Agios Pharmaceuticals, Inc. (Nasdaq:AGIO), a leader in the fields of
cancer metabolism and rare genetic disorders of metabolism, presented
today new, final data from its Phase 1 multiple ascending dose (MAD)
clinical trial of AG-348 in healthy volunteers in an oral presentation
at the 20th Congress of the European Hematology Association
(EHA) taking place June 11-14, 2015 in Vienna. In addition, the first
data from the global natural history study of PK deficiency will be
presented by Dana-Farber Boston Children's Cancer and Blood Disorder
Center.
The data from the MAD trial establish clear proof-of-mechanism for
AG-348, a novel, first-in-class, oral activator of both wild-type
(normal) and mutated pyruvate kinase-R (PKR) enzymes that is wholly
owned by Agios. These data support the hypothesis that AG-348 enhances
PKR activity and has the potential to correct the underlying defect of
pyruvate kinase (PK) deficiency, a rare, potentially severe, genetic
hemolytic disorder. The sensitivity of the wild-type PKR enzyme to the
activating effects of AG-348 allowed the study of enzyme activation in
healthy volunteers, and provided an opportunity to understand the
safety, dosing and pharmacodynamic activity of AG-348 prior to entering
a proof-of-concept study in patients.
“There are currently no approved or disease-modifying treatments for PK
deficiency, and to date, there has been little research to address the
condition or understand the degrees of severity and prevalence of
complications associated with it,” said Chris Bowden, M.D., chief
medical officer of Agios. “We are encouraged by the data presented today
in healthy volunteers that provide further evidence that AG-348
activates the glycolytic pathway across a range of doses with a
favorable safety profile. The final MAD data coupled with the findings
from the natural history study represent important new developments as
we initiate enrollment for DRIVE PK, our Phase 2 clinical trial of
AG-348 in patients with this rare genetic disease.”
Data Summary from Completed Phase 1 MAD Trial for AG-348
Complete results are being reported from the Phase 1 MAD, randomized,
double-blind, placebo-controlled study in 48 healthy volunteers who
received either placebo or AG-348 for 14 days at 15 mg, 60 mg, 120 mg,
360 mg or 700 mg twice daily or 120 mg once daily in six sequential
cohorts. The study showed that AG-348 was well tolerated, with most
adverse events (AE) occurring in the highest dose group (700 mg), with
all but one being mild to moderate. Thirty-two of 36 healthy volunteers
receiving AG-348 completed the study. Two volunteers receiving AG-348
withdrew due to adverse events, including drug eruption (60 mg) and
Grade 3 liver function test abnormalities (700 mg), which resolved after
treatment discontinuation. Two additional AG-348 volunteers (both 700
mg) withdrew consent due to nausea or vomiting. Serum hormone changes
consistent with reversible aromatase inhibition were observed. AG-348
also showed a favorable pharmacokinetic profile with rapid absorption,
low to moderate variability and a dose-proportional increase in exposure
following multiple doses.
As predicted by the mechanism of action of AG-348, there was a robust
activation of the glycolytic pathway as evidenced by a decrease in
2,3-DPG (2,3-diphosphoglycerate) and increase in ATP (adenosine
triphosphate) in blood. The decrease in 2,3-DPG was approximately 50
percent for doses 120 mg and higher with levels returning back to
baseline approximately 72 hours after AG-348 was discontinued. There was
also an approximately 50 percent increase in ATP in blood with AG-348 at
doses 60 mg and higher.
Clinical Development Plans for AG-348
Based on these findings and those from the single ascending dose (SAD)
portion of the Phase 1 study of AG-348 in healthy volunteers, Agios has
opened DRIVE PK, a global Phase 2, first-in-patient, open-label safety
and efficacy trial in adult, transfusion-independent patients with PK
deficiency. The multi-center, randomized study will include two arms
with 25 patients each. The patients in the first arm will receive 50 mg
twice daily, and the patients in the second arm will receive 300 mg
twice daily. The study will include a six-month dosing period with the
opportunity for continued treatment beyond six months based on safety
and clinical activity. Please refer to www.clinicaltrials.gov
for additional clinical trial information.
Data Summary from the Natural History Study of PK Deficiency
“This natural history study features the largest cohort of patients with
PK deficiency assembled to date, giving us a unique opportunity to
understand the characteristics of this disorder,” said Rachael Grace,
M.D., Dana-Farber Boston Children's Cancer and Blood Disorder Center.
“These data show not only the range of severity of the disorder, but
also the unifying characteristics such as iron overload, which was
common in all age groups regardless of transfusion history. We are
hopeful that these findings will lead to improved supportive care and
help guide the development of new treatments for these patients.”
The e-poster titled, “The Clinical Features and Treatment of Iron
Overload in Pyruvate Kinase Deficiency (PKD): Data from the PKD Natural
History Study,” by researchers from the Dana-Farber Boston Children's
Cancer and Blood Disorder Center, Agios and other collaborators describe
the demographic features, iron monitoring and chelation practices in PK
deficiency patients with iron overload. Iron overload is characterized
by an excess of iron in the body, which can be acquired by blood
transfusions that are often used as supportive care for patients with PK
deficiency. The study enrolled 105 PK deficiency patients, including
patients who have not received transfusions to date. Findings revealed
that iron overload was common in all age groups, regardless of
transfusion history, and is likely related to the chronic hemolysis.
Despite this finding, iron monitoring is not routinely performed in PK
deficiency patients.
The poster titled, “Categorization of Clinical Severity in Pyruvate
Kinase Deficiency (PKD) in an International, Observational Cohort,” by
researchers from the Dana-Farber Boston Children's Cancer and Blood
Disorder Center, Agios and other collaborators categorized PK deficiency
clinical severity based on the degree of anemia, transfusion history and
splenectomy status and identified predictors and prevalence of
complications in the various severity groups. The study enrolled 105 PK
deficiency patients. The patients were categorized into four distinct
severity groups ranging from never transfused to splenectomized and
regularly transfused. The study found that complications such as
cholecystectomy and iron overload are correlated with severity of
disease, and this classification may be helpful for determining
monitoring and treatment practices.
Conference Call Information
Agios will host a conference call and webcast from the congress to
review the data on Friday, June 12, 2015 beginning at 8:00 a.m. ET (2:00
p.m. CEST). To participate in the conference call, please dial (877)
377-7098 (domestic) or (631) 291-4547 (international) and refer to
conference ID 53010830. The webcast will be accessible live or in
archived form under "Events & Presentations" in the Investors and Media
section of the company's website at www.agios.com.
About AG-348 and Pyruvate Kinase (PK) Deficiency
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 a decline in the energy
metabolite ATP and a build-up of the metabolite 2,3-DPG. Agios
scientists have previously reported that AG-348 is a potent activator of
the wild-type and mutated PKR enzymes, resulting in restoration of ATP
levels and a decrease in 2,3-DPG levels in blood sampled from patients
with PK deficiency. 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. Currently, there is no approved therapy to
treat the underlying cause of PK deficiency. AG-348, a first-in-class
orally available, potent, selective small molecule activator of PKR, was
discovered in the laboratory of Agios, and the company retains worldwide
development and commercialization rights.
About Agios Pharmaceuticals, Inc.
Agios Pharmaceuticals is focused on discovering and developing novel
investigational medicines to treat cancer and rare genetic disorders of
metabolism 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 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 Agios' product candidate targeting pyruvate kinase R
mutations, including AG-348; its plans and timelines for the clinical
development of AG-348; and the benefit of its strategic plans and focus.
The words “anticipate,” “believe,” “estimate,” “expect,” “intend,”
“may,” “plan,” “predict,” “project,” “potential,” “possible,” “hope,”
“could,” “would” 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, 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 agreement 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’ Quarterly
Report on Form 10-Q for the quarter ended March 31, 2015, and other
filings that Agios may make with the Securities and Exchange Commission
in the future. 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.
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