Agios Pharmaceuticals, Inc. (NASDAQ: AGIO), a leader in the field
of cellular metabolism to treat genetically defined diseases, today
reported a full analysis of updated data, including
patient-reported outcome (PRO) measures, from its global Phase 3
ACTIVATE and ACTIVATE-T studies of mitapivat in adults with
pyruvate kinase (PK) deficiency. Data from the studies will be
featured in oral presentations on Tuesday, June 15, at the European
Hematology Association (EHA) Virtual Congress.
Consistent with previously announced topline data, the ACTIVATE
and ACTIVATE-T studies met primary and secondary endpoints,
including PRO outcomes that address symptom burden and
quality-of-life impact of PK deficiency in adults. The safety
profile observed in both studies was generally consistent with
previously published data. Mitapivat is a first-in-class,
investigational, oral, small molecule allosteric activator of
wild-type and a variety of mutated pyruvate kinase R (PKR)
enzymes.
“Results from the ACTIVATE and ACTIVATE-T Phase 3 studies
underscore the potential of mitapivat to be the first
disease-modifying therapy for individuals with pyruvate kinase
deficiency, a disease characterized by chronic hemolysis and
associated long-term complications affecting multiple organ
systems, regardless of the degree of anemia or transfusion status.
New disease-modifying treatment approaches are needed, as current
management strategies are supportive and include regular blood
transfusions, which can lead to iron overload and splenectomy,
which is also associated with short- and long-term risks,” said
Andreas Glenthøj, M.D., Ph.D., associate professor, Department of
Hematology, Rigshospitalet; Copenhagen, Denmark.
ACTIVATE Results Summary
- The Phase 3 ACTIVATE trial of mitapivat achieved its primary
endpoint. Mitapivat demonstrated a sustained, statistically
significant increase in hemoglobin in patients with PK deficiency
who are not regularly transfused.
- 40 percent (n=16) of patients randomized to mitapivat achieved
a hemoglobin response, compared to 0 patients randomized to placebo
(2-sided p<0.0001).
- The effect of mitapivat on hemoglobin response compared to
placebo was observed consistently across all predefined
subgroups.
- Statistically significant improvements compared to placebo were
also demonstrated for all pre-specified key secondary endpoints,
including markers of hemolysis and ineffective erythropoiesis, as
well as PRO measures.
- The increase in hemoglobin occurred early and was sustained,
with an average change from baseline of 1.67 g/dL for mitapivat
compared with -0.15 g/dL for placebo (2-sided p<0.0001) at Weeks
16, 20 and 24.
- Pyruvate Kinase Deficiency Daily Diary (PKDD), a daily diary of
signs and symptoms, captures changes in symptom burden (e.g.,
tiredness, energy levels, jaundice, bone pain and shortness of
breath).
- Pyruvate Kinase Deficiency Impact Assessment (PKDIA), a weekly
measure of disease impacts, measures health-related quality of
life, (e.g., daily activities, concentration, physical activity and
the need for additional rest or sleep).
- The safety profile of mitapivat was consistent with previously
reported data.
- The most common treatment-emergent adverse events (TEAEs) with
mitapivat were nausea and headache, which were less frequent for
mitapivat compared to placebo (n=7; 17.5% vs. n=9; 23.1% and n=6;
15.0% vs n=13; 33.3%, respectively).
- There were no TEAEs leading to dose reduction, interruption,
discontinuation or death in the mitapivat arm.
ACTIVATE-T Results Summary
- The Phase 3 ACTIVATE-T trial of mitapivat achieved its primary
endpoint. Mitapivat demonstrated a statistically significant and
clinically meaningful reduction in transfusion burden for patients
who are regularly transfused.
- 37 percent (n=10) of patients achieved a transfusion reduction
response, defined as a ≥33% reduction in transfusion burden in the
24-week fixed dose period compared with individual historical
transfusion burden standardized to 24 weeks (1-sided p = 0.0002); 9
responders achieved a ≥50% reduction.
- 22 percent (n=6) of patients were transfusion-free during the
fixed-dose period.
- 11 percent (n=3) of patients achieved hemoglobin concentrations
in the normal range at least once, eight weeks or more after a
transfusion, during the fixed dose period.
- Improvements were also observed for the PK deficiency-specific
PRO measures, PKDD and PKDIA scores.
- The safety profile of mitapivat was consistent with previously
reported data.
- The most frequently reported adverse events in patients
receiving mitapivat included alanine aminotransferase increase
(n=10; 37%), headache (n=10; 37%), aspartate aminotransferase
increase (n=5; 18.5%), fatigue (n=5; 18.5%) and nausea (n=5;
18.5%).
- No serious TEAE was considered by the investigator to be
related to study treatment.
- There were no TEAEs leading to interruption, discontinuation or
death, and only one patient experienced a TEAE leading to dose
reduction.
“For nearly a decade, Agios has been pioneering the science of
PK activation. Results reported today from ACTIVATE and ACTIVATE-T
continue to demonstrate the therapeutic impact of activating this
pathway and provide the foundation for the first potential approval
of a PK activator,” said Chris Bowden, M.D., chief medical officer
at Agios. “In the weeks ahead, we look forward to working with
regulatory authorities in both the U.S. and EU to rapidly bring
mitapivat to pyruvate kinase deficiency patients as the first
potentially disease-modifying therapy.”
Agios remains on track to submit a new drug application (NDA) in
the U.S. in the second quarter of 2021 and a marketing
authorization application (MAA) in the EU in mid-2021 for mitapivat
in adults with PK deficiency.
ACTIVATE Trial DesignACTIVATE is a Phase 3
global, double-blind, placebo-controlled trial with a 1:1
randomization evaluating the efficacy and safety of mitapivat as a
potential treatment for adults with PK deficiency who do not
receive regular transfusions. Patients were required to have a
hemoglobin concentration less than or equal to 10.0g/dL. The trial
randomized 80 patients.
The study was designed with two parts. Part 1 was a dose
escalation period in which patients started at 5 mg of mitapivat or
placebo twice daily, with two potential dose escalations to 20 mg
twice daily and 50 mg twice daily over a 12-week period. After the
dose escalation period, patients received a fixed dose for an
additional 12 weeks in Part 2.
The primary endpoint of the study was hemoglobin response,
defined as a ≥1.5 g/dL increase in hemoglobin concentration from
baseline that is sustained at two or more scheduled assessments at
Weeks 16, 20 and 24 during Part 2 of the trial.
ACTIVATE-T Trial DesignACTIVATE-T is a Phase 3
global, open-label study to evaluate the efficacy and safety of
mitapivat as a potential treatment for adults with PK deficiency
who are regularly transfused, defined as receiving six or more
transfusions in the past 52 weeks. The trial enrolled 27
patients.
The study was designed with two parts. Part 1 was a dose
escalation period in which patients started at 5 mg twice daily of
mitapivat, with two potential dose increases to 20 mg twice daily
and 50 mg twice daily for up to 16 weeks. After the dose escalation
period, patients received a fixed dose for an additional 24 weeks
in Part 2.
The primary endpoint of the study was reduction in transfusion
burden, defined as a reduction of ≥33 percent in the number of red
blood cell units transfused during the 24-week fixed dose period
compared with the historical transfusion burden standardized to 24
weeks. Participants who discontinued the study before completing at
least 12 weeks of treatment in the fixed dose period were
considered non-responders. The p-value is based on the binomial
exact test of H0: transfusion reduction response rate ≤10% vs. H1:
transfusion reduction response rate >10% at a 1-sided
α=0.025.
Oral Presentation Information
Title: ACTIVATE: A Phase 3, randomized,
multicenter, double-blind, placebo-controlled study of mitapivat in
adults with pyruvate kinase deficiency who are not regularly
transfusedLive Q&A Session Date and
Time: Tuesday, June 15, 2021, at 7:45 p.m.
CEST / 1:45 p.m. ETOral Abstract
Session: Changing the scene in congenital
anemiasAbstract:
S270Presenter: Hanny Al-Samkari,
M.D., Division of Hematology, Massachusetts General
Hospital, Harvard Medical School, Boston, MA, United
States
Title: ACTIVATE-T: A Phase 3, open-label,
multicenter study of mitapivat in adults with pyruvate kinase
deficiency who are regularly transfusedLive Q&A Session
Date and Time: Tuesday, June 15,
2021, at 7:45 p.m. CEST / 1:45 p.m.
ETOral Abstract Session: Changing the scene on
congenital anemiasAbstract:
S271Presenter: Andreas Glenthøj,
M.D., Department of Hematology,
Rigshospitalet Copenhagen, Denmark
Mitapivat Clinical DevelopmentACTIVATE and
ACTIVATE-T are intended to support global regulatory filings for
mitapivat in adults with PK deficiency in the U.S. in the second
quarter of 2021 and the EU in mid-2021. Agios also is conducting an
extension study for adults with PK deficiency previously enrolled
in ACTIVATE or ACTIVATE-T, which is designed to evaluate the
long-term safety, tolerability and efficacy of treatment with
mitapivat.
In addition, Agios completed a Phase 2 study evaluating the
efficacy, safety, pharmacokinetics and pharmacodynamics of
treatment with mitapivat in adults with non-transfusion-dependent
α- or β-thalassemia. The primary endpoint for the Phase 2 study was
hemoglobin response, defined as a ≥1.0 g/dL increase in hemoglobin
concentration from baseline at one or more assessments between Week
4 and Week 12. These results are also being reported as part of an
oral presentation at the EHA Virtual Congress. Agios is
conducting an extension study of mitapivat for adults previously
enrolled in the Phase 2 study and is initiating two Phase 3
studies, ENERGIZE and ENERGIZE-T, in not regularly transfused and
regularly transfused adults with thalassemia in the second half of
2021.
Mitapivat is also being evaluated as a potential treatment for
sickle cell disease under a Cooperative Research and
Development Agreement (CRADA) with the U.S. National
Institutes of Health. 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 S polymerization and red blood cell
sickling. Preliminary clinical data establishing
proof-of-concept for mitapivat in sickle cell disease were
disclosed in June 2020, and updated data were
presented at the American Society of
Hematology (ASH) Annual Meeting in December 2020. Agios
is initiating its pivotal Phase 2/3 study in sickle cell disease by
year-end 2021.
Mitapivat has been granted orphan drug designation for the
treatment of PK deficiency by the U.S. Food and Drug
Administration (FDA) and the European Medicines Agency.
Additionally, mitapivat has received orphan drug designation from
the FDA for the treatment of thalassemia and sickle
cell disease.
Mitapivat is not approved for use by any regulatory
authority.
About PK DeficiencyPyruvate kinase (PK)
deficiency is a rare, inherited disease that presents as chronic
hemolytic anemia, which is the accelerated destruction of red blood
cells. The inherited mutations in PKR genes cause a deficit in
cellular energy within the red blood cell, as evidenced by lower PK
enzyme activity, a decline in adenosine triphosphate (ATP) levels
and a build-up of upstream metabolites, including 2,3-DPG
(2,3-diphosphoglycerate).
PK deficiency is associated with serious complications,
including gallstones, pulmonary hypertension, extramedullary
hematopoiesis, osteoporosis and iron overload and its sequelae,
which can occur regardless of the degree of anemia or transfusion
burden. PK deficiency can also cause quality of life problems,
including challenges with work and school activities, social life
and emotional health. Current management strategies for PK
deficiency, including red blood cell transfusions and splenectomy,
are associated with both short- and long-term risks. There are no
currently approved therapies for PK deficiency. For more
information, please visit www.knowpkdeficiency.com.
Agios, in partnership with PerkinElmer Genomics, launched the
Anemia ID program to offer no-cost genetic testing to eligible
patients in the U.S. with suspected hereditary anemias,
including PK deficiency. The program was created in response to
feedback from patients, advocates and physicians about the need for
improved diagnosis to inform disease management decisions. To learn
more, please visit www.AnemiaID.com.
CONFERENCE CALL INFORMATION
Agios will host a virtual investor event today at 7:30 a.m.
ET to review the mitapivat clinical data. The event will be
webcast live and can be accessed under "Events & Presentations"
in the Investors and Media section of the company's website
at www.agios.com. The archived webcast will be available on
the company's website beginning approximately two hours after the
event.
About AgiosAgios is focused on discovering and
developing novel investigational medicines to treat genetically
defined diseases through scientific leadership in the field of
cellular metabolism. The company’s most advanced drug candidate is
a first-in-class pyruvate kinase R (PKR) activator, mitapivat, that
is currently being evaluated for the treatment of three distinct
hemolytic anemias. In addition to its active late-stage clinical
pipeline, Agios has multiple novel, investigational therapies in
clinical and preclinical development. 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 Agios’ plans, strategies and expectations for the
preclinical, clinical and commercial advancement of its drug
development programs, including mitapivat; the potential benefits
of Agios’ products and product candidates, including mitapivat;
Agios’ key milestones and guidance for 2021; and the potential
benefits of Agios’ strategic plans and focus. The words
“anticipate,” “expect,” “goal,” “hope,” “milestone,” “plan,”
“potential,” “possible,” “strategy,” “will,” “vision,” 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. 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 failure of Agios to receive milestone
or royalty payments related to the sale of its oncology business,
the uncertainty of the timing of any receipt of any such payments,
and the uncertainty of the results and effectiveness of the use of
proceeds from the transaction; 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
future approved products, and launching, marketing and selling
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 and 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 establish and maintain
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, or SEC, including
the risks and uncertainties set forth under the heading Risk
Factors in our filings with the SEC. While the list of factors
presented here is considered representative, this list should not
be considered to be a complete statement of all potential risks and
uncertainties. Any forward-looking statements contained in this
communication are made only as of the date hereof, and we undertake
no obligation to update forward-looking statements to reflect
developments or information obtained after the date hereof and
disclaim any obligation to do so other than as may be required by
law.
Contacts
Investors:1ABSteve Klasssteve@1abmedia.com
Media:1AB Josie Butlerjosie@1abmedia.com
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