Response to Mitapivat: A Quinolone Sulfonamide to Manage Hemolytic Anemia in Adults With Pyruvate Kinase Deficiency

To the Editor:

The article “Mitapivat: A Quinolone Sulfonamide to Manage Hemolytic Anemia in Adults With Pyruvate Kinase Deficiency” by Wills et al and published in the American Journal of Therapeutics,¹ is an overview of mitapivat treatment in adults with pyruvate kinase (PK) deficiency; however, it contains incorrect statements that should be corrected.

Authors write “Mitapivat is the first approved therapy indicated for hemolytic anemia in adults with PK deficiency with the potential for delaying splenectomy in mild–moderate disease and is currently under investigation for beta-thalassemia and sickle cell disease. Coadministration of folic acid is used to avoid folate deficiency.” These statements should be revised to accurately reflect information in the approved label and to correct language for indications under investigation. Mitapivat is approved in the United States by the Food and Drug Administration for the treatment of hemolytic anemia in adults with PK deficiency.² The “potential for delaying splenectomy in mild-moderate disease” should be removed because this is not part of the approved indication; this has not been tested, nor do the authors provide any evidence-based data to support their statement. In addition, the approved label does not include language requiring coadministration of folic acid.² Mitapivat is currently under investigation in pediatric PK deficiency, thalassemia (both alpha and beta), and sickle cell disease.^3–7

Wills et al state “Pivotal trials that serve the primary focus throughout this article are ACTIVATE, ACTIVATE-T, and RISE.” The correct name of the phase 2/3 study evaluating the efficacy and safety of mitapivat in participants with sickle cell disease is RISE UP.⁷ The description “adults with sickle cell disease” is incorrect, as the RISE UP study population includes individuals “age 16 years or older (18 years or older [France and Germany]).”⁷

In addition, incorrect data were reported for DRIVE PK, “sustained response up to 35 weeks” is reported when the correct published time frame is “up to 35 months.”⁸

The CLINICAL TRIALS section contains inaccurate statements and editorial mistakes. The ACTIVATE takeaway is incorrect. Authors summarize that “Overall, mitapivat proved to be a safe and efficacious molecule while increasing hemoglobin in patients with no infusion history.” In fact, eligibility criteria for the ACTIVATE trial allowed up to 4 transfusion episodes in the previous year and no transfusion episodes within 3 months before randomization; 28% of patients in the mitapivat arm and 25% of patients in the placebo arm received 1 or more transfusions in the year prior.^2,9 In the ACTIVATE-T subsection, the authors begin with “Because mitapivat was effective in adult patients with PK deficiency who were not receiving regular transfusions (ACTIVATE), ACTIVATE-T aimed to…” implying the ACTIVATE-T clinical trial was conducted after ACTIVATE. This is incorrect: ACTIVATE and ACTIVATE-T ran concurrently. The last sentence of the ACTIVATE-T subsection states “Overall, investigators found mitapivat to be pivotal in reducing transfusion burden in some adults with PK deficiency because they received regular transfusion.” This statement is incorrect and misleading; the study met its primary end point, a reduction in transfusion burden (defined as ≥33% reduction in number of red blood cell units transfused during the fixed-dose period, compared with the participant's individual historical transfusion burden, standardized to 24 weeks) was found in 10 patients (37%) (P = 0.0002).^2,10 The entire subsection titled “RISE UP” does not describe the RISE UP phase 2/3 clinical trial, but rather describes a phase 1 dose escalation study in adults with sickle cell disease; this subsection should be revised to accurately report and reference the information the authors intended to describe.^2,11

Important key statements about safety are absent. Authors should review the approved label for language. References in the SAFETY PROFILE section are not correct. The reference the authors cite for the DRIVE PK phase 2 efficacy and safety data (reference 25) is the ACTIVATE phase 3 efficacy and safety publication; the correct reference would be Grace et al.⁸ Similarly, the reference the authors cite for the ACTIVATE-T trial (reference 24) is a congress abstract focusing on iron overload. For their statement on bone mineral density, the authors cite a congress abstract on maintenance of effect (reference 26); absolutely no bone mineral density–related safety information is included in this citation. References should be revised to support the statement the authors are making. A recent publication (Al-Samkari et al)¹² should be considered.

Several statements made by Wills et al in the COST-BENEFIT ANALYSIS section are not correct. The authors cite a cost of illness study developed by Agios and incorrectly state “the main cost-drivers are the adoption rate and acquisition cost of mitapivat along with that of chelation, recurrent phlebotomy, transfusions, procedures, monitoring, hospitalization, and costs associated with complications.” Mitapivat was not included in this analysis, as it was conducted before regulatory approval. The presentation cited states the main cost drivers were (1) the utilization rate and cost of chelation therapies, (2) cost and frequency of transfusions, and (3) cost associated with disease-related complications.¹³ The authors go on to report that mitapivat is approximately $28,000 monthly ($336,000/year) “at most retail pharmacies”; however, mitapivat is not available at any retail pharmacies; it is only available through a specialty pharmacy. The last paragraph states “Most patients in clinical trials to date had low hemoglobin levels, recurrent and necessary transfusions, and high rates of splenectomy and cholecystectomy, indicating a patient population with severe anemia (phase 3 ACTIVATE trial) under careful management. The ENERGIZE trial inclusion criteria included beta or alpha-thalassemia and need for transfusions while…” These sentences are not accurate; most patients in ACTIVATE did not have “recurrent and necessary transfusions”⁹ and the ENERGIZE trial included patients with non–transfusion-dependent thalassemia.⁶

Errors contained in the Wills et al article should be corrected to minimize any potential negative consequences resulting from the incorrect content and to ensure that readers have accurate information needed to make informed health care decisions, and disease management and treatment plans.