EFFECTS OF AG-348, A PYRUVATE KINASE ACTIVATOR, IN PATIENTS WITH PYRUVATE KINASE DEFICIENCY: UPDATED RESULTS FROM THE DRIVE PK STUDY
Author(s): ,
Rachael F Grace
Affiliations:
Dana-Farber Boston Children's Cancer and Blood Disorders Center,Boston,United States
,
D Mark Layton
Affiliations:
Hammersmith Hospital,Imperial College Healthcare NHS Trust,London,United Kingdom
,
Frédéric Galactéros
Affiliations:
Unité des Maladies Génétiques du Globule Rouge,CHU Henri Mondor,Créteil,France
,
Christian Rose
Affiliations:
Hôpital Saint Vincent de Paul,Lille,France
,
Wilma Barcellini
Affiliations:
Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico,Milan,Italy
,
D Holmes Morton
Affiliations:
Central Pennsylvania Clinic,Belleville,United States
,
Eduard van Beers
Affiliations:
Universitair Medisch Centrum Utrecht,Utrecht,Netherlands
,
Hassan Yaish
Affiliations:
University of Utah,Salt Lake City,United States
,
Yaddanapudi Ravindranath
Affiliations:
Wayne State University School of Medicine,Children's Hospital of Michigan,Detroit,United States
,
Kevin Kuo
Affiliations:
University of Toronto,Toronto,Canada
,
Sujit Sheth
Affiliations:
Weill Cornell Medical College,New York,United States
,
Janet L Kwiatkowski
Affiliations:
Children's Hospital of Philadelphia and Perelman School of Medicine of the University of Pennsylvania,Philadelphia,United States
,
Bruce Silver
Affiliations:
Bruce A Silver Clinical Science and Development,Dunkirk,United States
,
Charles Kung
Affiliations:
Agios Pharmaceuticals, Inc.,Cambridge,United States
,
Marvin Cohen
Affiliations:
MBC Pharma Solutions,Newtown,United States
,
Hua Yang
Affiliations:
Agios Pharmaceuticals, Inc.,Cambridge,United States
,
Penelope A Kosinski
Affiliations:
Agios Pharmaceuticals, Inc.,Cambridge,United States
,
Lei Hua
Affiliations:
Agios Pharmaceuticals, Inc.,Cambridge,United States
,
Ann Barbier
Affiliations:
Agios Pharmaceuticals, Inc.,Cambridge,United States
Bertil Glader
Affiliations:
Stanford University School of Medicine,Palo Alto,United States
EHA Library. F Grace R. Jun 24, 2017; 181738; S451
Dr. Rachael F Grace
Dr. Rachael F Grace
Contributions
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Abstract

Abstract: S451

Type: Oral Presentation

Presentation during EHA22: On Saturday, June 24, 2017 from 11:30 - 11:45

Location: Room N109

Background
Pyruvate kinase (PK) deficiency is a congenital hemolytic anemia caused by deficiency of the glycolytic enzyme, red cell PK (PK-R). AG-348 is an orally available, small molecule, allosteric activator of PK-R that activates the wild-type and a range of mutated PK-R enzymes in vitro, and increases PK-R activity and restores adenosine triphosphate levels in red blood cells from patients with PK deficiency ex vivo.

Aims
To report on preliminary efficacy and safety data from the use of AG-348 in the ongoing DRIVE PK study (NCT02476916), an open-label dose-ranging trial of AG-348 in transfusion-independent adults with PK deficiency.

Methods
After providing informed consent, patients were randomized to AG-348 50 mg or 300 mg orally twice daily (BID) for 6 months (Core Period). At the end of the Core Period, patients can continue on treatment for another 2 years in the Extension Period. Transfusion independence is defined as ≤3 units of red blood cells transfused in the 12 months preceding the first dose of AG-348 and no transfusions in the 4 months preceding the first dose. Patients are followed weekly for Weeks 1–3, every 3 weeks for Weeks 4–12, monthly for Weeks 13–24 and then every 3 months until the end of the study. Hormone and iron status are evaluated at Baseline, Week 12 and End of Core Period, and then every 6 months in the Extension Period.

Results
As of 18 Jan 2017, goal enrolment has been met and all 52 patients are evaluable for safety and efficacy; 24 have completed the Core Period and 23 are ongoing in the Core Period. Five patients discontinued from the Core Period, owing to adverse events (AEs) (n=2) or consent withdrawal (n=3). Of the 24 subjects who completed the Core Period, 21 entered the Extension Period and 20 are still on treatment; 1 was discontinued by the investigator. Patients are currently receiving doses ranging between <25 mg BID and 300 mg BID. As of the previous data cutoff date of 23 Sep 2016 (where N=34), AG-348 had an acceptable AE profile, with headache (44%), nausea (41%) and insomnia (38%) being the most frequently reported events. Serum levels of sex steroids measured at Baseline, Week 12 and Week 24 in the Core Period demonstrated increases in free and total testosterone, and decreases in estradiol and estrone, consistent with the known effect of aromatase inhibition by AG-348. Of the 32 patients evaluable for efficacy at 23 Sep 2016, 15 (47%) had a maximal increase in hemoglobin (Hb) >1 g/dL. Hb responses were seen across a range of four doses, and were rapid and sustained. For a subset of patients (n=8), the rate of glycolytic metabolism in peripheral blood samples was assessed before and after treatment, and a positive correlation was observed between increases in glycolytic flux through the PK-R pathway and increases in Hb. Updates on safety, clinical efficacy measures (including Hb levels) and genotype–response correlations will be provided.

Conclusion
AG-348 is a novel, first-in-class PK-R activator undergoing clinical testing in patients with PK deficiency. The ongoing DRIVE PK study has now met goal enrolment of 52 patients, and data from these patients will be available at the time of presentation. Chronic daily dosing with AG-348 is well tolerated and has demonstrated clinically relevant, durable increases in Hb across a range of doses from <25 mg BID to 300 mg BID. These data highlight the potential of AG-348 to be the first disease-altering treatment for patients with PK deficiency.

Session topic: 27. Enzymopathies, membranopathies and other anemias

Keyword(s): Treatment, Hemolytic anemia, Clinical Trial

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