– AG-348 Is Well-Tolerated and Demonstrates
Clinically Relevant, Rapid and Sustained Hemoglobin Increases in 25
of 52 Patients Overall –
Agios Pharmaceuticals, Inc. (Nasdaq:AGIO) presented updated data
from its wholly owned pyruvate kinase-R (PKR) activator
demonstrating the potential for the first disease-modifying
treatment for patients with pyruvate kinase (PK) deficiency at the
22nd Congress of the European Hematology Association (EHA). PK
deficiency is a rare, potentially debilitating, congenital anemia.
DRIVE PK is an ongoing global open-label, Phase 2, safety and
efficacy trial evaluating AG-348 in adult, transfusion-independent
patients with PK deficiency. As of the March 27, 2017 data cut-off,
48% of all 52 treated patients (n=25/52) and 57% of patients with
at least 1 missense mutation (n=24/42) treated with AG-348
experienced a maximum Hb increase from baseline of >1.0 g/dL. Hb
increases were rapid with a median time to a Hb increase of >1.0
g/dL of 10 days.
Enrollment in DRIVE PK was completed in November 2016 with 52
patients. Patients were randomized to a starting dose of 50 mg or
300 mg twice daily, treated for six months in a core treatment
period and then offered up to two years of treatment in an
extension period. As of the data cut-off, 15 patients remain in the
core period, 29 patients completed the core treatment period and 21
remain in the extension period. The median baseline hemoglobin (Hb)
for all patients was 8.9 gram per deciliter (g/dL) (ranging from
6.5 to 12.3 g/dL). Forty-three of the 52 patients (83%) had been
splenectomized prior to study entry and 25 (48%) have received
prior iron chelation therapy.
“With data now available from all 52 patients, AG-348 continues
to demonstrate clinically relevant and sustained increases in
hemoglobin in adults with PK deficiency,” said Rachael Grace, M.D.,
of the Dana-Farber Boston Children's Cancer and Blood Disorder
Center and a principal investigator for the study. “These findings
offer patients and physicians a well-tolerated, oral therapy as the
first potential disease-altering treatment for people suffering
from this chronic anemia and its associated complications.”
“The rapid and sustained hemoglobin increases shown in DRIVE PK,
combined with improvements in hemolysis related parameters,
indicate that AG-348 is having a meaningful impact on the biology
of PK deficiency,” said Chris Bowden, M.D., chief medical officer
at Agios. “We look forward to advancing this novel investigational
therapy into a planned global pivotal program in the first half of
2018.”
Safety Data
A safety analysis conducted for all 52 treated patients as of
the data cut-off shows that AG-348 continues to be well
tolerated.
- The majority of treatment-related adverse events (AEs) were
Grade 1-2; the most frequent were headache, insomnia and
nausea.
- Three patients experienced treatment related AEs leading to
discontinuation: chest discomfort/pleural effusion (n=1),
pharyngitis/nausea (n=1) and anemia (n=1).
- Five patients experienced drug-related serious adverse events:
withdrawal hemolysis followed by anemia (n=1), anemia (n=1),
osteoporosis (n=1), hypertriglyceridemia (n=1) and pharyngitis
(n=1).° Grade 4 hypertriglyceridemia at week 24 resolved upon
AG-348 discontinuation (patient had Grade 1 hypertriglyceridemia at
baseline).
- Preliminary measurements of testosterone in men suggest
aromatase inhibition by AG-348 with the majority of testosterone
changes remaining within the normal range. Longer follow-up is
required to assess clinical significance.
Efficacy Data
In the efficacy analysis of all 52 treated patients, 25 patients
overall and 24 of 42 patients with at least one missense mutation
achieved rapid, robust and sustained Hb increases from baseline of
>1.0 g/dL as of the data cut-off.
- In patients who had Hb increases of >1.0 g/dL, the mean
maximum Hb increase was 3.5 g/dL (range 1.1-5.8 g/dL).
- The median time to a Hb increase of >1.0 g/dL was 10 days
(range 7–141 days).
- Median baseline Hb in patients who experienced a maximum Hb
increase of >1.0 g/dL was 9.7 g/dL (range 7.5–12.3 g/dL) vs. 8.0
g/dL (range 6.5–10.1 g/dL) in patients who did not experience the
increase.
- In patients with a Hb increase of >1.0 g/dL improvements in
hemolysis associated parameters were observed:° An increase in
haptoglobin and decrease in lactate dehydrogenase (LDH) were
observed in the first weeks of dosing.° Rapid decreases in
reticulocytes were observed.
About Pyruvate Kinase Deficiency and Genetic
Background
PK deficiency is a rare inherited disease that presents as
hemolytic anemia, which is the accelerated destruction of red blood
cells. The inherited mutations in PKR enzymes cause a deficit in
cellular energy within the red blood cell, as evidenced by lower
pyruvate kinase enzyme activity and a decline in ATP (adenosine
triphosphate) levels and a build-up of upstream metabolites,
including 2,3-DPG (2,3-diphosphoglycerate).
The current standard of care for PK deficiency is supportive,
including blood transfusions, splenectomy, chelation therapy to
address iron overload and/or interventions for other treatment- and
disease-related morbidities. There is no approved therapy to treat
the underlying cause of PK deficiency.
PK deficiency is an autosomal recessive disease whereby all
patients inherit two mutations, one from each parent. More than 250
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 53 percent of patients with PK
deficiency have two missense mutations, 25 percent have one
missense and one non-missense mutation, and 22 percent have two
non-missense mutations1.
Boston Children’s Hospital, in collaboration with Agios, is
conducting a Natural History Study to better understand the
symptoms and complications of PK deficiency, identify patients and
treatment centers, and capture other clinical data, including
quality of life measures and genetic information.
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.
In addition to an active research and discovery pipeline across
both therapeutic areas, Agios has multiple first-in-class
investigational medicines 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
Statements
This 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 AG-348; Agios’ plans for the further clinical
development of AG-348; 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, such as its agreements with
Celgene; 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, 2015
ASH Annual Meeting
Contacts
Investors:
Kendra Adams, 617-844-6407
Senior Director, Investor & Public Relations
Kendra.Adams@agios.com
Renee Leck, 617-649-8299
Senior Manager, Investor & Public Relations
Renee.Leck@agios.com
Media:
Holly Manning, 617-844-6630
Associate Director, Corporate Communications
Holly.Manning@agios.com
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