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news.Agios Pharmaceuticals announced initial data demonstrating that AG-348 achieved proof-of-concept in an ongoing Phase 2 study (DRIVE-PK) of patients with pyruvate kinase (PK) deficiency, a rare, potentially debilitating, congenital anemia. AG-348 is a novel, first-in-class, oral activator of both wild-type (normal) and mutated pyruvate kinase-R (PKR) enzymes.
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AG-348 is wholly owned by Agios. Data will be presented today at the 21st Congress of the European Hematology Association (EHA) taking place June 9-12, 2016 in Copenhagen.
DRIVE-PK is the first study to evaluate the safety and efficacy of AG-348 in patients with PK deficiency. As of the March 27, 2016 data cut-off, 18 transfusion-independent patients (13 with at least one missense mutation and five with two non-missense mutations) were treated with twice-daily dosing of AG-348 for up to six months.
Treatment resulted in rapid and sustained hemoglobin increases of >1.0 g/dL in nine out of 18 patients (nine of 13 patients with at least one missense mutation), ranging from 2.3-4.9 g/dL with a mean maximum hemoglobin increase of 3.4 g/dL. It is estimated that approximately 80 percent of all PK deficiency patients carry at least one missense mutation. These data support the hypothesis that AG-348 restores metabolic function and has the potential to correct the underlying defect in the red blood cells of patients with PK deficiency.
"People with PK deficiency suffer from chronic anemia and a range of other complications brought on by both their disease and existing supportive therapies, including blood transfusions and splenectomy," 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 data are exciting for the hematology community and patients, as they demonstrate the potential for AG-348 to provide the first disease-modifying treatment with impressive and prolonged increases in hemoglobin levels."
"These data have established proof-of-concept for AG-348, validating our novel approach to the treatment of rare genetic metabolic disorders by correcting the underlying enzymatic defect with a small molecule," said Chris Bowden, M.D., chief medical officer at Agios.
"The rapid and sustained hemoglobin increases and well-tolerated safety profile shown in this trial to date support continued study and moving into late-stage development. In addition, these data demonstrate the important potential role that PK activation may have in transforming treatment of PK deficiency."
About the DRIVE-PK Study
DRIVE-PK is a global Phase 2, open-label safety and efficacy trial evaluating AG-348 in adult, transfusion-independent patients with PK deficiency. The study includes two arms of up to 25 patients each, receiving a dose of 50 milligrams (mg) or 300 mg twice daily for at least six months. Hemoglobin levels are assessed in weekly intervals for the first 3 weeks of study and then at weeks 6, 9, 12, 16, 20 and 24.
As of the March 27, 2016 data cut-off, 18 patients had been treated with AG-348 for at least three weeks in the DRIVE-PK study. Three of the 18 patients had completed 24 weeks of treatment with either 50 mg or 300 mg twice daily. The mean patient age was 31. The mean baseline hemoglobin was 9.3 g/dL. Thirteen of the 18 patients underwent prior splenectomy.
Safety Data
A safety analysis was conducted based on all 18 treated patients as of the data cut-off.
AG-348 was well tolerated, and no patients discontinued treatment early.
The majority of adverse events (AEs) reported by investigators were mild to moderate (Grade 1-2) and transient.
The most frequent AEs included nausea, headache, hot flush and insomnia.
One patient received a dose reduction due to rapidly increasing hemoglobin. This patient was dose-reduced from 300 mg to 50 mg and remained on study.
One Grade 2 AE of osteoporosis has been reported since the cut-off date. This patient had osteopenia at baseline assessment.
Sex steroids were assessed at baseline, week 12 and week 24. Free testosterone and estradiol were available for four and five male patients, respectively. An upward trend in free testosterone and a downward trend in estradiol were observed. Additional data and longer follow up are needed to determine if hormonal changes are clinically significant.
Efficacy Data
Nine of 18 total patients and nine of 13 patients with at least one missense mutation achieved rapid, robust and sustained hemoglobin increases of >1.0 grams per deciliter (g/dL) as of the data cut-off.
Both doses of AG-348 demonstrated clinical activity, with four patients in the 50 mg group and five patients in the 300 mg group experiencing increases of >1.0 g/dL.
In patients who had hemoglobin increases of >1.0 g/dL, the mean maximum hemoglobin increase was 3.4 g/dL (range 2.3-4.9 g/dL).
The median time to a hemoglobin increase of >1.0 g/dL was 1.9 weeks (range 1.1-9.1 weeks).
Further data are needed to obtain a greater understanding of the relationship between genotype and response. Preliminary observations show:
Of the 13 patients with at least one missense mutation, nine have shown an increase in hemoglobin of >1.0 g/dL.
None of the five patients with two non-missense mutations showed increases in hemoglobin of >1.0 g/dL.
Pharmacokinetics were favorable and consistent with those observed in healthy volunteers.
Pharmacodynamics data did not demonstrate a correlation with hemoglobin increases and ATP (adenosine triphosphate) elevation. More data are needed to clarify if any correlation exists between 2,3-DPG (2,3-diphosphoglycerate) decreases and Hb increases of >1.0 g/dL.