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Enzyme activator could be ‘disease-modifying’ treatment for pyruvate kinase deficiency

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Enzyme activator AG-348 sustained hemoglobin increases in adults with pyruvate kinase deficiency, according to updated data from a phase 2 trial presented at the Congress of the European Hematology Association in Madrid.

“Pyruvate kinase deficiency has not been studied extensively in the clinical setting and has no approved targeted therapies,” Rachael Grace, MD, director of the hematology clinic at Dana-Farber Boston Children’s Cancer and Blood Disorder Center, told HemOnc Today. “AG-348 has the potential to be the first disease-modifying treatment for patients with this lifelong anemia. DRIVE PK was designed as a phase 2 proof-of-concept study evaluating AG-348 in adults with pyruvate kinase deficiency. As of the data cutoff, findings from the study have demonstrated that AG-348 is well tolerated and induces clinically relevant, rapid and sustained hemoglobin increases in patients.”

Rachael Grace

Pyruvate kinase (PK) deficiency is a rare inherited disease that presents as hemolytic anemia, which is the accelerated destruction of red blood cells. Standard treatment for PK deficiency includes blood transfusions, splenectomy, chelation therapy to address iron overload, and interventions for other treatment- and disease-related morbidities. However, no approved therapy exists to treat the underlying cause of the disease.

AG-348 (Agios Pharmaceuticals) — which received FDA orphan drug designation in 2015 — is a first-in-class, orally available activator of pyruvate kinase-R enzymes.

DRIVE PK is an ongoing global, open-label safety and efficacy trial evaluating AG-348 in transfusion-independent adults with PK deficiency.

Enrollment in the trial ended in November 2016 and included 52 patients randomly assigned to a starting dose of 50 mg to 300 mg of AG-348 twice daily for 6 months, followed by 2 years of extended treatment.

At the March 27, 2017, cutoff, 15 patients remained in the initial 6-month treatment phase. Twenty-nine patients had completed the 6-month phase, 21 of whom remained in the 2-year extended treatment.

Patients had a baseline median hemoglobin level of 8.9 g/dL (range, 6.5-12.3). Forty-three patients (83%) received splenectomies prior to the study and 25 (48%) received prior iron chelation therapy.

At follow-up, 48% (n = 25) of all patients and 57% (n = 24) of patients with at least one missense mutation treated with AG-348 experienced a maximum hemoglobin increase from baseline of more than 1 g/dL.

Researchers observed rapid increases of hemoglobin; increases of more than 1 g/dL occurred after a median 10 days (range, 7-141). Baseline median hemoglobin was 9.7 g/dL (range, 7.5-12.3) in patients who achieved at least 1 g/dL increase compared with 8 g/dL (range, 6.5-10.1) in patients who did not.

Patients who achieved at least 1 g/dL increase in hemoglobin also demonstrated an increase in haptoglobin and decrease in lactate dehydrogenase in the first weeks of dosing, as well as rapid decreases in reticulocytes.

Researchers noted responses occurred across dose levels.

“I was surprised that the hemoglobin response to AG-348 is so rapid with a median time to hemoglobin response of 10 days from dose initiation,” Grace said. “I was also surprised that many patients had such a robust hemoglobin response that they required dose reductions of AG-348.”

Most treatment-related adverse events presented as grade 1 and grade 2 and included headache (44%), insomnia (38%) and nausea (41%). Three patients discontinued treatment due to chest discomfort/pleural effusion, pharyngitis/nausea and anemia. Five patients experienced drug-related adverse events, including anemia, withdrawal hemolysis followed by anemia, osteoporosis, hypertriglyceridemia and pharyngitis.

“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,” Chris Bowden, MD, chief medical officer at Agios, said in a press release, adding that a global pivotal program is planned for the first half of 2018.

Findings from DRIVE PK are being used to design a global pivotal Phase 3 study planned for the first half of 2018, Grace said.

“The Pyruvate Kinase Deficiency Natural History Study is collecting observational data in a large international cohort of patients with PK deficiency, and we hope the information we learn from this registry will help with the creation of future management guidelines,” Grace told HemOnc Today. – by Chuck Gormley

Reference:

Grace RF, et al. Abstract S451. Presented at: Congress of European Hematology Association; June 22-25, 2017; Madrid.