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In a small study, the allosteric pyruvate kinase (PK) modulator mitapivat (Pyrukynd) was effective in treating hemolytic anemia in patients with α-thalassemia and β-thalassemia who are not dependent on transfusions.

Sixteen of the 20 patients (80%) had a hemoglobin response -- defined as an increase of 1.0 g/dL or more in hemoglobin concentration from baseline -- when treated with mitapivat, reported Kevin H.M. Kuo, MD, of the University of Toronto in Ontario, and colleagues.

The study "establishes proof of concept that activation of PK by the oral agent mitapivat improves anaemia in patients with [non-transfusion-dependent] α-thalassemia and β-thalassemia," Kuo and colleagues wrote in , adding that the efficacy and safety results "provide rationale for the continued investigation of mitapivat for the treatment of both α-thalassemia and β-thalassemia."

A total of 15 of the patients had β-thalassemia and five α-thalassemia. All five of the latter had a hemoglobin response, along with 11 of the 15 (73%) with β-thalassemia.

Nineteen (95%) patients completed the core treatment period in which they were given a starting dose of oral mitapivat 50 mg twice daily for the first 6 weeks of the 24-week core study period. If the drug was well tolerated, the dose was escalated to 100 mg twice daily.

One patient who had β-thalassemia discontinued after week 4 due to a treatment-emergent adverse event (TEAE) unrelated to mitapivat. All patients except the one who discontinued early received an escalated dose of mitapivat at week 6.

Of the 16 patients with a primary hemoglobin response, 13 had a response while receiving 50 mg twice daily in the first 6 weeks, and three had a response while receiving 100 mg twice daily in the following 6 weeks. Additionally, a delayed hemoglobin response (after week 12 and after dose increase to 100 mg twice a day) was observed in two patients, both of whom had β-thalassemia.

In a , Antonis Kattamis, MD, of the National and Kapodistrian University of Athens School of Medicine, wrote that while the study was "restricted both in the number of participating patients and the length of observation," the "results are undeniably positive."

He did raise several questions, including that of an optimal dose, which he suggested needs further assessment.

The differences in mean change in hemoglobin concentration from baseline after increasing the dose at week 6, suggest "there is no linear dose–efficacy correlation," Kattamis wrote.

"Although the safety profile seems similar between 50 mg and 100 mg dosing, increased doses might not be necessary for response and might affect long-term compliance," he continued. "Furthermore, should the drug be approved, the treatment at an increased dose will be associated with increased costs, which might be difficult to cover by different health systems, especially in countries with low resources, where many patients with thalassemia reside."

Kuo and co-authors noted that mitapivat's safety profile was similar to that seen in previous studies. A total of 17 patients had a TEAE during the core period, with 13 considered to be treatment related.

The most commonly reported TEAEs (occurring in ≥10% of patients) were initial insomnia, dizziness, and headache, with median durations of 34 days for initial insomnia, 2 days for dizziness, and 14.5 days for headache. Grade 3 or worse TEAEs were reported in five patients and included initial insomnia, arthralgia, renal impairment, anemia, and positional vertigo. Initial insomnia was the only grade 3 or worse TEAE considered to be treatment related.

The researchers noted that non-transfusion-dependent thalassemia is of increasing global significance because of the migration of individuals from areas of high incidence of the disease -- such as the Mediterranean and southeast Asia -- to areas that have typically had low incidences, such as the U.S. and U.K. In addition, the authors said, non-transfusion-dependent thalassemia is one of the most frequent hemoglobinopathies identified in some screening programs for newborns.

While regular blood transfusions are not required for survival in these patients, they "still have a substantial burden of disease-related comorbidities and complications and a reduced quality of life," the investigators said.

The open-label phase II study was conducted at four academic clinical sites in North America and the U.K. between December 2018 and February 2020. Patients were eligible if they were age 18 or older, had non-transfusion-dependent thalassemia (including β-thalassemia with or without α-globin gene mutations, hemoglobin E β-thalassemia, or α-thalassemia), and a baseline hemoglobin concentration of 10.0 g/dL or lower.

The median age of patients at baseline was 44, and the majority (75%) were female. All patients with α-thalassemia were of Asian race and a third of patients with β-thalassemia identified as Asian.

Study limitations, the researchers said, included the single-arm, open-label design without a control group and the small number of participants. In addition, the researchers didn't perform hypothesis testing on changes in markers of hemolysis and erythropoietin, and the sequential dose escalation prevented definitive inferences regarding dose-dependent effects.

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