Agios Pharmaceuticals, Inc. (NASDAQ: AGIO), a leader in the field
of cellular metabolism to treat cancer and rare genetic diseases,
today announced that new data from the core and extension phases of
the DRIVE PK Phase 2 study of mitapivat (AG-348) in adults with
pyruvate kinase (PK) deficiency were published in the September 5,
2019 issue of the New England Journal of Medicine. 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 that directly targets the underlying metabolic defect
in PK deficiency, a rare, potentially debilitating, hemolytic
anemia.
“The DRIVE PK study is the first clinical trial in adults with
PK deficiency, which is a rare disease characterized by chronic
hemolysis and long-term serious complications. Data from the study
demonstrated rapid, clinically significant increases in hemoglobin
in 50 percent of patients, and for patients in the extension phase,
the response was sustained for up to 35 months,” said Rachael
Grace, M.D., of the Dana-Farber/Boston Children's Cancer and Blood
Disorder Center and a principal investigator for the study. “There
are no approved therapies for PK deficiency, and there are
significant risks associated with current disease management
strategies. By directly targeting the underlying metabolic defect
in PK deficiency, mitapivat has the potential to be the first
disease-altering therapy for these patients.”
“Data from the extension phase of the DRIVE PK study showed that
patients who respond to long-term treatment with mitapivat had
continued evidence of decreased hemolysis as demonstrated by
directionally appropriate changes over time in hemoglobin, absolute
reticulocyte counts, indirect bilirubin, haptoglobin and lactate
dehydrogenase,” said Chris Bowden, M.D., chief medical officer at
Agios. “We are currently evaluating the safety and efficacy of
mitapivat in adults with PK deficiency in our ongoing Phase 3
ACTIVATE and ACTIVATE-T studies, and we look forward to exploring
mitapivat in the pediatric population.”
DRIVE PK is an ongoing global, open-label, Phase 2, safety and
efficacy study evaluating mitapivat in adults with PK deficiency
who do not receive regular transfusions. Patients were randomly
assigned to receive either 50 mg or 300 mg of mitapivat twice daily
for a 24-week core period and eligible patients could continue
treatment in an ongoing extension phase. As of the August 31, 2018
data cutoff, 52 patients were randomized and 43 (83%) completed the
core period. Thirty-six (69%) patients entered and 19 (37%) remain
in the extension phase with a median treatment duration of 28.9
months [range 21.6-34.8]. The median baseline hemoglobin was 8.9
g/dL (range, 6.5–12.3 g/dL). Nearly half (48%) of the patients
reported a history of treatment with iron chelation despite the
absence of regular transfusions, while the majority of patients had
a prior splenectomy (83%) and cholecystectomy (73%).
Safety DataA safety analysis conducted for all
52 treated patients as of the data cut-off shows that adverse
events associated with mitapivat were mainly low-grade and
transient. The cumulative safety profile (core plus extension
phase) remained similar to that observed in the core period and
continues to support long-term twice daily dosing.
- The majority of adverse events (AEs) were Grade 1-2; the most
frequent were headache (46%), insomnia (42%) and nausea (40%).
These events resolved within seven days after the initiation of
treatment in 92% of episodes of headache, 47% of episodes of
insomnia, and 78% of episodes of nausea.
- Nine patients experienced Grade ≥3 treatment-related adverse
events: hypertriglyceridemia (n=4), hemolytic anemia (n=2) and
hemolysis, dizziness, headache, left renal cell carcinoma and
insomnia (n=1 each).
- Changes from baseline in sex hormone levels were observed in
men, the result of mild off-target aromatase inhibition, with most
values of testosterone and estradiol remaining within the normal
range. Interpretation of sex hormone data in females was confounded
by variability in menopausal status and hormonal contraception use
and will be assessed further in the Phase 3 studies.
Efficacy DataIn the efficacy analysis, 26 of 52
patients (50%) achieved a clinically significant maximum hemoglobin
increase of >1.0 g/dL in the Core Period with improvement in
other markers of hemolysis as of the data cutoff.
- In patients who had hemoglobin increases of >1.0 g/dL in the
Core Period, the mean maximum hemoglobin increase was 3.4 g/dL
(range, 1.1–5.8 g/dL).
- The median time to first hemoglobin increase of >1.0 g/dL
was 10 days (range 7–187 days).
- Twenty patients maintained a hemoglobin response >1.0 g/dL
for >50% of assessments in the Core Period.
- The hemoglobin response was maintained in 19 patients who
continued to be treated in the extension phase, all of whom had at
least 21.6 months of treatment.
- In the patients with a hemoglobin response, directionally
appropriate changes over time in absolute reticulocytes counts,
indirect bilirubin, haptoglobin and lactate dehydrogenase provide
additional evidence of decreased hemolysis with mitapivat
treatment.
Mitapivat Pivotal Development PlanAgios has two
ongoing global, pivotal trials in adults with PK deficiency that
are on track to complete enrollment by year-end 2019.
- ACTIVATE: A placebo-controlled trial with a 1:1 randomization,
expected to enroll approximately 80 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 up to 40 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.
Learn more at activatetrials.com. Mitapivat is not approved for
use by any regulatory authority.
About Pyruvate Kinase Deficiency and Genetic
BackgroundPyruvate 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 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,
cirrhosis, osteoporosis, and iron overload and its sequelae, which
occur regardless of the degree of anemia or transfusion burden.
Current management strategies for PK deficiency, including blood
transfusion and splenectomy, are associated with both short- and
long-term risks.
More than 300 different mutations have been identified to date.
The mutations observed in PK deficiency patients are classified in
two main categories. A missense mutation causes a single amino acid
change in the protein, generally resulting in some functional
protein. A non-missense mutation is any mutation other than a
missense mutation, generally resulting in little functional
protein. It is estimated that 58 percent of patients with PK
deficiency have two missense mutations, 27 percent have one
missense and one non-missense mutation, and 15 percent have two
non-missense mutations1. For more information about PK deficiency,
including the signs and symptoms, how to test for it, and how it is
currently managed, visit knowpkdeficiency.com.
The Peak Registry, a global, longitudinal study of children and
adults with PK deficiency, has been established to better
understand the full spectrum of disease variability, including
impact on quality of life. The Registry is open and recruiting
patients. Learn more at www.peakregistry.com.
About Agios Agios 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 and adjacent areas of biology. 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
is developing will successfully commence or complete necessary
preclinical and clinical development phases; that positive safety
and efficacy findings observed in early stage clinical trials will
be replicated in later stage trials; 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: 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 and 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.
______________________________ 1 Bianchi P et
al. poster, 2017 ASH Annual
Meeting
Investor & Media Contact: Holly Manning,
617-844-6630 Associate Director, Investor Relations
Holly.Manning@agios.com
A PDF accompanying this announcement is available
at http://ml.globenewswire.com/Resource/Download/0fbe26a2-08f9-48c0-86f5-0b1640cdc726
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