Mitapivat for sickle cell disease: the time is ripe for a new therapy

Introduction

Sickle cell disease (SCD) is an inherited hemoglobinopathy that causes significant morbidity and premature mortality. Clinically, SCD is characterized by complications such as acute and chronic pain, acute chest syndrome, stroke, kidney disease, pulmonary hypertension, and avascular necrosis, among many others (1). Despite major advances in supportive care and the routine use of hydroxyurea, the modern therapeutic landscape for SCD is unstable. In 2024, voxelotor was withdrawn globally after safety concerns emerged (2). Earlier, crizanlizumab lost its authorization in the European Union after a confirmatory trial failed to show a clinical benefit (3,4). Even with these agents, the unmet need in SCD was substantial, and now it is even more pronounced.

A discussion of therapeutics in SCD would be incomplete without mentioning the growing promise of gene therapy as a functionally curative approach. With two new gene therapies approved by the U.S. Food and Drug Administration now available for SCD, it may seem as though the problem is largely solved (5,6). However, there are major practical limitations to gene therapy. In real-world practice, only a small fraction of patients will be able to access the intensive and expensive infrastructure needed to deliver gene therapy. Gene therapy requires myeloablative conditioning, imparting a lifelong cancer risk and causing sterility. Furthermore, these therapies are extremely expensive, costing over $2 million for a single patient, while the burden of SCD overwhelmingly occurs internationally and in resource-limited settings (1,7). Although research efforts are under way to develop in vivo gene therapy, which may eventually broaden the reach of genetic medicines, today gene therapy is inaccessible to the vast majority of patients with SCD (8,9). To deliver population-level impact today, safe oral therapies are greatly needed.

The absence of universally accepted clinical endpoints complicates the study of therapeutics in SCD. The most patient-centered endpoint for sickle cell trials—pain—is subjective, difficult to measure, and influenced by environmental factors and social context (10). There remains no reliable biomarker that tracks significantly with vaso-occlusive episodes. Moreover, major longitudinal objective outcomes like stroke, organ failure, or death are not feasible endpoints in time-limited clinical trials.

In this context, pyruvate kinase (PK) activators have broad appeal. PK activators target red cell biology through mechanisms that are biologically plausible to improve hemolysis and vaso-occlusion, and may translate into improvements in clinical outcomes that matter to patients. Here, we examine the RISE UP trial studying mitapivat in SCD and provide insight into its strengths, limitations, and implications in the evolving landscape of SCD management.

Mitapivat and RISE UP

Mitapivat is an oral PK activator that affects red cell metabolism in two important ways. First, it increases adenosine triphosphate (ATP) and supports membrane integrity and red cell resilience under stress (11-13). Second, it decreases 2,3-diphosphoglyceric acid (2,3-DPG), thereby increasing hemoglobin oxygen affinity and reducing hemoglobin S (HbS) polymerization under low oxygen tension (14). Early-phase studies of multiple different PK activators have reliably demonstrated these effects, as well as in improvements in red cell deformability (15,16).

RISE UP is a phase 2/3 international double-blind, randomized, placebo-controlled trial evaluating mitapivat in patients with SCD (17). In this trial, patients 16 years or older with baseline anemia and a recent history of vaso-occlusive events were eligible. Patients on a stable dose of hydroxyurea were allowed, while those on regular transfusions or other SCD medications (L-glutamine or crizanlizumab) were excluded. In the phase 2 portion of the trial, 79 patients were randomized 1:1:1 to mitapivat 50 mg, mitapivat 100 mg, or placebo, twice daily. The primary endpoint was a hemoglobin response, defined as an increase in hemoglobin of at least 1 g/dL on average from baseline during weeks 10–12.

The phase 2 portion of the RISE UP trial met its primary endpoint. Hemoglobin response occurred in 46% (12 of 26) of the 50 mg group and 50% (13 of 26) of the 100 mg group, compared to 4% (1 of 27) in the placebo arm. Additionally, improvements were observed in markers of hemolysis and erythropoiesis. Fatigue [as assessed by the Patient-Reported Outcomes Measurement Information System (PROMIS) Fatigue 13a Short Form] improved from baseline in the 50 mg treatment group but did not significantly change from baseline in the 100 mg group. Although the study was not powered for vaso-occlusive events, the improvements seen in the mitapivat groups relative to the placebo group—a dose-dependent reduction in annualized vaso-occlusive event rate of approximately 50% and 70% for the mitapivat 50 mg group and mitapivat 100 mg group, respectively—were striking and the headlining result for many. As it has been in many prior studies in PK deficiency and thalassemia, mitapivat was well tolerated. The most common adverse events included headache, arthralgia, nausea, fatigue, and flu-like symptoms (notably, these were at least as common with placebo as with mitapivat), and no serious adverse events were attributed to mitapivat. Notably, liver toxicity—which was reported in thalassemia trials—was not observed in RISE UP (18).

The HIBISCUS trial was a separate randomized, placebo-controlled phase 2 clinical trial of another PK activator, etavopivat. In the intent-to-treat analysis, etavopivat was associated with higher rates of hemoglobin response and lower annualized vaso-occlusive episode rates than placebo, although the reduction in vaso-occlusive events was not statistically significant. These findings provide supportive preliminary evidence that PK activators may improve anemia and potentially reduce vaso-occlusive events in SCD (19). However, as seems to be unavoidable in SCD drug development, the picture was clouded somewhat with the recent announcement of the topline results of the phase 3 portion of RISE UP, which included 176 patients. This study had co-primary endpoints of both hemoglobin and vaso-occlusive events. The study was positive, meeting the primary hemoglobin endpoint, but unfortunately did not meet the vaso-occlusive event co-primary (20). Change from baseline in PROMIS fatigue score was not statistically significant. Importantly, in a post-hoc subgroup analysis, hemoglobin responders did have statistically significant reductions in vaso-occlusive episodes, hospitalizations, and fatigue. As post-hoc analyses, these results must be interpreted cautiously, but it is certainly plausible that those 40–50% of hemoglobin responders may also reap the benefits of less vaso-occlusion and fewer hospitalizations. The percent of responders in RISE UP phase 3 was very similar to that observed in ACTIVATE, ACTIVATE-T, and ENERGIZE, the pivotal phase 3 trials of mitapivat in PK deficiency and thalassemia (18,21-23). Furthermore, prior studies of mitapivat in PK deficiency and thalassemia have clearly shown greater improvements in a wide range of relevant clinical endpoints such as markers of hemolysis, erythropoiesis, and iron homeostasis; similar post hoc analyses have demonstrated greater improvements in patient-reported outcomes (PROs) among protocol-defined responders as compared with nonresponders (24-26).

However, the absence of a statistically significant reduction in vaso-occlusive episodes in the primary analysis warrants consideration of the mechanistic uncertainties associated with mitapivat. Prior commentaries have raised the concern by lowering 2,3-DPG and thereby increasing oxygen affinity; mitapivat could theoretically worsen tissue hypoxia and offset anti-sickling effects, blunting the potential for clinical benefit (27-29). It is therefore reasonable to ask whether the modest signal for improving vaso-occlusion in the Phase 3 trial may reflect this phenomenon. At the same time, several considerations support the biological plausibility that mitapivat could reduce vaso-occlusive episodes among hemoglobin responders. First, its effects are not limited to reducing 2,3-DPG. Mitapivat also increases erythrocyte ATP and may improve membrane stability through the maintenance of red blood cell (RBC) hydration and through the reduction of band 3 phosphorylation on the RBC membrane, introducing additional mechanisms by which it could mitigate vaso-occlusion (30-33). Second, the phase 2 portion of the RISE UP trial showed no increase in erythropoietin levels among those treated with mitapivat compared to placebo. Although erythropoietin is an imperfect marker for tissue hypoxia in SCD, this finding offers at least some reassurance that treatment does not substantially worsen hypoxia (17). Ultimately, how the balance of these mechanistic considerations translates to clinical outcomes remains uncertain. We await the full results from the phase 3 portion of RISE UP in order to draw more firm conclusions about these data.

Moving forward

Taken together, the phase 2 and 3 results of RISE UP suggest that mitapivat effectively raises hemoglobin in patients with SCD and may reduce sickle cell pain crises (SCPCs) in those with a hemoglobin response. This signal in SCPC reduction, however, comes from a post-randomization subgroup analysis and therefore may be confounded by factors such as baseline phenotype, adherence, and underlying genetic heterogeneity. In particular, differences in α- and β-globin genotypes, co-inherited enzymopathies such as glucose-6-phosphate dehydrogenase deficiency, and baseline fetal hemoglobin could conceivably influence both the likelihood of hemoglobin response and the risk of SCPCs. Post-hoc subgroup analyses are also vulnerable to inflation of type I error if multiple comparisons are not appropriately accounted for, as well as other statistical artifacts such as chance imbalances (34). The mature phase 3 dataset will be important for a complete analysis, including an examination of potential differences in characteristics between responders and non-responders.

The nuances in defining and measuring SCPC are worth discussing. RISE UP, like many other trials, relies on healthcare encounter-driven SCPC events, which are difficult to standardize between institutions (let alone across countries) even with adjudication. Many people with SCD manage significant vaso-occlusive pain at home and may experience substantial pain that is not quantified or captured using typical trial endpoints. This may explain why, in the phase 2 trial for crizanlizumab, there was a discordance between the primary SCPC endpoint and the pain PROs; interestingly, while the primary pain endpoint was met, the pain PRO (using the Brief Pain Inventory questionnaire) did not significantly improve (35). Indeed, the phase 3 trial for crizanlizumab may have been affected by the inability to fully capture the spectrum of pain manifestations, which has been proposed as one possible explanation for its negative results despite the positive phase 2 trial, particularly in the context of the coronavirus disease 2019 pandemic and its likely effects on care-seeking behavior (4,36). In these scenarios, PROs are important complementary secondary endpoints to incorporate into additional analyses that may more reliably capture the day-to-day patient experience.

Pivotal trials in SCD have not consistently utilized the same primary endpoints. As summarized in Table 1, major SCD trials vary substantially in their primary endpoints, which can make comparison between trials difficult. A frequently raised concern in modern SCD discourse is the fact that historical trials in SCD suggest that hemoglobin improvement alone is not always indicative of meaningful clinical benefit. For instance, voxelotor produced a robust hemoglobin response in the HOPE trial but did not achieve a significant reduction in SCPCs, and now has been removed from the market worldwide (39). However, tempting as it may be, we must not generalize this reasoning between different drugs with entirely different mechanisms of action, particularly given the potential multimodal benefits of PK activation in SCD. If additional data and analyses—perhaps with correlative biomarkers collected during the RISE UP study—provide for strong corroborating evidence that hemoglobin responders demonstrate clear improvements in parameters such as point of sickling and red cell deformability not seen in non-responders—we must be willing to use reason and not be ruled by P values alone. In a disease that is defined by its unmet need and so many challenges in performing trials, we must not let the perfect be the enemy of the good. Moreover, a trial of mitapivat and discontinuation for non-response is exactly how we use this drug successfully in PK deficiency and thalassemia—there is no reason SCD should be any different.

The preliminary RISE UP trial data invite several other questions. First, could other PK activators—with greater potency or improved pharmacokinetic profiles—capable of providing for greater improvements in hemolysis and hemoglobin result in more consistent improvements in other clinical endpoints? For instance, tebapivat, a second-generation PK activator, demonstrated early potential in a phase 1 clinical trial and achieved a robust hemoglobin response (with an average improvement of nearly 2 g/dL) with once daily dosing, a feature that could matter greatly if adherence is key to deriving clinical benefit (40). Second, how closely will real-world effectiveness mirror trial results? Twice-daily dosing is not trivial for many people with SCD, many of whom experience polypharmacy and social demands that may make adherence difficult. If the benefit of mitapivat is concentrated among responders as the RISE UP phase 3 subgroup analysis suggests, then adherence (which is notoriously difficult to sustain or measure) becomes critical. Etavopivat, another PK activator with once-daily dosing, is currently being studied in this context (19).

Ultimately, for patients and for clinicians, the key question is whether the improvement in hemoglobin can durably translate into less pain, better long-term outcomes, and a meaningful day-to-day benefit. We excitedly await the full RISE UP phase 3 data to better define the role of PK activators in the treatment of SCD.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Annals of Translational Medicine. The article has undergone external peer review.

Peer Review File: Available at https://atm.amegroups.com/article/view/10.21037/atm-2026-1-0021/prf

Funding: This work was funded by the Hematology Clinical Research Training Program (NIH T32 HL07439 to A.N.C.).

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://atm.amegroups.com/article/view/10.21037/atm-2026-1-0021/coif). H.A.S. reports grants or contracts (research funding to the institution) (Agios, Sobi, Vaderis, Novartis, Amgen, and Alnylam) and consulting fees (Agios, Amgen, Alnylam, Alpine, Diagonal, Sobi, Takeda, Terremoto, Pharmacosmos, Novartis, Sanofi, and Vaderis). The other author has no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Kavanagh PL, Fasipe TA, Wun T. Sickle Cell Disease: A Review. JAMA 2022;328:57-68. [Crossref] [PubMed]
2. Pfizer. Pfizer Voluntarily Withdraws All Lots of Sickle Cell Disease Treatment OXBRYTA® (voxelotor) From Worldwide Markets. 2024 [cited 2026 Jan 26]. Available online: https://www.pfizer.com/news/press-release/press-release-detail/pfizer-voluntarily-withdraws-all-lots-sickle-cell-disease
3. Novartis. European Commission (EC) adopts decision endorsing CHMP recommendation to revoke the conditional marketing authorization for Adakveo® (crizanlizumab). 2023 [cited 2026 Jan 26]. Available online: https://www.novartis.com/news/european-commission-ec-adopts-decision-endorsing-chmp-recommendation-revoke-conditional-marketing-authorization-adakveo-crizanlizumab
4. Abboud MR, Cançado RD, De Montalembert M, et al. Crizanlizumab with or without hydroxyurea in patients with sickle cell disease (STAND): primary analyses from a placebo-controlled, randomised, double-blind, phase 3 trial. Lancet Haematol 2025;12:e248-57. [Crossref] [PubMed]
5. Kanter J, Walters MC, Krishnamurti L, et al. Biologic and Clinical Efficacy of LentiGlobin for Sickle Cell Disease. N Engl J Med 2022;386:617-28. [Crossref] [PubMed]
6. Frangoul H, Locatelli F, Sharma A, et al. Exagamglogene Autotemcel for Severe Sickle Cell Disease. N Engl J Med 2024;390:1649-62. [Crossref] [PubMed]
7. GBD 2021 Sickle Cell Disease Collaborators. Global, regional, and national prevalence and mortality burden of sickle cell disease, 2000-2021: a systematic analysis from the Global Burden of Disease Study 2021. Lancet Haematol 2023;10:e585-99. [Crossref] [PubMed]
8. Li C, Georgakopoulou A, Newby GA, et al. In vivo HSC prime editing rescues sickle cell disease in a mouse model. Blood 2023;141:2085-99. [Crossref] [PubMed]
9. Li C, Georgakopoulou A, Newby GA, et al. In vivo base editing by a single i.v. vector injection for treatment of hemoglobinopathies. JCI Insight 2022;7:e162939.
10. Ataga KI. The challenge of clinical end points in sickle cell disease. Blood 2023;142:2047-54. [Crossref] [PubMed]
11. Quezado ZMN, Kamimura S, Smith M, et al. Mitapivat increases ATP and decreases oxidative stress and erythrocyte mitochondria retention in a SCD mouse model. Blood Cells Mol Dis 2022;95:102660. [Crossref] [PubMed]
12. Al-Samkari H, van Beers EJ. Mitapivat, a novel pyruvate kinase activator, for the treatment of hereditary hemolytic anemias. Ther Adv Hematol 2021;12:20406207211066070. [Crossref] [PubMed]
13. Lundt M, Asomaning N, Frey I, et al. The pyruvate kinase activator mitapivat improves red blood cell deformability and sickling kinetics in adult patients with sickle cell disease. Blood 2022;140:2508-9.
14. Rab MAE, Bos J, van Oirschot BA, et al. Decreased activity and stability of pyruvate kinase in sickle cell disease: a novel target for mitapivat therapy. Blood 2021;137:2997-3001. [Crossref] [PubMed]
15. van Dijk MJ, Rab MAE, van Oirschot BA, et al. Safety and efficacy of mitapivat, an oral pyruvate kinase activator, in sickle cell disease: A phase 2, open-label study. Am J Hematol 2022;97:E226-9. [Crossref] [PubMed]
16. Xu JZ, Conrey A, Frey I, et al. A phase 1 dose escalation study of the pyruvate kinase activator mitapivat (AG-348) in sickle cell disease. Blood 2022;140:2053-62. [Crossref] [PubMed]
17. Idowu M, Otieno L, Dumitriu B, 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. Lancet Haematol 2025;12:e35-44. [Crossref] [PubMed]
18. Taher AT, Al-Samkari H, Aydinok Y, et al. Mitapivat in adults with non-transfusion-dependent α-thalassaemia or β-thalassaemia (ENERGIZE): a phase 3, international, randomised, double-blind, placebo-controlled trial. Lancet 2025;406:33-42. [Crossref] [PubMed]
19. Delicou S, El Rassi F, Andemariam B, et al. Etavopivat reduces incidence of Vaso-occlusive crises in patients with Sickle Cell Disease: HIBISCUS Trial Phase 2 results through 52 weeks. Blood 2024;144:179.
20. Agios. Agios Announces Topline Results from RISE UP Phase 3 Trial of Mitapivat in Sickle Cell Disease. 2025 [cited 2026 Jan 26]. Available online: https://investor.agios.com/news-releases/news-release-details/agios-announces-topline-results-rise-phase-3-trial-mitapivat
21. Kuo KHM, Layton DM, Lal A, et al. Safety and efficacy of mitapivat, an oral pyruvate kinase activator, in adults with non-transfusion dependent α-thalassaemia or β-thalassaemia: an open-label, multicentre, phase 2 study. Lancet 2022;400:493-501. [Crossref] [PubMed]
22. Al-Samkari H, Galactéros F, Glenthøj A, et al. Mitapivat versus Placebo for Pyruvate Kinase Deficiency. N Engl J Med 2022;386:1432-42. [Crossref] [PubMed]
23. Glenthøj A, van Beers EJ, Al-Samkari H, et al. Mitapivat in adult patients with pyruvate kinase deficiency receiving regular transfusions (ACTIVATE-T): a multicentre, open-label, single-arm, phase 3 trial. Lancet Haematol 2022;9:e724-32. [Crossref] [PubMed]
24. Kuo KHM, Layton DM, Lal A, et al. Long-term efficacy and safety of mitapivat in non-transfusion-dependent α- or β-thalassaemia: An open-label phase 2 study. Br J Haematol 2025;206:1764-73. [Crossref] [PubMed]
25. van Beers EJ, Al-Samkari H, Grace RF, et al. Mitapivat improves ineffective erythropoiesis and iron overload in adult patients with pyruvate kinase deficiency. Blood Adv 2024;8:2433-41. [Crossref] [PubMed]
26. Kuo KHM, Grace RF, van Beers EJ, et al. Clinically meaningful improvements in patient-reported outcomes in mitapivat-treated patients with pyruvate kinase deficiency. Am J Hematol 2024;99:1415-9. [Crossref] [PubMed]
27. Parekh DS, Eaton WA, Thein SL. Recent developments in the use of pyruvate kinase activators as a new approach for treating sickle cell disease. Blood 2024;143:866-71. [Crossref] [PubMed]
28. Bunn HF. Oxygen Delivery in the Treatment of Anemia. N Engl J Med 2022;387:2362-5. [Crossref] [PubMed]
29. Henry ER, Metaferia B, Li Q, et al. Treatment of sickle cell disease by increasing oxygen affinity of hemoglobin. Blood 2021;138:1172-81. [Crossref] [PubMed]
30. Park Y, Best CA, Auth T, et al. Metabolic remodeling of the human red blood cell membrane. Proc Natl Acad Sci U S A 2010;107:1289-94. [Crossref] [PubMed]
31. Ferru E, Giger K, Pantaleo A, et al. Regulation of membrane-cytoskeletal interactions by tyrosine phosphorylation of erythrocyte band 3. Blood 2011;117:5998-6006. [Crossref] [PubMed]
32. Noomuna P, Risinger M, Zhou S, et al. Inhibition of Band 3 tyrosine phosphorylation: a new mechanism for treatment of sickle cell disease. Br J Haematol 2020;190:599-609. [Crossref] [PubMed]
33. Terra HT, Saad MJ, Carvalho CR, et al. Increased tyrosine phosphorylation of band 3 in hemoglobinopathies. Am J Hematol 1998;58:224-30. [Crossref] [PubMed]
34. Kaul S, Diamond GA. Trial and error. How to avoid commonly encountered limitations of published clinical trials. J Am Coll Cardiol 2010;55:415-27.
35. Ataga KI, Kutlar A, Kanter J, et al. Crizanlizumab for the Prevention of Pain Crises in Sickle Cell Disease. N Engl J Med 2017;376:429-39. [Crossref] [PubMed]
36. Mendez-Marti S, Thein SL. Now where do we STAND with crizanlizumab? Lancet Haematol 2025;12:e232-3. [Crossref] [PubMed]
37. Charache S, Terrin ML, Moore RD, et al. Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. Investigators of the Multicenter Study of Hydroxyurea in Sickle Cell Anemia. N Engl J Med 1995;332:1317-22.
38. Niihara Y, Miller ST, Kanter J, et al. A Phase 3 Trial of l-Glutamine in Sickle Cell Disease. N Engl J Med 2018;379:226-35. [Crossref] [PubMed]
39. Vichinsky E, Hoppe CC, Ataga KI, et al. A Phase 3 Randomized Trial of Voxelotor in Sickle Cell Disease. N Engl J Med 2019;381:509-19. [Crossref] [PubMed]
40. Xu JZ, Novelli EM, Ribeil JA, et al. Results from a phase 1 study to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of tebapivat (AG-946) in patients with sickle cell disease. Blood 2024;144:2496.