Agios Pharmaceuticals, Inc. (NASDAQ:AGIO), a leader in the field of
cellular metabolism to treat cancer and rare genetic diseases,
today announced that clinical proof-of-concept has been established
based on a preliminary analysis in the Phase 1 trial of mitapivat
(AG-348) in patients with sickle cell disease. The study is being
conducted in collaboration with the National Institutes of Health
(NIH) as part of a cooperative research and development agreement.
Mitapivat is an investigational, first-in-class, oral, small
molecule allosteric activator of wild-type and a variety of mutated
pyruvate kinase-R (PKR) enzymes. Mitapivat has been shown to
decrease 2,3-diphosphoglycerate (2,3-DPG) and increase adenosine
triphosphate (ATP), and through this mechanism, it may reduce
hemoglobin (Hb) S polymerization and red blood cell sickling.
The ongoing Phase 1 study has enrolled nine patients to date.
Eight patients have completed all planned dose levels, and one
patient discontinued within the first week due to a pre-existing
condition and was subsequently lost to follow-up. Six patients were
treated with three ascending dose levels of mitapivat (5 mg BID, 20
mg BID, 50 mg BID) for two weeks duration, respectively, followed
by 9 or 12-day drug taper, and two patients received an additional
ascending dose of 100 mg BID for two weeks before initiating the
drug taper. Adverse events (AEs) reported during the study were
generally consistent with those previously reported in pyruvate
kinase (PK) deficiency or are to be expected in the context of
sickle cell disease. One severe AE, a vaso-occlusive crisis,
occurred during drug taper and was attributed as possibly related
to the drug.
Seven of eight (88%) patients who completed all planned dose
levels of mitapivat experienced a Hb increase, with five of eight
patients (63%) achieving a hemoglobin increase of ≥1.0 g/dL from
baseline (range 1.0-2.7 g/dL). All five patients who achieved a
hemoglobin increase of ≥1.0 g/dL did so at doses of 50 mg BID or
lower. Treatment with mitapivat was associated with decreases in
hemolytic markers such as bilirubin, lactic acid dehydrogenase and
reticulocytes. As expected, decreases in 2,3-DPG and increases in
ATP levels were observed, consistent with the proposed mechanism of
action and comparable to that observed in healthy volunteer studies
with mitapivat. Evaluation of sickling curves (t50) and oxygen
dissociation curves (p50) were consistent with decreases in both
sickling and HbS polymerization, further supporting the proposed
mechanism of action.
“The interim results from the Phase 1 study of mitapivat
demonstrate for the first time that PKR activation has the
potential to address chronic hemolytic anemia and impact markers of
sickling in sickle cell disease patients as hypothesized based on
the mechanism of action,” said Swee Lay Thein, M.B.B.S., F.R.C.P.,
F.R.C.Path., D.Sc., chief of the Sickle Cell Branch of the National
Heart, Lung, and Blood Institute, NIH, and the principal
investigator of the study. “The safety profile of mitapivat
continues to be consistent with prior studies in both mutated and
wildtype PKR, and hemoglobin responses were seen in 63% of
patients. We are excited about these preliminary results, and I
look forward to continuing to collaborate with Agios to advance
this treatment for sickle cell disease patients.”
“First, I would like to thank the NIH and Dr. Thein for the
incredible collaboration on this study. These data build on our six
years of clinical experience with this mechanism and establish
proof-of-concept for mitapivat as a potential novel approach for
the treatment of sickle cell disease, a chronic lifelong condition
with few treatment options,” said Chris Bowden, M.D., chief medical
officer at Agios. “Looking ahead, we are focused on advancing
mitapivat to pivotal development, with the goal of initiating a
pivotal study next year.”
Mitapivat Phase 1 Trial in Sickle Cell Disease
The ongoing Phase 1 study, which can enroll up to 25
patients, is evaluating the efficacy, safety, pharmacokinetics and
pharmacodynamics of treatment with mitapivat in adults with sickle
cell disease. Six patients received three ascending dose levels of
mitapivat (5 mg BID, 20 mg BID, 50 mg BID) for 2 weeks duration,
respectively, followed by 9 or 12-day drug taper. The two patients
most recently enrolled and all subsequent patients receive an
additional ascending dose of 100 mg BID for two weeks before
initiating the drug taper in order to further explore dose-response
relationship. The primary endpoint of the study is safety and
tolerability as assessed by frequency and severity of adverse
events and laboratory parameters. Secondary endpoints included
changes in hemoglobin, markers of hemolysis, 2,3-DPG and ATP levels
and HbS polymerization.
Mitapivat Clinical Development Agios has two
ongoing global, pivotal trials in adults with PK deficiency that
are fully enrolled.
- ACTIVATE: A placebo-controlled trial with a 1:1 randomization
evaluating patients who do not receive regular transfusions. The
primary endpoint of the trial is the proportion of patients who
achieve a sustained hemoglobin increase of ≥1.5 g/dL.
- ACTIVATE-T: A single arm trial of regularly transfused patients
with a primary endpoint of reduction in transfusion burden over six
months compared to individual historical transfusion burden over
prior 12 months.
In addition, mitapivat is being studied in an ongoing Phase 2
study in adults with non-transfusion-dependent β- and
α-thalassemia. Interim results from the study were reported today
in an oral presentation at the 25th European Hematology Association
Annual Congress (EHA).
Mitapivat is not approved for use by any regulatory
authority.
Investor Webcast InformationAgios will host an
investor webcast today at 7:30 a.m. ET to review the mitapivat
proof-of-concept data in sickle cell disease and Phase 2
thalassemia data presented at EHA. The event will be webcast live
and can be accessed under "Events & Presentations" in the
Investors section of Agios’ website at www.agios.com. The archived
webcast will be available on Agios’ website beginning approximately
two hours after the event.
About AgiosAgios is focused on discovering and
developing novel investigational medicines to treat cancer and rare
genetic diseases through scientific leadership in the field of
cellular metabolism. In addition to an active research and
discovery pipeline across both therapeutic areas, Agios has two
approved oncology precision medicines and multiple first-in-class
investigational therapies in clinical and/or preclinical
development. All Agios programs focus on genetically identified
patient populations, leveraging our knowledge of metabolism,
biology and genomics. For more information, please visit the
company's website at www.agios.com.
Cautionary Note Regarding Forward-Looking
StatementsThis press release contains forward-looking
statements within the meaning of The Private Securities Litigation
Reform Act of 1995. Such forward-looking statements include those
regarding: the potential benefits of mitapivat; Agios’ plans for
the further clinical development of mitapivat; and Agios’ strategic
plans and prospects. The words “anticipate,” “believe,” “estimate,”
“expect,” “intend,” “may,” “plan,” “predict,” “project,” “would,”
“could,” “potential,” “possible,” “hope” and similar expressions
are intended to identify forward-looking statements, although not
all forward-looking statements contain these identifying words.
Such statements are subject to numerous important factors, risks
and uncertainties that may cause actual events or results to differ
materially from Agios' current expectations and beliefs. For
example, there can be no guarantee that any product candidate Agios
or its collaborators is developing will successfully commence or
complete necessary preclinical and clinical development phases, or
that development of any of Agios’ product candidates will
successfully continue. There can be no guarantee that any positive
developments in Agios’ business will result in stock price
appreciation. Management's expectations and, therefore, any
forward-looking statements in this press release could also be
affected by risks and uncertainties relating to a number of other
important factors, including, without limitation: risks and
uncertainties related to the impact of the COVID-19 pandemic to
Agios’ business, operations, strategy, goals and anticipated
milestones, including its ongoing and planned research activities,
ability to conduct ongoing and planned clinical trials, clinical
supply of current or future drug candidates, commercial supply of
current or future approved products, and launching, marketing and
selling current or future approved products; Agios’ results of
clinical trials and preclinical studies, including subsequent
analysis of existing data and new data received from ongoing and
future studies; the content and timing of decisions made by the
U.S. FDA, the EMA or other regulatory authorities, investigational
review boards at clinical trial sites and publication review
bodies; Agios’ ability to obtain and maintain requisite regulatory
approvals and to enroll patients in its planned clinical trials;
unplanned cash requirements and expenditures; competitive factors;
Agios' ability to obtain, maintain and enforce patent and other
intellectual property protection for any product candidates it is
developing; Agios’ ability to maintain key collaborations; and
general economic and market conditions. These and other risks are
described in greater detail under the caption "Risk Factors"
included in Agios’ public filings with the Securities and Exchange
Commission. Any forward-looking statements contained in this press
release speak only as of the date hereof, and Agios expressly
disclaims any obligation to update any forward-looking statements,
whether as a result of new information, future events or otherwise,
except as required by law.
Contacts
Investors:Holly Manning, 617-844-6630Director,
Investor RelationsHolly.Manning@agios.com
Media:Jessica Rennekamp, 857-209-3286Associate
Director, Corporate
CommunicationsJessica.Rennekamp@agios.com
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