Mitapivat Shows Promise for Sickle Cell Disease in Phase 2 RISE UP Trial


Results of the phase 2 RISE UP trial offer additional perspective into the benefit-risk profile of mitapivat in patients with sickle cell disease.

Modupe  Idowu, MD | Credit: UT Health

Modupe Idowu, MD
Credit: UTHealth

Data from the phase 2 RISE UP trial are offering further insight into the potential of mitapivat (Pyrukynd) in management of sickle cell disease (SCD).

Presented at the 65th American Society of Hematology (ASH) Annual Meeting, data from the study provide an overview of the safety and efficacy of mitapivat in its first placebo-controlled trial among patients with SCD.1

“These data suggest that mitapivat, through its dual mechanism of action, may provide clinical benefit to patients with SCD and support continued development in the phase 3 portion of the RISE UP trial,” wrote investigators.1

A pyruvate kinase activator marketed by Agios Pharmaceuticals Inc., mitapivat was approved by the US Food and Drug Administration in February 2022 for the treatment of hemolytic anemia in adults with pyruvate kinase deficiency based on the results of the ACTIVATE and ACTIVATE-T studies.2 A first-in-class agent administered orally in the form of a tablet, the development program for mitapivat also included in a phase 1 proof-of-concept trial in SCD. In this trial, treatment with mitapivat was associated with increasing Hb concentrations, restoration of the thermostability of PKR, and decreasing 2,3-diphosphoglycerate (2,3-DPG) levels in sickle erythrocytes.

In the ASH 2023 study, which was led by Modupe Idowu, MD, professor in the Department of Internal Medicine with McGovern Medical School at UTHealth Houston and medical director of the UT Physicians Adult Sickle Cell Center, investigators proved insight into the effects of mitapivat from the double-blind period of the phase 2/3 RISE UP trial. The first placebo-controlled trial assessing the effects of mitapivat in patient with SCD, the study enrolled patients aged 16 years or older with a hemoglobin (Hb) level of 5.5 to 10.5 g/dL Hb and 2 to 10 sickle cell pain crises in the year prior to entry.

In the double-blind period of the phase 2 portion of the trial, 2 dose levels of mitapivat were evaluated against placebo for 12 weeks, with Hb response and adverse events, including type, severity, and relationship to study drug, serving as primary endpoints of interest. For the purpose of analysis, investigators defined an Hb response as a 1.0 g/dL increase or greater in average Hb concentrations from weeks 10 through 12 compared with baseline.

Overall, 79 patients were enrolled in the double-blind period. Of these, 26, 26, and 27 were randomized to mitapivat 50 mg twice daily, mitapivat 100 mg twice daily, and placebo therapy, respectively. In the mitapivat 50 mg, mitapivat 100 mg, and placebo arms, the mean age was 29.9 (Standard Deviation [SD], 7.79), 30.2 (SD, 10.52), and 28.5 (SD, 10.30) years, respectively. As it pertains to patient sex, 57.7%, 61.5%, and 74.1% of the mitapivat 50 mg, mitapivat 100 mg, and placebo arms were female. Investigators also pointed out the mean number of sickel cell pain crises during the previous year were 3.1 (SD, 1.83), 3.2 (SD, 1.65), and 3.4 (1.91), respectively.1

Results of the primary endpoint analysis indicated a Hb response was achieved in 46.2% of the mitapivat 50 mg arm, 50.0% of the mitapivat 100 mg arm, and 3.7% of the placebo arm (2-sided P=.0003 and P=.0001, respectively). Further analysis suggested the annualized rates of sickle cell pain crises for patients among the mitapivat 50 mg and mitapivat 100 mg arms were 0.83 (95% Confidence interval [CI], 0.34-1.99) and 0.51 (95% CI, 0.16-1.59), respectively, compared to 1.71 (95% CI, 0.95-3.08) for patients among the placebo arms.1

Analysis of adverse events revealed there were no adverse events leading to discontinuation in the double-blind period of the trial and the safety profile for mitapivat was generally consistent with previously reported data in other studies of sickle cell disease and other hemolytic anemias. Of the 79 patients in the double-blind portion of the phase 2 trial, 73 continued into the open-label extension period.1

“It gives me great satisfaction to see the positive results from the Phase 2 portion of the RISE UP study. Mitapivat has a high potential to address aspects of the disease of greatest concern to patients,” said Idowu, in a June 2023 statement from Agios Pharmaceuticals announcing phase 2 results.3 “Sickle cell disease is a complex and debilitating disease characterized by anemia, pain crises, fatigue, cognitive effects and more. The sickle cell community is in dire need of effective disease-modifying therapies – particularly novel oral therapies – to address these unmet needs. I look forward to continuing the Phase 3 RISE UP study and am hopeful this will deliver a potential new treatment option for sickle cell warriors.”


  1. Idowu M, Otieno L, Dumitriu B, et al. A Phase 2/3, Double-Blind, Randomized, Placebo-Controlled, Multicenter Study of Mitapivat in Patients with Sickle Cell Disease: RISE UP Phase 2 Results. Presented at: December 9-12, 2023. San Diego, CA.
  2. Pilo F, Angelucci E. Mitapivat for sickle cell disease and thalassemia. Drugs Today (Barc). 2023;59(3):125-134. doi:10.1358/dot.2023.59.3.3521880
  3. Agios Pharmaceuticals, Inc. Agios announces positive results from phase 2 portion of rise up pivotal study in sickle cell disease with both Mitapivat dose arms achieving statistically significant hemoglobin response. Agios Pharmaceuticals, Inc. June 26, 2023. Accessed December 8, 2023.
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