First-in-Class Drug Thwarts Hemolytic Anemia in Adults With PK Deficiency

Treatment with mitapivat (Pyrukynd) increased hemoglobin levels and decreased hemolysis in patients with pyruvate kinase (PK) deficiency who did not require regular blood transfusions, the randomized ACTIVATE trial showed.

For the phase III study’s primary endpoint, 40% of patients randomized to oral mitapivat — a first-in-class erythrocyte PK activator — had a hemoglobin response at 24 weeks versus none of those assigned to placebo (P<0.001), reported Hanny Al-Samkari, MD, of Massachusetts General Hospital in Boston, and colleagues.

Patients in the mitapivat group had a significantly greater change in hemoglobin level from baseline to weeks 16, 20, and 24 — a key secondary endpoint — compared with those in the placebo group (least squares mean [LSM] change of 1.7 g/dL vs -0.1 g/dL, respectively; P<0.001), according to findings published in the New England Journal of Medicine.

All other secondary endpoints favored the mitapivat group as well, including average change from baseline in levels of indirect bilirubin, lactate dehydrogenase (LDH), and haptoglobin, as well as average change in percentage of reticulocytes.

“Mitapivat significantly increased hemoglobin levels and improved hemolysis, hematopoiesis, and measures of health-related quality of life in a substantial minority of this patient population by specifically targeting the underlying enzymatic defect,” the group wrote.

Characterized by mutations in the PKLR gene, PK deficiency is a rare hereditary condition that causes premature red blood cell destruction, leading to anemia, and is estimated to affect anywhere from three to nine in every million individuals.

Symptoms of the condition may include unusually pale skin or jaundice, shortness of breath, and an accelerated heart rate, “along with serious complications that include gallstones, pulmonary hypertension, thrombotic complications, osteoporosis, and iron overload,” explained Al-Samkari and co-authors.

“These complications may occur regardless of the degree of anemia or whether a patient receives red-cell transfusions,” they added. “Independent of complications, chronic anemia itself in patients with pyruvate kinase deficiency is often severe, resulting in highly limiting constitutional symptoms and fatigue.”

Management of PK deficiency can consist of splenectomy or repeated red-cell transfusions, but both are considered supportive therapies and can carry short- and long-term risks.

Results from ACTIVATE and ACTIVATE-T — a single-arm phase III trial involving patients with PK deficiency who did require regular blood transfusions — supported the recent FDA approval of mitapivat as a treatment for hemolytic anemia in adults with PK deficiency.

In ACTIVATE, there were no dose discontinuations, interruptions, or reductions among patients randomized to mitapivat. Common adverse events (AEs) of any grade between the mitapivat and placebo groups, respectively, included nausea (18% vs 23%) headache (15% vs 33%), nasopharyngitis (12% vs 15%), fatigue (12% vs 10%), back pain (12% vs 8%), diarrhea (10% vs 18%), dizziness (10% vs 8%), and abdominal pain (10% vs 5%).

Grade ≥3 AEs occurred in 25% of patients in the mitapivat group versus 13% of placebo patients, and serious AEs occurred in 10% and 5%, respectively.

The international phase III trial randomized 80 adults with PK deficiency who were not receiving regular blood transfusions 1:1 to either 24 weeks of mitapivat (5 mg twice daily, which could be escalated to 20-50 mg twice daily) or placebo. The primary endpoint of hemoglobin response was defined as a minimum 1.5 g/dL increase over baseline in hemoglobin level that was maintained at two or more later assessments (at weeks 16, 20, or 24).

Patients were eligible if they had adequate organ function, a hemoglobin level of ≤10.0 g/dL, and two mutant alleles in PKLR, with one being a missense mutation, to confirm PK deficiency.

Based on findings from the phase II DRIVE-PK study showing lack of response in patients who only had non-missense mutations or who were homozygous for a PKLR R479H mutation, these individuals were excluded from ACTIVATE. Other exclusion criteria included planned splenectomy, or a splenectomy in the past year, and prior bone marrow or stem-cell transplantation.

Patients had a median age of 36-37 years, 60% were women, and 73% had undergone prior splenectomy and cholecystectomy. Their baseline hemoglobin level was 8.5-8.6 g/dL, ferritin level was 688-748 μg/L, indirect bilirubin level was 82-89 μmol/liter, LDH level was 260-348 U/L, haptoglobin level was 0.08 g/L, and the percentage of reticulocytes was 37.1-40.1%.

From baseline to weeks 16, 20, and 24, mitapivat led to significant LSM changes versus placebo for:

• Indirect bilirubin: -26.3 μmol/L (95% CI -37.8 to -14.7)
• LDH: -70.8 U/L (95% CI -115.9 to -25.7)
• Haptoglobin: 0.16 g/L (95% CI 0.04-0.27)
• Reticulocytes: -10.1% (95% CI -13.9 to -6.3)

Patient-reported scores on the PK deficiency diary and PK deficiency impact assessment both significantly favored the mitapivat group as well.