Written By: Pharmacally Medical News Desk
Agios announced topline data from the Phase 3 RISE UP trial evaluating oral pyruvate kinase activator Mitapivat in patients with sickle cell disease aged 16 years and older. The company reported that the study met its primary hemoglobin response endpoint and two key hemolysis‑related secondary endpoints, while showing only a non‑significant trend toward fewer sickle cell pain crises and no benefit on fatigue. Agios plans to share the full data package with the U.S. FDA and is preparing a regulatory submission for potential U.S. approval in sickle cell disease.
RISE UP Trial
RISE UP is a global, double‑blind, randomized, placebo‑controlled Phase 3 trials that enrolled 207 patients with sickle cell disease aged 16 years or older. Patients were randomized in a 2:1 ratio to receive Mitapivat 100 mg twice daily or matched placebo for a 52‑week double‑blind treatment period. The trial was designed with two co‑primary endpoints and five key secondary endpoints to capture both objective markers of hemolysis and broader clinical outcomes such as pain crises, hospitalizations, and patient‑reported fatigue.
Primary endpoints: hemoglobin and pain crises
The RISE UP trial incorporated two primary efficacy endpoints: hemoglobin response and annualized rate of sickle cell pain crises (SCPCs). Hemoglobin response was rigorously defined as at least a 1.0 g/dL increase from baseline in average hemoglobin concentration measured from Week 24 through Week 52. The co‑primary clinical endpoint, annualized SCPC rate, captured vaso‑occlusive events requiring medical attention over the 52‑week treatment period.
Mitapivat achieved statistical significance on the hemoglobin response endpoint, with 40.6% of treated patients meeting the response definition compared with 2.9% on placebo, representing a strongly positive result. On the other hand, while Mitapivat numerically reduced the yearly rate of sickle cell pain crises versus placebo, this reduction did not cross the threshold for statistical significance in the intention‑to‑treat analysis, meaning the second co‑primary endpoint was not officially met.
Key secondary endpoints and hemolysis markers
Among the five prespecified key secondary endpoints, Mitapivat demonstrated statistically significant benefit on hemoglobin levels and indirect bilirubin, a marker of hemolysis, but did not meet the fatigue endpoint. The average change from baseline in hemoglobin concentration from Week 24 through Week 52 favored Mitapivat by 7.69 g/L versus 0.26 g/L with placebo, with a highly significant p‑value. Indirect bilirubin levels also decreased significantly with Mitapivat, indicating reduced ongoing red blood cell destruction and improvement in hemolytic burden.
The trial further reported improvements in percent reticulocyte levels, with Mitapivat showing a more pronounced reduction in reticulocytosis compared with placebo, consistent with lower hemolytic stress and more effective erythropoiesis. However, the key secondary endpoint evaluating mean change from baseline in the PROMIS Fatigue 13a score from Week 24 through Week 52 was not met, suggesting that objective hematologic improvements did not uniformly translate into a statistically significant benefit in patient‑reported fatigue across the entire study population.
Post hoc analysis of hemoglobin responders
A prespecified or exploratory post hoc analysis focused on patients in the Mitapivat arm who achieved the primary hemoglobin response threshold. In this responder subgroup, clinically meaningful reductions in the annualized rate of sickle cell pain crises and hospitalizations for SCPCs were observed compared with non‑responders, with a rate ratio of 0.74 for crises and similar benefit for crisis‑related hospitalizations. Hemoglobin responders also showed better PROMIS Fatigue outcomes than non‑responders, suggesting that patients deriving robust hematologic benefit may experience broader clinical and quality‑of‑life gains.
These responder‑level findings support the biological plausibility that increasing hemoglobin and improving red blood cell health can meaningfully impact painful vaso‑occlusive events and fatigue, even though the overall trial failed to meet statistical significance for SCPC rate and fatigue in the full randomized cohort. Such post hoc data are hypothesis‑generating and cannot replace a formally positive primary endpoint, but they may inform regulatory review and clinical positioning if Mitapivat reaches the market.
Safety profile and tolerability
Mitapivat safety profile in RISE UP was described as favorable and consistent with earlier sickle cell disease studies of the agent. The incidence and nature of treatment‑emergent adverse events were reportedly similar to prior Mitapivat programs, with no new safety signals emerging over the 52‑week double‑blind period. Prior open‑label and Phase 2 data have already indicated that long‑term Mitapivat use in sickle cell disease is generally well tolerated, supporting its potential as a chronic maintenance therapy.
About Mitapivat (Pyrukynd)
Mitapivat is a first‑in‑class, oral allosteric activator of red blood cell pyruvate kinase (PKR), a key glycolytic enzyme responsible for the conversion of phosphoenolpyruvate to pyruvate with concomitant ATP generation. By activating PKR, Mitapivat increases intracellular ATP and lowers levels of 2,3‑diphosphoglycerate (2,3‑DPG), shifting hemoglobin oxygen affinity and improving red blood cell energy balance. In sickle cell disease, this combined effect has been shown ex vivo and in early clinical studies to reduce red blood cell sickling, improve PKR thermostability, and decrease the partial pressure of oxygen at which cells begin to sickle.
Regulatory implications
Despite the mixed profile on primary clinical endpoints, Agios intends to file for U.S. regulatory approval of Mitapivat in sickle cell disease, leveraging the robust hemoglobin and hemolysis data, favorable safety, and responder analyses linking hematologic benefit with fewer crises and improved fatigue.
Sarah Gheuens, M.D., Ph.D., Chief Medical Officer and Head of R&D at Agios, stated that the RISE UP Phase 3 results reinforce mitapivat’s strong anti-hemolytic effects, which can help tackle debilitating symptoms of sickle cell disease and improve quality of life. She emphasized plans to engage with the FDA to bring this innovative treatment to patients, thanking the RISE UP community for their invaluable contributions.
Biree Andemariam, M.D., Professor of Medicine at University of Connecticut Health and RISE UP investigator, highlighted that Mitapivat significantly improved hemoglobin levels and reduced hemolysis. She noted that patients meeting the hemoglobin response threshold experienced meaningful benefits in pain crisis rates, hospital visits, and fatigue, supporting mitapivat’s potential as a novel treatment for sickle cell disease.
Reference
Agios Announces Topline Results from RISE UP Phase 3 Trial of Mitapivat in Sickle Cell Disease, 19 Nov 2025, Agios, https://investor.agios.com/news-releases/news-release-details/agios-announces-topline-results-rise-phase-3-trial-mitapivat
A Study Evaluating the Efficacy and Safety of Mitapivat (AG-348) in Participants with Sickle Cell Disease (RISE UP), ClinicalTrials.gov ID NCT05031780, https://www.clinicaltrials.gov/study/NCT05031780
Idowu, Modupe et al., Safety and efficacy of mitapivat in sickle cell disease (RISE UP): results from the phase 2 portion of a global, double-blind, randomised, placebo-controlled trial, The Lancet Haematology, Volume 12, Issue 1, e35 – e44
Agios Announces Topline Results from RISE UP Phase 3 Trial of Mitapivat in Sickle Cell Disease, 19 November 2025, Globe Newswire, https://www.globenewswire.com/news-release/2025/11/19/3190791/31990/en/Agios-Announces-Topline-Results-from-RISE-UP-Phase-3-Trial-of-Mitapivat-in-Sickle-Cell-Disease.html
PYRUKYND® (mitapivat), Highlights of Prescribing Information, https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/216196s000lbl.pdf