Updated etavopivat Phase 1 trial results
presented in two 2021 ASH Annual Meeting Oral Sessions
Etavopivat was well tolerated with a safety
profile consistent with underlying sickle cell disease
Clinical data in 15 patients dosed for up to 12
weeks showed sustained increase in hemoglobin and improvement in
biomarkers of hemolysis and red blood cell health
Decreasing vaso-occlusive crisis trend observed
during the 12 week treatment period compared to 12 months prior to
trial entry
Forma Therapeutics Holdings, Inc. (Nasdaq: FMTX), a
clinical-stage biopharmaceutical company focused on sickle cell
disease (SCD), prostate cancer and other rare hematologic diseases
and cancers, today announced etavopivat, the company's
investigational oral, once-daily, selective pyruvate kinase-R (PKR)
activator, significantly improved anemia and red blood cell (RBC)
health with a favorable tolerability and safety profile in patients
with SCD.
These Phase 1 trial findings, presented in two oral sessions on
Dec. 11 at the 63rd American Society of Hematology (ASH) Annual
Meeting, support a highly differentiated etavopivat profile to
potentially improve the lives of patients with SCD, including
increases in hemoglobin, improvements in RBC health, and decreases
in vaso-occlusive crises (VOCs). “Patients with SCD have limited
therapeutic options to address symptoms like anemia and painful
VOCs. The data presented today at ASH highlight etavopivat’s
potential as a disease-modifying therapy that addresses the
underlying mechanisms that drive sickle cell disease,” said Patrick
Kelly, M.D., chief medical officer of Forma Therapeutics. “We are
continuing to investigate the safety and efficacy of etavopivat in
our ongoing Phase 2/3 Hibiscus Study, with primary endpoints to
improve hemoglobin levels and to reduce VOCs, and secondary
endpoints including quality of life and pharmaco-economic
impacts.”
In the open label cohort of a randomized, placebo-controlled
Phase 1 trial (NCT03815695), 15 patients received etavopivat 400 mg
once daily for up to 12 weeks, with a data cutoff as of Nov. 23,
2021.
Significant and sustained improvement in anemia and RBC
health
Etavopivat administered for up to 12 weeks reduced anemia by
significantly raising and sustaining hemoglobin levels. A
hemoglobin increase >1 g/dL was experienced by 73.3 percent
(11/15) of patients (p<0.0001), with a maximal mean increase of
1.5 g/dL.
Etavopivat therapy also significantly increased the lifespan of
RBCs and decreased hemolysis, as measured by three biomarkers that
together indicate enhanced survival of RBCs. Durability of these
improvements was sustained throughout the 12 weeks of treatment:
absolute reticulocyte count (ARC, p<0.05), indirect bilirubin
(p<0.0001), and lactate dehydrogenase (p<0.05).
In addition, an analysis of all patients in the 12-week open
label cohort showed a decreasing trend in VOCs requiring
hospitalization when compared to the rate 12 months prior to trial
entry. Of the 15 patients receiving etavopivat, only a single VOC
was reported while on treatment, which was precipitated by a grade
3 COVID-19 infection, representing an annualized VOC rate of 0.3.
The cohort’s pre-study annualized VOC rate was 0.93 (13
events).
Etavopivat was well tolerated, consistent with safety profile
of underlying SCD
The primary endpoint of the Phase 1 trial was the incidence,
frequency, and severity of adverse events (AEs). In the 12-week
open-label extension, most AEs were grades 1 and 2. Two patients
reported three serious grade 3 AEs on treatment, including a VOC
following a COVID-19 infection unrelated to treatment, and a
previously reported deep vein thrombosis. During the four weeks
post-treatment, three patients reported four serious AEs, all grade
3 and considered unrelated to etavopivat, including VOC, syncope,
and acute chest syndrome and VOC following a respiratory
infection.
Etavopivat multimodal mechanism of action improved biomarkers
of RBC health and SCD in exploratory analyses
Findings from exploratory analyses showed improvements in RBC
health and function as measured by biomarkers of SCD during 12
weeks of etavopivat therapy.
Etavopivat’s multimodal mechanism of action via PKR activation
resulted in increased adenosine triphosphate (ATP), and decreased
2,3-diphosphoglycerate (2,3 DPG), which was sustained during 12
weeks of etavopivat treatment. Four weeks post treatment, ATP and
DPG levels gradually returned to pre-treatment levels, suggesting
the potential durability of etavopivat on RBC health may persist
for 1-4 weeks following the treatment period.
Surrogate marker results showed etavopivat normalized the
affinity of hemoglobin for oxygen, resulting in improved oxygen
release in the peripheral tissues and reducing RBC sickling.
Further analysis after two weeks of etavopivat treatment support
improved RBC membrane health, with increased levels of two enzymes
important to reducing oxidative stress in sickled RBCs: superoxide
dismutase activity (SOD, p<0.05) and glutathione reductase
activity (GSH, p<0.001), as well as significantly repairing
membrane damage, as measured by phosphatidylserine (PS, p<0.01).
Additionally, up to 12 weeks of etavopivat showed promising trends
in reducing systemic biomarkers of inflammation and coagulation.
Significant decreases were observed in TNF-alpha (p<0.001),
prothrombin 1.2 (p<0.05), and D-dimer (p<0.01). In addition,
improved oxygen delivery was observed as measured by significant
decreases in erythropoietin levels (p<0.05).
Oral Presentations Details
- Abstract 147091: Activation of Pyruvate Kinase-R with
Etavopivat (FT-4202) Is Well Tolerated, Improves Anemia, and
Decreases Intravascular Hemolysis in Patients with Sickle Cell
Disease Treated for up to 12 Weeks. Session 114 on Saturday, Dec.
11, at 9:45 a.m. ET Presenter: R. Clark Brown, M.D., Ph.D.
- Abstract: 147078: Etavopivat, an Allosteric Activator of
Pyruvate Kinase-R, Improves Sickle RBC Functional Health and
Survival and Reduces Systemic Markers of Inflammation and
Hypercoagulability in Patients with Sickle Cell Disease: An
Analysis of Exploratory Studies in a Phase 1 Study. Session: 114 on
Saturday, Dec. 11, at 10:00 a.m. ET Presenter: Theodosia A. Kalfa,
M.D., Ph.D.
For more information, please visit
https://www.formatherapeutics.com/clinical-trials/ or
https://clinicaltrials.gov/ct2/show/NCT03815695.
Forma Webcast
Forma is hosting a webcast Monday, Dec. 13 at 8:00 a.m. ET to
discuss these etavopivat results being presented at the ASH Annual
Meeting. The webcast can be accessed in the “News & Investors”
section of Forma’s website at www.formatherapeutics.com.
Ongoing Hibiscus Trial
Forma is enrolling patients aged 12 to 65 years with SCD into
the Hibiscus Study, a registrational Phase 2/3 randomized,
placebo-controlled, double-blind, multicenter trial to further
evaluate the safety and efficacy of etavopivat in this patient
population. The study is enrolling participants in France, Spain,
and the United States. For more information, please visit
clinicaltrials.gov/NCT04624659.
About Sickle Cell Disease
Sickle cell disease (SCD) is a chronic and progressive inherited
disorder associated with a decrease in the health and lifespan of
red blood cells (RBCs). Individuals living with SCD have RBCs that
are crescent shaped, rendering them inflexible, fragile, and unable
to effectively deliver oxygen. The health of these sickle RBCs is
impaired and characterized by reduced cellular energy, poor
deformability, decreased membrane repair, and increased
adhesion.
SCD affects approximately 100,000 people in the United States,
as well as approximately 30,000 in France, Germany, Italy, Spain,
and the United Kingdom. SCD can cause serious health problems,
including anemia, fatigue, episodes of pain known as vaso-occlusive
crises (VOCs), and chronic, progressive end-organ damage. Despite
recent advances in treatment, most patients with SCD still suffer
from pain crises, lifelong disability, reduced quality of life, and
decreased survival.
About Etavopivat
Etavopivat is an investigational, once-daily, selective pyruvate
kinase-R (PKR) activator designed to be a disease-modifying therapy
with the potential to improve RBC health and transform the lives of
people living with SCD. Employing a multimodal approach, etavopivat
works by activating the RBCs' natural PKR activity to decrease
levels of the metabolite 2,3-DPG, allowing sickle hemoglobin to
hold on to oxygen longer, resulting in decreased polymerization,
hemolysis, and sickling. Etavopivat-mediated PKR activation also
increases adenosine triphosphate (ATP) levels, to improve RBC
function, which can lead to improved deformability, capacity for
membrane repair, RBC health, and lifespan. Together, these effects
are anticipated to improve the health of sickle RBCs and lead to a
reduction in anemia, hemolysis, vaso-occlusive crises, and end
organ damage.
The need for new SCD treatment options is recognized broadly,
and the U.S. Food and Drug Administration (FDA) has granted
etavopivat Fast Track, Rare Pediatric Disease and Orphan Drug
designations. Additionally, etavopivat was granted Orphan Drug
designation from the European Commission based on a positive
opinion from the Committee for Orphan Medicinal Products of the
European Medicines Agency for the treatment of patients with
SCD.
About Forma Therapeutics
Forma Therapeutics is a clinical-stage biopharmaceutical company
focused on the research, development and commercialization of novel
therapeutics to transform the lives of patients with rare
hematologic diseases and cancers. Our R&D engine combines deep
biology insight, chemistry expertise and clinical development
capabilities to create drug candidates with differentiated
mechanisms of action focused on indications with high unmet need.
Our work has generated a broad proprietary portfolio of programs
with the potential to provide profound patient benefit. For more
information, please visit www.FormaTherapeutics.com or follow us on
Twitter @FORMAInc and LinkedIn.
Forward-looking Statements
This press release contains forward-looking statements within
the meaning of the Private Securities Litigation Reform Act of
1995, as amended, including, without limitation, express or implied
statements regarding our beliefs and expectations regarding: future
plans for etavopivat, including expectations regarding timing,
trial enrollment, success and data announcements of our current
ongoing clinical trials; initial results for the etavopivat open
label extension cohort of our Phase 1 clinical trial; therapeutic
potential, clinical benefits, mechanisms of action as well as
tolerability and safety of our product candidates; upcoming
milestones and planned additional trials for the company’s product
candidates; presentation of data at upcoming scientific
conferences; and the potential impact of COVID-19 on patient
retention and enrollment, future operations, clinical trials or
investigational new drug (IND) applications. The words “may,”
“will,” “could,” “would,” “should,” “expect,” “plan,” “anticipate,”
“intend,” “believe,” “estimate,” “predict,” “project,” “potential,”
“continue,” “target” and similar expressions are intended to
identify forward-looking statements, although not all
forward-looking statements contain these identifying words.
Any forward-looking statements in this press release are based
on management’s current expectations and beliefs and are subject to
a number of risks, uncertainties and important factors that may
cause actual events or results to differ materially from those
expressed or implied by any forward-looking statements contained in
this press release, including, without limitation, those risks and
uncertainties associated with the following: the impact of the
COVID-19 pandemic on the company’s business, operations, patient
enrollment and retention, strategy, goals and anticipated
milestones; the therapeutic potential of etavopivat; the timing and
completion of our Phase 1 clinical study in etavopivat and final
audit and quality controlled verification of initial data and
related analyses; the timing associated with the initiation or
continuation of any trials and success of ongoing clinical trials
of etavopivat; our ability to execute on our strategy; positive
results from a clinical study may not necessarily be predictive of
the results of future or ongoing clinical studies; any one or more
of our product candidates may not be successfully developed and
commercialized; regulatory developments in the United States and
foreign countries; our ability to protect and maintain our
intellectual property position; the impact of COVID-19 our supply
chain and production as well as global economies and financial
markets; and our ability to fund operations; as well as those risks
and uncertainties set forth more fully under the caption "Risk
Factors" in our Quarterly Report on Form 10-Q for the quarter ended
September 30, 2021, to be filed with the U.S. Securities and
Exchange Commission (SEC) and subsequent filings with the SEC. We
disclaim any obligation to publicly update or revise any such
statements to reflect any change in expectations or in events,
conditions or circumstances on which any such statements may be
based, or that may affect the likelihood that actual results will
differ from those set forth in the forward-looking statements. Any
forward-looking statements contained in this press release
represent our views only as of the date hereof and should not be
relied upon as representing our views as of any subsequent
date.
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version on businesswire.com: https://www.businesswire.com/news/home/20211211005010/en/
Media Adam Silverstein, +1
917-697-9313 Porter Novelli adam.silverstein@porternovelli.com
Investor Mario Corso, +1
781-366-5726 Forma Therapeutics mcorso@formatherapeutics.com
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