combination with Prednisolone in patients who have progressed on androgen receptor (AR)-targeted therapy and in docetaxel-pretreated
metastatic Castration-Resistant Prostate Cancer (mCRPC) patients. In this protocol, patients are screened using a LP-100-specific
response biomarker signature and eligible patients likely to respond to and benefit from treatment with LP-100 are recruited in
the trial. Allarity Therapeutics dosed the first patient in the trial in the fourth quarter of 2018. Continuing enrollment for
this Phase II clinical trial has slowed during the COVID-19 pandemic. Allarity Therapeutics has also stated that it is focusing
its existing resources on other programs that are currently higher priority for Allarity than LP-100. As of the date of this report,
we are unable to forecast the timeline for the completion of the Phase II clinical trial. Recently published data (also supported
by prior publications on (Irofulven) indicates that tumors carrying mutations in ERCC2 and ERCC3 genes are likely to be sensitive
to LP-100, and that the drug will be synthetically lethal in these tumors, in a fashion similar to the activity of PARP inhibitors
in BRCA deficient tumors. These observations expand the potential treatment indications for LP-100 to include urothelial tumors,
including bladder cancers, since as many as 10% of bladder cancers carry ERCC2/ERCC3 mutations. These indications may represent
a more rapid and efficient path to potential approval of LP-100, and we are evaluating possibilities aimed at maximizing the value
of these additional observations.
AF Chemicals
In January 2015,
we entered into a Technology License Agreement to exclusively license global patent rights from AF Chemicals, LLC (“AF Chemicals”)
for the treatment of cancer in humans for the compounds LP-100 (Irofulven) and LP-184. In February 2016, we and AF Chemicals entered
into an Addendum (the “Addendum”) providing for additions and amendments to the Technology License Agreement. In December
2020, we and AF Chemicals entered into a Second Addendum (the “Second Addendum”) providing for further additions and
amendments to the Technology License Agreement. The Technology License Agreement, Addendum and Second Addendum are collectively
referred to as the “AFC License Agreement”.
The Second Addendum
provides for us to make specified payments to AF Chemicals within 10 days after signing and by March 31, 2021. The Second Addendum
also provides that, from December 30, 2020 until January 15, 2025, we will have no obligation to pay annual licensing fees, development
diligence extension payments, or patent maintenance fee payments to AFC under the AFC License Agreement.
As part of the Second
Addendum, we have agreed to apply for specified orphan drug designations for LP-184 in the US and EU. The Second Addendum also
amends and clarifies other provisions of the Technology License Agreement, and provides us with the ability to recover a portion
of initial payments made under the Second Addendum from sublicense fees or royalty payments that may be made to AFC by us or third
parties prior to January 15, 2025.
Pursuant to the AFC
License Agreement we made annual licensing fee payments relating to LP-184 to AF Chemicals in the amount of $30,000 during each
of the years ended December 31, 2020 and 2019. In addition, we are obligated to make milestone payments to AF Chemicals at the
time of an Investigational New Drug Application (“IND”) filing relating to LP-184 and also upon reaching additional
specified milestones in connection with the development and potential marketing approval of LP-184 in the United States, specified
countries in Europe, and other countries. We estimate that these payments could be as much as approximately $3,780,000 if all milestones
were achieved and LP-184 obtained marketing approval in multiple countries and for multiple therapeutic indications.
In the event of a sublicense
of the LP-184 rights, we are obligated to pay AF Chemicals (a) low double digit percentage of the gross income and fees received
by us with respect to the United States in connection with such sublicense, and (b) a lower double digit percentage of the gross
income and fees received by us with respect to Europe and Japan in connection with such sublicense. We are obligated to pay royalties
under the AFC License Agreement for a term that expires upon the later of the expiration of the last patent licensed to us under
the agreement, and the last to expire orphan drug designation, if any, relating to our product candidate LP-184 or other specified
licensed technology under the agreement.
The
AFC License Agreement also provides that we will pay AF Chemicals a royalty of at least very small single digit percentage of specified
net sales of LP-184 and other analogs. In addition, the AFC License Agreement contains specified time requirements for us to file
an IND, enroll patients in clinical trials, and file a potential NDA with respect to LP-184, with the ability for us to pay AF
Chemicals additional amounts ranging up to an amount in the low hundreds of thousands of dollars for each one, two, three and four
year extension to such development time requirements, with additional extensions beyond four years to be negotiated by us and AF
Chemicals. Pursuant to the Second Addendum, no additional payments of annual licensing fees or development diligence extension
payments are required to be made by us until January 15, 2025, at which time these obligations will resume. We will also be obligated
to make annual licensing fee payments to AF Chemicals relating to LP-100 beginning January 15, 2025, as described below under Allarity
Therapeutics.
The
AFC License Agreement has a term that expires upon the later of the expiration of the last patent licensed to us under the agreement,
and the last to expire orphan drug designation, if any, relating to our product candidate LP-184 or other specified licensed technology
under the agreement, unless sooner terminated. The AFC License Agreement may be sooner terminated by AF Chemicals if we fail to
make any payments required to be made under the agreement when due, upon a material breach of any other provision of the agreement
that is not cured within the time period specified, and upon our bankruptcy or insolvency.
Allarity Therapeutics
Allarity Therapeutics
has begun a Phase II trial of Irofulven in Denmark. With Allarity Therapeutics, we won a joint Massachusetts-Denmark grant to provide
matching funds for production of LP-100 in Massachusetts and clinical studies in Denmark. The clinical studies utilize Allarity
Therapeutics’ proprietary DRP® biomarker screening of potential patients to select those most likely to respond
to the drug.
With our help, Allarity
Therapeutics has had cGMP LP-100 produced at Albany Molecular Research Inc., PCI Synthesis, a division of SEQENS CDMO and Piramal
Pharma Solutions (Lexington, KY USA). Allarity Therapeutics has used a proprietary DRP® bioinformatics approach
to identify putative biomarkers that can predict which patients will respond based on gene expression profiles. Allarity Therapeutics
started a Phase II clinical trial in Denmark for treatment of castration-resistant metastatic prostate cancer, with the first patient
enrolled in the fourth quarter of 2018. The trial is over half way through enrollment for the first stage of the trial, although
enrollment has slowed during the COVID-19 pandemic. The trial is estimated to enroll up to approximately 27 patients. If the study
has a successful outcome, we anticipate that Allarity Therapeutics may out-license the drug.
Allarity Therapeutics Drug License and
Development Agreement
In May 2015, we licensed
various rights to LP-100 (Irofulven) to Allarity Therapeutics pursuant to a drug license and development agreement.
Pursuant to the agreement,
Allarity Therapeutics is responsible for the development of LP-100 pursuant to a defined clinical development plan. The agreement
also provides for a joint development committee, including representatives from Allarity Therapeutics and us, to regularly discuss,
plan and inform the development of products under the agreement. In connection with the license under the agreement, Allarity Therapeutics
also agreed to directly pay to AF Chemicals on our behalf various specified amounts owed to AF Chemicals with respect to LP-100
under the AFC License Agreement, which amounts will then be deducted from payments to be made by Allarity Therapeutics to us.
Development Milestone Payments
Pursuant
to the agreement, Allarity Therapeutics has agreed to make milestone payments to us in connection with the development of LP-100
by Allarity Therapeutics or its affiliates, or by a third party (a “Program Acquirer”) that assumes control of the
LP-100 development program from Allarity Therapeutics corresponding to: (i) initiation of treatment of first patient in a Phase
III clinical trial; (ii) first filing for regulatory approval in the EU; (iii) first filing for regulatory approval in the US;
(iv) first regulatory approval in the EU; and (v) first regulatory approval in the US. We and Allarity Therapeutics have also agreed
that a portion of these milestone payments will be paid directly to AF Chemicals to satisfy our obligations under the AFC License
Agreement.
The above milestones
to be paid to us under the agreement are also subject to caps and floors providing that: the development milestones discussed above
for initiation of Phase III treatment and for the first filing for regulatory approval in the EU and the US shall not be less than
a specified percentage of the amount Allarity Therapeutics receives from a Program Acquirer upon the occurrence of a substantially
similar milestone; and the development milestones discussed above for first regulatory approval in the EU and the US shall not
be greater than a specified percentage of the amount Allarity Therapeutics receives from a Program Acquirer upon the occurrence
of a substantially similar milestone. With certain exceptions, the maximum aggregate amount of development milestone payments described
above to be paid by Allarity Therapeutics to us is $13,875,000 and to AF Chemicals is $7,125,000 for an aggregate total of $21,000,000.
In addition to the
above milestones, Allarity Therapeutics has agreed to pay us a specified percentage of any milestone payments Allarity Therapeutics
receives from a Program Acquirer that are different than the milestones described above, or a one-time payment in an amount in
the low seven figures, whichever is higher. AF Chemicals would also receive a portion of any amounts to be received by us pursuant
to this provision. The Allarity Therapeutics agreement also provides that development milestone payments (including the payments
described above) will be paid not more than once even if additional indications are developed for LP-100.
Alternate Payment Structure in Event
of Third Party Program Acquirer Agreement.
As an alternative to
the development milestone payments to be paid as discussed above, and without the $21 million payment limitation, Allarity Therapeutics
has agreed that we may select an alternate payment structure for all payments Allarity Therapeutics receives (other than royalty
payments which are described below) in the event Allarity Therapeutics enters into an agreement for LP-100 with a Program Acquirer
regarding a particular territory. We only have 15 days to make this selection from the date we receive notice from Allarity Therapeutics
that they have entered into an agreement with a Program Acquirer.
If we select the alternate
payment structure, then we would generally be entitled to receive a specified percentage of all amounts, other than royalty payments,
received by or on behalf of Allarity Therapeutics from the Program Acquirer, after subtraction of amounts paid or payable by Allarity
Therapeutics pursuant to the Program Acquirer agreement for taxes, other fees and payments to governmental authorities, and payments
made by the Program Acquirer to reimburse Allarity Therapeutics’ regulatory and other costs. Selection of the alternate payment
structure would not change our right to receive royalty payments from Allarity Therapeutics as described below. We have agreed
to obtain the consent of AF Chemicals prior to electing to receive payments pursuant to the alternate payment structure and no
assurances can be given that AF Chemicals would provide their consent.
Royalty Payments
In addition to the
milestone payments described above, Allarity Therapeutics has agreed to pay us royalties based on annual incremental sales of product
derived from LP-100 in an amount equal to a low single digit percentage of annual sales of between $0 and $50 million, a slightly
higher single digit percentage of annual sales between $50 million and $150 million, a mid-level single digit percentage of annual
sales between $150 million and $300 million, and a slightly higher mid-level single digit percentage of annual sales in excess
of $300 million.
Royalties are subject
to a cap of a specified percentage of any royalty payment Allarity Therapeutics receives from a Program Acquirer. The royalty amounts
to be received by us may be subject to reduction in the event of generic competition, patent expiry, or if additional third-party
licenses are required to be obtained for the development, use or commercialization of LP-100. Royalties will generally be received
on a country by country basis until the later of: expiration of an applicable patent in a particular country; 10 years after the
first commercial sale in the country; expiration of the last to expire valid claim of a relevant patent covering the LP-100 related
product together with the use of the DRP® biomarker, provided the product is approved only for use with the DRP
biomarker in the country; or expiration of any FDA (or any foreign equivalent) regulatory approval in each country that requires
use of the DRP® biomarker as a companion diagnostic for the relevant product.
Allarity Therapeutics
is obligated to pay royalties under the agreement on a country-by-country and product-by-product basis for a period that commences
with the first commercial sale of a product until the later of (i) the expiration of the last valid claim on the patent that covers
the product sold, or (ii) ten years after the first commercial sale of the covered product, or (iii) expiration of the last valid
claim covered by a patent using a DRP® Biomarker as a companion diagnostic to the product sold, or (iv) on a country-by-country
basis when the regulatory approval of the DRP® Biomarker as a companion diagnostic expires. However, the agreement
may be sooner terminated without cause by Allarity Therapeutics upon 120 days prior written notice, or immediately upon certain
regulatory actions that impede ongoing or future clinical trials, or upon written notice of a material breach of the agreement
by us that we do not cure within 60 days. We also have the right to terminate the agreement upon written notice of a material breach
of the agreement by Allarity Therapeutics that is not cured within 60 days.
Third Party Research and Development
Programs for Our Drug Candidates
Virtually all of our
developmental work is expected to be performed in contract labs in the near future, and most of it requires close collaboration
with these groups. Our strategic collaborations have specialized focus areas tailored to advancing our pipeline drug candidates
and provide expertise benefits.
Collaborator
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Focus Area
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Drug Candidate
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National Cancer Institute (NCI)
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Gene signature development and drug sensitivity prediction
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LP-184
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Georgetown University
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Evaluation of drug efficacy and sensitivity in prostate and pancreatic cancer organoid models and engineered pancreatic cancer cell lines
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LP-184
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Fox Chase Cancer Center (FCCC)
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Determination of drug efficacy in PDX tumor models
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LP-300 & LP-184
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Manufacturing Overview
We do not currently
own or operate any manufacturing facilities or have any manufacturing personnel. We currently rely, and expect to continue to rely,
on third party contract manufacturing organizations (“CMOs”) for the manufacturing of our drug candidates for preclinical
uses, clinical trials as well as for commercial manufacturing if our drug candidates receive marketing approval. We require that
our CMOs produce bulk drug substances and finished drug products in accordance with current Good Manufacturing Practices (“cGMPs”)
and all other applicable laws and regulations. We maintain agreements with our manufacturers that include confidentiality and intellectual
property provisions to protect our proprietary rights related to our drug candidates. We have a CMO contracted to manufacture LP-184
for preclinical use. We obtain our supplies from these CMOs on a purchase order basis and do not have long-term supply arrangements
in place. We do not currently have arrangements in place for redundant supply. For all of our drug candidates, we intend to identify
and qualify additional manufacturers to provide the active pharmaceutical ingredient and fill-and-finish services prior to seeking
regulatory approval.
LP-184 Manufacturing
We have contracted
to Southwest Research Institute® (“SwRI®”) the development of a fully synthetic route
to (-) and (+) LP-184. The synthesis process involves development and optimization of novel chemistry via multiple intermediates
to produce (-) and (+) enantiomers of LP-184. We have contracted to SwRI® the production of pre-GMP batch of the
desired enantiomer of fully synthetic LP-184. We intend to continue with the same supplier for manufacturing the GMP material intended
for IND-enabling animal studies as well as phase I clinical trials.
LP-300 Manufacturing Plans
For the supply of LP-300
for our phase II and/or III clinical program, we have identified potential CMOs, and we believe GMP grade API material will be
readily available. We have contracted with Patheon API Services, Inc., a division of Thermo Fisher Scientific, Inc., to manufacture
a sufficient quantity of the active pharmaceutical ingredient for LP-300 to conduct a phase II trial. Our manufacturing process
and protocol for LP-300 have been well established and substantial progress towards process validation has been made from previous
campaigns that were undertaken by BioNumerik Pharmaceuticals, Inc.
Commercialization
We retain worldwide
commercialization rights for our key candidates with the exception of LP-100, which we have out-licensed to Allarity Therapeutics.
We plan to continue considering out-license and collaboration opportunities in order to maximize returns and pursue successful
development of our key candidates. We currently have no sales, marketing or product distribution capabilities. However, once we
have key candidates closer to FDA approval, we may build our own specialty sales force, partner with a larger pharmaceutical organization,
or out-license our drug candidates.
We are continually
evaluating out-license opportunities for our candidates at later stages of development in order to focus on identifying and licensing
additional drug candidates for novel indications and/or patient subpopulations with an oncology focus for expansion of our pipeline.
Our commercial plans
and strategy for each particular program may change as our programs advance, the markets change, we receive more clinical data,
and depending on availability of capital.
Intellectual Property
We
have an extensive multi-national portfolio of intellectual property rights directed to our drug candidates, and their targeted
use and development in specific patient populations and in specific therapeutic indications.
As of the date of this
report, we own or control rights in over 70 active patents and patent applications across over 14 patent families whose claims
are directed to our drug candidates and what we plan to do with our drug candidates. We have in-licensed or acquired patents from
AF Chemicals, and BioNumerik directed to the compounds, LP-100, LP-184 and LP-300. Additionally, we have also filed patent applications
to further enhance and extend the use of these in-licensed compounds. Our patents are directed to our drug candidates, their usage,
manufacturing, and other matters. These matters are essential to precision oncology and relate to: (a) uniquely powerful, data-driven,
biologically relevant biomarker signatures, (b) patient selection and stratification approaches that rely on prediction of response
deriving from these signatures and, (c) the ability to develop novel, combination therapy approaches with existing approved therapeutics.
A recent application is directed to the use of LP-300 as a potential disulfide linker. We intend to pursue additional patent coverage
relating to the use of LP-300 as a potential linker or linking technology.
We
rely on a combination of patents, trade secrets, copyrights, trademarks, license agreements, nondisclosure and other contractual
provisions and technical measures to protect our intellectual property rights in our novel drug candidates as well as our rescue
drug candidates. Additionally, we also rely on the patent applications, trade secrets, and other contractual provisions and technical
measures to protect the development of our genomic and biomarker signatures that help us in making predictions about the sensitivity
to our drug candidates, patient stratification approaches, and the development of potential combination therapies with our drug
candidates.
Intellectual
Property Portfolio by the Numbers
As
of March 2021, our intellectual property portfolio consisted of over 14 patent families covered by:
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Over 50 issued patents across our portfolio of compounds in key, commercially important geographies;
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Over 20 pending patent applications, including three PCT applications;
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as well as two registered trademarks, two pending trademark registrations, and trademark applications in Japan, China, Europe, Canada and Australia.
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Our
policy is to protect the proprietary technologies, inventions, and improvements that are commercially important to our business
in the United States, Europe, Japan and other key jurisdictions important to our business. We fully expect that additional
advances will come out of our ongoing work in developing biomarker signatures and patient stratification approaches and that these
advances will form the basis of additional intellectual property protection through new patent filings, trademarks, trade secrets,
and copyrights. We will continue to file patent applications and use trade secret laws to protect the uses of our genomic
and biomarker signatures, response prediction and patient stratification discoveries. We plan to rely on these intellectual property
advances to develop, strengthen, and maintain our proprietary position for novel therapeutics and novel formulations and uses of
existing and new compounds across multiple therapeutic areas. We also plan to rely on data exclusivity, market exclusivity and
patent term extensions when available.
Patent Portfolio
We
have an extensive multi-national portfolio of intellectual property rights directed to our drug candidates, and their targeted
use and development in specific patient populations and in specific therapeutic indications. Our portfolio consists of 14 patent
families across issued patents and pending patent applications. For LP-100, we own and control two in-licensed patent families,
including issued US Patents, Japan Patents, and various issued EU Patents directed to LP-100. We have also filed seven patent applications
directed to our proprietary drug programs together with biomarkers and sensitivity parameters, two of which are being consolidated
into one application, and one additional patent application directed to our RADR® platform. These filings include
patent applications directed to LP-300 and additional patent applications directed to new manufacturing methods for novel, synthetic
illudins, and gene signatures and biomarker profiles indicating sensitivity to LP-184 and use of LP-184 and novel synthetic illudins
in glioblastoma and CNS cancers.
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Our patent family directed to LP-100 has patents that expire in August 2026.
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Our patent family directed to LP-184 has patents that expire in August 2026, and patent applications, if granted, that would expire as late as May 2040.
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Our patent family directed to LP-300 has patents that expire in March 2028, and patent applications, if granted, that would expire as late as March 2040.
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We typically file a
non-provisional patent application within 12 months of filing the corresponding provisional patent application. While we intend
to timely file non-provisional patent applications relating to our provisional patent applications, we cannot predict whether any
of our existing or future patent applications for our existing or future drug candidates will result in the issuance of patents
that effectively protect these candidates, or if any of our issued patents or if any of our licensor’s issued patents will
effectively prevent others from commercializing competitive products. Patent protection for the composition of matter of the LP-300
compound itself is unavailable because the compound was first identified many years ago. For more information regarding the
risks related to our intellectual property, see “Risk Factors – Risks Related to Our Intellectual Property.”
RADR® Platform
We do not own or in-license
any patents on our RADR® platform, but we have filed one patent application directed to our RADR® platform
and rely on trade secrets and confidential procedures directed to protecting:
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our A.I. and machine learning methodologies for our specific purposes in oncology drug development and drug rescue,
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our curation and normalization of select data from both public and proprietary data sources, and
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our developing insights that can be modeled to cover biological processes as algorithms inside our RADR® platform.
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LP-100
Our portfolio directed
to LP-100 consists of two families of in-licensed patents that were filed in 2006. The patents include European, Japanese and US
patents. US Patent No. 7655695 relates to acylfulvene analogs that are directed to tumor solid tumor growth inhibition.
The nominal expiration for our patents directed to LP-100 is August 2026 and does not account for any applicable patent term adjustments
or extensions.
LP-184& other Novel, Synthetic
Illudin Derivatives
Our portfolio directed
to LP-184 consists of six families of patents and patent applications and includes three PCT applications. US Patent
No. 7655695 relates to acylfulvene analogs that are directed to solid tumor growth inhibition. The PCT applications filed
in 2019 are related to synthetic preparation methods, additional indications, and treatment of cancers using genomic stratification.
A provisional patent application filed in 2020 was directed to using LP-184 or other novel, synthetic illudin analogs or deriviatives
to treat glioblastoma or other CNS cancers as either a mono or combination therapy. A provisional patent application filed in 2020
was directed to using LP-184 or other novel, synthetic illudin analogs or derivatives to treat pancreatic cancer also as either
a mono or combination therapy. The nominal expiration for patents and patent applications directed to LP-184 ranges from 2026 to
as late as 2040 and does not account for any applicable patent term adjustments or extensions. We intend to nationalize our
patent applications in the US, Canada, EU, China, and Japan.
We have in-licensed
patents from AF Chemicals related to the composition of matter of LP-184. We have also developed additional intellectual property
for this class of compounds related to the development of novel synthetic routes and the preparation of certain illudin derivatives
having therapeutic value. Additionally, in April of 2020, we filed a provisional patent on the use of LP-184 and these novel synthetic
illudin derivatives in the treatment of glioblastoma and other CNS cancers.
LP-300
Our portfolio directed
to LP-300 consists of seven families of owned patents. A more recent PCT patent application filed in 2020 is directed
to treatment of non-small cell lung cancer (NSCLC) in nonsmokers and never smoking patients using disodium 2,2’-dithio-bis-ethane
sulfonate (dimensa). The nominal expiration for NSCLC related patents and patent applications directed to LP-300 ranges from
2028 to as late as 2040 and does not account for any applicable patent term adjustments or extensions. We intend to nationalize
our patent applications in the US, Canada, EU, China, and Japan.
We filed an additional
PCT application in March 2020 directed to LP-300 and its application to NSCLC, as well as biomarkers that correlate to heightened
response or sensitivity to LP-300. A recent application is directed to the use of LP-300 as a potential disulfide linker.
Confidentiality & Trade Secrecy
Although we enter into
non-disclosure and confidentiality agreements with parties who have access to confidential or patentable aspects of our research
and development output, such as our employees, collaborators, contract research organizations, contract manufacturers, consultants,
advisors and other third parties, any of these parties may breach the agreements and disclose such output before a patent application
is filed, thereby jeopardizing our ability to seek patent protection. These agreements provide
that all confidential information developed or made known during the course of an individual or entities’ relationship with
us must be kept confidential during and after the relationship. These agreements also provide that all inventions resulting from
work performed for us or relating to our business and conceived or completed during the period of employment or assignment, as
applicable, shall be our exclusive property. Third parties may also be able to develop substantially equivalent proprietary information,
platforms or compounds, or otherwise gain access to our trade secret
Trademarks
We
own various trademarks, applications and unregistered trademarks in the United States and other commercially important markets,
including our company name, our A.I. platform, and certain compounds in development. Our trademark portfolio is designed to protect
the brands for our Company, our A.I. platform and our portfolio of compounds.
Other Intellectual Property
We believe that our
intellectual property rights on the RADR® platform are valuable and important to our business. We rely on a combination
of trademarks, copyrights, trade secrets, license agreements, confidentiality procedures, non-disclosure agreements, employee disclosure,
and invention assignment agreements, and other legal and contractual rights to establish and protect our proprietary rights.
Competition
We
exist at the intersection of rapidly moving, global industries, namely, the biotechnology industry and the A.I. drug development
industry. This is a unique and rapidly moving category with a variety of business models being developed globally. The pharmaceutical
and biotechnology industries are characterized by rapidly advancing technologies, intense competition and a strong emphasis on
intellectual property. A.I. is disrupting and changing all industries, including the biotechnology industry. Although these are
competitive industries, we believe we are uniquely positioned due to our focus on oncology drug development, prediction of patient
response, use of computational biology, and the ability to both rescue and develop compounds.
We
face potential competition from many different sources, including major pharmaceutical and biotechnology companies, academic institutions
and governmental agencies, and public and private research institutions.
Many
of the companies against which we may compete have significantly greater financial resources and expertise in research and development,
manufacturing, preclinical studies, conducting clinical trials, obtaining regulatory approvals and marketing approved products
than we do. Smaller or early-stage companies may also prove to be significant competitors, particularly through collaborative arrangements
with large and established companies. Mergers and acquisitions in the pharmaceutical, biotechnology and diagnostic industries may
result in even more resources being concentrated among a smaller number of our competitors. These competitors also compete with
us in recruiting and retaining qualified scientific and management personnel and establishing clinical trial sites and patient
registration for clinical trials, as well as in acquiring technologies complementary to, or necessary for, our programs.
Our
commercial opportunity could be reduced or eliminated if our competitors develop and commercialize medicines that are safer, more
effective, have fewer or less severe side effects, and are more convenient or less expensive than any medicines we may develop.
Our competitors also may obtain FDA or other regulatory approval for their medicines more rapidly than we may obtain approval for
ours, which could result in our competitors establishing a strong market position before we are able to enter the market. In addition,
our ability to compete may be affected in many cases by insurers or other third-party payors seeking to encourage the use of generic
medicines.
Any
drug candidates we successfully develop will compete with current and new therapies that may become available in the future. The
key competitive factors affecting the success of all of our drug candidates, if approved, are likely to be their efficacy, combinability,
safety profile, convenience, cost, the effectiveness of companion diagnostics in guiding the use of related therapeutics, if any,
the level of generic competition, level of promotional activity, intellectual property protection, and the availability of reimbursement
from government and other third-party payors. If any drug candidates under development are approved for the indications in which
we are currently planning clinical trials, they will compete with the drugs discussed below and will likely compete with other
drugs in development.
Artificial
Intelligence and Drug Development
We
believe our proprietary RADR® platform gives us a significant competitive advantage by using AI to select and license
drugs with a well-tolerated safety profile to quickly and cost-effectively bring drugs to market. Recently, there has been an increase
in the use of AI for drug development that we face competition in both for developing new drugs and in biomarker development. This
includes competition to the pool of already existing drug candidates that may be eligible for patient stratification. Our competition
in AI-driven drug development for oncology includes, but is not limited to, the following:
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Development of drug candidates: A2A Pharmaceuticals, AI Therapeutics, Atomwise, Benevolent AI, Berg Health, BioXcel, Celsius Therapeutics, Exscientia, Gritstone Oncology, Deep Genomics; and
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Development of biomarkers and/or signatures for patient stratification and improved drug development: Adaptive Biotechnologies, Concerto HealthAI, Datavant, Envisagenics, Erasca, and Genialis,.
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Prostate
Cancer
New
agents are being actively developed to treat specific subtypes of prostate cancer. Our approach is to leverage A.I. and biomarker
data to discover subtypes of prostate cancer and treatments for those subtypes of cancer. We believe our approach and our compounds
take advantage of this improved characterization of prostate cancer.
There
are approved standard of care agents for treating solid tumor prostate cancer, but there are a lack of approved therapeutic options
for non-metastatic castration-resistant prostate cancer (“nmCRPC”) patients and castration-resistant disease in metastatic
hormone-naïve prostate cancer (“mHNPC”). The competition we may face in regards to LP-100 and one of the indications
of LP-184, specifically mCRPC, includes without limitation the following drugs:
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Astellas/Pfizer’s Xtandi (enzalutamide) and Johnson & Johnson’s Zytiga (abiraterone acetate) and Clovis Oncology’s Rubraca (rucaparib) are approved for treatment of metastatic castration-resistant prostate cancer (mCRPC).
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Xtandi Zytiga and Androgen Deprivation Therapy (“ADT”) to treat mHNPC and nmCRPC, respectively.
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Pfizer has tested Talazoparib and Enzalutamide to treat mCRPC
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BeiGene has used Pamiparib treat mCRPC
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Millennium Pharmaceuticals has used ADT and TAK-700, a hormonal therapy that inhibits 17,20 lyase activity of the CYP17A1 enzyme, to treat Metastatic Prostate Cancer
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We
believe LP-184 is unique and it has promise for use in an expanded set of proposed indications including ovarian cancer and hepatocellular
carcinoma and other indications where specific biomarker profiles indicate likely sensitivity to the treatment. We are not aware
of any drugs in development or approved that are specifically addressing this range of proposed biomarker profile targeted indications.
Non Small
Cell Lung Cancer (NSCLC)
We
believe LP-300 may have an advantage to approved drugs on the market by serving as a well-tolerated agent in combination with multiple
existing standards of care drugs for the NSCLC patient population or female NSCLC patient population. LP-300 has shown potential
to alleviate adverse events associated with approved chemotherapeutics such as cisplatin and paclitaxel while also potentiating
their antitumor activities. LP-300 combined with cisplatin and/or paclitaxel has the potential to treat never-smoking NSCLC patients
with advanced adenocarcinoma. Due to its multi-modal mechanism of action and tolerability, LP-300 has the potential to be combined
with chemotherapy, targeted therapy and / or immunotherapy drugs. Beyond traditional chemotherapies, NSCLC treatments include
targeted small molecules and biologics, which include, without limitation, afatinib, brigatinib, ceritinib, crizotinib, pembrolizumab,
and ramucirumab that are used in specific NSCLC subtypes.
Government Regulation
Government authorities
in the United States at the federal, state and local level and in other countries regulate, among other things, the research, development,
testing, manufacture, quality control, approval, labeling, packaging, storage, record-keeping, promotion, advertising, distribution,
post-approval monitoring and reporting, marketing and export and import of drug and biological products. Generally, before a new
drug can be marketed, considerable data demonstrating its quality, safety and efficacy must be obtained, organized into a format
specific for each regulatory authority, submitted for review and approved by the regulatory authority.
U.S. Drug Development
In the United States,
the FDA regulates drugs under the Food, Drug, and Cosmetic Act (“FDCA”). Drugs also are subject to other federal, state
and local statutes and regulations. The process of obtaining regulatory approvals and the subsequent compliance with appropriate
federal, state, local and foreign statutes and regulations requires the expenditure of substantial time and financial resources.
Failure to comply with the applicable U.S. requirements at any time during the product development process, approval process or
post-market may subject an applicant to administrative or judicial sanctions. These sanctions could include, among other actions,
the FDA’s refusal to approve pending applications, withdrawal of an approval, a clinical hold, untitled or warning letters,
product recalls or market withdrawals, product seizures, total or partial suspension of production or distribution, injunctions,
fines, refusals of government contracts, restitution, disgorgement and civil or criminal penalties. Any agency or judicial enforcement
action could have a material adverse effect on us.
Our drug candidates
are considered small molecule drugs and must be approved by the FDA through the NDA process before they may be legally marketed
in the United States. The process generally involves the following:
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completion of extensive preclinical studies in accordance with applicable regulations;
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submission to the FDA of an IND, which must become effective before human clinical trials may begin;
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approval by an independent institutional review board (“IRB”), or ethics committee at each clinical trial site before each trial may be initiated;
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performance of adequate and well-controlled human clinical trials in accordance with applicable IND regulations, good clinical practice (“GCP”), requirements and other clinical trial-related regulations to establish substantial evidence of the safety and efficacy of the investigational product for each proposed indication;
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submission to the FDA of an NDA;
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a determination by the FDA within 60 days of its receipt of an NDA to accept the filing for review;
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satisfactory completion of a FDA pre-approval inspection of the manufacturing facility or facilities where the drug will be produced to assess compliance with cGMP, requirements to assure that the facilities, methods and controls are adequate to preserve the drug or biologic’s identity, strength, quality and purity;
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potential FDA audit of the preclinical study and/or clinical trial sites that generated the data in support of the NDA filing;
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FDA review and approval of the NDA, including consideration of the views of any FDA advisory committee, prior to any commercial marketing or sale of the drug in the United States; and
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compliance with any post-approval requirements, including the potential requirement to implement a Risk Evaluation and Mitigation Strategy (“REMS”), and the potential requirement to conduct post-approval studies.
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The data required to
support an NDA are generated in two distinct developmental stages: preclinical studies and clinical trials. The preclinical and
clinical testing and approval process requires substantial time, effort and financial resources, and we cannot be certain that
any approvals for any future drug candidates will be granted on a timely basis, or at all.
Preclinical Studies and IND
Preclinical studies
generally involve laboratory evaluations of drug chemistry, formulation and stability, as well as studies to evaluate toxicity
in animals, which support subsequent clinical testing. The sponsor must submit the results of the preclinical studies, together
with manufacturing information, analytical data, any available clinical data or literature and a proposed clinical protocol, to
the FDA as part of the IND. An IND is a request for authorization from the FDA to administer an investigational product to humans,
and must become effective before human clinical trials may begin.
Preclinical studies
include laboratory evaluation of product chemistry and formulation, as well as in vitro and animal studies to assess the
potential for adverse events and in some cases to establish a rationale for therapeutic use. The conduct of preclinical studies
is subject to federal regulations and requirements, including GLP regulations for safety/toxicology studies. An IND sponsor must
submit the results of the preclinical tests, together with manufacturing information, analytical data, any available clinical data
or literature and plans for clinical studies, among other things, to the FDA as part of an IND. Some long-term preclinical testing,
such as animal tests of reproductive adverse events and carcinogenicity, may continue after the IND is submitted. An IND automatically
becomes effective 30 days after receipt by the FDA, unless before that time the FDA raises concerns or questions related to one
or more proposed clinical trials and places the trial on clinical hold. In such a case, the IND sponsor and the FDA must resolve
any outstanding concerns before the clinical trial can begin. As a result, submission of an IND may not result in the FDA allowing
clinical trials to commence.
Clinical Trials
The clinical stage
of development involves the administration of the investigational product to healthy volunteers or patients under the supervision
of qualified investigators, generally physicians not employed by or under the trial sponsor’s control, in accordance with
GCP requirements, which include the requirement that all research subjects provide their informed consent for their participation
in any clinical trial. Clinical trials are conducted under protocols detailing, among other things, the objectives of the clinical
trial, dosing procedures, subject selection and exclusion criteria and the parameters to be used to monitor subject safety and
assess efficacy. Each protocol, and any subsequent amendments to the protocol, must be submitted to the FDA as part of the IND.
Furthermore, each clinical trial must be reviewed and approved by an IRB for each institution at which the clinical trial will
be conducted to ensure that the risks to individuals participating in the clinical trials are minimized and are reasonable in relation
to anticipated benefits. The IRB also approves the informed consent form that must be provided to each clinical trial subject or
his or her legal representative, and must monitor the clinical trial until completed. There also are requirements governing the
reporting of ongoing clinical trials and completed clinical trial results to public registries.
A sponsor who wishes
to conduct a clinical trial outside of the United States may, but need not, obtain FDA authorization to conduct the clinical trial
under an IND. If a foreign clinical trial is not conducted under an IND, the sponsor may submit data from the clinical trial to
the FDA in support of an NDA. The FDA will accept a well-designed and well-conducted foreign clinical trial not conducted under
an IND if the trial was conducted in accordance with GCP requirements and the FDA is able to validate the data through an onsite
inspection, if deemed necessary, and the practice of medicine in the foreign country is consistent with the United States.
Clinical trials in
the United States generally are conducted in three sequential phases, known as Phase I, Phase II and Phase III, and may overlap.
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Phase I clinical trials generally involve a small number of healthy volunteers or disease-affected patients who are initially exposed to a single dose and then multiple doses of the drug candidate. The primary purpose of these clinical trials is to assess the metabolism, pharmacologic action, tolerability and safety of the drug.
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Phase II clinical trials involve studies in disease-affected patients to determine the dose and dosing schedule required to produce the desired benefits. At the same time, safety and further pharmacokinetic and pharmacodynamic information is collected, possible adverse effects and safety risks are identified and a preliminary evaluation of efficacy is conducted.
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Phase III clinical trials generally involve a large number of patients at multiple sites and are designed to provide the data necessary to demonstrate the effectiveness of the product for its intended use, its safety in use and to establish the overall benefit/risk relationship of the product and provide an adequate basis for product approval. These trials may include comparisons with placebo and/or other comparator treatments. The duration of treatment is often extended to mimic the actual use of a product during marketing.
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Post-approval trials,
sometimes referred to as Phase IV clinical trials, are conducted after initial marketing approval. These trials are used to gain
additional experience from the treatment of patients in the intended therapeutic indication. In certain instances, the FDA may
mandate the performance of Phase 4 clinical trials as a condition of approval of an NDA.
Progress reports detailing
the results of the clinical trials, among other information, must be submitted at least annually to the FDA and written IND safety
reports must be submitted to the FDA and the investigators for serious and unexpected suspected adverse events, findings from other
studies suggesting a significant risk to humans exposed to the drug, findings from animal or in vitro testing that suggest
a significant risk for human subjects and any clinically important increase in the rate of a serious suspected adverse reaction
over that listed in the protocol or investigator brochure.
Phase I, Phase II and
Phase III clinical trials may not be completed successfully within any specified period, if at all. The FDA or the sponsor may
suspend or terminate a clinical trial at any time on various grounds, including a finding that the research subjects or patients
are being exposed to an unacceptable health risk. Similarly, an IRB can suspend or terminate approval of a clinical trial at its
institution if the clinical trial is not being conducted in accordance with the IRB’s requirements or if the drug has been
associated with unexpected serious harm to patients. Additionally, some clinical trials are overseen by an independent group of
qualified experts organized by the clinical trial sponsor, known as a data safety monitoring board or committee. This group provides
authorization for whether a trial may move forward at designated check-points based on access to certain data from the trial. Concurrent
with clinical trials, companies usually complete additional animal safety studies and also must develop additional information
about the chemistry and physical characteristics of the drug as well as finalize a process for manufacturing the product in commercial
quantities in accordance with cGMP requirements. The manufacturing process must be capable of consistently producing quality batches
of our drug candidates. Additionally, appropriate packaging must be selected and tested and stability studies must be conducted
to demonstrate that our drug candidates do not undergo unacceptable deterioration over their labeled shelf life.
NDA Review Process
Following completion
of the clinical trials, data is analyzed to assess whether the investigational product is safe and effective for the proposed indicated
use or uses. The results of preclinical studies and clinical trials are then submitted to the FDA as part of an NDA, along with
proposed labeling, chemistry and manufacturing information to ensure product quality and other relevant data. In short, the NDA
is a request for approval to market the drug for one or more specified indications and must contain proof of safety and efficacy
for a drug.
The application
must include both negative and ambiguous results of preclinical studies and clinical trials, as well as positive findings. Data
may come from company-sponsored clinical trials intended to test the safety and efficacy of a product’s use or from a number
of alternative sources, including studies initiated by investigators. To support marketing approval, the data submitted must be
sufficient in quality and quantity to establish the safety and efficacy of the investigational product to the satisfaction of FDA.
FDA approval of an NDA must be obtained before a drug may be marketed in the United States.
Under the Prescription
Drug User Fee Act (“PDUFA”), as amended, each NDA must be accompanied by a user fee. The FDA adjusts the PDUFA user
fees on an annual basis. According to the FDA’s fiscal year 2019 fee schedule, effective through September 30, 2020, the
user fee for an application requiring clinical data, such as an NDA, was approximately $2.94 million. PDUFA also imposes an annual
program fee for each marketed human drug ($325,424 in 2020) and an annual establishment fee on facilities used to manufacture prescription
drugs. Fee waivers or reductions are available in certain circumstances, including a waiver of the application fee for the first
application filed by a small business. Additionally, no user fees are assessed on NDAs for products designated as orphan drugs,
unless the product also includes a non-orphan indication.
The FDA reviews all
submitted NDAs before it accepts them for filing, and may request additional information rather than accepting the NDA for filing.
The FDA must make a decision on accepting an NDA for filing within 60 days of receipt. Once the submission is accepted for filing,
the FDA begins an in-depth review of the NDA. Under the goals and policies agreed to by the FDA under PDUFA, the FDA has 10 months,
from the filing date, in which to complete its initial review of a new molecular-entity NDA and respond to the applicant, and six
months from the filing date of a new molecular-entity NDA designated for priority review. The FDA does not always meet its PDUFA
goal dates for standard and priority NDAs, and the review process is often extended by FDA requests for additional information
or clarification.
Before approving an
NDA, the FDA will conduct a pre-approval inspection of the manufacturing facilities for the new product to determine whether they
comply with cGMP requirements. The FDA will not approve the product unless it determines that the manufacturing processes and facilities
are in compliance with cGMP requirements and adequate to assure consistent production of the product within required specifications.
The FDA also may audit data from clinical trials to ensure compliance with GCP requirements. Additionally, the FDA may refer applications
for novel drug products or drug products which present difficult questions of safety or efficacy to an advisory committee, typically
a panel that includes clinicians and other experts, for review, evaluation and a recommendation as to whether the application should
be approved and under what conditions, if any. The FDA is not bound by recommendations of an advisory committee, but it considers
such recommendations when making decisions on approval. The FDA likely will reanalyze the clinical trial data, which could result
in extensive discussions between the FDA and the applicant during the review process. After the FDA evaluates an NDA, it will issue
an approval letter or a Complete Response Letter. An approval letter authorizes commercial marketing of the drug with specific
prescribing information for specific indications. A Complete Response Letter indicates that the review cycle of the application
is complete and the application will not be approved in its present form. A Complete Response Letter usually describes all of the
specific deficiencies in the NDA identified by the FDA. The Complete Response Letter may require additional clinical data, additional
pivotal Phase 3 clinical trial(s) and/or other significant and time-consuming requirements related to clinical trials, preclinical
studies or manufacturing. If a Complete Response Letter is issued, the applicant may either resubmit the NDA, addressing all of
the deficiencies identified in the letter, or withdraw the application. Even if such data and information are submitted, the FDA
may decide that the NDA does not satisfy the criteria for approval. Data obtained from clinical trials are not always conclusive
and the FDA may interpret data differently than we interpret the same data.
Orphan Drugs
Under the Orphan Drug
Act, the FDA may grant orphan designation to a drug or biological product intended to treat a rare disease or condition, which
is generally a disease or condition that affects fewer than 200,000 individuals in the United States, or more than 200,000 individuals
in the United States and for which there is no reasonable expectation that the cost of developing and making the product available
in the United States for this type of disease or condition will be recovered from sales of the product.
Orphan drug designation
must be requested before submitting an NDA. After the FDA grants orphan drug designation, the identity of the therapeutic agent
and its potential orphan use are disclosed publicly by the FDA. Orphan drug designation does not convey any advantage in or shorten
the duration of the regulatory review and approval process.
If a product that has
orphan designation subsequently receives the first FDA approval for the disease or condition for which it has such designation,
the product is entitled to orphan drug exclusivity, which means that the FDA may not approve any other applications to market the
same drug for the same indication for seven years from the date of such approval, except in limited circumstances, such as a showing
of clinical superiority to the product with orphan exclusivity by means of greater effectiveness, greater safety or providing a
major contribution to patient care or in instances of drug supply issues. However, competitors may receive approval of either a
different product for the same indication or the same product for a different indication but that could be used off-label in the
orphan indication. Orphan drug exclusivity also could block the approval of one of our products for seven years if a competitor
obtains approval before we do for the same product, as defined by the FDA, for the same indication we are seeking approval, or
if a drug candidate is determined to be contained within the scope of the competitor’s product for the same indication or
disease. If one of our products designated as an orphan drug receives marketing approval for an indication broader than that which
is designated, it may not be entitled to orphan drug exclusivity. Orphan drug status in the European Union has similar, but not
identical, requirements and benefits.
Expedited Development and Review
Programs
The FDA has a fast
track program that is intended to expedite or facilitate the process for reviewing new drugs that meet certain criteria. Specifically,
new drugs are eligible for fast track designation if they are intended to treat a serious or life-threatening condition and preclinical
or clinical data demonstrate the potential to address unmet medical needs for the condition. Fast track designation applies to
both the product and the specific indication for which it is being studied. The sponsor can request the FDA to designate the product
for fast track status any time before receiving NDA approval, but ideally no later than the pre-NDA meeting with the FDA.
Any product submitted
to the FDA for marketing, including under a fast track program, may be eligible for other types of FDA programs intended to expedite
development and review, such as priority review and accelerated approval. Any product is eligible for priority review if it treats
a serious or life-threatening condition and, if approved, would provide a significant improvement in safety and effectiveness compared
to available therapies.
A product may also
be eligible for accelerated approval, if it treats a serious or life-threatening condition and generally provides a meaningful
advantage over available therapies. In addition, it must demonstrate an effect on a surrogate endpoint that is reasonably likely
to predict clinical benefit or on a clinical endpoint that can be measured earlier than irreversible morbidity or mortality (“IMM”),
which is reasonably likely to predict an effect on IMM or other clinical benefit. As a condition of approval, the FDA may require
that a sponsor of a drug or biologic receiving accelerated approval perform adequate and well-controlled post-marketing clinical
trials. If the FDA concludes that a drug or biologic shown to be effective can be safely used only if distribution or use is restricted,
it may require such post-marketing restrictions as it deems necessary to assure safe use of the product.
Additionally, a drug
may be eligible for designation as a breakthrough therapy if the product is intended, alone or in combination with one or more
other drugs or biologics, to treat a serious or life-threatening condition and preliminary clinical evidence indicates that the
product may demonstrate substantial improvement over currently approved therapies on one or more clinically significant endpoints.
The benefits of breakthrough therapy designation include the same benefits as fast track designation, plus intensive guidance from
the FDA to ensure an efficient drug development program. Fast track designation, priority review, accelerated approval and breakthrough
therapy designation do not change the standards for approval, but may expedite the development or approval process.
Post-Approval Requirements
Following approval
of a new product, the manufacturer and the approved product are subject to continuing regulation by the FDA, including, among other
things, monitoring and record-keeping requirements, requirements to report adverse experiences and comply with promotion and advertising
requirements, which include restrictions on promoting drugs for unapproved uses or patient populations, known as “off-label
use,” and limitations on industry-sponsored scientific and educational activities. Although physicians may prescribe legally
available drugs for off-label uses, manufacturers may not market or promote such uses. Prescription drug promotional materials
must be submitted to the FDA in conjunction with their first use. Further, if there are any modifications to the drug, including
changes in indications, labeling or manufacturing processes or facilities, the applicant may be required to submit and obtain FDA
approval of a new NDA or NDA supplement, which may require the development of additional data or preclinical studies and clinical
trials.
The FDA may also place
other conditions on approvals including the requirement for REMS, to assure the safe use of the product. A REMS could include medication
guides, physician communication plans or elements to assure safe use, such as restricted distribution methods, patient registries
and other risk minimization tools. Any of these limitations on approval or marketing could restrict the commercial promotion, distribution,
prescription or dispensing of products. Product approvals may be withdrawn for non-compliance with regulatory standards or if problems
occur following initial marketing.
The FDA may withdraw
approval if compliance with regulatory requirements and standards is not maintained or if problems occur after the product reaches
the market. Later discovery of previously unknown problems with a product, including adverse events of unanticipated severity or
frequency, or with manufacturing processes, or failure to comply with regulatory requirements, may result in revisions to the approved
labeling to add new safety information; imposition of post-market studies or clinical studies to assess new safety risks or imposition
of distribution restrictions or other restrictions under a REMS program. Other potential consequences include, among other things:
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restrictions on the marketing or manufacturing of the product, complete withdrawal of the product from the market, or product recalls;
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fines, warning letters, or holds on post-approval clinical studies;
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refusal of the FDA to approve pending applications or supplements to approved applications;
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applications, or suspension or revocation of product license approvals;
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product seizure or detention, or refusal to permit the import or export of products; or
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injunctions or the imposition of civil or criminal penalties.
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The FDA strictly regulates
marketing, labeling, advertising and promotion of products that are placed on the market. Drugs may be promoted only for the approved
indications and in accordance with the provisions of the approved label. The FDA and other agencies actively enforce the laws and
regulations prohibiting the promotion of off-label uses, and a company that is found to have improperly promoted off-label uses
may be subject to significant liability.
Other U.S. Regulatory Matters
Manufacturing, sales,
promotion and other activities following product approval are also subject to regulation by numerous regulatory authorities in
the United States in addition to the FDA, including the Centers for Medicare & Medicaid Services, other divisions of the Department
of Health and Human Services, the Department of Justice, the Drug Enforcement Administration, the Consumer Product Safety Commission,
the Federal Trade Commission, the Occupational Safety & Health Administration, the Environmental Protection Agency, and state
and local governments.
For example,
in the United States, sales, marketing and scientific and educational programs also must comply with state and federal fraud and
abuse laws, false claims laws, transparency laws, government price reporting, and health information privacy and security laws.
These laws include the following:
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the federal Anti-Kickback Statute, which makes it illegal for any person, including a prescription drug manufacturer (or a party acting on its behalf), to knowingly and willfully solicit, receive, offer or pay any remuneration that is intended to induce or reward referrals, including the purchase, recommendation, order or prescription of a particular drug, for which payment may be made under a federal healthcare program, such as Medicare or Medicaid. Moreover, the ACA provides that the government may assert that a claim including items or services resulting from a violation of the federal Anti-Kickback Statute constitutes a false or fraudulent claim for purposes of the civil False Claims Act;
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the federal false claims and civil monetary penalties laws, including the civil False Claims Act that can be enforced by private citizens through civil whistleblower or qui tam actions, prohibit individuals or entities from, among other things, knowingly presenting, or causing to be presented, to the federal government, claims for payment that are false or fraudulent or making a false statement to avoid, decrease or conceal an obligation to pay money to the federal government;
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the Federal Health Insurance Portability and Accountability Act of 1996 (“HIPAA”), prohibits, among other things, executing or attempting to execute a scheme to defraud any healthcare benefit program or making false statements relating to healthcare matters;
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HIPAA, as amended by the Health Information Technology for Economic and Clinical Health Act and their implementing regulations, also imposes obligations, including mandatory contractual terms, with respect to safeguarding the privacy, security and transmission of individually identifiable health information;
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the federal Physician Payments Sunshine Act requires applicable manufacturers of covered drugs, devices, biologics and medical supplies for which payment is available under Medicare, Medicaid or the Children’s Health Insurance Program, with specific exceptions, to annually report to CMS information regarding payments and other transfers of value to physicians and teaching hospitals as well as information regarding ownership and investment interests held by physicians and their immediate family members; and
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analogous state and foreign laws and regulations, such as state anti-kickback and false claims laws which may apply to sales or marketing arrangements and claims involving healthcare items or services reimbursed by non-governmental third-party payors, including private insurers, state laws that require biotechnology companies to comply with the biotechnology industry’s voluntary compliance guidelines and the relevant compliance guidance promulgated by the federal government and may require drug manufacturers to report information related to payments and other transfers of value to physicians and other healthcare providers or marketing expenditures, state laws that require biotechnology companies to report information on the pricing of certain drug products, and state and foreign laws that govern the privacy and security of health information in some circumstances, many of which differ from each other in significant ways and often are not preempted by HIPAA, thus complicating compliance efforts.
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Pricing and rebate
programs must also comply with the Medicaid rebate requirements of the U.S. Omnibus Budget Reconciliation Act of 1990 and more
recent requirements in the ACA. If products are made available to authorized users of the Federal Supply Schedule of the General
Services Administration, additional laws and requirements apply. Products must meet applicable child-resistant packaging requirements
under the U.S. Poison Prevention Packaging Act. Manufacturing, sales, promotion and other activities also are potentially subject
to federal and state consumer protection and unfair competition laws.
The distribution of
pharmaceutical products is subject to additional requirements and regulations, including extensive record-keeping, licensing, storage
and security requirements intended to prevent the unauthorized sale of pharmaceutical products.
The failure to comply
with any of these laws or regulatory requirements subjects firms to possible legal or regulatory action. Depending on the circumstances,
failure to meet applicable regulatory requirements can result in significant civil, criminal and administrative penalties, including
damages, fines, disgorgement, individual imprisonment, exclusion from participation in government funded healthcare programs, such
as Medicare and Medicaid, integrity oversight and reporting obligations, contractual damages, reputational harm, diminished profits
and future earnings, injunctions, requests for recall, seizure of products, total or partial suspension of production, denial or
withdrawal of product approvals or refusal to allow a firm to enter into supply contracts, including government contracts.
U.S. Patent-Term Restoration and
Marketing Exclusivity
Depending upon the
timing, duration and specifics of FDA approval of any future drug candidates, some of our U.S. patents may be eligible for limited
patent term extension under the Hatch-Waxman Act. The Hatch-Waxman Act permits restoration of the patent term of up to five years
as compensation for patent term lost during product development and FDA regulatory review process. Patent-term restoration, however,
cannot extend the remaining term of a patent beyond a total of 14 years from the product’s approval date. The patent-term
restoration period is generally one-half the time between the effective date of an IND or the issue date of the patent, whichever
is later, and the submission date of an NDA plus the time between the submission date of an NDA or the issue date of the patent,
whichever is later, and the approval of that application, except that the review period is reduced by any time during which the
applicant failed to exercise due diligence. Only one patent applicable to an approved drug is eligible for the extension and the
application for the extension must be submitted prior to the expiration of the patent. The USPTO, in consultation with the FDA,
reviews and approves the application for any patent term extension or restoration. In the future, we may apply for restoration
of patent term for our currently owned or licensed patents to add patent life beyond its current expiration date, depending on
the expected length of the clinical trials and other factors involved in the filing of the relevant NDA.
Market exclusivity
provisions under the FDCA also can delay the submission or the approval of certain applications. The FDCA provides a five-year
period of non-patent marketing exclusivity within the United States to the first applicant to gain approval of an NDA for a new
chemical entity. A drug is a new chemical entity if the FDA has not previously approved any other new drug containing the same
active moiety, which is the molecule or ion responsible for the action of the drug substance. During the exclusivity period, the
FDA may not accept for review an abbreviated new drug application (“ANDA”), or a 505(b)(2) NDA submitted by another
company for another version of such drug where the applicant does not own or have a legal right of reference to all the data required
for approval. However, an application may be submitted after four years if it contains a certification of patent invalidity or
non-infringement. The FDCA also provides three years of marketing exclusivity for a NDA, 505(b)(2) NDA or supplement to an existing
NDA if new clinical investigations, other than bioavailability studies, that were conducted or sponsored by the applicant are deemed
by the FDA to be essential to the approval of the application, for example, new indications, dosages or strengths of an existing
drug. This three-year exclusivity covers only the conditions of use associated with the new clinical investigations and does not
prohibit the FDA from approving ANDAs for drugs containing the original active agent. Five-year and three-year exclusivity will
not delay the submission or approval of a full NDA. However, an applicant submitting a full NDA would be required to conduct or
obtain a right of reference to all of the preclinical studies and adequate and well-controlled clinical trials necessary to demonstrate
safety and effectiveness.
European Union Drug Development
Similar to the United
States, the various phases of preclinical and clinical research in the European Union are subject to significant regulatory controls.
Although the EU Clinical Trials Directive 2001/20/EC has sought to harmonize the EU clinical trials regulatory framework, setting
out common rules for the control and authorization of clinical trials in the EU, the EU Member States have transposed and applied
the provisions of the Directive differently. This has led to significant variations in the member state regimes. Under the current
regime, before a clinical trial can be initiated it must be approved in each of the EU countries where the trial is to be conducted
by two distinct bodies: the National Competent Authority (“NCA”), and one or more Ethics Committees (“ECs”).
Under the current regime all suspected unexpected serious adverse reactions to the investigated drug that occur during the clinical
trial have to be reported to the NCA and ECs of the Member State where they occurred.
The EU clinical
trials legislation currently is undergoing a transition process mainly aimed at harmonizing and streamlining clinical-trial authorization,
simplifying adverse-event reporting procedures, improving the supervision of clinical trials and increasing their transparency.
Recently enacted Clinical Trials Regulation EU No 536/2014 ensures that the rules for conducting clinical trials in the EU will
be identical. In the meantime, Clinical Trials Directive 2001/20/EC continues to govern all clinical trials performed in the EU.
European Union Drug Review and Approval
In the European Economic
Area (“EEA”), which is comprised of the 27 Member States of the European Union (including Norway and excluding Croatia),
Iceland and Liechtenstein, medicinal products can only be commercialized after obtaining a Marketing Authorization (“MA”).
There are two types of marketing authorizations.
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The Community MA is issued by the European Commission through the Centralized Procedure, based on the opinion of the Committee for Medicinal Products for Human Use (“CHMP”), of the EMA, and is valid throughout the entire territory of the EEA. The Centralized Procedure is mandatory for certain types of products, such as biotechnology medicinal products, orphan medicinal products, advanced-therapy medicines such as gene-therapy, somatic cell-therapy or tissue-engineered medicines and medicinal products containing a new active substance indicated for the treatment of HIV, AIDS, cancer, neurodegenerative disorders, diabetes, auto-immune and other immune dysfunctions and viral diseases. The Centralized Procedure is optional for products containing a new active substance not yet authorized in the EEA, or for products that constitute a significant therapeutic, scientific or technical innovation or which are in the interest of public health in the EU.
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National MAs, which are issued by the competent authorities of the Member States of the EEA and only cover their respective territory, are available for products not falling within the mandatory scope of the Centralized Procedure. Where a product has already been authorized for marketing in a Member State of the EEA, this National MA can be recognized in another Member States through the Mutual Recognition Procedure. If the product has not received a National MA in any Member State at the time of application, it can be approved simultaneously in various Member States through the Decentralized Procedure. Under the Decentralized Procedure an identical dossier is submitted to the competent authorities of each of the Member States in which the MA is sought, one of which is selected by the applicant as the Reference Member State (“RMS”). The competent authority of the RMS prepares a draft assessment report, a draft summary of the product characteristics (“SPC”), and a draft of the labeling and package leaflet, which are sent to the other Member States (referred to as the Member States Concerned) for their approval. If the Member States Concerned raise no objections, based on a potential serious risk to public health, to the assessment, SPC, labeling or packaging proposed by the RMS, the product is subsequently granted a national MA in all the Member States (i.e., in the RMS and the Member States Concerned).
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Under the above described
procedures, before granting the MA, EMA or the competent authorities of the Member States of the EEA make an assessment of the
risk-benefit balance of the product on the basis of scientific criteria concerning its quality, safety and efficacy. Similar to
the U.S. patent term-restoration, Supplementary Protection Certificates (“SPCs”) serve as an extension to a patent
right in Europe for up to five years. SPCs apply to specific pharmaceutical products to offset the loss of patent protection due
to the lengthy testing and clinical trials these products require prior to obtaining regulatory marketing approval.
Coverage and Reimbursement
Sales of our products
will depend, in part, on the extent to which our products will be covered by third-party payors, such as government health programs,
commercial insurance, and managed healthcare organizations. There is significant uncertainty related to third-party payor coverage
and reimbursement of newly approved products. In the United States, for example, principal decisions about reimbursement for new
products are typically made by CMS. CMS decides whether and to what extent a new product will be covered and reimbursed under Medicare,
and private third-party payors often follow CMS’s decisions regarding coverage and reimbursement to a substantial degree.
However, no uniform policy of coverage and reimbursement for drug products exists. Accordingly, decisions regarding the extent
of coverage and amount of reimbursement to be provided for any of our products will be made on a payor-by-payor basis.
Increasingly, third-party
payors are requiring that drug companies provide them with predetermined discounts from list prices and are challenging the prices
charged for medical products. Further, such payors are increasingly challenging the price, examining the medical necessity and
reviewing the cost effectiveness of medical drug candidates. There may be especially significant delays in obtaining coverage and
reimbursement for newly approved drugs. Third-party payors may limit coverage to specific drug candidates on an approved list,
known as a formulary, which might not include all FDA-approved drugs for a particular indication. We may need to conduct expensive
pharmaco-economic studies to demonstrate the medical necessity and cost effectiveness of our products. As a result, the coverage
determination process is often a time-consuming and costly process that will require us to provide scientific and clinical support
for the use of our products to each payor separately, with no assurance that coverage and adequate reimbursement will be obtained.
In addition, in most
foreign countries, the proposed pricing for a drug must be approved before it may be lawfully marketed. The requirements governing
drug pricing and reimbursement vary widely from country to country. For example, the European Union provides options for its member
states to restrict the range of medicinal products for which their national health insurance systems provide reimbursement and
to control the prices of medicinal products for human use. A member state may approve a specific price for the medicinal product
or it may instead adopt a system of direct or indirect controls on the profitability of the company placing the medicinal product
on the market. There can be no assurance that any country that has price controls or reimbursement limitations for pharmaceutical
products will allow favorable reimbursement and pricing arrangements for any of our products. Historically, products launched in
the European Union do not follow price structures of the United States and generally prices tend to be significantly lower.
Healthcare Reform
The United States government,
state legislatures, and foreign governments have shown significant interest in implementing cost containment programs to limit
the growth of government-paid healthcare costs, including price-controls, restrictions on reimbursement, and requirements for substitution
of generic products for branded prescription drugs. For example, in March 2010, the Patient Protection and Affordable Care Act
of 2010, as amended by the Health Care and Education Reconciliation Act of 2010 (collectively, the “ACA”), was passed
which substantially changed the way healthcare is financed by both the government and private insurers, and significantly impacts
the U.S. pharmaceutical industry. The ACA contains provisions that may reduce the profitability of drug products through increased
rebates for drugs reimbursed by Medicaid programs, extension of Medicaid rebates to Medicaid managed care plans, mandatory discounts
for certain Medicare Part D beneficiaries and annual fees based on pharmaceutical companies’ share of sales to federal health
care programs. The Medicaid Drug Rebate Program requires pharmaceutical manufacturers to enter into and have in effect a national
rebate agreement with the HHS Secretary as a condition for states to receive federal matching funds for the manufacturer’s
outpatient drugs furnished to Medicaid patients. The ACA made several changes to the Medicaid Drug Rebate Program, including increasing
pharmaceutical manufacturers’ rebate liability by raising the minimum basic Medicaid rebate on most branded prescription
drugs from 15.1% of average manufacturer price (“AMP”), to 23.1% of AMP and adding a new rebate calculation for “line
extensions” (i.e., new formulations, such as extended release formulations) of solid oral dosage forms of branded products,
as well as potentially impacting their rebate liability by modifying the statutory definition of AMP. The ACA also expanded the
universe of Medicaid utilization subject to drug rebates by requiring pharmaceutical manufacturers to pay rebates on Medicaid managed
care utilization and by enlarging the population potentially eligible for Medicaid drug benefits. The Centers for Medicare &
Medicaid Services (“CMS”), have proposed to expand Medicaid rebate liability to the territories of the United States
as well. Additionally, for a drug product to receive federal reimbursement under the Medicaid or Medicare Part B programs or to
be sold directly to U.S. government agencies, the manufacturer must extend discounts to entities eligible to participate in the
340B drug pricing program. The required 340B discount on a given product is calculated based on the AMP and Medicaid rebate amounts
reported by the manufacturer.
Some of the provisions
of the ACA have yet to be implemented, and there have been judicial and Congressional challenges to certain aspects of the ACA
Congress has recently considered legislation that would repeal or repeal and replace all or part of the ACA. While Congress has
not passed comprehensive repeal legislation, two bills affecting the implementation of certain taxes under the ACA have passed.
On December 22, 2017, the Tax Cuts and Jobs Act (the “Tax Act”) was enacted, which includes a provision repealing,
effective January 1, 2019, the tax-based shared responsibility payment imposed by the ACA on certain individuals who fail to maintain
qualifying health coverage for all or part of a year that is commonly referred to as the “individual mandate.” The
Bipartisan Budget Act of 2018 (the “BBA”), among other things, amended the ACA, effective January 1, 2019, to close
the coverage gap in most Medicare Part D drug plans. In July 2018, CMS published a final rule permitting further collections and
payments to and from certain ACA-qualified health plans and health insurance issuers under the ACA risk adjustment program in response
to the outcome of federal district court litigation regarding the method CMS uses to determine this risk adjustment. On December
14, 2018, a Texas U.S. District Court Judge ruled that the ACA is unconstitutional in its entirety because the “individual
mandate” was repealed by Congress as part of the Tax Act. On December 18, 2019, the United States Court of Appeal for the
Fifth Circuit ruled that the “individual mandate” of the ACA is unconstitutional, but remanded the case to the U.S.
District Court to reconsider whether the entire ACA is unconstitutional. The remanded case is still pending in the U.S. District
Court and other than on the application of the “individual mandate,” the ruling will have no immediate effect on the
remaining provisions of the ACA pending a decision on remand by the U.S. District Court. Consequently, it is unclear how this decision,
subsequent appeals, and other efforts to repeal and replace the ACA will impact the ACA.
Other legislative changes
have been proposed and adopted in the United States since the ACA was enacted. These changes included aggregate reductions to Medicare
payments to providers of up to 2% per fiscal year, effective April 1, 2013, which, due to subsequent legislative amendments, will
stay in effect through 2027 unless additional congressional action is taken. In January 2013, President Obama signed into law the
American Taxpayer Relief Act of 2012, which, among other things, reduced Medicare payments to several providers, and increased
the statute of limitations period for the government to recover overpayments to providers from three to five years. These new laws
may result in additional reductions in Medicare and other healthcare funding, which could have a material adverse effect on customers
for our drugs, if approved, and accordingly, our financial operations.
Additionally, there
has been heightened governmental scrutiny recently over the manner in which drug manufacturers set prices for their marketed products,
which has resulted in several Congressional inquiries and proposed and enacted federal and state legislation designed to, among
other things, bring more transparency to product pricing, review the relationship between pricing and manufacturer patient programs,
and reform government program reimbursement methodologies for drug products. For example, At the state level, legislatures have
increasingly passed legislation and implemented regulations designed to control pharmaceutical and biological product pricing,
including price or patient reimbursement constraints, discounts, restrictions on certain product access and marketing cost disclosure
and transparency measures, and, in some cases, designed to encourage importation from other countries and bulk purchasing.
Moreover, the
Medicare Prescription Drug, Improvement, and Modernization Act of 2003 (“MMA”), established the Medicare Part D program
to provide a voluntary prescription drug benefit to Medicare beneficiaries. Under Part D, Medicare beneficiaries may enroll in
prescription drug plans offered by private entities that provide coverage of outpatient prescription drugs. Unlike Medicare Part
A and B, Part D coverage is not standardized. While all Medicare drug plans must give at least a standard level of coverage set
by Medicare, Part D prescription drug plan sponsors are not required to pay for all covered Part D drugs, and each drug plan can
develop its own drug formulary that identifies which drugs it will cover and at what tier or level. However, Part D prescription
drug formularies must include drugs within each therapeutic category and class of covered Part D drugs, though not necessarily
all the drugs in each category or class. Any formulary used by a Part D prescription drug plan must be developed and reviewed by
a pharmacy and therapeutic committee. Government payment for some of the costs of prescription drugs may increase demand for products
for which we receive marketing approval. However, any negotiated prices for our products covered by a Part D prescription drug
plan likely will be lower than the prices we might otherwise obtain. Moreover, while the MMA applies only to drug benefits for
Medicare beneficiaries, private third-party payors often follow Medicare coverage policy and payment limitations in setting their
own payment rates.
Employees
As of the date of this report, we employed a total of 15 professionals:
11 full-time and four part-time employees. None of our employees are represented by a labor union or covered under a collective
bargaining agreement. We believe that we maintain strong relations with our employees.
We also engage outside
consultants to assist with research and development, clinical development and regulatory matters, business development, operations
and other functions from time to time.
Human Capital Resources.
Our employees drive
our mission and we place a high level of importance on employee engagement and corporate culture. Fostering and maintaining a strong,
healthy culture is a key strategic focus for us, and we regularly engage in independent third party surveys to gauge the satisfaction
and engagement of our team.
Our compensation approach
is aimed at attracting, retaining, motivating and rewarding superior employees who operate in a highly competitive and technologically
challenging environment. The structure of our compensation aims to balance incentives for both short-term and long-term performance.
Some examples of the benefits we offer include
medical insurance, dental insurance, vision insurance, and an unlimited paid-time off policy.
A substantial portion
of our employees are focused on leading and advancing our drug development, biology and data science efforts. As we progress our
product candidates and grow and expand our team, we intend to continue to place a significant focus on our human capital resources.
Available Information
We maintain a website
at www.lanternpharma.com. The contents of our website are not incorporated in, or otherwise to be regarded as part of, this Annual
Report on Form 10-K. We make available, free of charge on our website, access to our Annual Report on Form 10-K, our Quarterly
Reports on Form 10-Q, our Current Reports on Form 8-K and amendments to those reports filed or furnished pursuant to Section 13(a)
or 15(d) of the Securities Exchange Act of 1934, as amended (the “Exchange Act”), as soon as reasonably practicable after
we file or furnish them electronically with the Securities and Exchange Commission (“SEC”).
Copies of our Annual
Report on Form 10-K, our Quarterly Reports on Form 10-Q, our Current Reports on Form 8-K and other filings we make with the SEC
are also available at the SEC’s Public Reference Room at 100 F Street, N.E., Washington, D.C. 20549. Please call the SEC
at 1-800-SEC-0330 for further information on the Public Reference Room. Our SEC filings are also available on the SEC’s website
at www.sec.gov. Statements contained in this Annual Report on Form 10-K concerning the contents of any contract or any other documents
are not necessarily complete. If a contract or document has been filed as an exhibit to this Annual Report on Form 10-K, please
see the copy of the contract or document that has been filed. Each statement in this this Annual Report on Form 10-K relating to
a contract or document filed as an exhibit is qualified in all respects by the filed exhibit.