Agios Pharma Announces Updated Data from Fully Enrolled DRIVE PK Study Demonstrating AG-348's Potential as First Disease-modifying Treatment for Patients with PKR #EHA2017

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Agios Pharmaceuticals, Inc. 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.
 
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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.
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