BUSINESS
Overview
We are a clinical-stage
pharmaceutical company focused on the discovery, development and subsequent commercialization of novel, first-in-class drugs directed against nuclear transport and related targets for the treatment of cancer and other major diseases. Our scientific
expertise is focused on understanding the regulation of intracellular communication between the nucleus and the cytoplasm. We have discovered and are developing wholly-owned, novel, small molecule
S
elective
I
nhibitor of
N
uclear
E
xport,
or
SINE
, compounds that inhibit the nuclear export protein XPO1. These SINE compounds represent a new class of drug candidates with a novel mechanism of action that have the potential to treat a variety
of diseases in areas of unmet medical need. Our SINE compounds were the first oral XPO1 inhibitors in clinical development.
Our initial
focus is on seeking the regulatory approval and commercialization of our lead drug candidate, selinexor (KPT-330), as an oral agent in cancer indications with significant unmet clinical need, initially for hematologic malignancies. We then plan to
seek additional approvals for the use of selinexor in combination therapies to expand the patient populations that are eligible for selinexor, as well as to move selinexor towards front-line cancer therapy. We are also advancing the clinical
development of selinexor in multiple solid tumor indications. To date, over 1,900 patients have been treated with oral selinexor in company- and investigator-sponsored clinical trials in advanced hematologic malignancies and solid tumors. Selinexor
is currently being evaluated in several mid- and later-stage clinical trials, including, among others, the Phase 2b STORM (
S
elinexor
T
reatment
o
f
R
efractory
M
yeloma) study in
multiple myeloma, the Phase 1b/2 STOMP (
S
elinexor and Backbone
T
reatments
o
f
M
ultiple Myeloma
P
atients) study in combination with backbone therapies in multiple myeloma, the Phase
2b SADAL (
S
elinexor
A
gainst
D
iffuse
A
ggressive
L
ymphoma) study in diffuse large B-cell lymphoma (DLBCL), and the Phase 2/3 SEAL (
Se
linexor in
A
dvanced
L
iposarcoma) study in liposarcoma.
3
We plan to initiate the pivotal, randomized Phase 3 BOSTON (
Bo
rtezomib,
S
elinexor and Dexame
t
has
on
e) study in multiple myeloma in early
2017. We expect to provide data for the SADAL study in early 2017 with final topline data in mid-2018, topline data for the Phase 2 portion of the SEAL study in mid-2017 and topline data from the expanded cohort for the STORM study in early 2018. We
are also preparing to establish the commercial infrastructure to support a potential launch of selinexor in North America and Western Europe.
Recent
Regulatory Events
In February 2017, following the conclusion of a joint inspection conducted by the U.S. Food and Drug Administration,
or FDA, and Danish Medicines Agency at our corporate headquarters, the FDA issued a Form 483 noting certain deficiencies in procedures and documentation that were identified in our selinexor development program. We have implemented corrective
actions, preventative actions and other initiatives directed at resolving the deficiencies identified in the Form 483 observations. We provided the FDA with our responses to the Form 483 observations in February 2017.
In March 2017, the FDA notified us that it had placed the clinical trials under our investigational new drug application, or IND, for
selinexor on partial clinical hold, which is an order by the FDA to delay or suspend part of a sponsors clinical work requested under its IND as well as investigator-sponsored trials. The FDA has requested that we (i) revise relevant sections
of our investigator brochure to, among other things, include a summary table of serious adverse events, or SAEs, associated with selinexor that was omitted from the existing version in order to accurately reflect the safety profile of selinexor,
(ii) update the description of potential risks in our informed consent documents, and (iii) submit to the FDA recently completed narrative summaries of safety reporting events.
Under the partial clinical hold, new patients may not start treatment on any protocols. Patients who are responding to treatment with
selinexor, which includes patients with progressive disease at study entry that currently have stable disease, may continue selinexor therapy after signing the updated informed consent.
We believe we have addressed the FDAs requests and, as of March 10, 2017, we had provided all requested materials to the FDA that we
believe are required to lift the partial clinical hold. The FDA has 30 days from the date of its receipt of our submission to notify us if the partial hold is lifted. We can provide no assurances that the FDA will lift the partial clinical hold in a
timely manner or at all.
Summary of Clinical Development
Oral selinexor is being evaluated in multiple later-phase clinical trials in patients with relapsed and/or refractory hematological and solid
tumor malignancies. In general, relapsed disease refers to disease that progresses more than 60 days after discontinuation of therapy and refractory disease refers to disease that progresses while the patient is on therapy or within 60 days after
discontinuation of therapy. To date, oral selinexor has been administered to more than 1,900 patients across company- and investigator-sponsored clinical trials. Evidence of single-agent anti-cancer activity has been observed in many patients and
selinexor has been sufficiently well-tolerated to allow several of these patients to remain on therapy for prolonged periods. Over 30 patients have remained on study for over 12 months, with the longest patients on study for over 24 months.
During 2016, we reported several important clinical data sets for selinexor and communicated our plan to pursue a clinical development
initiative focused on obtaining our first regulatory approval for selinexor in multiple myeloma. This strategy is based on the positive results reported to date from the ongoing Phase 2b STORM study and the ongoing Phase 1b/2 STOMP study. The STORM
study is a single-arm clinical trial evaluating oral selinexor in combination with low-dose dexamethasone in patients with quad-refractory or penta-refractory myeloma. Patients with quad-refractory disease have previously received prior treatments
with alkylating agents, glucocorticoids, two proteasome inhibitors, or PIs, bortezomib (Velcade
®
) and carfilzomib (Kyprolis
®
), and two
immunomodulatory drugs, or IMiDs, lenalidomide (Revlimid
®
) and pomalidomide
4
(Pomalyst
®
), and their disease is refractory to at least one PI, at least one IMiD, and has progressed following their most recent
therapy. Patients with penta-refractory myeloma have quad-refractory disease that is also refractory to an anti-CD38 monoclonal antibody, such as daratumumab (Darzalex
®
) or isatuximab. The
STOMP study is a multi-arm clinical trial evaluating selinexor and low-dose dexamethasone in combination with backbone therapies, including bortezomib, pomalidomide, lenalidomide or daratumumab, in patients with heavily pretreated
relapsed/refractory multiple myeloma.
In the first part of the STORM study, selinexor demonstrated robust response rates and duration of
response, compelling overall survival and a favorable safety profile in patients with heavily pretreated refractory multiple myeloma. In the STOMP study, selinexor demonstrated high response rates when combined with the proteasome inhibitor
bortezomib, including in patients whose disease was previously refractory to proteasome inhibitors. Based on the positive results from these two studies, we have expanded the STORM study to include approximately 120 additional patients with
penta-refractory multiple myeloma. We expect to report top-line data from the expanded STORM study in early 2018. Assuming a positive outcome, we intend to use the data from the expanded STORM study to support a request for accelerated approval for
selinexor in multiple myeloma. In parallel, we plan to initiate the BOSTON study, which will evaluate selinexor in combination with bortezomib and low-dose dexamethasone compared to bortezomib and low-dose dexamethasone in patients with multiple
myeloma who have had one to three prior lines of therapy. We have identified the combination dose of selinexor (100mg oral weekly), bortezomib (1.3 mg/m
2
weekly given sub-cutaneously for 4 of 5
weeks) and dexamethasone (40mg weekly) to be used in the BOSTON study and expect that the study will enroll approximately 360 patients. We expect to commence the BOSTON study in early 2017. If successful, the BOSTON study may qualify as a full
approval study and we believe can serve as a confirmatory study if the STORM study is successful and results in accelerated approval.
Selinexor data were also previously presented showing preliminary safety and efficacy in combination with carfilzomib and dexamethasone to
treat patients with multiple myeloma and in combination with standard of care chemotherapy to treat patients with acute myeloid leukemia, and as a single agent in patients with solid tumors including sarcoma, gynecological malignancies and
glioblastoma.
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Our ongoing company-sponsored clinical trials of selinexor, along with anticipated timing of key
data points, are summarized in the chart below. In addition, there are several ongoing investigator-sponsored clinical trials in a variety of hematological and solid tumor malignancies.
We have previously announced data from the STORM, STOMP, SIGN and KING studies and these data are further
described herein. We currently expect to provide additional data related to STOMP later in 2017 and data related to the other studies of selinexor listed above as follows:
STORM: Phase 2b expansion topline data (overall response rate) in early 2018
BOSTON: Randomized Phase 3 topline data (Progression Free Survival) in 2019
SADAL: Phase 2b topline data (overall response rate) in early 2017 and mid-2018
SEAL: Randomized Phase 2 topline data (progression free survival) in mid-2017
In addition to selinexor, we are also advancing a pipeline of novel drug candidates in oncology as well as neurological, inflammatory,
autoimmune and viral indications. We began clinical testing of oral KPT-8602, a second generation SINE compound, in late 2015 to treat patients with relapsed/refractory multiple myeloma, and we began clinical testing of oral KPT-9274, a dual
PAK4/NAMPT inhibitor, during 2016 in patients with lymphoma or solid tumors. KPT-350 is an investigational new drug application-ready oral compound with a preclinical data package supporting potential efficacy in a number of neuro-inflammatory
conditions. We plan to partner with a collaborator to undertake the clinical development and potential commercialization of KPT-350 in one or more mutually agreed indications. We began clinical testing of oral verdinexor (KPT-335) in 2015 in healthy
human volunteers, and we are preparing to advance verdinexor for certain viral indications with an initial focus on influenza. Preclinical data provide strong support for other potential indications for verdinexor, including
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human immunodeficiency virus, or HIV, and respiratory syncytial virus, or RSV. Our pipeline of drug candidates is summarized in the chart below.
Since our founding by Dr. Sharon Shacham in 2008, our goal has been to establish a leading,
independent oncology business. We are led by Dr. Shacham, our President and Chief Scientific Officer, and Dr. Michael Kauffman, our Chief Executive Officer. Dr. Kauffman played a leadership role in the development and approval of
Velcade
®
at Millennium Pharmaceuticals and of Kyprolis
®
while serving as Chief Medical Officer at Proteolix and then Onyx
Pharmaceuticals. Dr. Shacham has played a leadership role in the discovery and development of many novel drug candidates, which have been or are being tested in human clinical trials, prior to her founding of Karyopharm and while at Karyopharm.
Since our inception, we have devoted substantially all of our efforts to research and development, and we have not generated any revenue
to date from sales of any drugs. As of December 31, 2016, we had an accumulated deficit of $366.1 million. We had net losses of $109.6 million, $118.2 million and $75.8 million for the years ended December 31, 2016, 2015 and 2014,
respectively. See our Consolidated Statements of Operations and Note 2 to our consolidated financial statements for further information regarding our research and development expenses and financial information regarding the geographic areas in which
we operate.
Summary of Mechanism of Action: Transient XPO1 Inhibition by SINE Compounds
One of the ways in which a cell regulates the function of a particular protein is by controlling the proteins location within the cell,
as certain functions may only occur within a particular location in the cell. In healthy cells, nuclear transport, both into and out of the nucleus, is a normal and regular occurrence that is tightly regulated and requires specific carrier proteins
to be present. XPO1 mediates the export of over 220 different mammalian cargo proteins, including the vast majority of tumor suppressor proteins, as well as the transport of certain growth-promoting mRNAs which, when transported into the cytoplasm,
are translated into functional proteins at high levels. Moreover, XPO1 appears to be the only nuclear exporter for the majority of these tumor suppressor proteins and for particular growth-promoting mRNAs. Cancer cells have increased levels of XPO1,
causing the increased export of these tumor suppressor proteins from the nucleus. Since the tumor suppressor proteins must be located in the nucleus to promote programmed cell death, or apoptosis, XPO1 overexpression in cancer cells counteracts the
natural apoptotic process that protects the body from cancer. Due to XPO1 inhibition by our SINE compounds, the export of tumor suppressor proteins is prevented, which leads to their accumulation in the nucleus. This accumulation subsequently
reinitiates and amplifies their natural apoptotic function in cancer
7
cells with minimal effects on normal cells. Further, SINE compounds reduce the translation of certain growth-promoting proteins (including some cancer-causing proteins) by inhibiting the
XPO1-mediated transport of their mRNAs to the cytoplasm. The figure below depicts the process by which our SINE compounds inhibit the XPO1 nuclear export of tumor suppressor proteins.
We believe that the XPO1-inhibiting SINE compounds that we have discovered and developed to date, including
selinexor, have the potential to provide a novel, oral, targeted therapy that enables tumor suppressor proteins to remain in the nucleus and promote the apoptosis of potentially any type of cancer cell. Moreover, our SINE compounds spare normal
cells, which, unlike cancer cells, do not have significant damage to their genetic material, and we believe this selectivity for cancer cells minimizes side effects. We believe that the novel mechanism of action and oral administration of selinexor
and the low levels of major organ toxicities observed to date in patients treated with selinexor in clinical trials create the potential for selinexors broad use across many cancer types, including both hematological and solid tumor
malignancies. Patient tumor biopsies have confirmed that selinexor treatment induces the nuclear localization of tumor suppressor proteins as well as cancer cell death, or apoptosis, in multiple different cancer types. We believe that no currently
approved cancer treatments and only one current clinical-stage cancer drug candidate are selectively targeting the restoration and increase in the levels of multiple tumor suppressor proteins in the nucleus. Our SINE compounds were the first oral
XPO1 inhibitors in clinical development. We own all intellectual property rights related to the compounds that we are developing, including composition of matter and method of use patents covering selinexor that were issued by the U.S. Patent and
Trademark Office in 2015 and which provide patent protection through at least 2032, absent any adjustments or extensions.
Our Strategy
As a clinical-stage pharmaceutical company focused on the discovery and development of orally available, novel first-in-class drugs directed
against nuclear transport targets for the treatment of cancer and other major diseases, the critical components of our business strategy are to:
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Develop and Seek Regulatory Approval of Selinexor, Our Lead Novel Drug Candidate, in North America and
Western Europe.
We plan to seek regulatory approvals of selinexor in North America and Western Europe in each indication with respect to which we receive positive clinical trial results in
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a trial with a survival endpoint that is designed to be registration-enabling. We may also seek regulatory approvals where a clinical trial demonstrates sufficiently significant data in a
surrogate endpoint such as overall response rate that could allow for accelerated approval. We may seek full or conditional approvals in other geographies as well.
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Maximize the Commercial Value of Selinexor.
We currently have global development, marketing and commercialization rights for selinexor and are positioned to develop selinexor and to seek regulatory
approval for its use in oncology indications without a collaborator in North America and Western Europe. We will evaluate potential collaborations within these geographies that enable us to further extend the selinexor development program into
additional tumor types, earlier lines of therapy and additional combination regimens. We intend to enter into collaborations for further development, marketing and commercialization of selinexor in particular geographies outside of North America and
Western Europe at an appropriate time.
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Maintain Our Competitive Advantage and Scientific Expertise in the Field of Nuclear Transport.
We plan to continue to conduct research in the field of nuclear transport and related areas to further our
understanding of the role it plays in the underlying biology of cancer, as well other major diseases, primarily by fostering relationships with top scientific advisors and physicians. We believe that investing in the recruitment of exceptional
advisors, employees and management is critical to our continued leadership in the nuclear transport field. We are collaborating with leading patient advocacy groups to provide education on the science behind our SINE compounds and to support the
development and execution of clinical trials. We have advanced the understanding and potential application of selinexor to treat cancer through a broad range of collaborations with leading institutions engaged in clinical trials evaluating selinexor
in the United States, Canada, Europe, Singapore and Israel.
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Continue Developing our Pipeline of Novel Drug Candidates.
To date, we have identified several drug candidates: our oral SINE compounds selinexor (KPT-330), verdinexor (KPT-335), KPT-350 and KPT-8602 and
our oral dual PAK4/NAMPT inhibitor, KPT-9274. While we may identify or in-license novel drug candidates for development in oncology in the future, we are currently focused on the development of our existing pipeline of drug candidates.
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Collaborate with Key Opinion Leaders to Conduct Investigator-Sponsored Trials of Selinexor.
A significant part of our strategy for continuing to efficiently assess and confirm the breadth of activity of
selinexor alone or in combination with other anti-cancer drugs includes the initiation of investigator-sponsored trials. We plan to continue to facilitate the investigation of the breadth of the clinical activity of selinexor through our established
network of scientific advisors and physicians.
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Maximize the Value of Our Other SINE Compounds in Non-Oncology Indications through Collaborations.
We may seek to enter into global or regional development, marketing and commercialization collaboration
arrangements for our other SINE compounds in non-oncology indications. With respect to KPT-350, we plan to enter into one or more collaboration arrangements.
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Our Focus: Nuclear Transport
A human
cell is divided into various compartments, including the nucleus and the cytoplasm. The nucleus contains a cells genetic material, or DNA, and is the compartment where gene expression and consequently cellular function is regulated. The
cytoplasm is the compartment around the nucleus where translation of gene transcripts, or mRNA, to proteins, assembly of proteins into cellular structural elements, and cellular metabolism of fats, carbohydrates, and proteins, occur. One of the ways
in which the cell regulates the function of a particular protein is by controlling the proteins location within the cell, as a specific function may only occur within a particular location. Certain proteins, including tumor suppressor proteins
and other growth regulatory proteins, need to be transported from the cytoplasm, where they are made, into the nucleus where they need to be located for their primary functions to occur. The nuclear pore is a complex gate between the nucleus and
cytoplasm,
9
closely regulating the import and export of most large molecules, called macromolecules, including many proteins, into and out of the nucleus. In healthy cells, nuclear transport processes of
macromolecules in either direction through the nuclear pore is tightly regulated and requires specific carrier proteins, including nuclear export proteins, to occur. There are eight known nuclear export proteins. The most heavily studied export
protein was discovered in 1999 and is called Exportin 1, or XPO1 (also called CRM1). XPO1 mediates the export of over 220 different mammalian cargo proteins, including some growth regulatory proteins and the vast majority of tumor suppressor
proteins. Moreover, XPO1 appears to be the only nuclear exporter for the majority of these tumor suppressor proteins, including those generally referred to as p53, p73, FOXO, pRB, BRCA1, BRCA2, NPM1, IkB and PP2A.
Cancer is a disease characterized by unregulated cell growth. Cancer typically develops when DNA in normal cells begins to accumulate
mutations or other abnormalities, causing genes that regulate cell growth to become disrupted. Tumor suppressor proteins are an integral part of the bodys natural defense mechanism to identify and prevent cancer. When DNA damage is detected,
tumor suppressor proteins promote apoptosis. Tumor suppressor proteins can also have an anti-cancer effect by dampening unregulated cell growth and division. Because tumor suppressor proteins need to be located in the nucleus in order to carry out
their anti-cancer activities, their nuclear export, or exit from the nucleus, leads to their being unavailable in the nucleus to identify cancer cells and initiate their death. As XPO1 levels have been shown to be elevated by two- to four-fold in
nearly all cancer cells compared to their normal cell counterparts, it appears that cancer cells have co-opted XPO1 to move tumor suppressor proteins out of the nucleus, thereby adversely affecting their ability to identify and initiate the death of
cancer cells. Increased levels of XPO1 in cancer cells also lead to excessive nuclear export of growth regulatory proteins as well as oncoprotein mRNAs. All of these XPO1 effects allow cancer cells to divide continuously and inappropriately. Higher
levels of XPO1 expression are also generally correlated with poor prognosis and/or resistance to chemotherapies.
In addition to
transporting tumor suppressor proteins, XPO1 is the sole transporter of the eukaryotic initiation factor 4E (eIF4E) protein, also called the mRNA cap binding protein. eIF4E carries the mRNAs for many growth promoting proteins, including
certain growth-promoting oncoproteins such as c-myc, Pim1, Atk1, hDM2 and cyclin D from the nucleus into the cytoplasm (dependent on XPO1) followed by association with ribosomes for translation into proteins. Blockade of XPO1 leads to accumulation
of eIF4E in the cell nucleus and concomitant nuclear trapping of bound growth-promoting mRNAs, leading to reduced translation of these mRNAs, and reductions in their protein levels.
XPO1 is also the only exporter of the anti-inflammatory protein I
k
B, the inhibitor of NF-
k
B. NF-
k
B is known to play a role in cancer metastasis and resistance to chemotherapy as well as in many inflammatory and autoimmune diseases. Blockade of XPO1 leads
to accumulation of I
k
B in the cell nucleus where it binds to and inhibits NF-
k
B function. SINE-mediated inhibition of
NF-
k
B may be beneficial in overcoming chemotherapy resistance and in treating autoimmune, inflammatory and neuro-inflammatory disease.
10
The figure below depicts the process by which XPO1 mediates the nuclear transport process.
XPO1 Mediation of Nuclear Transport
Our Approach: Targeting Nuclear Export with SINE Compounds
Since the discovery of XPO1, a growing body of research has documented that the high levels of XPO1 found in cancer cells are associated with
the transport of tumor suppressor and other growth regulatory proteins from their site of action in the nucleus into the cytoplasm, where their anti-cancer activity is minimal. The inhibition of XPO1 cargo binding has been studied for over ten
years. XPO1 inhibitors block the nuclear export of tumor suppressor and other cargo proteins, leading to accumulation of these proteins in the nucleus and enhancing their anti-cancer activity in the cell. The forced nuclear retention of these
proteins can counteract a multitude of the oncogenic pathways that allow cancer cells with severe DNA damage to continue to grow and divide in an unrestrained fashion. XPO1 inhibitors also force the nuclear retention of eIF4E and its cargo
growth-promoting protein mRNAs, preventing their transport to the cytoplasm for ribosomal translation, leading to reduced levels of oncoproteins. One naturally occurring XPO1 inhibitor called leptomycin B, which must be given intravenously, has been
shown to have potent anti-cancer activity
in vitro
, but is toxic to normal cells. These toxicities to normal cells have been observed in both animals and humans, which we believe are most likely caused by the
irreversible
nature of
leptomycin B binding to XPO1. Because of its observed toxicities in animals and humans, to our knowledge, leptomycin B is no longer being developed.
Our lead drug candidates are first-in-class, oral
S
elective
I
nhibitor of
N
uclear
E
xport
, or
SINE
, compounds. We have discovered SINE compounds by applying our proprietary drug discovery and optimization expertise to the published X-ray structure of XPO1. SINE compounds inhibit XPO1-mediated nuclear-cytoplasmic transport by
transiently
binding to the XPO1 cargo binding site, meaning that they block XPO1 cargo binding over an extended period of time, but do not permanently do so. Transient XPO1 inhibition, or inhibition for approximately 12 to 24 hours,
which corresponds to the inhibition period that we have observed to date with our SINE compounds, appears to be sufficient for nuclear retention and elevation of tumor suppressor protein levels in the nucleus. During this period, the inhibition of
XPO1 cargo binding enables tumor suppressor proteins to accumulate in the nucleus of cancer cells and perform their normal role of detecting DNA damage,
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thereby inhibiting a cancer cells ability to divide and promoting apoptosis. Healthy cells also build up tumor suppressor proteins in the presence of a SINE compound, but are able to resume
normal activity after transient XPO1 inhibition because they have an intact genome with minimal or no DNA damage. The figure below depicts the process by which SINE compounds inhibit the XPO1 nuclear export of tumor suppressor proteins.
Transient XPO1 Inhibition by SINE Compounds
The XPO1-inhibiting SINE compounds that we have discovered and developed to date, including selinexor, have
the potential to provide a novel targeted therapy that force tumor suppressor proteins to remain in the nucleus and promote apoptosis of cancer cells. Moreover, our SINE compounds spare normal cells, which, unlike cancer cells, do not have
significant damage to their genetic material, and we believe this selectivity for cancer cells minimizes side effects. We believe that novel mechanism of action and oral administration of selinexor and the low levels of major organ toxicities
observed to date in over 1,900 patients treated with oral selinexor in Phase 1 and Phase 2 clinical trials create the potential for its broad use across many cancer types, including both hematological and solid tumor malignancies. We believe
that no currently approved cancer treatments are selectively targeting the restoration and increase in the levels of multiple tumor suppressor proteins in the nucleus.
In addition to cancer, our SINE compounds have the potential to provide therapeutic benefit in a number of other indications. Specifically, we
have discovered and are developing a pipeline of SINE compounds that have shown evidence of activity in preclinical models of viral infections, neurological disorders and inflammation and autoimmune diseases.
Verdinexor (KPT-335) is our lead compound in development for the treatment of viral indications. Several viruses, such as influenza, HIV and
RSV, exclusively utilize XPO1 to shuttle cargos necessary for virion replication and assembly from the nucleus to the cytoplasm. Verdinexor has the potential to treat viral diseases through both inhibition of viral replication and suppression of
inflammatory cytokine-mediated symptoms and shows significant anti-influenza activity in murine and ferret models. In 2015, we conducted a randomized,
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double-blind, placebo-controlled, multiple dose-escalating Phase 1 clinical trial of oral verdinexor in healthy human volunteers in Australia. This study was designed to evaluate the safety and
tolerability of verdinexor in healthy adult subjects. Verdinexor was found to be generally safe and well tolerated. Mild to moderate AEs of similar number and grade as placebo were reported and no serious or severe adverse events were observed. No
serious laboratory abnormalities or cardiac changes were observed. We plan to continue to explore strategies to pursue the clinical development of verdinexor as a treatment for influenza, including potentially partnering with a collaborator or
through government-funded grant or contract opportunities. Preclinical data also show efficacy of verdinexor and related SINE compounds in additional viral models, including HIV and RSV.
KPT-350 is our lead compound in development for the treatment of neurological disorders and inflammatory and autoimmune diseases. XPO1
mediates the nuclear export of multiple proteins that impact autoimmune, inflammatory and neurodegenerative processes. Consequently, inhibition of XPO1 by KPT-350 results in a reduction in autoimmunity and inflammation and an increase in
anti-inflammatory and neuroprotective responses. KPT-350 penetrates the blood brain barrier to a greater degree than other SINE compounds. Preclinical data generated largely by external collaborators show efficacy of orally-administered KPT-350 and
related SINE compounds in animal models of amyotrophic lateral sclerosis, or ALS, multiple sclerosis, or MS, traumatic brain injury, or TBI, epilepsy, systemic lupus erythematosus, or SLE, and rheumatoid arthritis, or RA.
Our Initial Indication: Cancer
Cancer is
a leading cause of death worldwide, with approximately 8.2 million cancer deaths globally in 2012, according to the American Cancer Society. In the United States, the American Cancer Society estimates that in 2017, approximately 600,000 people
will die of cancer and approximately 1.7 million new cancer cases will be diagnosed. The International Agency for Research on Cancer projects that in 2030, 21.7 million people will be diagnosed with cancer, and 13 million people will
die of cancer worldwide, as compared to 14.1 million new cancer diagnoses and 8.2 million cancer deaths worldwide in 2012.
The
most common methods of treating patients with cancer are surgery, radiation and drug therapy. A cancer patient often receives treatment with a combination of these methods. Surgery and radiation therapy are particularly effective in patients in whom
the disease is localized. Physicians generally use systemic drug therapies in situations in which the cancer has spread beyond the primary site or cannot otherwise be treated through surgery. In many cases, drug therapy entails the administration of
several different drugs in combination. An early approach to cancer treatment was to develop drugs, referred to as cytotoxic drugs, that kill rapidly proliferating cancer cells through non-specific mechanisms, such as disrupting cell metabolism or
causing damage to cellular components required for survival and rapid growth. While these drugs have been effective in the treatment of some cancers, they act in an indiscriminate manner, killing healthy cells, as well as cancer cells. Due to their
mechanism of action, many cytotoxic drugs have a narrow dose range above which the toxicity causes unacceptable or even fatal levels of damage and below which the drugs are not effective in promoting cancer cell death. A different approach to
pharmacological cancer treatment has been to develop drugs, referred to as targeted therapeutics, that target specific biological molecules in the human body that play a role in rapid cell growth and the spread of cancer. Targeted therapeutics are
designed to specifically enable the death of cancer cells and spare normal cells, to improve efficacy, and to minimize side effects. The drugs are designed to either attack a target that causes uncontrolled growth of cancer cells because of either a
specific genetic alteration primarily found in cancer cells, but not in normal cells, or a target that cancer cells are more dependent on for their growth in comparison to normal cells.
Our SINE compounds are novel therapies specifically designed to force nuclear localization and elevation in the levels of multiple tumor
suppressor and growth regulatory proteins. Tumor suppressor proteins assess a cells DNA and in cells, like most cancer cells, with heavily damaged DNA, these proteins induce cell death, or apoptosis. Unlike many other targeted therapeutic
approaches which only work for a specific set of cancers or in
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a specific sub-group of patients, we believe that by restoring tumor suppressor proteins to the nucleus where they can assess a cells DNA, our SINE compounds have the potential to provide
therapeutic benefits across a broad range of both hematological and solid tumor malignancies and benefit a wide range of patients. Additionally, and further supported by its mechanism of action and supported by preclinical and clinical data, we
believe that selinexor has the potential to be additive or synergistic with approved and experimental therapies in treating many of these cancer patients. As a result, we believe that selinexor has the potential to serve as a backbone therapy across
multiple hematological and solid tumor malignancies as part of a variety of combination therapies.
Our Oncology Drug Candidates
Selinexor (KPT-330)
Selinexor is
being evaluated in multiple later phase clinical trials in patients with relapsed and/or refractory hematological malignancies and solid tumors. Anti-cancer activity has been observed with tumor reductions and durable disease control across many
hematologic malignancies and solid tumors. Over 30 patients have remained on oral selinexor, either as a single-agent or in combination with other agents, for over 12 months, with some patients on therapy for over 24 months. To date, selinexor has
been generally well tolerated, with adverse events that are responsive to standard supportive care and/or dose modification, often decrease over time, and are consistent with those previously reported in patients in our initial clinical trials.
We have determined that the recommended Phase 2 dose of selinexor in most settings is 60mg dosed twice weekly. In December 2015, we and our
collaborators presented an analysis of our Phase 1 clinical data in hematological malignancies at the American Society of Hematology, or ASH, annual meeting. The analysis demonstrated that doses of selinexor from 45-65mg (median 60mg) were better
tolerated than doses greater than 65mg and showed less weight loss, lower incidence of high grade adverse events and greater numbers of days on study. 266 heavily pretreated patients with multiple myeloma, or MM, non-Hodgkins lymphoma, or
NHL, acute myeloid leukemia, or AML, and other hematological malignancies were included in the analysis and divided into three groups of evaluable patients: those that received 4-44mg (median 30mg), those that received 45-65mg (median 60mg) and
those that received greater than 65mg (70-160mg; median 90mg) for comparison of safety and efficacy endpoints. Patients in the 4-44mg and 45-65mg groups remained on study longer than those receiving greater than 65mg, with average treatment duration
of 120 days in the first two groups versus 90 days in the highest dose group, respectively. Overall efficacy was numerically superior in the 45-65mg dose group across multiple hematologic indications. The most common adverse events, or AEs, were
nausea (63%), fatigue (62%), anorexia (57%), vomiting (38%), which were mostly grade 1/2, and thrombocytopenia (41%), which was mostly grade 3/4, but with very low incidents of bleeding. The incidence of certain selinexor-related high grade
(3/4) AEs was lower in patients receiving 45-65mg selinexor as compared to those receiving greater than 65mg. These data from our extensive Phase 1 experience with selinexor are consistent with our belief that a flat dose of 60mg is the most
appropriate selinexor dose for both efficacy and tolerability in most settings. However, as is the case for many other anti-cancer drugs, certain indications would likely be treated with different doses.
A preliminary analysis of safety and tolerability of selinexor was performed on unaudited AE data for 1,175 patients enrolled in our
company-sponsored hematological malignancy and solid tumor clinical trials as of the data cutoff point of May 31, 2016. Overall, the most commonly reported selinexor-related AEs in ongoing clinical studies included generally low-grade nausea
(62%), fatigue (55%), anorexia (50%), thrombocytopenia (43%), and vomiting (38%). Thrombocytopenia, the most common hematologic drug-related treatment emergent adverse event, was reported among 43% of patients, and approximately half of these were
grades 3 or 4.
We describe below the key company- and investigator-sponsored studies evaluating selinexor in hematological malignancies
and solid tumors, both as a single-agent and in combination. Additional data from company- and investigator-sponsored combination studies may be presented on an ongoing basis by us and/or our collaborators at scientific conferences or through other
publications at various times. We expect such data will continue to inform our Phase 2 and Phase 3 dosing for selinexor in these combinations and allow us to
14
evaluate the combinations with the greatest potential for durable responses and increased survival. Response data presented herein are interim unaudited data based on reports by physicians at the
clinical trial sites. Responses in hematological trials are measured using commonly accepted evaluation criteria for the specific indication. Responses in solid tumor trials are evaluated using RECIST unless otherwise noted.
Advanced Hematological Malignancies
Multiple Myeloma
MM is a
hematological malignancy characterized by the accumulation of monoclonal plasma cells in the bone marrow, the presence of monoclonal immunoglobulin, or M protein, in the serum or urine, bone disease, kidney disease and immunodeficiency. It is more
common in elderly patients, with a median age at diagnosis of 65-70 years. In the United States, the American Cancer Society estimates that there will be approximately 30,000 new cases of MM, with about 12,600 attributable deaths, in 2017. The
World Health Organization estimated that approximately 114,000 new cases of MM were diagnosed worldwide in 2012.
The treatment of MM has
improved in the last 20 years due to the use of high-dose chemotherapy and autologous stem cell transplantation, which is restricted to healthier, often younger patients, and the subsequent introduction of IMiDs, such as lenalidomide (Revlimid
®
) and pomalidomide (Pomalyst
®
), and the PIs bortezomib (Velcade
®
), carfilzomib
(Kyprolis
®
), and ixazomib (Ninlaro
®
). Two monoclonal antibodies, daratumumab
(Darzalex
®
) and elotuzumab (Empliciti), have also recently been approved, as has the histone deacetylase inhibitor panobinostat
(Farydak
®
). The introduction of non-chemotherapeutic agents has led to a significant increase in the survival of patients with MM. Although a wide variety of newly approved or experimental
therapies are being used in relapsed and/or refractory patients, including new proteasome inhibitors (oprozomib and marizomib), monoclonal antibodies and cellular therapies like chimeric antigen receptor T-cell, or CAR-T, therapy, nearly all
patients will eventually relapse and succumb to their disease. With around 37,000 deaths from MM in the United States and Europe expected, we believe that there remains a need for therapies for patients whose disease has relapsed after, or is
refractory to, available therapy.
STORM: Phase 2b Clinical Trial of Selinexor and Low-Dose Dexamethasone in Multiple Myeloma
In May 2015, we initiated a Phase 2b clinical trial evaluating oral selinexor and low-dose dexamethasone, or low-dose dex, in patients with
heavily pretreated MM. The
S
elinexor
T
reatment
o
f
R
efractory
M
yeloma
, or
STORM
, study is a single-arm study evaluating the treatment of relapsed/refractory MM with 80mg of selinexor and 20mg of
dexamethasone, each dosed twice weekly. This 40mg per week dose of dexamethasone is considered low dose in the treatment of MM, compared with the high dose dexamethasone which uses three times more of the steroid.
At the ASH annual meeting in December 2016, we presented results, adjudicated by an independent review committee, from the first cohort of
patients enrolled in the STORM study, which included patients with either quad-refractory or penta-refractory MM. Patients with quad-refractory disease have previously received prior treatments with alkylating agents, glucocorticoids, two proteasome
inhibitors bortezomib (Velcade
®
) and carfilzomib (Kyprolis
®
), and two IMiDs lenalidomide (Revlimid
®
) and pomalidomide (Pomalyst
®
), and their disease is refractory to at least one PI, at least one IMiD, and has progressed following their
most recent therapy. Patients with penta-refractory myeloma have quad-refractory disease that is also refractory to an anti-CD38 monoclonal antibody, such as daratumumab (Darzalex
®
) or
isatuximab.
Among the 78 evaluable patients, who had a median of seven prior treatment regimens, the overall response rate, or ORR, was
21% and included very good partial responses, or VGPRs, and partial responses, or PRs. Among the 48 patients in the quad-refractory group, the ORR was 21%. For comparison, in a similar patient population with quad-refractory disease, the anti-CD38
monoclonal antibodies Darzalex
®
and isatuximab had ORRs of 21% and 20%, respectively. Among the 30 patients in the penta-refractory group, the ORR was 20%.
15
Clinical benefit rate, or CBR, which is percentage of patients with a minor response, or MR, or better, was 33% across all 78 patients, 29% among the patients with quad-refractory disease, and
40% among the patients with penta-refractory disease. To our knowledge, no other agents have reported response rates in patients with penta-refractory MM. Median overall survival, or OS, was 9.3 months for all patients, longer than 11 months without
a median reached in patients with a minor response or better, and 5.7 months for patients who did not have any response. Median duration of response, or DOR, was 5 months. Cytopenias of grade 3 or grade 4 were the most common side effects and were
generally not associated with clinical sequellae. Nausea, anorexia and fatigue were the most common non-hematological side effects, primarily grades 1 and 2, and were treatable with supportive care and/or dose modification. There were low rates of
non-hematologic toxicities of grade 3 or 4, with no new safety signals identified. In particular, there was one reported case of grade 4 infection (1.3%), one reported case of grade 2 neuropathy (1.3%) and one reported case of sepsis (1.3%).
Based on these positive results, we have expanded the STORM study to include approximately 120 additional patients with penta-refractory
multiple myeloma. To our knowledge, this will be the largest study ever undertaken in this patient population. We expect to report top-line data from the expanded STORM cohort in early 2018. Assuming a positive outcome, we intend to use the data
from the expanded STORM study to support a request for accelerated approval for selinexor in multiple myeloma.
The primary endpoint of the
STORM study is ORR. The trial has several secondary endpoints, including ORR in patients whose disease is relapsed/refractory to an anti-CD38 monoclonal antibody and DOR.
STOMP: Phase 1b/2 Clinical Trial of Selinexor in Combination with Backbone Therapies in Multiple Myeloma
Based on preclinical synergy in animal models of MM, in October 2015, we initiated a Phase 1b/2 clinical study of oral selinexor in combination
with backbone treatments for relapsed/refractory MM. In this multi-arm study,
S
elinexor and Backbone
T
reatments
o
f Multiple
M
yeloma
P
atients
, or
STOMP
, we are evaluating the combination of selinexor
and low-dose dex with backbone therapies bortezomib (Velcade
®
), lenalidomide (Revlimid
®
), pomalidomide (Pomalyst
®
) or daratumumab (Darzalex
®
) in patients with previously treated MM. Each combination is evaluated on a separate arm of the STOMP study and
within each combination, two treatment cohorts will evaluate once weekly versus twice weekly dosing of selinexor. The primary objectives of the Phase 1 portion are to determine the maximum tolerated dose and recommended Phase 2 and Phase 3 doses for
selinexor in these combination therapies. The primary objectives of the Phase 2 portion are to assess preliminary efficacy through ORR, CBR and DOR.
In December 2016, we presented updated results from the selinexor, bortezomib
(Velcade
®
) and dexamethasone arm of the STOMP study, referred to as SVd, at the ASH 2016 annual meeting. The patients in this cohort were heavily pretreated and the majority (73%) had MM
refractory to the proteasome inhibitors bortezomib (Velcade
®
) and/or carfilzomib (Kyprolis
®
). Across the 22 patients enrolled in the
SVd arm, the median number of treatment regimens was four with a range of one to 11 prior treatment regimens. Seventeen of the 22 patients responded, with one patient having a stringent complete response, or sCR, two patients having a complete
response, or CR, four patients having a VGPR and 10 patients having a PR. As a result, the ORR was 77%. An additional three patients experienced an MR, for a CBR of 91%. Only one patient had progressive disease. All seven patients whose disease was
not refractory to a PI responded (one patient with a CR, two patients with a VGPR and four patients with a PR) for an ORR and CBR of 100%. Fifteen of the 22 patients in the SVd combination arm had MM previously refractory to a proteasome inhibitor
and nine patients had high-risk cytogenetics including deletion of chromosome 17p. Ten of these 15 patients responded (one patient with a sCR, one with a CR, two with a VGPR and six with a PR) for an ORR of 67%. Three additional patients achieved an
MR for a CBR of 87% in this subgroup with PI-refractory disease. Median DOR across the 22 patients was 7.8 months.
16
The recommended Phase 2 dose regimen was identified as selinexor (100mg once weekly), bortezomib
(1.3 mg/m
2
weekly given sub-cutaneously for four of five weeks) and dexamethasone (40mg weekly). Approximately 42 patients have been enrolled into an expansion cohort at the recommended Phase
2 dose. The most commonly reported AEs from the recommended Phase 2 dose were fatigue, nausea, anorexia and vomiting, which were primarily grade 1 and reversible. Grade 3 AEs included fatigue, diarrhea, thrombocytopenia and abdominal pain and each
occurred at a rate of 6%, meaning only one occurrence of each event across all 22 patients. The only grade 4 AE was thrombocytopenia and occurred at a rate of 12%, meaning two occurrences across all 22 patients.
Also in December 2016, we presented preliminary data from 15 patients in the selinexor, pomalidomide and dexamethasone arm of the STOMP study,
referred to as SPd, at the ASH 2016 annual meeting. The patients in this cohort had received a median of five prior therapies, with a range of two to nine prior therapies. All 15 patients had received prior treatment with lenalidomide and a PI. Nine
of the 15 patients responded, with three patients having a VGPR and six patients having a PR. As a result, the ORR was 60%. An additional two patients experienced an MR, for a CBR of 73%. Only one patient had progressive disease. Five of the 15
patients had high-risk cytogenetics including deletion of chromosome 17p. Median progression-free survival, or PFS, was 10.3 months, with a follow up of 7.6 months. The most common AEs were anorexia, nausea, fatigue, and thrombocytopenia, mainly
grades 1 and 2, and were similar to selinexor or pomalidomide used separately.
In addition, we plan to initiate a new arm of the STOMP
study to evaluate oral selinexor in combination with the anti-CD38 monoclonal antibody daratumumab (Darzalex
®
) and low-dose dexamethasone, referred to as SDd, in patients with heavily
pretreated MM. We expect the SDd arm of STOMP will enroll approximately 44 patients and top-line data will be reported in late 2017 or early 2018.
BOSTON: Pivotal Phase 3 Clinical Trial of Selinexor, Bortezomib and Low-Dose Dexamethasone vs. Bortezomib and Low-Dose Dexamethasone in
Multiple Myeloma
Based on the data from the SVd arm of the STOMP study and following consultation with the FDA and the European
Medicines Agency, or EMA, we are planning a pivotal randomized Phase 3 study, known as the BOSTON (
Bo
rtezomib,
S
elinexor and dexamethas
on
e
) study, which is evaluating SVd compared to bortezomib and low-dose dexamethasone,
or Vd, in patients with MM who have had one to three prior lines of therapy. We expect that the BOSTON study will enroll approximately 360 patients who will be randomized in a one-to-one fashion to receive either SVd or Vd. The dosing schedule
allows for only one scheduled clinic visit per week for patients on the SVd with selinexor and bortezomib to be dosed not more frequently than once per week. In addition, dosing on the SVd arm will use 40% less bortezomib and 25% less dexamethasone
than the Vd arm, which will follow the standard Vd dosing schedule. We expect that the reduced exposure provided by the SVd dosing schedule may significantly reduce common bortezomib- and dexamethasone-related toxicities, which is consistent with
the safety data from the 22 patients described above who were treated with SVd on the STOMP study at the recommended Phase 2 and Phase 3 dose. For the Vd arm, cross-over to the SVd arm based on objective progression will be permitted. The primary
endpoint of the study is PFS and key secondary endpoints include ORR, DOR, PFS, OS, and certain other duration and quality of life endpoints. Topline data from the Phase 3 BOSTON study is anticipated in 2019.
Investigator-Sponsored Clinical Trials
The safety and efficacy of selinexor is currently being evaluated in multiple investigator-sponsored trials, including in combination with
existing therapies to treat MM: (i) carfilzomib, low-dose dex and selinexor and (ii) pegylated liposomal doxorubicin and selinexor.
In December 2016, final results from the Phase 1 investigator-sponsored study evaluating the tolerability and efficacy of the combination of
oral selinexor with PI carfilzomib (Kyprolis
®
) and low-dose dex in patients with very heavily pretreated MM were presented at the ASH Annual Meeting. This study is being led by the University
of Chicago and supported by a collaboration between Karyopharm, Onyx Pharmaceuticals (owned by
17
Amgen Inc.) and the Multiple Myeloma Research Consortium. The primary objectives of this study were to determine the maximum tolerated dose, or MTD, and recommended Phase 2, or RP2D, doses for
selinexor in combination with carfilzomib and dexamethasone, to assess preliminary efficacy through ORR, CBR, and DOR and to determine the efficacy of this combination in carfilzomib refractory patients.
The study enrolled 21 patients in 3 dose levels including an expansion cohort of 6 patients, and enrollment of an additional 12 carfilzomib
refractory is planned. Patients had a median of four prior treatment regimens (with a range of 2 to 10), 17 patients had MM that was quad-refractory to carfilzomib, lenalidomide, bortezomib or pamolidomide, and all patients had received
carfilzomib-based treatments to which their MM became refractory. Dexamethasone was dosed at either 20 mg or 10 mg twice weekly. Eight patients received 30 mg/m
2
(approximately 50 mg) of selinexor
in combination with either 20/27 mg/m
2
or 20/36 mg/m
2
of carfilzomib, seven patients received a 60 mg flat dose of selinexor in combination
with 20/27 mg m
2
of carfilzomib, which was identified to be the RP2D, and an additional six patients were dosed at the RP2D level as part of the dose expansion phase.
The combination achieved a 63% ORR and a 67% response rate in patients whose disease is refractory to carfilzomib in their last therapy.
Median progression free survival on the study was 3.7 months in patients who responded with a PR or better, and median DOR was 3.3 months with a range of 0.6 to 13 months. The selinexor, carfilzomib and dexamethasone combination appears safe and has
acceptable tolerability in these heavily pretreated MM patients. No unexpected toxicities were observed. Only one patient experienced a dose limiting toxicity at 60 mg flat dose selinexor in combination with 20/27 mg m
2
of carfilzomib. The most commonly reported AEs were thrombocytopenia and neutropenia, which were reversible and manageable with dose modifications and supportive care. Grade 3 and 4 AEs were
predominantly hematological and included thrombocytopenia (64%), neutropenia (27%), lymphopenia (27%) and anemia (14%). The most common grade 3 and 4 non-hematologic AEs were GI-related (18%) and fatigue (14%). We believe these results
provide early clinical evidence that the addition of selinexor has the ability to overcome carfilzomib resistance, warranting further investigation of the regimen.
Company-Sponsored Phase 1 Clinical Trial Data
As part of our Phase 1 clinical trial of oral selinexor in patients with advanced hematological malignancies, patients with MM were
treated with either single-agent selinexor or selinexor in combination with low-dose (20mg) dexamethasone, all dosed twice weekly. As of December 6, 2015, 12 evaluable patients were treated with 45mg/m
2
of oral selinexor and 20mg of dexamethasone, each dosed twice weekly. This dose of selinexor, equivalent to approximately 80mg, was determined to be the recommended Phase 2 and Phase 3 dose for this
combination therapy as higher doses like 60 mg/m
2
were not well tolerated. While the recommended phase 2 dose of selinexor in most settings is 60mg twice weekly, the addition of a steroid like
dexamethasone in the multiple myeloma setting allows for higher dosing of selinexor. Additionally, this dose of dexamethasone is the standard low-dose dexamethasone (40mg weekly or 20mg twice weekly) used with nearly all other anti-myeloma drugs.
The patients enrolled in this study had received a median of seven prior lines of therapy, each line typically consisting of two to four separate anti-myeloma agents. All had received prior therapy with at least one PI, such as carfilzomib or
bortezomib, and at least one IMiD, such as lenalidomide or pomalidomide, and steroids (typically two or more times).
As of
December 6, 2015, the best responses among the 12 evaluable patients were one sCR (8%), seven PRs (58%), two MRs (17%) and two PD (17%). Two patients left the trial before disease assessment and were therefore not evaluable for
response. The CBR was 83% and the ORR was 67%. The median duration of response is approximately seven months and the longest response lasted over one year. AEs in patients receiving single-agent selinexor were generally low-grade, consistent with
events observed in patients with other hematological malignancies and responsive to standard supportive care. Compared with selinexor given alone, fewer AEs in patients receiving selinexor in combination with low-dose dexamethasone were reported,
particularly levels of nausea, vomiting and weight loss. These observations are consistent with dexamethasones expected reduction in nausea, anorexia and fatigue, which are selinexors primary constitutional side effects.
18
Non-Hodgkins Lymphoma
NHL is a cancer that starts in cells called lymphocytes, which are part of the bodys immune system. Lymphocytes are found in the lymph
nodes and other lymphoid tissues, such as the spleen and bone marrow, as well as in the blood. The World Health Organization estimated that approximately 386,000 new cases of NHL would be diagnosed worldwide in 2012, and the American Cancer Society
projects that approximately 72,200 patients will be diagnosed with NHL in the United States in 2017.
SADAL: Phase 2b Clinical Trial of
Low vs. High Dose Selinexor in Diffuse Large B-Cell Lymphoma
Diffuse Large B-Cell Lymphoma, or DLBCL, is the most common of the
aggressive NHLs. We estimate that approximately 22,000 patients are diagnosed with DLBCL in the United States each year, with approximately 10,000 deaths per year. The fundamental treatment of DLBCL has changed little in the past two decades, with
no new or targeted agents approved for this indication. Initial therapy with multi-agent cytotoxic drugs in combination with the monoclonal antibody rituximab (Rituxan
®
), most often in a
combination therapy known as R-CHOP, leads to cures in approximately 50% of patients. Patients who are not cured with initial immune-chemotherapy have a poor prognosis. Of the approximately 30% of patients who are less than 65 years
old and have good organ function, high dose chemotherapy with stem cell transplantation can lead to cures in up to half. Older patients relapsing after initial chemotherapy, and those relapsing after stem cell transplantation, have a very poor
prognosis, and the expected survival of such patients is less than one year. Newer targeted agents such as the BTK inhibitor ibrutinib (Imbruvica
®
) and the immunomodulatory drug lenalidomide
(Revlimid
®
) have shown some activity in the immunoblastic (activated B-cell or ABC) type of DLBCL in clinical trials, but responses are generally short. Responses to these newer agents are
much lower in the germinal center, or GCB, type of DLBCL. Therefore, with approximately 10,000 deaths in United States each year due to DLBCL, we believe that novel, well-tolerated drugs are needed for the treatment of relapsed/refractory DLBCL.
Our
S
elinexor
A
gainst
D
iffuse
A
ggressive
L
ymphoma
, or
SADAL
, study is an open-label
Phase 2b clinical trial evaluating single-agent oral selinexor in patients that have relapsed and/or refractory DLBCL, either de novo or transformed from a more indolent NHL such as follicular lymphoma, after two to five lines of therapy. At
least 50% of patients on SADAL will have the GCB subtype of DLBCL, which represents a particularly high unmet medical need given the lack of available therapies for patients with this relapsed/refractory subtype. The SADAL study has been conducted
as a two arm study with patients randomized on a one-to-one basis to receive either 100mg or 60mg of selinexor, each given twice weekly, with about 200 patients expected to be randomized evenly between the two arms with an inclusion requirement of
least 14 weeks since a patients last systemic anti-DLBCL therapy. The primary endpoint would be ORR on each arm, with the goal of determining the more optimal dose for patients with heavily pretreated DLBCL.
In 2017, in consultation with the FDA, we decided to amend the SADAL study to become a single-arm study evaluating single-agent selinexor at
60mg given twice weekly and to make other protocol amendments, including to reduce the 14-week washout period to eight weeks in patients who achieved at least a PR on their most recent therapy. We reported to the FDA that we had observed an ORR of
28.4% across both the 100mg and 60mg arms in the first 63 patients with consistent response rates across both arms (adjudicated by independent Central Radiological Review per protocol), but greater durability and chronic tolerability were observed
in the 60mg arm. The FDA agreed that the change to a single-arm study was reasonable and that the proposed trial design and indication appeared appropriate for accelerated approval, though the availability of accelerated approval will depend on the
trial results and available therapies at the time of regulatory action. We expect to provide additional detailed information on the results in these first 63 patients in a late-breaking poster presentation at the American Associate for Cancer
Research Annual Meeting in April 2017. We expect to enroll up to an additional 90 patients to the new cohort and expect to announce topline data for the completed study in
mid-2018.
19
Investigator-Sponsored Trials
Ongoing investigator-sponsored clinical trials are evaluating the safety and efficacy of selinexor in combination with existing therapies to
treat various lymphomas: (i) rituximab, ifosfamide, carboplatin and etoposide, or R-ICE, and selinexor to treat relapsed (at least one prior therapy) DLBCL and other aggressive lymphomas, (ii) ibrutinib and selinexor to treat chronic
lymphocytic leukemia or NHL, and (iii) R-DHaOx and R-GDP in combination with selinexor in relapsed refractory B-cell lymphomas including DLBCL.
Company-Sponsored Phase 1 Clinical Trial Data
As of June 1, 2015, 77 heavily pretreated patients with relapsed and/or refractory NHL were enrolled in our Phase 1 clinical trial for
oral selinexor. Of this group, 67 patients were evaluable for response. The DCR was 67% across all doses of selinexor and the ORR was 33%. Responses were observed across all subtypes of NHL, independent of genetic abnormalities, with durable cancer
control observed across several patients who remained on study for longer than nine months, with the longest remaining on study for over 24 months.
Among the 41 patients with heavily pretreated DLBCL who were evaluable as of June 1, 2015, ORR and DCR were similar across the two major
subtypes of DLBCL, namely GCB and ABC, also called non-GCB. Many targeted therapies such as ibrutinib or lenalidomide show activity primarily against the ABC subtype (although all patients relapse), but there are no viable treatment options for
patients with relapsed/refractory GCB. However, consistent with the broadly applicable mechanism of action of selinexor, selinexor showed activity across both major subtypes of DLBCL with DCR equal to 60% and 40% between the GCB and non-GCB
subtypes, respectively, and ORR equal to 35% and 20% between the GCB and non-GCB subtypes, respectively.
Acute Myeloid Leukemia
AML in elderly populations remains a vexing clinical problem with little progress in the last decade. There are no treatment agents
specifically approved for this population in the United States. AML is a cancer that starts in the bone marrow and in most cases quickly moves into the blood. The incidence of AML dramatically increases after the age of 55. The American Cancer
Society estimates that approximately 21,000 new cases of AML, most of which will be in adults, will be diagnosed in the United States in 2017, with approximately 10,600 deaths from AML in the United States in 2017. Approximately 40% of AML
patients are young enough with sufficient major organ function to undergo stem cell transplantation for their AML, and approximately 50% of these patients can be cured of their disease. Therefore, approximately 20% of adults with AML are currently
curable. Those who are not cured, and those patients who are elderly or unfit for transplant, have a very poor prognosis with a median survival of less than one year. Moreover, prognosis worsens continuously with advancing age to a median survival
of as low as one month for those who are older than 85 years of age.
Over the past two decades, many compounds have been evaluated in
elderly patients with AML, but due to significant toxicities and/or lack of efficacy, none has been approved to date in the United States. Adults who are not transplant candidates, and cannot safely receive intensive chemotherapy, such as
anthracyclines and cytosine arabinoside, or Ara-C (often referred to as the 7+3 regimen), are usually treated with best supportive care, or BSC, including blood transfusions, antibiotics and hydroxyurea if indicated, along with
hypomethylating agents decitabine (Dacogen
®
) or azacytidine (Vidaza
®
). These hypomethylating agents are approved in certain AML
populations in the European Union. Some patients are treated with low dose Ara-C. All of these agents are given parenterally (subcutaneously or intravenously) in the clinic or hospital, and none of these agents are associated with cures,
meaning that all older patients unfit for chemotherapy will relapse and eventually succumb to their disease. Median survival following initial treatment with front-line therapy in these patients is reported to be less than three months.
Three new therapies for specific subsets of AML patients may be approved in 2017. Novartis submitted a new drug application, or NDA, in late
2016 for midostaurin as a first line treatment in combination with 7+3 in
20
patients with FLT3 mutations. The FDA has granted priority review and an approval is anticipated mid-year. Jazz Pharmaceuticals initiated a rolling NDA submission for Vyxeos/CPX-351 (cytarabine
and daunorubicin liposome injection) in September 2016 with plans to complete the submission in early 2017 and request a priority review. Vyxeos was granted Breakthrough Therapy Designation for adults with therapy-related AML (tAML) or AML with
myelodysplasia-related changes. In addition, Celgene submitted an NDA for the IDH2m inhibitor AG-221 (enasidenib) in patients with relapsed/refractory AML based on data from the ongoing Phase I/II study (NCT01915498) of enasidenib in patients with
IDH2m+ hematologic malignancies.
SOPRA: Phase 2 Clinical Trial of Selinexor vs. Physicians Choice in Elderly AML
Our Phase 2 study of oral selinexor in patients 60 years of age or older with relapsed or refractory AML enrolled patients who were
ineligible for standard intensive chemotherapy and/or transplantation. In our
S
elinexor in
O
lder
P
atient with
R
elapsed/Refractory
A
ML
, or
SOPRA
, study we enrolled 176 patients who have AML that
has relapsed after, or was refractory to, first line therapy. Patients were randomized in a 2:1 fashion to selinexor provided orally twice weekly in a dose of 60mg plus BSC versus one of three physician choices, or PC. Patients must have
received at least one prior line of AML therapy given at standard doses and must have progressed after their most recent therapy. Prior therapy must have included at least two cycles of a hypomethylating agent. PCs include (i) BSC alone,
(ii) BSC plus either azacytidine or decitabine or (iii) BSC plus low-dose Ara-C. OS is the primary endpoint. The SOPRA study was designed based on data from the Phase 1 study of selinexor in patients with advanced hematologic
malignancies, including AML.
In March 2017, we reported that we had determined, in concert with SOPRAs Independent Data Safety
Monitoring Board, or DSMB, that the study would not reach statistical significance for showing superiority of OS on selinexor versus OS on PC, the studys primary endpoint.
Based on unaudited site data, SOPRA enrolled 176 patients, with a median of two prior treatment regimens, in the U.S., Canada, Europe and
Israel. Among patients on the selinexor arm, 13% demonstrated a CR with or without full hematologic recovery, or CRi, compared to 3% of patients on the PC control arm. Some patients remained on selinexor for over one year, but this did not result in
a statistically superior OS compared to the PC arm. However, since the 13% of selinexor-treated patients who achieved a CR (with or without full hematologic recovery) showed a substantial OS benefit as compared with the PC arm, we and the DSMB
agreed that patients would be permitted to continue on the selinexor arm or the PC arm, as applicable, following discussion between the patient and their treating physician.
The DSMB found no new clinically significant AEs in the patients receiving selinexor. Rates of sepsis and febrile neutropenia, or FN, were
lower on the selinexor arm where the rate of sepsis was 4.9% and the rate of FN was 14.7%. In comparison, the rate of sepsis on the PC arm was 6.1% and the rate of FN was 36.4%. As expected, the most common selinexor-related AEs were nausea,
anorexia, fatigue, vomiting, and thrombocytopenia.
We plan to continue clinical development of selinexor in AML through
investigator-sponsored trials in multiple combination regimens, including with chemotherapy, given encouraging data to date across these settings.
Investigator-Sponsored Trials
SAIL: Phase 2 Clinical Trial of Selinexor, Ara-C and Idarubicin in AML
In December 2016, Walter Fiedler, MD of the University Medical Center Hamburg-Eppendorf in Germany and his colleagues presented updated data
from the SAIL study, an investigator-sponsored trial evaluating the combination of selinexor, Ara-C and idarubicin in patients with relapsed/refractory AML. Patients in this study had a range of one to five prior therapies and 39% had undergone a
prior stem cell transplant or donor lymphocyte
21
infusion. Data from 42 patients evaluable for safety (range of prior treatment regimens, all including intensive chemotherapy is 1-5), as of October 2016, demonstrated an ORR of 55% (with 4
patients excluded from evaluation due to early death) and included CR of 22% and 36% and CRi of 33% and 9% in Cohort 1 and 2, respectively. Median relapse free survival was 333 days and median OS was 435 days.
The most frequent Grade 3 or higher non-hematologic AEs of this intensive chemotherapy-containing regimen were diarrhea (50%) and nausea
(12%). The most common Grade 3 or higher hematologic AEs were neutropenia (100%) and thrombocytopenia (100%) as expected with any intensive chemotherapy regimen. Two deaths occurred that were deemed possibly treatment-related, which were
one reported case of systemic inflammatory response syndrome (SIRS; 2%) and one reported case of hemophagocytosis syndrome (2%). Other Ara-C-based combination therapies for AML have shown significantly lower response rates in patients with heavily
pretreated AML: combination of Ara-C with gemtuzumab ozogamicin (Mylotarg
®
) 11.5% ORR; combination of Ara-C with doxorubicin
(Doxil
®
) 6.9%. We believe the combination of selinexor with chemotherapy is a promising regimen, particularly in this difficult-to-treat patient population with poor prognoses.
Approximately half of patients on the SAIL study were able to proceed to their first or second allogeneic stem cell translation. Ara-C and idarubicin represent the standard of care for AML patients who are candidates for intensive therapy, and the
SAIL study provides support for the tolerability of selinexor in combination with standard of care therapy. Accordingly, we believe that selinexor in combination with Ara-C and idarubicin may be an effective treatment option and serve as a bridge to
stem cell transplantation for patients with relapsed/refractory AML.
Additional investigator-sponsored studies are evaluating the safety
and efficacy of selinexor as a single agent and in combination with existing therapies: (i) daunorubicin, cytarabine and selinexor in patients with high risk, naïve AML, (ii) topoisomerase-II inhibition and selinexor in AML,
(iii) sorafenib and selinexor in AML, (iv) cladribine and cytarabine, or CLAG, and selinexor in AML, (v) high dose cytarabine, or HiDAC, mitoxantrone chemotherapy and selinexor for remission induction in AML, (vi) decitabine and
selinexor in AML, (vii) fludarabine, cytarabine and selinexor in pediatric patients with relapsed/refractory leukemia or myelodysplastic syndrome, or MDS, (viii) single-agent selinexor to eliminate minimal residual disease and maintain
remission in patients with AML and high risk MDS after allogenic stem cell transplant and (ix) single-agent selinexor in MDS.
Eighteen pediatric patients with relapsed or refractory leukemia were enrolled in the investigator-sponsored SELHEM (Selinexor with
Fludarabine and Cytarabine for Treatment of Refractory or Relapsed Leukemia or Myelodysplastic Syndrome) clinical trial. Data from this study were presented in May 2016 at the American Society of Pediatric Hematology/Oncology Annual Meeting and
published in August 2016 in the Journal of Clinical Oncology. In the SELHEM study, selinexor was given orally six times per 28-day cycle. Among the 17 patients who were evaluable for toxicity, three were treated with selinexor at 30mg/m
2
, three at 40mg/m
2
, six at 55mg/m
2
, and five at 70mg/m
2
. Fludarabine (30mg/m
2
) and cytarabine (2g/m
2
) were each administered twice during
each 28-day cycle.
In this group of heavily pretreated, relapsed and/or refractory patients, seven of 15 evaluable patients
(47%) achieved CR or CRi. Five of the responses were negative for minimal residual disease, or MRD. Two patients experienced MRD negative CRs within the first cycle after receiving only selinexor therapy. The most common grade 3 nonhematologic
toxicity was asymptomatic hyponatremia. Two patients who were treated with selinexor at 70mg/m
2
experienced reversible cerebellar toxicity, thereby defining the dose-limiting toxicity. The SELHEM
study concluded that selinexor, in combination with fludarabine and cytarabine, is tolerable at doses up to 55mg/m
2
in pediatric patients with relapsed or refractory leukemia. Given the promising
response rates, further exploration of this combination is expected in a Phase 2 clinical trial.
Company-Sponsored Phase 1 Clinical
Trial Data
In December 2015, we presented data, based on 95 patients with AML enrolled on our Phase 1 study as of December 6,
2015, of which 78 were evaluable for response. These patients were heavily pretreated with
22
progressive, relapsed and/or refractory AML, most with three or more prior treatment regimens. These patients typically received between
16.8-70mg/m
2
of selinexor in a four-week cycle, with lower doses initially given ten times per cycle and higher doses given twice weekly. Of these 78 evaluable patients, the complete response rate
with or without full hematologic recovery was 10%. Forty-five patients (58%) experienced SD and the disease control rate, or DCR, across the evaluable patients was 68% (53 of 78 patients). Responses were observed across multiple genetic
subtypes of AML. Higher doses of selinexor were associated with greater reductions in bone marrow blast counts, which were also observed across different AML subtypes.
Advanced or Metastatic Solid Tumor Malignancies
Solid tumors represent the vast majority of cancer incidences. The International Agency for Research on Cancer estimates that approximately
13.1 million adults were diagnosed with solid tumor malignancies worldwide in 2012. Given this large patient population and the mechanistic activity of selinexor that makes it potentially suitable for treating any type of cancer, we are
developing selinexor to potentially play a meaningful role across multiple solid tumor indications, either alone or in combination as a backbone therapy. We have seen encouraging single agent data for selinexor in a variety of solid tumors including
PRs and durable SD with disease control greater than three months. Our Phase 1b study in patients with liposarcoma and other sarcomas demonstrated durable stable disease with single-agent selinexor, and our Phase 2 studies of selinexor in
gynecological malignancies and glioblastoma multiforme, or GBM, also demonstrated anti-cancer activity and disease control. Given the promising single-agent activity in difficult-to-treat indications and the potential to enhance activity in
combination with existing therapies, we plan to seek opportunities in unmet needs like endometrial cancer, ovarian cancer and GBM, and to advance combination therapy development with both standard of care and emerging therapies like immune
checkpoint inhibitors.
SEAL: Phase 2/3 Clinical Trial of Selinexor vs. Placebo in Liposarcoma
Liposarcoma represents an area of high unmet need with limited treatment options. Liposarcoma arises from fat cells or their precursors and,
according to the nonprofit organization the Sarcoma Alliance for Research through Collaboration (SARC), represents 18% of all soft tissue sarcoma, or an estimated 2,500 new cases per year in the United Sates. We estimate that approximately 18,000
people in the United States suffer from liposarcoma. Liposarcoma most commonly occurs in the thigh, behind the knee, the groin, the gluteal area or behind the abdominal cavity. Soft tissue sarcomas can invade surrounding tissue and can spread to
other organs of the body. Dedifferentiated liposarcoma is an aggressive form of soft tissue sarcoma that is resistant to both standard chemotherapy and radiation. Liposarcoma has a particularly high rate of recurrence following surgery, especially
in cases involving the abdomen. Except for cases that are cured with surgery, most patients with liposarcoma will succumb to this disease, and novel therapies are needed.
In our Phase 1b trial to evaluate the effects of food and formulation on selinexor pharmacokinetics in patients with soft-tissue or bone
sarcoma, 31 of 54 sarcoma patients (57%) experienced SD with single-agent selinexor treatment. Of the 18 patients with liposarcoma, 14 (78%) experienced SD and eight (44%) experienced SD of four months or longer. Fifteen of these 18
patients with liposarcoma had dedifferentiated liposarcoma. Of these 15 patients with dedifferentiated liposarcoma, 13 (87%) experienced SD and seven (47%) experienced SD of four months or longer. In addition, in patients with previously
treated liposarcoma, PFS on selinexor was longer than the patients most recent anti-cancer regimen.
In light of the Phase 1b data,
we designed the
Se
linexor in
A
dvanced
L
iposarcoma
, or
SEAL
, study, a multi-center, randomized, double-blind, placebo-controlled Phase 2/3 clinical trial evaluating single-agent oral selinexor in patients with
advanced unresectable dedifferentiated liposarcoma who received at least one line of prior systemic therapy. Patients will be randomized to receive either 60mg of selinexor or placebo given twice weekly until progression or intolerability. The Phase
2 portion of the study has been fully enrolled with 50 patients and enrollment may begin in the Phase 3 portion following an interim analysis. The study design, including the primary endpoint of PFS, was acceptable to the FDA and will be evaluated
for futility in an interim
23
analysis of the Phase 2 portion of this study, which we expect to occur during the middle of 2017. Tumor response will be assessed according to the World Health Organization response criteria.
SIGN: Phase 2 Clinical Trial of Selinexor in Gynecological Malignancies
The SIGN study is a Phase 2, open-label study of efficacy and safety of oral selinexor in patients with heavily pre-treated, progressive
gynecological cancers. In October 2016, we presented updated data at the European Society of Medical Oncology, or ESMO, 2016 annual meeting that showed selinexors promising anti-tumor activity and disease control in gynecological malignancies.
Of the 59 evaluable patients with ovarian cancer, 29 met the primary endpoint (8 patients (14%) achieved a confirmed PR and 21 patients achieved stable disease for at least 12 weeks, or SD
³
12 weeks),
for a DCR of 49%. Median PFS for the ovarian cancer arm was 3 months and median OS was 7 months. Of the 20 evaluable patients with endometrial cancer, 9 met the primary endpoint (3 confirmed PRs and 6 with
SD
³
12 weeks), for a DCR of 45%. Median PFS for the endometrial cancer arm was 3 months and median OS was 8 months. Across all arms, the most common grade 2 or 3 AEs were fatigue, nausea, anemia, anorexia,
vomiting, weight loss and thrombocytopenia, which were manageable with supportive care. Notably, Grade 3 AEs were significantly reduced in patients with ovarian cancer receiving once weekly dosing compared to twice weekly dosing. One incidence of
grade 4 thrombocytopenia without bleeding was also reported. For the 44 patients who met the DCR criteria, the median time on study was 20 weeks. Fifteen patients remained on single-agent selinexor for greater than 6 months, including 4 patients
continuing on treatment for greater than 12 months.
An investigator-sponsored Phase 3 randomized double-blinded maintenance study in
advanced or recurrent endometrial cancer is in development and expected to initiate enrollment in late 2017.
KING: Phase 2 Clinical
Trial of Selinexor in Glioblastoma Multiforme
The KING study is a Phase 2 study evaluating the efficacy and safety of oral selinexor
in patients with recurrent GBM. In June 2016, we presented data at the American Society of Clinical Oncology Annual Meeting where we showed that single-agent oral selinexor demonstrated anti-tumor activity in patients with glioblastoma that recurred
after temozolomide and radiation therapy, including selinexor brain penetration at clinically relevant levels, leading to durable anti-cancer activity and disease control of up to 6 months. Specifically, data as of May 23, 2016 from 33
surgically ineligible patients with GBM that progressed after treatment with temozolomide and radiation showed that selinexor dosed twice weekly at 50 mg/m
2
demonstrated anti-tumor activity with a
12% ORR (PR or better) and a 33% DCR (SD or better) with durability of up to six months in two patients. The most common AEs were thrombocytopenia, fatigue, anorexia, and nausea.
Investigator-Sponsored Trials
Investigator-sponsored clinical trials are evaluating the safety and efficacy of selinexor as a single agent and in combination with existing
therapies: (i) selinexor and standard capecitabine-based chemoradiation as a neoadjuvant treatment in locally advanced rectal cancer, (ii) selinexor, paclitaxel and carboplatin in ovarian or endometrial malignancies, (iii) selinexor
and mFOLFOX6 in metastatic colorectal cancer, (iv) selinexor and standard chemotherapy agents in advanced solid tumors, (v) selinexor in metastatic castration resistant prostate cancer, (vi) selinexor in unresectable melanoma,
(vii) selinexor in genomic profiling and matched therapy for recurrent or metastatic salivary gland neoplasms, (viii) selinexor in Asian patients with advanced malignancies and (ix) selinexor in recurrent refractory pediatric solid
tumors.
Company-Sponsored Phase 1 Clinical Trial Data
The primary objectives of our Phase 1 dose escalation trial in solids tumors were to determine the safety, tolerability and recommended
Phase 2 dose of oral selinexor. All patients entered the study with advanced or metastatic solid tumor cancers relapsed or refractory after multiple previous treatments and objectively
24
progressing on study entry. These patients were dosed 3-85mg/m
2
(equivalent to approximately 5-145mg) of oral selinexor over a four-week
cycle, with lower doses initially given ten times per cycle and higher doses given twice weekly. Response evaluation was done every two cycles in accordance with RECIST criteria.
As of September 15, 2015, 189 patients were enrolled in this Phase 1 clinical trial. Enrolled patients had received a median of
three prior therapeutic regimens. Of these patients, 157 were evaluable for response and the DCR was 47%. PRs were observed in six patients, one each with colorectal cancer (KRAS mutant), melanoma, prostate cancer, ovarian adenocarcinoma, thymoma
and cervical cancer, and one CR was observed in a patient with melanoma whose disease progressed on immunotherapy. SD was noted in 67 patients, with 27 patients (17%) experiencing SD for four months or longer, which we believe is an indication
of clinically significant
anti-tumor
activity. In February 2016, data from this Phase 1 clinical trial were published in the
Journal of Clinical Oncology
.
KPT-8602
KPT-8602 is a
second generation SINE compound that, like selinexor, selectively blocks the nuclear export protein XPO1. Most of the key tumor suppressor proteins, or TSPs, are cargos of XPO1. Inhibition of XPO1 by KPT-8602 sequesters TSPs in the nucleus where
they can carry out their normal functions, including evaluating the cells genome for damage. KPT-8602 and other SINE compounds are not intrinsically cytotoxic. Rather, they can restore the highly effective tumor suppressing pathways that lead
to selective elimination of genomically damaged or neoplastic cells. Cancer cells with damaged genomes are induced to undergo apoptosis. Normal cells, with an intact genome, remain in a transient, reversible cell cycle arrest until the export block
is relieved. Tumors of hematopoietic lineage are particularly susceptible to apoptosis induction by XPO1 inhibition while normal hematopoietic cells are largely spared.
KPT-8602 differs from selinexor primarily because it has much lower penetration into the brain, and may therefore cause fewer side effects
such as nausea, fatigue and anorexia. Following oral administration, animals treated with KPT-8602 show lower percentage of body weight loss and improved food consumption, as well as less fatigue behavior, in comparison to animals
similarly treated with selinexor. This allows more frequent dosing of KPT-8602, enabling a longer period of exposure at higher levels than is possible with selinexor. In many preclinical model systems, the more intensive dosing regimen leads to
superior efficacy in comparison to selinexor treatment. As a result, we believe that KPT-8602 represents a second generation SINE compound and are evaluating safety, tolerability and efficacy in humans.
Following the completion of toxicology studies, we filed an IND for KPT-8602 with the FDA in November 2015 and initiated our first-in-humans
Phase 1/2 clinical trial for KPT-8602 in patients with relapsed/refractory multiple myeloma in January 2016. In December 2016, we reported preliminary data from the ongoing Phase 1/2 study demonstrating good tolerability, with low levels of nausea,
anorexia and fatigue, as well as early signals of anti-myeloma activity. The study protocol is being amended to include patients with myelodysplastic syndromes, heavily preatreated colorectal cancer and castrate-resistant prostate cancers. We expect
to report topline data from the new cancers being treated in this study in early 2018.
KPT-9274
In addition to our SINE compounds, we also investigate XPO1 cargo proteins and their role in the cell cycle and cell division. As part of this
investigation, we have identified several XPO1 cargo proteins whose inhibition leads to the selective death of cancer cells. One of the XPO1 cargo proteins that we identified was p21-activated kinase 4, or PAK4. PAK4 is a signaling protein
regulating numerous fundamental cellular processes, including several involved in the development of cancer. PAK4 interacts with many key signaling molecules involved in cancer such as beta-catenin, CDC42, Raf-1, BAD and myosin light chain. Based on
this biology, we used our drug discovery and optimization expertise to identify oral small molecule modulators of PAK4. Our oral PAK4 allosteric modulators have shown broad evidence of anti-cancer activity against hematological and solid tumor
25
malignant cells while showing minimal toxicity to normal cells in vitro. In mouse and rat xenograft studies, our PAK4 inhibitors given orally have shown evidence of anti-cancer activity and
tolerability. To our knowledge, we are the only company with an allosteric, PAK4 specific inhibitor currently in Phase 1.
Recently, we
identified an additional target for our clinical candidate KPT-9274 known as NAMPT (Nicotinamide phosphoribosyltransferase; also known as PBEF or Visfatin). NAMPT is a pleiotropic protein with multiple intra- and extra-cellular functions that can be
found in complex with PAK4 in the cell. NAMPT is of interest as an oncology target because it catalyzes the rate-limiting step in one of the two intracellular salvage pathways that generate nicotinamide adenine dinucleotide, or NAD. NAD is a
universal energy- and signal-carrying molecule involved in mitochondrial function and energy metabolism, as well as other functions.
KPT-9274 is a first-in-class orally bioavailable small molecule that is a non-competitive dual modulator of PAK4 and NAMPT. Co-inhibition of
these targets leads to synergistic anti-tumor effects through energy depletion, inhibition of DNA repair, cell cycle arrest, inhibition of proliferation, and ultimately apoptosis. Normal cells are more resistant to inhibition by KPT-9274 due in part
to their relative genomic stability and lower metabolic rates. Hematologic and solid tumor cells become dependent on both PAK4 and NAMPT pathways and are therefore susceptible to single-agent cytotoxicity by KPT-9274. We are planning to develop
KPT-9274 for a variety of neoplastic disease indications. Following the completion of IND-enabling toxicology studies, we filed an IND in February 2016 and initiated a first-in-humans Phase 1/2 open-label clinical trial evaluating the safety,
tolerability, and efficacy of KPT-9274 in patients with advanced solid malignancies or
non-Hodgkins
lymphoma. We expect to report topline safety and tolerability data from this study during 2017.
Verdinexor (KPT-335): Oral SINE Compound for Lymphoma in Companion Canines
We have used spontaneously occurring canine cancers as a surrogate model for human malignancies. It is widely known that canine lymphomas
display a comparable genetic profile and respond to chemotherapy in a fashion similar to their human counterparts (human NHL, most closely DLBCL). Lymphomas are one of the most common tumors in pet dogs. Lymphoma in dogs is very aggressive and,
without treatment, the tumors are often fatal within weeks. The majority of dog lymphomas are DLBCL and most of the others are T-cell lymphomas. Given the similarities of dog and human lymphomas, prior to initiating clinical trials of selinexor in
humans, we investigated verdinexor (KPT-335), a closely-related, orally available SINE compound in pet dogs with lymphomas. We have received a Minor Use / Minor Species, or MUMS, designation from the FDAs Center for Veterinary Medicine, or
CVM, for the treatment of newly-diagnosed or first relapse after chemotherapy lymphomas in pet dogs with verdinexor.
Several different
dog tumor cell lines, including those derived from lymphomas, exhibited growth inhibition and apoptosis in vitro upon exposure to nanomolar concentrations of verdinexor. Data from a Phase 1 clinical trial of verdinexor as well as dose expansion
study involving pet dogs with cancer, primarily with lymphoma, show efficacy of verdinexor to treat dogs with lymphoma. Side effects included anorexia, weight loss, vomiting and diarrhea and were manageable with dose modulation and supportive care.
We conducted an owner observation-based survey and the data indicated that the overall quality of life did not change significantly in dogs treated with verdinexor. Based on these findings, a Phase 2b clinical trial, intended to support
regulatory approval under the MUMS designation in the United States, was performed in 58 pet dogs with either newly-diagnosed or first relapse after chemotherapy lymphomas. In this Phase 2b clinical trial, Verdinexor was administered initially at
doses ranging from 25mg/m
2
to 30mg/m
2
two or three days per week. Minimal or no supportive care was given. The total CRs and PRs of the 58 dogs
was 34%, with one CR and 19 PRs. An additional 33 of 58 dogs (57%) experienced SD for at least four weeks. The median time to disease progression was approximately five weeks, with 20 dogs (34%) remaining on study for longer than eight
weeks. A few dogs that received verdinexor in the Phase 1 or 2b studies remained on therapy for longer than eight months.
26
We submitted the safety and effectiveness sections of a New Animal Drug Application, or NADA, for
verdinexor to the CVM in December 2013. We expect to seek to enter into a collaboration with a third party for the commercialization of verdinexor for dog lymphoma, if we obtain regulatory approval. We believe that verdinexor, if approved, would
represent the first oral, targeted therapy for the treatment of dog lymphoma.
Our Non-Oncology Drug Candidates
Verdinexor (KPT-335): Oral SINE Compound for Viral Indications
Verdinexor (KPT-335) is an oral SINE compound and our lead compound that is being evaluated as a potential therapy for viral indications in
addition to the canine lymphoma indication described above. Several viruses exclusively utilize XPO1 to shuttle cargos necessary for virion assembly such as viral ribonucleoproteins, or vRNA, and proteins from the nucleus to the cytoplasm. Due to
the stability of host gene targets compared to viruses which rapidly adapt for best fitness in hosts, targeting host genes also offers an approach to limit drug resistance. We have observed that SINE compounds mediate the inhibition of the nuclear
export of influenza vRNP, leading to suppression of
in vitro
and
in vivo
replication of both A and B influenza strains. We have also observed potent activity of verdinexor across a broad panel of strains, including avian influenzas
H5N1 and H7N9. Orally administered verdinexor showed activity in a therapeutic regimen against an H1N1 influenza strain in ferrets and mice with a reduction in lung viral titer to a similar extent as neuraminidase inhibitors such as oseltamivir
(Tamiflu
®
). In contrast to existing anti-influenza agents, however, verdinexor also reduced the expression of the pro-inflammatory cytokines IFN-
g
,
IL-1
b
, IL-6 and TNF-
a
in H1N1-infected mouse lungs, allowing for the possibility that verdinexor could reduce flu-like symptoms and potentially
severe inflammatory reactions, which can be fatal in human infections. In addition, KPT-335 shows activity against influenza strains resistant to neuraminidase inhibitors.
Based upon the anti-influenza activity of verdinexor in animal models, we believe that verdinexor has the potential to serve as an effective
antiviral and anti-inflammatory therapy for influenza. In 2015, we conducted a randomized, double-blind, placebo-controlled, dose-escalating Phase 1 clinical trial of verdinexor in healthy human volunteers in Australia. This study was designed to
evaluate the safety and tolerability of verdinexor in healthy adult subjects. Verdinexor was found to be generally safe and well tolerated. Mild to moderate AEs of similar number and grade as placebo were reported, and no serious or severe AEs were
observed. We plan to continue to explore strategies to pursue the clinical development of verdinexor as a treatment for influenza, including potentially partnering with a collaborator or through government-funded grant or contract opportunities. In
addition, preclinical data also show efficacy of verdinexor and related SINE compounds in models of multiple additional viruses that utilize XPO1, including HIV.
KPT-350: Oral SINE Compound for Neurological, Inflammatory and Autoimmune Indications
KPT-350 is an IND-ready oral SINE compound with a preclinical data package supporting potential efficacy across a number of neurological,
autoimmune and inflammatory conditions. XPO1 mediates the nuclear export of multiple proteins that impact neurological, autoimmune and inflammatory processes. Consequently, inhibition of XPO1 by KPT-350 results in a reduction in autoimmunity and
inflammation and an increase in anti-inflammatory and neuroprotective responses. KPT-350 penetrates the blood brain barrier, or BBB, to a greater degree than other SINE compounds. Preclinical data generated largely by external collaborators show
efficacy of orally-administered KPT-350 and related SINE compounds in animal models of amyotrophic lateral sclerosis, or ALS, multiple sclerosis, or MS, traumatic brain injury, or TBI, epilepsy, systemic lupus erythematosus, or SLE, and rheumatoid
arthritis, or RA.
The ability of KPT-350 to affect TBI outcome was evaluated in three different rat models of TBI that are designed to
mimic the heterogeneity of TBI observed in clinical practice: unilateral cortical (brain) injury, bilateral cortical injury, and fluid percussion injury models. In these studies, KPT-350 was administered orally with various dosing regimens from two
to 72 hours post-injury. Efficacy was observed in each of the models,
27
involving amelioration of TBI-induced cognitive and motor deficits. This functional activity was accompanied by KPT-350-mediated reduction of TBI lesion size, enhanced neuronal survival and
suppression of inflammatory markers. We believe this indicates KPT-350 exerted a neuroprotective effect to prevent permanent neuronal loss due to the blunt force injury and subsequent inflammatory and neurotoxic effects. Importantly, KPT-350 was
effective even when treatment was initiated at 72 hours post injury. KPT-350 was also found to ameliorate corticospinal fluid leakage (signifying blood-brain barrier breakdown) associated with TBI, which has anti-inflammatory consequences
independent of the other mechanisms of KPT-350 activity.
The neuroprotective effect of KPT-350 was further evaluated in neurotoxicity
models of TNFalpha- and glutamate-induced neurotoxicity in primary rat cortical neurons, believed to be relevant to MS. Treatment with KPT-350 prevented reductions in mitochondrial velocity and length, prevented reductions in spare respiratory
capacity, a measure of neuron capacity, and prevented neurite beading, an overall indicator of neuronal dysfunction. In the standard murine EAE model of MS, KPT-350 treatment reversed hind-limb paralysis and spinal cord inflammatory lesions
consistent with true neuroprotective effects. We also tested KPT-350 in a TDP-43 adeno-associated virus or AAV rat model of ALS to determine if the compound could protect against TDP-43-induced neuro-toxicity and motor impairments. KPT-350 (7 mg/kg)
or vehicle solution was administered orally twice weekly for three weeks followed by evaluation by the hang test, an assessment of grip strength Animals in the TDP/KPT-350 group had improved grip strength on the hang test, similar to healthy animals
and higher than animals in the vehicle control group. Additional preclinical studies were run to evaluate the safety and efficacy of KPT-350 in a pilocarpine model of chronic seizures in mice. In this study, 24 epileptic mice were treated with
KPT-350. In six (25%) of the mice, seizure activity was eliminated entirely and all mice had at least a 50% reduction in seizure activity.
Our SINE compounds have also shown broad evidence of anti-inflammatory activity across various preclinical models suggesting that SINE
compounds have multiple anti-inflammatory effects. Nuclear factor
k
B, or NF-
k
B, is a protein found in the nucleus that binds DNA and drives the expression of
genes involved in many types of inflammation. In cells, NF-
k
B can be inhibited by another protein called I
k
B, or Inhibitor of
NF-
k
B, that binds to NF-
k
B and prevents NF-
k
B from binding to DNA and activating inflammatory effects. When
inflammation occurs, XPO1 transports I
k
B out of the nucleus into the cytoplasm where it cannot inhibit NF-
k
B activity. When KPT-350 or a similar SINE compound
inhibits XPO1, I
k
B export to the cytoplasm is blocked and I
k
B accumulates in the nucleus. The I
k
B in the nucleus
binds to NF-
k
B and blocks its inflammatory (transcriptional) activity. KPT-350 or a similar SINE compound also increase the concentrations of other natural (endogenous) inhibitors of NF-
k
B in the nucleus, including FOXO3a and COMMD1 proteins. Thus, XPO1 inhibition with oral SINE compounds leads to potent, multifaceted inhibition of the potent inflammatory mediator NF-
k
B in a unique fashion.
We plan to partner with a collaborator to undertake the clinical
development and potential commercialization of KPT-350 in one or more mutually agreed indications.
Intellectual Property
Our commercial success depends in part on our ability to obtain and maintain proprietary or intellectual property protection for our drug
candidates, our core technologies, and other know-how, to operate without infringing on the proprietary rights of others and to prevent others from infringing our proprietary or intellectual property rights. Our policy is to seek to protect our
proprietary and intellectual property position by, among other methods, filing patent applications in the United States and in foreign jurisdictions related to our proprietary technology and drug candidates. We also rely on trade secrets, know-how
and continuing technological innovation to develop and maintain our proprietary and intellectual property position.
We file patent
applications directed to the composition of matter and methods of use and manufacture for our drug candidates. As of March 1, 2017 , we were the sole owner of nine patents in the United States and we had 16 pending patent applications in the
United States, one of which is co-owned with a third party, eight
28
pending international applications filed under the Patent Cooperation Treaty (PCT), twenty-one granted patents and 139 pending patent applications in foreign jurisdictions. The PCT is an
international patent law treaty that provides a unified procedure for filing a single initial patent application to seek patent protection for an invention simultaneously in each of the member states. Although a PCT application is not itself
examined and cannot issue as a patent, it allows the applicant to seek protection in any of the member states through national-phase applications. The technology underlying such pending patent applications has been developed by us and was not
acquired from any in-licensing agreement.
The intellectual property portfolios for our key drug candidates as of March 1, 2017 are
summarized below.
|
|
|
Selinexor (KPT-330)
: Our selinexor patent portfolio covers the composition of matter and methods of use of selinexor, as well as methods of making selinexor, and consists of two issued U.S. patents (one patent is
specific to selinexor, and the other patent covers both selinexor and verdinexor), seven issued foreign patents, 40 pending foreign patent applications, two pending U.S. non-provisional application, one directed to polymorphs of selinexor, and three
pending U.S. provisional patent applications, one of which is co-owned with a third party. Any patents that may issue in the United States as part of our selinexor patent portfolio, with the exception of a patent directed to the polymorphs of
selinexor, will expire in 2032, absent any terminal disclaimer, patent term adjustment due to administrative delays by the United States Patent and Trademark Office, or USPTO, or patent term extension under the Drug Price Competition and Patent Term
Restoration Act of 1984, commonly referred to as the Hatch-Waxman Act. Any patents that may issue in foreign jurisdictions will likewise expire in 2032. Any patents that may issue in the United States directed to the polymorphs of selinexor will
expire in 2035, absent any terminal disclaimer, patent term adjustment due to administrative delays by the USPTO or patent term extension under the Hatch-Waxman Act. Any patent issued in foreign jurisdictions will likewise expire in 2035. If
non-provisional patent applications claiming the benefit of the three pending U.S. provisional patent applications referenced above are filed in 2017, any patents that may issue from such applications will expire no earlier than 2037.
|
|
|
|
Selinexor (Wound Healing)
: Our patent portfolio covering selinexor for wound healing, including acute and chronic wounds, burns and scars, covers methods of using selinexor or verdinexor for wound healing,
including systemic and topical uses, and consists of one pending U.S. application and one pending European application. Any patents that may issue in the United States will expire in 2034, absent any terminal disclaimer, patent term adjustment due
to administrative delay by the USPTO or patent term extension under the Hatch-Waxman Act. Any patents issued in Europe will likewise expire in 2034.
|
|
|
|
Verdinexor (KPT-335)
: Our selinexor patent portfolio described above, with the exception of the applications directed to polymorphs of selinexor, also covers both the composition of matter and methods of use of
verdinexor, as well as methods of making verdinexor. There are two issued U.S. Patents that cover verdinexor. One patent is specific to verdinexor and the other patent covers both verdinexor and selinexor (also referenced above with respect to
selinexor).
|
|
|
|
KPT-350
: Our KPT-350 patent portfolio covers both the composition of matter and methods of use of KPT-350, and consists of two issued U.S. patents, three pending non-provisional U.S. patent applications, one
pending U.S. provisional patent application, 24 pending foreign patent applications and two foreign patents. Any patents that may issue in the United States as part of our KPT-350 patent portfolio will expire in 2033, absent any terminal disclaimer,
patent term adjustment due to administrative delays by the USPTO or patent term extension under the Hatch-Waxman Act. Any patents issued in foreign jurisdictions will likewise expire in 2033. If a non-provisional patent application claiming the
benefit of the U.S. provisional patent application referenced above is filed in 2017, any patents that may issue from the non-provisional application will expire no earlier than 2037.
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KPT-8602
: Our KPT-8602 patent portfolio covers both the composition of matter and methods of use of
KPT-8602, and consists of one pending non-provisional U.S. patent application, 21 pending foreign
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patent applications and two pending U.S. provisional patent applications. Any patents that may issue in the United States as part of our KPT-8602 patent portfolio will expire in 2034, absent any
terminal disclaimer, patent term adjustment due to administrative delays by the USPTO or patent term extension under the Hatch-Waxman Act. Any patents issued in foreign jurisdictions will likewise expire in 2034. If non-provisional patent
applications claiming the benefit of the two pending U.S. provisional applications referenced above are filed in 2017, any patents that may issue from such applications will expire no earlier than 2037.
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PAK4/NAMPT Inhibitors
: Our PAK4/NAMPT inhibitors patent portfolio covers both the composition of matter and methods of use of the PAK4/NAMPT inhibitors described therein, such as KPT-9274, and consists of nine
patent families with three pending U.S. non-provisional patent applications, 23 pending foreign patent applications and six pending PCT applications in total. The PCT Applications provide the opportunity for seeking protection in all PCT member
states. Any patents that may issue in the United States based on the pending U.S. non-provisional applications will expire in 2033 for the earliest filed application and 2034 for the remaining applications, one of which covers the composition
of matter and methods of use of KPT-9274, absent any terminal disclaimer, patent term adjustment due to administrative delays by the USPTO or patent term extension under the Hatch-Waxman Act. Any patents that may issue based on the pending foreign
patent applications will likewise expire in 2033 and 2034. Foreign patent applications covering the composition of matter and methods of use of KPT-9274 have been filed in 21 countries/regions. Any patents that may issue in the United States based
on the pending PCT applications will expire in 2035 for the earliest filed application and 2036 for the remaining applications, absent any terminal disclaimer, patent term adjustment due to administrative delays by the USPTO or patent term extension
under the Hatch-Waxman Act. Any patents issued in foreign jurisdictions will likewise expire in 2034 and 2035, respectively.
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In addition to the patent portfolios covering our key drug candidates, as of March 1, 2017, our patent portfolio also includes three
patents (U.S. Patent Nos. 8,513,230, 9,303,000 and 9,550,757) and seven granted foreign patents and pending patent applications in both the U.S. and foreign jurisdictions relating to other XPO1 inhibitors and their use in targeted therapeutics.
We also filed three Intent to Use Trademark Applications on August 29, 2013 covering our name, our logo and the two used together. Marks for the name and name and logo together were registered in the United States on January 20, 2015 as
Registration Nos. 4,676,255 and 4,676,226. The mark for our logo was registered in the United States on February 24, 2015 as Registration No. 4,693,100. We also have six pending Intent to Use Trademark Applications in the United States
that we filed in 2014 and 2015, five for drug names for selinexor and one for SINE, all of which have been allowed by the USPTO, and a registration for PORE for our online portal. We also filed applications for the five drug names outside the United
States. From these filings there are five registrations in the European Union. Applications for two of the drug names were filed in 14 other jurisdictions some of which have also proceeded to registration.
The term of individual patents depends upon the legal term for patents in the countries in which they are obtained. In most countries,
including the United States, the patent term is 20 years from the earliest filing date of a non-provisional patent application. In the United States, a patents term may be lengthened by patent term adjustment, which compensates a patentee for
administrative delays by the USPTO in examining and granting a patent, or may be shortened if a patent is terminally disclaimed over an earlier filed patent. The term of a patent that covers a drug may also be eligible for patent term extension when
FDA approval is granted, provided statutory and regulatory requirements are met. See Government RegulationPatent Term Restoration and Extension below for additional information on such extensions. In the future, if and when
our drug candidates receive approval by the FDA or foreign regulatory authorities, we expect to apply for patent term extensions on issued patents covering those drugs, depending upon the length of the clinical trials for each drug candidate and
other factors. There can be no assurance that any of our pending patent applications will issue or that we will benefit from any patent term extension or favorable adjustment to the term of any of our patents.
30
As with other biotechnology and pharmaceutical companies, our ability to maintain and solidify
our proprietary and intellectual property position for our drug candidates and technologies will depend on our success in obtaining effective patent claims and enforcing those claims if granted. However, patent applications that we may file or
license from third parties may not result in the issuance of patents. We also cannot predict the breadth of claims that may be allowed or enforced in our patents. Our issued patents and any issued patents that we may receive in the future may be
challenged, invalidated or circumvented. For example, we cannot be certain of the priority of inventions covered by pending third-party patent applications. If third parties prepare and file patent applications that also claim technology or
therapeutics to which we have rights, we may have to participate in interference proceedings to determine priority of invention, which could result in substantial costs to us, even if the eventual outcome is favorable to us. In addition, because of
the extensive time required for clinical development and regulatory review of a drug candidate we may develop, it is possible that, before any of our drug candidates can be commercialized, any related patent may expire or remain in force for only a
short period following commercialization, thereby reducing any advantage of any such patent.
In addition to patents, we rely upon
unpatented trade secrets and know-how and continuing technological innovation to develop and maintain our competitive position. We seek to protect our proprietary information, in part, using confidentiality agreements with our collaborators,
scientific advisors, employees and consultants, and invention assignment agreements with our employees. We also have agreements with selected consultants, scientific advisors and collaborators requiring assignment of inventions. The confidentiality
agreements are designed to protect our proprietary information and, in the case of agreements or clauses requiring invention assignment, to grant us ownership of technologies that are developed through our relationship with a third party.
With respect to our proprietary drug discovery and optimization platform, we consider trade secrets and know-how to be our primary
intellectual property. Trade secrets and know-how can be difficult to protect. We anticipate that with respect to this technology platform, these trade secrets and know-how may over time be disseminated within the industry through independent
development, the publication of journal articles describing the methodology, and the movement of personnel skilled in the art from academic to industry scientific positions.
Competition
The biotechnology and
pharmaceutical industries are characterized by rapidly advancing technologies, intense competition and a strong emphasis on proprietary products. While we believe that our technology, knowledge, experience and scientific resources provide us with
competitive advantages, we face potential competition from many different sources, including major pharmaceutical, specialty pharmaceutical and biotechnology companies, academic institutions and governmental agencies and public and private research
institutions. Any drug candidates that we successfully develop and commercialize will compete with existing therapies and new therapies that may become available in the future.
There are several companies developing or marketing treatments for cancer and the other indications on which we currently plan to focus,
including many major pharmaceutical and biotechnology companies. To our knowledge, only one other company with an XPO1 inhibitor has enrolled patients in clinical trials at the present time. Stemline Therapeutics, Inc. announced in January 2015 that
it had exclusively licensed the rights to develop and commercialize SL-801, an oral XPO1 inhibitor, from CanBas Co., Ltd. In December 2015, Stemline announced the opening of its IND and planned initiation of a clinical development program
in multiple cancer types and, in February 2017, it announced the enrollment of patients in a Phase 1 dose escalation study of
SL-801.
Many of the companies against which we are competing or against which we may compete in the future have significantly greater financial
resources and expertise in research and development, manufacturing, preclinical testing, conducting clinical trials, obtaining regulatory approvals and marketing approved products than we do. Mergers and acquisitions in the pharmaceutical and
biotechnology industries may result in even more resources being concentrated among a smaller number of our competitors. Smaller or early-stage companies may also prove
31
to be significant competitors, particularly through collaborative arrangements with large and established companies. 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 that may be necessary for, our programs.
The key competitive factors affecting the success of all of our drug candidates, if approved, are likely to be their efficacy, safety,
convenience, price, the availability of generic chemotherapy and other cancer therapies and the availability of reimbursement from government and other third-party payors.
Our commercial opportunity could be reduced or eliminated if our competitors develop and commercialize drugs that are safer, more effective,
have fewer or less severe side effects, are more convenient or are less expensive than any drugs that we may develop. Our competitors also may obtain FDA or other regulatory approval for their drugs 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 drugs. Generic drugs for the treatment of cancer and the other indications on which we currently plan to initially focus are currently on the market, and additional drugs are expected to become available on a generic basis over the
coming years. If we obtain marketing approval for our drug candidates, we expect that they will be priced at a significant premium over generic versions of older chemotherapy agents and other cancer therapies.
The most common methods of treating patients with cancer are surgery, radiation and drug therapy. There are a variety of available drug
therapies marketed for cancer. In many cases, these drugs are administered in combination to enhance efficacy. While our drug candidates may compete with many existing drugs and other therapies, to the extent they are ultimately used in combination
with or as an adjunct to these therapies, our drug candidates will be complimentary with them. Some of the currently-approved drug therapies are branded and subject to patent protection, and others are available on a generic basis. Many of these
approved drugs are well-established therapies and are widely-accepted by physicians, patients and third-party payors.
In addition to
currently-marketed therapies, there are also a number of drugs in late stage clinical development to treat cancer and the other indications on which we plan to initially focus. These drugs in development may provide efficacy, safety, convenience and
other benefits that are not provided by currently-marketed therapies. As a result, they may provide significant competition for any of our drug candidates for which we obtain marketing approval.
If our lead drug candidates are approved for the indications of our initial focus, they may compete with the investigational therapies and
currently marketed drugs discussed below.
Multiple Myeloma (MM)
Over the past 12 years, ten agents have been approved in the U.S. for the treatment of patients with MM: bortezomib (Velcade
®
, Takeda), lenalidomide (Revlimid
®
, Celgene), thalidomide (Thalomid
®
, Celgene),
liposomal doxorubicin (Doxil
®
, Janssen), carfilzomib (Kyprolis
®
, Amgen), pomalidomide (Pomalyst
®
, Celgene), panobinostat (Farydak
®
, Novartis), daratumumab (Darzalex
®
, Janssen),
elotuzumab (Empliciti
®
, BMS), and ixazomib (Ninlaro
®
, Takeda). Approved indications range from the treatment of newly diagnosed
patients to those with relapsed and/or refractory MM.
Several other anti-cancer agents are in late-stage development for the treatment of
patients with MM such as vorinistat (Zolinza
®
, Merck), plitidepsin (PharMar), masitinib (AB Sciences), pembrolizumab (Keytruda
®
Merck),
nivolumab (Opdivo
®
BMS), filanesib (Array Biopharma), and ricolinostat (Celegene).
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Non-Hodgkins Lymphoma (NHL)
The initial therapy for DLBCL typically consists of multi-agent cytotoxic drugs in combination with the monoclonal antibody rituximab (Rituxan
®
, Roche). In patients with DLBCL who are not elderly and who have good organ function, high dose chemotherapy with stem cell transplantation is often used. Newer targeted agents such as the BTK
inhibitor ibrutinib (Imbruvica
®
, Pharmacyclics) and the immunomodulatory drug lenalidomide (Revlimid
®
, Celgene) have shown activity in
DLBCL. There are also a number of other widely used anti-cancer agents that have broad labels which include NHL, and some of these are being evaluated alone or in combination for the treatment of patients with DLBCL that have relapsed after
treatment with chemotherapy. Other anti-cancer agents are also being evaluated in the treatment of DLBCL, including but not limited to, obinutuzumab (Gazyva
®
, Roche) everolimus (Afinitor
®
, Novartis), lenalidomide (Revlimid
®
, Celgene), ofatumumab (Arzerra
®
, GSK),
ibrutinib (Imbruvica
®
, Pharmacyclics), venetoclax (Abbvie), acalabrutinib (Acerta Pharma), nivolumab (Opdivo
®
, BMS) and brentuximab
vedotin (Adcetris
®
, Seattle Genetics). In addition, chimeric antigen receptor T-cell therapies or CAR-T therapies, are currently in clinical development for the treatment of DLBCL by companies
including Novartis, Juno and Kite, and may present future competition.
Acute Myeloid Leukemia (AML)
Patients with AML typically are treated with intensive multi-agent chemotherapy, and high risk patients who enter remission and have a matched
donor often receive an allogeneic stem cell transplant. Because these chemotherapy regimens have marked toxicities, elderly patients with AML are often treated with less intensive chemotherapy regimens or drugs called hypomethylating agents such as
decitabine (Dacogen
®
, Otsuka) or azacitadine (Vidaza
®
, Celgene). Once elderly patients with AML experience disease progression on their
initial treatment, their expected survival is very poor. Because of their advanced age, multiple other medical conditions and requirements for multiple other drugs, the treatment of relapsed and/or refractory AML in elderly persons is complicated.
Three new therapies for specific subsets of AML patients may be approved in 2017. Novartis submitted an NDA in late 2016 for midostaurin as a first line treatment in combination with 7+3 in patients with FLT3 mutations. The FDA has granted priority
review, and an approval is anticipated mid-year. Jazz Pharmaceuticals initiated a rolling NDA submission for Vyxeos/CPX-351 (cytarabine and daunorubicin liposome injection) in September 2016 with plans to complete the submission in early 2017 and
request a priority review. Vyxeos was granted Breakthrough Therapy Designation for adults with therapy-related AML (tAML) or AML with myelodysplasia-related changes. In addition, Celgene submitted an NDA for the IDH2m inhibitor AG-221 (enasidenib)
in patients with relapsed/refractory AML based on data from its ongoing Phase I/II study (NCT01915498) of enasidenib in patients with IDH2m+ hematologic malignancies. A number of additional anti-cancer agents (often in combination) are being
investigated in this population, including but not limited to, quizartinib (Daiichi Sankyo), volasertib (Boehringer Ingelheim), SGI-110 (Otsuka/Astex),AG-221 (Agios), venetoclax (Abbvie), SGN-CD33A (Seattle Genetics).
Competition with XPO1 Inhibitors
Drug compounds currently in preclinical studies, if developed and approved, could also be competitive with our drug candidates, if approved. In
January 2015, Stemline Therapeutics, Inc. announced that it had exclusively licensed the rights to develop and commercialize SL-801, an XPO1 inhibitor, from CanBas Co., Ltd. In December 2015, Stemline announced the opening of its IND
application and planned initiation of a clinical development program in multiple cancer types and, in February 2017, it announced the enrollment of patients in a Phase 1 dose escalation study of SL-801. Additionally, Kosan Biosciences Inc.
(acquired by Bristol-Myers Squibb Company) has evaluated compounds derived from leptomycin B in preclinical studies. To our knowledge, the Kosan compounds are not currently being developed and have never entered human studies.
With respect to indications other than cancer, there are many currently-marketed therapies and drugs in late-stage clinical development to
treat non-oncology indications on which we plan to initially focus development of our XPO1 inhibitors. However, to our knowledge, there are no other XPO1 inhibitors in clinical development for
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the treatment of any diseases other than cancer, including indications such as autoimmune and inflammatory diseases or wound healing. There is no published information on the use of the
preclinical compounds that have been developed by Kosan Biosciences or CanBas Co. in models other than cancer.
Competition with PAK4/NAMPT
Dual Inhibitors
Our first-in-class PAK4/NAMPT dual inhibitor KPT-9274, if developed and approved, would compete with
currently-marketed therapies and drugs in clinical development to treat cancer. However, there are currently no marketed therapies that selectively target PAK4 and/or NAMPT. Pfizer Inc. developed PF-03758309, a non-selective PAK inhibitor,
meaning that this compound inhibited several of the PAK family members, and not solely PAK4, through Phase 1 clinical development, but that compound had poor oral bioavailability in both animals and humans and, to our knowledge, development has
been discontinued. We are aware that PAK4 biology is being evaluated preclinically by AstraZeneca plc and Genentech, Inc. (acquired by Roche Holding AG). We are not aware of any PAK4 inhibitors that are in clinical development at the
present time.
In addition to KPT-9274, we are aware of three NAMPT inhibitors that have advanced into human clinical trials. These
compounds include GMX1778 (also known as CHS-828), GMX1777 (water-soluble derivative of GMX1778), and APO866 (also known as FK866 and WK175). To our knowledge development of these inhibitors were discontinued. We are aware that NAMPT biology is
being evaluated by Genentech, Inc., Eli Lilly & Company, Millennium/Takeda Pharmaceutical Company Ltd., OncoTartis, Inc., Aurigene Discovery Technologies Limited, and at some academic institutions. We are not aware of any other NAMPT
inhibitors in clinical development.
Manufacturing
We do not have any manufacturing facilities or personnel. We currently rely, and expect to continue to rely, on third parties for the
manufacture of our drug candidates for preclinical and clinical testing, as well as for commercial manufacture if our drug candidates receive marketing approval. We have engaged one third party manufacturer to obtain the active pharmaceutical
ingredient for selinexor for preclinical and clinical testing. We have engaged a separate third-party manufacturer for fill-and-finish services. We obtain our selinexor supplies from these manufacturers on a purchase order basis and do not have a
long-term supply arrangement in place at this time. 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 as a part of our commercialization plans.
All of our drug candidates are small molecules and are
manufactured in reliable and reproducible synthetic processes from readily available starting materials. The chemistry is amenable to scale up and does not require unusual equipment in the manufacturing process. We expect to continue to develop drug
candidates that can be produced cost-effectively at contract manufacturing facilities.
Government Regulation
Government authorities in the United States, at the federal, state and local level, and in other countries and jurisdictions, including the
European Union, extensively regulate, among other things, the research, development, testing, manufacture, quality control, approval, packaging, storage, recordkeeping, labeling, advertising, promotion, distribution, marketing, post-approval
monitoring and reporting, and import and export of pharmaceutical products. The processes for obtaining regulatory approvals in the United States and in foreign countries and jurisdictions, along with subsequent compliance with applicable statutes
and regulations and other regulatory authorities, require the expenditure of substantial time and financial resources.
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Review and Approval of Drugs in the United States
In the United States, the FDA approves and regulates drugs under the Federal Food, Drug, and Cosmetic Act, or FDCA, and implementing
regulations. The failure to comply with the FDCA and other applicable laws at any time during the product development process, approval process or after approval may subject an applicant and/or sponsor to a variety of administrative or judicial
sanctions, including refusal by the FDA to approve pending applications, withdrawal of an approval, imposition of a clinical hold, issuance of warning letters and other types of letters, product recalls, product seizures, total or partial suspension
of production or distribution, injunctions, fines, refusals of government contracts, restitution, disgorgement of profits, or civil or criminal investigations and penalties brought by the FDA and the Department of Justice, or DOJ, or other
governmental entities.
An applicant seeking approval to market and distribute a new drug product in the United States must typically
undertake the following:
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completion of preclinical laboratory tests, animal studies and formulation studies in compliance with the FDAs good laboratory practice, or GLP, regulations;
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submission to the FDA of an investigational new drug application, or IND, which must take effect before human clinical trials may begin;
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approval by an independent institutional review board, or IRB, representing each clinical site before each clinical trial may be initiated;
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performance of adequate and well-controlled human clinical trials in accordance with good clinical practices, or GCP, to establish the safety and efficacy of the proposed drug product for each indication;
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preparation and submission to the FDA of a new drug application, or NDA, requesting marketing for one or more proposed indications;
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review of the product candidate by an FDA advisory committee, where appropriate or if applicable;
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satisfactory completion of one or more FDA inspections of the manufacturing facility or facilities at which the product, or components thereof, are produced to assess compliance with current Good Manufacturing
Practices, or cGMP, requirements and to assure that the facilities, methods and controls are adequate to preserve the products identity, strength, quality and purity;
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satisfactory completion of FDA audits of clinical trial sites to assure compliance with GCPs and the integrity of the clinical data;
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payment of user fees and securing FDA approval of the NDA; and
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compliance with any post-approval requirements, including Risk Evaluation and Mitigation Strategies, or REMS, and post-approval studies required by the FDA.
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Preclinical Studies
Before an applicant
begins testing a compound with potential therapeutic value in humans, the drug candidate enters the preclinical testing stage. Preclinical studies include laboratory evaluation of product chemistry, toxicity and formulation, and the purity and
stability of the drug substance, as well as
in vitro
and animal studies to assess the potential safety and activity of the drug for initial testing in humans and to establish a rationale for therapeutic use. The conduct of preclinical studies
is subject to federal regulations and requirements, including GLP regulations. Applicants usually must complete some long-term nonclinical testing, such as animal tests of reproductive adverse events and carcinogenicity, and must also develop
additional information about the chemistry and physical characteristics of the drug and finalize a process for manufacturing the drug in commercial quantities in accordance with cGMP requirements.
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The IND and IRB Processes
An IND is an exemption from the FDCA that allows an unapproved drug to be shipped in interstate commerce for use in an investigational clinical
trial and a request for FDA authorization to administer an investigational drug to humans. Such authorization must be secured prior to interstate shipment and administration of any new drug that is not the subject of an approved NDA. In support of a
request for an IND, applicants must submit a protocol for each clinical trial and any subsequent protocol amendments must be submitted to the FDA as part of the IND. In addition, the results of the preclinical tests, together with manufacturing
information, analytical data, any available clinical data or literature and plans for clinical trials, among other things, are submitted to the FDA as part of an IND. The FDA requires a 30-day waiting period after the filing of each IND before
clinical trials may begin. This waiting period is designed to allow the FDA to review the IND to determine whether human research subjects will be exposed to unreasonable health risks. At any time during this 30-day period, or thereafter, the FDA
may raise concerns or questions about the conduct of the trials as outlined in the IND and impose a clinical hold or partial clinical hold. In this case, the IND sponsor and the FDA must resolve any outstanding concerns before clinical trials can
begin.
In addition to the foregoing IND requirements, an IRB representing each institution participating in the clinical trial must
review and approve the plan for any clinical trial before it commences at that institution, and the IRB must conduct continuing review and reapprove the study at least annually. The IRB must review and approve, among other things, the study protocol
and informed consent information to be provided to study subjects. An IRB must operate in compliance with FDA regulations. Information about certain clinical trials must be submitted within specific timeframes to the National Institutes of Health,
or NIH, for public dissemination on its ClinicalTrials.gov website. An IRB can suspend or terminate approval of a clinical trial at its institution, or an institution it represents, if the clinical trial is not being conducted in accordance with the
IRBs requirements or if the drug has been associated with unexpected serious harm to patients
Human Clinical Studies in Support of an NDA
Clinical trials involve the administration of the investigational product to human subjects under the supervision of qualified
investigators in accordance with GCP requirements, which include, among other things, the requirement that all research subjects provide their informed consent in writing before their participation in any clinical trial. Clinical trials are
conducted under written study protocols detailing, among other things, the objectives of the study, inclusion and exclusion criteria, the parameters to be used in monitoring safety and the effectiveness criteria to be evaluated.
Human clinical trials are typically conducted in four sequential phases, which may overlap or be combined:
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Phase 1:
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The drug is initially introduced into a small number of healthy human subjects or patients with the target disease (e.g. cancer) or condition and tested for safety, dosage tolerance, absorption, metabolism, distribution,
excretion and, if possible, to gain an early indication of its effectiveness and to determine optimal dosage.
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Phase 2:
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The drug is administered to a limited patient population to identify possible adverse effects and safety risks, to preliminarily evaluate the efficacy of the product for specific targeted diseases and to determine dosage
tolerance and optimal dosage.
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Phase 3:
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The drug is administered to an expanded patient population, generally at geographically dispersed clinical trial sites, in well-controlled clinical trials to generate enough data to statistically evaluate the efficacy and safety
of the product for approval, to establish the overall risk-benefit profile of the product, and to provide adequate information for the labeling of the product. These clinical trials are commonly referred to as pivotal studies, which
denotes a study that presents the data that the FDA or other relevant regulatory agency will use to determine whether or not to approve a drug.
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Phase 4:
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Post-approval studies may be conducted after initial marketing approval. These studies are used to gain additional experience from the treatment of patients in the intended therapeutic indication.
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Progress reports detailing the results of the clinical trials must be submitted at least annually
to the FDA and more frequently if SAEs occur. In addition, IND safety reports must be submitted to the FDA for any of the following: serious and unexpected suspected adverse reactions; findings from other studies or animal or in vitro testing that
suggest a significant risk in humans exposed to the drug; and any clinically important increase in the case of a serious suspected adverse reaction over that listed in the protocol or investigator brochure Phase 1, Phase 2 and Phase 3 clinical
trials may not be completed successfully within any specified period, or at all. Furthermore, the FDA or the sponsor or the data monitoring committee may suspend or terminate a clinical trial at any time on various grounds, including a finding that
the research subjects are being exposed to an unacceptable health risk. The FDA will typically inspect one or more clinical sites to assure compliance with GCP and the integrity of the clinical data submitted.
Review of an NDA by the FDA
Assuming
successful completion of required clinical testing and other requirements, the results of the preclinical and clinical studies, together with detailed information relating to the products chemistry, manufacture, controls and proposed labeling,
among other things, are submitted to FDA as part of an NDA requesting approval to market the drug product for one or more indications. The NDA must contain a description of the manufacturing process and quality control methods, as well as results of
preclinical tests, toxicology studies, clinical trials and proposed labeling, among other things. Every new drug must be the subject of an approved NDA before it may be commercialized in the United States. Under federal law, the submission of most
NDAs is subject to an application user fee, currently exceeding $2.3 million, and the sponsor of an approved NDA is also subject to annual product and establishment user fees, currently exceeding $114,000 per product and $585,000 per
establishment. These fees are typically increased annually. Certain exceptions and waivers are available for some of these fees, such as an exception from the application fee for drugs with orphan designation and a waiver for certain small
businesses, an exception from the establishment fee when the establishment does not engage in manufacturing the drug during a particular fiscal year, and an exception from the product fee for a drug that is the same as another drug approved under an
abbreviated pathway.
Following submission of an NDA, the FDA conducts a preliminary review of an NDA within 60 calendar days of its
receipt and strives to inform the sponsor by the 74
th
day after FDAs receipt of the submission to determine whether the application is sufficiently complete to permit substantive review. The
FDA may request additional information rather than accept an NDA for filing. In this event, the application must be resubmitted with the additional information. The resubmitted application is also subject to review before FDA accepts it for filing.
Once the submission is accepted for filing, FDA begins an in-depth substantive review. The FDA has agreed to specified performance goals in the review process of NDAs. Under that agreement, 90% of applications seeking approval of New Molecular
Entities, or NMEs, are meant to be reviewed within ten months from the date on which FDA accepts the NDA for filing, and 90% of applications for NMEs that have been designated for priority review are meant to be reviewed within six
months of the filing date. For applications seeking approval of drugs that are not NMEs, the ten-month and six-month review periods run from the date that FDA receives the application. The review process and the Prescription Drug User Fee Act goal
date may be extended by the FDA for three additional months to consider new information or clarification provided by the applicant to address an outstanding deficiency identified by the FDA following the original submission.
Before approving an NDA, the FDA typically will inspect the facility or facilities where the product is or will be manufactured. These
pre-approval inspections may cover all facilities associated with an NDA submission, including drug component manufacturing (such as active pharmaceutical ingredients), finished drug product manufacturing, and control testing laboratories. The FDA
will not approve an application 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. Additionally,
before approving an NDA, the FDA will typically inspect one or more clinical sites to assure compliance with GCP.
In addition, as a
condition of approval, the FDA may require an applicant to develop a REMS. REMS use risk minimization strategies beyond the professional labeling to ensure that the benefits of the product outweigh
37
the potential risks. To determine whether a REMS is needed, the FDA will consider the size of the population likely to use the product, seriousness of the disease, expected benefit of the
product, expected duration of treatment, seriousness of known or potential AEs, and whether the product is a new molecular entity. REMS can include medication guides, physician communication plans for healthcare professionals, and elements to assure
safe use, or ETASU. ETASU may include, but are not limited to, special training or certification for prescribing or dispensing, dispensing only under certain circumstances, special monitoring, and the use of patient registries. The FDA may require a
REMS before approval or post-approval if it becomes aware of a serious risk associated with use of the product. The requirement for a REMS can materially affect the potential market and profitability of a product.
The FDA is required to refer an application for a novel drug to an advisory committee or explain why such referral was not made. Typically, an
advisory committee is a panel of independent experts, including clinicians and other scientific experts, that reviews, evaluates and provides a recommendation as to whether the application should be approved and under what conditions. The FDA is not
bound by the recommendations of an advisory committee, but it considers such recommendations carefully when making decisions.
Fast Track, Breakthrough
Therapy and Priority Review Designations
The FDA is authorized to designate certain products for expedited review if they are intended
to address an unmet medical need in the treatment of a serious or life-threatening disease or condition. These programs are fast track designation, breakthrough therapy designation and priority review designation.
Specifically, the FDA may designate a product for fast track review if it is intended, whether alone or in combination with one or more other
drugs, for the treatment of a serious or life-threatening disease or condition, and it demonstrates the potential to address unmet medical needs for such a disease or condition. For fast track products, sponsors may have greater interactions with
the FDA and the FDA may initiate review of sections of a fast track products NDA before the application is complete. This rolling review may be available if the FDA determines, after preliminary evaluation of clinical data submitted by the
sponsor, that a fast track product may be effective. The sponsor must also provide, and the FDA must approve, a schedule for the submission of the remaining information and the sponsor must pay applicable user fees. However, the FDAs time
period goal for reviewing a fast track application does not begin until the last section of the NDA is submitted. In addition, the fast track designation may be withdrawn by the FDA if the FDA believes that the designation is no longer supported by
data emerging in the clinical trial process.
Second, in 2012, Congress enacted the Food and Drug Administration Safety and Innovation
Act, or FDASIA. This law established a new regulatory scheme allowing for expedited review of products designated as breakthrough therapies. A product may be designated as a breakthrough therapy if it is intended, either alone or in
combination with one or more other drugs, to treat a serious or life-threatening disease or condition and preliminary clinical evidence indicates that the product may demonstrate substantial improvement over existing therapies on one or more
clinically significant endpoints, such as substantial treatment effects observed early in clinical development. The FDA may take certain actions with respect to breakthrough therapies, including holding meetings with the sponsor throughout the
development process; providing timely advice to the product sponsor regarding development and approval; involving more senior staff in the review process; assigning a cross-disciplinary project lead for the review team; and taking other steps to
design the clinical trials in an efficient manner.
Third, the FDA may designate a product for priority review if it is a drug that treats
a serious condition and, if approved, would provide a significant improvement in safety or effectiveness. The FDA determines, on a case-by-case basis, whether the proposed drug represents a significant improvement when compared with other available
therapies. Significant improvement may be illustrated by evidence of increased effectiveness in the treatment of a condition, elimination or substantial reduction of a treatment-limiting drug reaction, documented enhancement of patient compliance
that may lead to improvement in serious outcomes, and evidence of safety
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and effectiveness in a new subpopulation. A priority designation is intended to direct overall attention and resources to the evaluation of such applications, and to shorten the FDAs goal
for taking action on a marketing application from ten months to six months.
Accelerated Approval Pathway
The FDA may grant accelerated approval to a drug for a serious or life-threatening condition that provides meaningful therapeutic advantage to
patients over existing treatments based upon a determination that the drug has an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit. The FDA may also grant accelerated approval for such a condition when the product
has an effect on an intermediate clinical endpoint that can be measured earlier than an effect on irreversible morbidity or mortality, or IMM, and that is reasonably likely to predict an effect on irreversible morbidity or mortality or other
clinical benefit, taking into account the severity, rarity, or prevalence of the condition and the availability or lack of alternative treatments. Drugs granted accelerated approval must meet the same statutory standards for safety and effectiveness
as those granted traditional approval.
For the purposes of accelerated approval, a surrogate endpoint is a marker, such as a laboratory
measurement, radiographic image, physical sign, or other measure that is thought to predict clinical benefit, but is not itself a measure of clinical benefit. Surrogate endpoints can often be measured more easily or more rapidly than clinical
endpoints. An intermediate clinical endpoint is a measurement of a therapeutic effect that is considered reasonably likely to predict the clinical benefit of a drug, such as an effect on IMM. The FDA has limited experience with accelerated approvals
based on intermediate clinical endpoints, but has indicated that such endpoints generally may support accelerated approval where the therapeutic effect measured by the endpoint is not itself a clinical benefit and basis for traditional approval, if
there is a basis for concluding that the therapeutic effect is reasonably likely to predict the ultimate clinical benefit of a drug.
The
accelerated approval pathway is most often used in settings in which the course of a disease is long and an extended period of time is required to measure the intended clinical benefit of a drug, even if the effect on the surrogate or intermediate
clinical endpoint occurs rapidly. Thus, accelerated approval has been used extensively in the development and approval of drugs for treatment of a variety of cancers in which the goal of therapy is generally to improve survival or decrease morbidity
and the duration of the typical disease course requires lengthy and sometimes large trials to demonstrate a clinical or survival benefit.
The accelerated approval pathway is usually contingent on a sponsors agreement to conduct, in a diligent manner, additional
post-approval confirmatory studies to verify and describe the drugs clinical benefit. As a result, a drug candidate approved on this basis is subject to rigorous post-marketing compliance requirements, including the completion of Phase 4 or
post-approval clinical trials to confirm the effect on the clinical endpoint. Failure to conduct required post-approval studies, or confirm a clinical benefit during post-marketing studies, would allow the FDA to withdraw the drug from the market on
an expedited basis. All promotional materials for drug candidates approved under accelerated regulations are subject to prior review by the FDA.
The
FDAs Decision on an NDA
On the basis of the FDAs evaluation of the NDA and accompanying information, including the results
of the inspection of the manufacturing facilities, the FDA may issue an approval letter or a complete response letter. An approval letter authorizes commercial marketing of the product with specific prescribing information for specific indications.
A complete response letter generally outlines the deficiencies in the submission and may require substantial additional testing or information in order for the FDA to reconsider the application. If and when those deficiencies have been addressed to
the FDAs satisfaction in a resubmission of the NDA, the FDA will issue an approval letter. The FDA has committed to reviewing such resubmissions in two or six months depending on the type of information included. Even with submission of this
additional information, the FDA ultimately may decide that the application does not satisfy the regulatory criteria for approval.
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If the FDA approves a product, it may limit the approved indications for use for the product,
require that contraindications, warnings or precautions be included in the product labeling, require that post-approval studies, including Phase 4 clinical trials, be conducted to further assess the drugs safety after approval, require
testing and surveillance programs to monitor the product after commercialization, or impose other conditions, including distribution restrictions or other risk management mechanisms, including REMS, which can materially affect the potential market
and profitability of the product. The FDA may prevent or limit further marketing of a product based on the results of post-market studies or surveillance programs. After approval, many types of changes to the approved product, such as adding new
indications, manufacturing changes and additional labeling claims, are subject to further testing requirements and FDA review and approval.
Post-Approval Requirements
Drugs
manufactured or distributed pursuant to FDA approvals are subject to pervasive and continuing regulation by the FDA, including, among other things, requirements relating to recordkeeping, periodic reporting, product sampling and distribution,
advertising and promotion and reporting of adverse experiences with the product. After approval, most changes to the approved product, such as adding new indications or other labeling claims, are subject to prior FDA review and approval. There also
are continuing, annual user fee requirements for any marketed products and the establishments at which such products are manufactured, as well as new application fees for supplemental applications with clinical data.
In addition, drug manufacturers and other entities involved in the manufacture and distribution of approved drugs are required to register
their establishments with the FDA and state agencies, and are subject to periodic unannounced inspections by the FDA and these state agencies for compliance with cGMP requirements. Changes to the manufacturing process are strictly regulated and
often require prior FDA approval before being implemented. FDA regulations also require investigation and correction of any deviations from cGMP and impose reporting and documentation requirements upon the sponsor and any third-party manufacturers
that the sponsor may decide to use. Accordingly, manufacturers must continue to expend time, money, and effort in the area of production and quality control to maintain cGMP compliance.
Once an approval is granted, the FDA may withdraw the 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 AEs 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 trials to assess new safety risks; or imposition of distribution 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, suspension of the approval, complete withdrawal of the product from the market or product recalls;
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fines, warning letters or holds on post-approval clinical trials;
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refusal of the FDA to approve pending NDAs or supplements to approved NDAs, 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.
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In addition, the distribution of prescription pharmaceutical products is subject to the
Prescription Drug Marketing Act, or PDMA, and its implementing regulations, as well as the Drug Supply Chain Security Act, or DSCA, which regulate the distribution and tracing of prescription drugs and prescription drug samples at the federal level,
and set minimum standards for the regulation of drug distributors by the states. The PDMA, its implementing regulations and state laws limit the distribution of prescription pharmaceutical product samples, and the DSCA imposes requirements to ensure
accountability in distribution and to identify and remove counterfeit and other illegitimate products from the market.
Section 505(b)(2) NDAs
NDAs for most new drug products are based on two full clinical studies which must contain substantial evidence of the safety and
efficacy of the proposed new product. These applications are submitted under Section 505(b)(1) of the FDCA. The FDA is, however, authorized to approve an alternative type of NDA under Section 505(b)(2) of the FDCA. This type of application
allows the applicant to rely, in part, on the FDAs previous findings of safety and efficacy for a similar product, or published literature. Specifically, Section 505(b)(2) applies to NDAs for a drug for which the investigations made to
show whether or not the drug is safe for use and effective in use and relied upon by the applicant for approval of the application were not conducted by or for the applicant and for which the applicant has not obtained a right of reference or
use from the person by or for whom the investigations were conducted.
Thus, Section 505(b)(2) authorizes the FDA to approve an
NDA based on safety and effectiveness data that were not developed by the applicant. NDAs filed under Section 505(b)(2) may provide an alternate and potentially more expeditious pathway to FDA approval for new or improved formulations or new
uses of previously approved products. If the 505(b)(2) applicant can establish that reliance on the FDAs previous approval is scientifically appropriate, the applicant may eliminate the need to conduct certain preclinical or clinical studies
of the new product. The FDA may also require companies to perform additional studies or measurements to support the change from the approved product. The FDA may then approve the new drug candidate for all or some of the label indications for which
the referenced product has been approved, as well as for any new indication sought by the Section 505(b)(2) applicant.
Abbreviated New Drug
Applications for Generic Drugs
In 1984, with passage of the Hatch-Waxman Amendments to the FDCA, Congress established an abbreviated
regulatory scheme authorizing the FDA to approve generic drugs that are shown to contain the same active ingredients as, and to be bioequivalent to, drugs previously approved by the FDA pursuant to NDAs. To obtain approval of a generic drug, an
applicant must submit an abbreviated new drug application, or ANDA, to the agency. An ANDA is a comprehensive submission that contains, among other things, data and information pertaining to the active pharmaceutical ingredient, bioequivalence, drug
product formulation, specifications and stability of the generic drug, as well as analytical methods, manufacturing process validation data and quality control procedures. ANDAs are abbreviated because they generally do not include
preclinical and clinical data to demonstrate safety and effectiveness. Instead, in support of such applications, a generic manufacturer may rely on the preclinical and clinical testing previously conducted for a drug product previously approved
under an NDA, known as the reference-listed drug, or RLD.
Specifically, in order for an ANDA to be approved, the FDA must find that the
generic version is identical to the RLD with respect to the active ingredients, the route of administration, the dosage form, the strength of the drug and the conditions of use of the drug. At the same time, the FDA must also determine that the
generic drug is bioequivalent to the innovator drug. Under the statute, a generic drug is bioequivalent to a RLD if the rate and extent of absorption of the drug do not show a significant difference from the rate and extent of
absorption of the listed drug. Upon approval of an ANDA, the FDA indicates whether the generic product is therapeutically equivalent to the RLD in its publication Approved Drug Products with Therapeutic Equivalence
Evaluations, also referred to as the Orange Book. Physicians and pharmacists consider a therapeutic equivalent generic drug
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to be fully substitutable for the RLD. In addition, by operation of certain state laws and numerous health insurance programs, the FDAs designation of therapeutic equivalence often results
in substitution of the generic drug without the knowledge or consent of either the prescribing physician or patient.
Under the
Hatch-Waxman Amendments, the FDA may not approve an ANDA until any applicable period of non-patent exclusivity for the RLD has expired. The FDCA provides a period of five years of non-patent data exclusivity for a new drug containing a new chemical
entity. For the purposes of this provision, a new chemical entity, or NCE, is a drug that contains no active moiety that has previously been approved by the FDA in any other NDA. An active moiety is the molecule or ion responsible for the
physiological or pharmacological action of the drug substance. In cases where such NCE exclusivity has been granted, an ANDA may not be filed with the FDA until the expiration of five years unless the submission is accompanied by a Paragraph IV
certification, in which case the applicant may submit its application four years following the original product approval. The FDCA also provides for a period of three years of exclusivity if the NDA includes reports of one or more new clinical
investigations, other than bioavailability or bioequivalence studies, that were conducted by or for the applicant and are essential to the approval of the application.