The Company is providing the following updated disclosure as
of the date of this Amendment:
Chimerix is a development-stage biopharmaceutical company dedicated
to accelerating the advancement of innovative medicines that make a meaningful impact in the lives of patients living with cancer
and other serious diseases. Our three most advanced clinical-stage development programs are brincidofovir (BCV), ONC201 and dociparstat
sodium (DSTAT). BCV is an antiviral drug candidate developed as a potential medical countermeasure for smallpox and is currently
under review for regulatory approval in the United States. ONC201 is currently in a registrational clinical trial for recurrent
H3 K27M-mutant glioma and a confirmatory response rate assessment is expected later this year. DSTAT is in development as a potential
first-line therapy in acute myeloid leukemia (AML) and as a potential treatment for acute lung injury (ALI) in COVID-19 patients.
On January 7, 2021, we acquired Oncoceutics, Inc., a privately-held,
clinical-stage biotechnology company developing imipridones, a novel class of compounds. Oncoceutics’ being evaluated in
a registrational program lead product candidate, ONC201, has selectively induced cell death in multiple cancer types in clinical
trials. ONC201 is currently for recurrent H3 K27M-mutant glioma and a response rate assessment of the registrational cohort is
expected in 2021.
Our pipeline, as of the date of the Amendment is illustrated
below.
Recent Developments
Dociparstat for the Treatment of Acute Lung Injury (ALI)
in COVID-19 Patients
In April 2020, we announced the initiation of a Phase 2/3 study
of DSTAT in patients with acute lung injury (ALI) from COVID-19. The study is a 1:1 randomized, double-blind, placebo-controlled,
Phase 2/3 trial to evaluate the safety and efficacy of DSTAT in adults with severe COVID-19 who are at high risk of respiratory
failure. Eligible subjects will be those with confirmed COVID-19 who require hospitalization and supplemental oxygen therapy.
The primary endpoint of the study is the proportion of subjects who survive and do not require mechanical ventilation through day
28. Additional endpoints include time to improvement as assessed by the National Institute of Allergy and Infectious Disease ordinal
scale, time to hospital discharge, time to resolution of fever, number of ventilator-free days, all-cause mortality, and changes
in key biomarkers (e.g. IL-6, TNF-α, HMGB1, C-reactive protein and d-dimer).
The Phase 2 portion of the study will enroll 24 subjects (12
subjects in each of 2 cohorts with different doses) to determine the maximum tolerated dose and will then expand to a third cohort
consisting of an additional 50 patients (74 total) at the selected dose. A formal analysis of all endpoints, including supportive
biomarkers will be performed at the conclusion of the Phase 2 portion of the study. Contingent upon positive results from the Phase
2 portion, the Phase 3 portion of the study will enroll approximately 450 subjects. The first cohort of 12 subjects has completed
enrollment and dosing. In December 2020, the independent data safety monitoring board, following a review of preliminary data from
the first cohort of patients, recommended that the trial proceed to enrollment of the second cohort of patients. The second cohort
has begun enrolling. Due to the complex and rapidly changing landscape of COVID infection rates and treatment responses, we cannot
predict with certainty when we will complete Phase 2 enrollment. We expect to report initial topline data from the first cohort
in the first quarter of 2021. The study protocol allows for the review of data by cohort.
Dociparstat for First-Line Acute Myeloid Leukemia (AML)
During 2020, we conducted an end of Phase 2 meeting with the
FDA related to our development of DSTAT in AML, which informed the design of the Phase 3 trial. Currently we are engaged in site
initiation for Phase 3 clinical study of DSTAT for the treatment of front line AML. We expect to enroll the first patient to in
early 2021.
This study will be a randomized, double-blinded trial of approximately
570 newly diagnosed AML patients. The trial includes patients 60 years of age and older who have an intermediate or adverse genetic
risk profile. It will also include patients between 18 and 60 years old who have an adverse genetic risk profile. Patients will
receive DSTAT in combination with standard cytarabine plus anthracycline (7+3) induction and cytarabine consolidation chemotherapy
or will receive standard of care (7+3) induction and consolidation chemotherapy alone. Patients with FLT-3 mutations are allowed
in the study and are eligible to receive midostaurin.
The primary endpoint of the study is overall survival (OS).
In addition, the FDA has indicated that event-free survival (EFS) using complete response with hematologic recovery to define induction
success (CR) may be acceptable as an endpoint to support submission of a New Drug Application (NDA). Other endpoints to be evaluated
in the proposed trial include: minimal residual disease (MRD), relapse-free survival (RFS), time to hematologic recovery, and induction
response.
In order to supplement the previously reported data from pilot
and Phase 2 studies and further evaluate DSTAT’s potential mechanism of action, the proposed Phase 3 trial includes an early
assessment of comparative CR and MRD rates among the first 80 evaluable patients. A recently published meta-analysis of 81 separate
studies covering 11,151 patients (Short, et. al., Journal of the American Medical Association Oncology, October 8, 2020) has suggested
a link between MRD status and outcomes in patients with AML. Specifically, this large cohort meta-analysis showed that MRD-negative
AML patients experience superior 5-year disease-free survival (average hazard ratio: 0.37) and 5-year overall survival (average
hazard ratio: 0.36) rates when compared to patients that are MRD-positive. This study suggests that evaluation of MRD status in
AML patients may allow for an earlier assessment of therapeutic effects and could lead to acceleration in the development of novel
AML therapeutics.
The data from the first 80 evaluable patients of the proposed
Phase 3 trial are expected to be unblinded, reported publicly, and available for ongoing analysis of later endpoints, unless the
independent Data Monitoring Committee (DMC) determines that exceptional pre-specified thresholds have been achieved, in which case
the DMC will have the discretion to maintain blinding, which would allow inclusion of these patients in the final analysis.
BCV Oral Treatment for Smallpox
We completed the rolling NDA submission for BCV tablets and
for BCV suspension for the approval of BCV as a medical countermeasure for smallpox. In December 2020 we announced that the FDA
had accepted the filing of the NDA. The FDA granted priority review and set a Prescription Drug User Fee Act (PDUFA) date of April
7, 2021.
Oncoceutics Acquisition
On January 7, 2021, we acquired Oncoceutics, Inc. (Oncoceutics),
a privately-held, clinical-stage biotechnology company developing imipridones, a novel potential class of compounds. Oncoceutics’
lead product candidate, ONC201, selectively induced cell death in multiple cancer types in clinical trials. ONC201 is currently
being evaluated in a registrational program for recurrent H3 K27M-mutant glioma and a response rate assessment of the registrational
cohort is expected in 2021. As consideration for the acquisition, we (a) paid an upfront cash payment of approximately $25.0 million,
(b) issued an aggregate of 8,723,769 shares of our common stock, (c) issued a promissory note to the representative of the securityholders
of Oncoceutics in the principal amount of $14.0 million, to be paid in cash, upon the one year anniversary of the closing of the
acquisition, and (d) agreed to make contingent payments up to an aggregate of $360.0 million based on the achievement of certain
development, regulatory and commercialization events, as well as additional tiered royalty payments based upon future net
sales of ONC-201 and ONC-206 products, subject to certain reductions, and a contingent payment in the event we receive any
proceeds from the sale of a rare pediatric disease priority review voucher based on the Oncoceutics products. We will also
pass through to the Oncoceutics securityholders the upfront payment received from China Resources Sanjiu Medical & Pharmaceutical
Co., Ltd. pursuant to a license agreement entered into with Oncoceutics prior to the acquisition. The closing payment may be adjusted
after the closing, pursuant to procedures, in connection with the finalization of the cash, transaction expenses, debt and working
capital amounts at closing.
Imipridones and ONC201
Imipridones are a potential new class of selective cancer therapies.
These drug candidates target specific G protein-coupled receptors (GPCRs) and mitochondrial caseinolytic protease P (ClpP), in
an effort to produce cancer cell death. The imipridone chemical scaffold provides an opportunity to target GPCRs and ClpP with
differential specificity and function. This presents an opportunity to develop potential imipridone therapies broadly within cancer
and in other diseases as well.
ONC201 selectively targets Dopamine Receptor D2 (DRD2) and ClpP.
ONC201 has selectively induced cell death in cancer by binding to and differentially altering activity of DRD2 and ClpP.
Clinical trials of ONC201 in glioma patients with the H3 K27M-mutation
are underway at several locations in the U.S. As many as 10% of patients with glioma have the H3 K27M-mutation. The H3 K27M-mutation
is found in 50-90% of patients with midline glioma, including 80-90% of children with diffuse intrinsic pontine glioma or DIPG.
Currently there is no effective therapy for patients with the H3 K27M-mutation beyond radiation that provides only transient benefit
in a fraction of the population. Often it is not possible to resect these tumors and chemotherapy in ineffective. The median overall
survival is less than 8 months.
Based on discussions with the FDA, we plan to integrate data
from ongoing ONC201 trials into a registration cohort with the potential for an NDA submission seeking accelerated approval. The
50 subject registration cohort includes patients meeting the following eligibility criteria: greater than 2 years of age with recurrent
diffuse midline glioma who harbor the H3 K27M-mutation in their tumor, evidence of measurable disease, completion of prior radiation
that was at least 90 days from starting ONC201 and evidence of progressive disease, among other criteria. The primary endpoint
of the study is Overall Response Rate (ORR) assessed by RANO-HGG criteria. Below is an interim response summary, which showed a
meaningful durability of response.
Figure 1: Waterfall plot reflects 47 subjects; 3 subjects
did not have on-treatment tumor assessments available but were reported by investigator to have progressive disease. Some eligibility
and response data were based on unlocked CRFs that remain subject to change with additional monitoring. PR is partial response,
SD is stable disease and PD is progressive disease.
A Blinded Independent Central Review analysis of ORR is expected
to take place in 2021 which, if favorable, may form the basis for an NDA submission seeking accelerated of ONC201 in the United
States. ONC201 has been generally well tolerated across a database of over 350 glioma patients. The most commonly reported adverse
events (AEs) were nausea/vomiting, fatigue and decreased lymphocyte counts. Dose limiting toxicities have not been observed with
weekly dosing in any indication.
The FDA has granted ONC201 Fast Track Designation for the treatment
of adult recurrent H3 K27M-mutant high-grade glioma, Rare Pediatric Disease Designation for treatment of H3 K27M-mutant glioma,
and Orphan Drug Designations for the treatment of glioblastoma and for the treatment of malignant glioma.
In addition to clinical trials in glioma, ONC201 is also being
studied in an ongoing Phase 2 trial in neuroendocrine tumors at the Cleveland Clinic. Interim investigator assessments as of a
cutoff date of August 20, 2020 showed a 50% ORR in paraganglioma which are adrenal-related tumors that are known to harbor elevated
DRD2 expression and dopamine secretion.
ONC206
ONC206 is a DRD2 antagonist and ClpP agonist that demonstrated
enhanced non-competitive DRD2 antagonism relative to ONC201, in preclinical studies and additionally showed disruption of DRD2
homodimers. Treatment of tumor cells with ONC206 elicits a distinct gene expression as compared to ONC201. ONC206 has demonstrated
syngergistic in vitro activity with ONC201 in cells that have acquired resistance to ONC201. ONC206 showed anti tumor activity
in preclinical models of difficult-to-treat neuroendocrine tumors and high-grade gliomas. In vitro, ONC2016 has affected some of
the same downstream pathways as ONC201, including activation of the integrated stress response and inhibition of Ras signaling,
leading to selective killing of tumor cells.
The first-in-human clinical trial of ONC206 for adults with
recurrent primary central nervous system tumors is ongoing at the National Institute of Health (NCT04541082).
ONC212
ONC212 is an investigational agonist of the orphan GPCR tumor
suppressor GPR132, as well as ClpP. Similar to the potential downstream effects of ONC201 and ONC206, in vitro studies ONC212 has
activated the integrated stress response, inhibited Ras signaling and selectively killed tumor cells. ONC212 showed broad-spectrum
activity across both solid tumors and hematological malignancies, including pancreatic cancer and leukemias prioritized as target
clinical indications that exhibit high GPR132 and/or ClpP expression.
Currently ONC212 is in IND-enabling studies. First-in-human
trials are expected to be conducted in conjunction with MD Anderson Cancer Center and Brown University.
Forward-Looking Statements
Statements contained in, or
incorporated by reference into, this Current Report on Form 8-K regarding matters that are not historical facts are
“forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995. Because
such statements are subject to risks and uncertainties, actual results may differ materially from those expressed or implied
by such forward-looking statements. Risks are described more fully in our filings with the Securities and Exchange
Commission, including without limitation our most recent Annual Report on Form 10-K, our most recent Quarterly Report on Form
10-Q and other documents subsequently filed with or furnished to the Securities and Exchange Commission. All forward-looking
statements contained in this Current Report on Form 8-K speak only as of the date on which they were made. We undertake no
obligation to update such statements to reflect events that occur or circumstances that exist after the date on which they
were made.