Mitapivat raises hemoglobin levels in Phase 3 sickle cell disease trial

Agios Pharmaceuticals’ medication mitapivat rapidly increased levels of the oxygen-carrying protein hemoglobin in patients ages 16 and older with sickle cell disease (SCD), while also being linked to a lower blood transfusion burden over 52 weeks.

These are new data from the Phase 3 portion of the global Phase 2/3 RISE UP clinical trial (NCT05031780), which tested mitapivat oral tablets, taken twice daily, against a placebo. The trial’s two main goals were to assess hemoglobin response and annualized rates of sickle cell pain crises, also called vaso-occlusive crises (VOCs).

“Mitapivat represents a differentiated anti-hemolytic approach that can provide meaningful clinical benefits for patients with sickle cell disease – an underserved population in desperate need of innovative therapies,” Sarah Gheuens, MD, PhD, Agios’ chief medical officer and head of research and development, said in a company press release. An anti-hemolytic approach is one designed to reduce hemolysis, or red blood cell destruction.

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Gheuens is one of the authors of an abstract accepted for presentation as a plenary session at the 31st European Hematology Association (EHA) Congress, held recently in Stockholm, Sweden. The abstract was titled “Efficacy and safety of mitapivat in sickle cell disease: Results from the global, randomized, Phase 3 RISE UP trial.”

Last month, the company filed an application with the U.S. Food and Drug Administration (FDA) seeking accelerated approval of mitapivat for SCD based on these and earlier Phase 2 data from RISE UP. The medication is already approved in the U.S. as Pyrukynd for hemolytic anemia in adults with pyruvate kinase (PK) deficiency and as Aqvesme for anemia in adults with alpha- or beta-thalassemia. Both PK deficiency and thalassemia are blood diseases.

SCD is caused by abnormal hemoglobin, the protein inside red blood cells that carries oxygen. The abnormal hemoglobin causes red blood cells to become stiff and take on a crescent (or sickle) shape.

These sickled red blood cells are prone to undergo hemolysis and can also block small blood vessels, causing painful VOCs and other symptoms.

Mitapivat is a small molecule that works by activating PK, an enzyme that helps red blood cells produce energy. By increasing levels of ATP, the cell’s main energy source, and reducing levels of 2,3-DPG, a molecule linked to sickling, mitapivat is expected to reduce the likelihood that red blood cells will become sickle-shaped and die, which may ease symptoms.

Trial tested mitapivat against placebo

RISE UP’s Phase 3 portion enrolled 207 patients ages 16 and older with SCD who received either 100 mg of mitapivat or a placebo twice daily over 52 weeks (about one year). Participants’ median age was 25 years, and 57.5% were female.

One main goal was to determine whether mitapivat could increase hemoglobin; the other was to assess annualized rates of sickle cell pain crises, also called VOCs. A hemoglobin response was defined as an increase of at least 1 g/dL from the study’s start, or baseline, between weeks 24 and 52.

While baseline levels of hemoglobin were similar in both groups, a significantly higher proportion of patients on mitapivat achieved a hemoglobin response (40.6% vs. 2.9%).

Alongside this rapid, durable increase in hemoglobin, mitapivat was associated with a significantly greater drop in blood levels of indirect bilirubin, a marker of hemolysis, relative to the placebo. Lower indirect bilirubin levels suggest reduced hemolysis and healthier red blood cells.

Although there was no significant reduction in the overall rate of sickle cell pain crises with mitapivat across all study participants, a post hoc analysis of mitapivat-treated patients found benefits among those who achieved a hemoglobin response. These responders experienced 26% fewer sickle cell pain crises and 34% fewer related hospitalizations than nonresponders.

Hemoglobin responders also required less emergency care. Compared with nonresponders, they had 53% fewer emergency room visits and 37% fewer hospitalization days related to sickle cell pain crises.

Those who achieved a hemoglobin response with mitapivat also experienced clinically meaningful reductions in fatigue, along with greater improvements in pain, physical functioning, and sleep quality.

Transfusion burden also was lower

Mitapivat also was associated with lower transfusion burden, including a smaller proportion of patients requiring blood transfusions (23.9% vs. 40.6%) and fewer red blood cell units transfused per patient on average (0.7 vs. 1.59), which translates into a 55.9% relative reduction compared with placebo. This may suggest reduced dependence on supportive care.

Mitapivat’s safety profile was consistent with that reported in previous trials. Nearly all participants experienced adverse events, but rates were similar between the mitapivat and placebo groups. No new safety signals were identified, and no treatment-related deaths occurred.

“The RISE UP Phase 3 data … showcase the strong anti-hemolytic profile of mitapivat, with rapid and durable improvements in both hemoglobin and … bilirubin as well as a meaningful reduction in transfusion burden,” said Biree Andemariam, MD, a RISE UP trial investigator and a professor of medicine and American Red Cross endowed chair in transfusion medicine at University of Connecticut Health.

Andemariam, who is the abstract’s first author, added that “this anti-hemolytic effect is translating to clear clinical benefits, including improvements for hemoglobin responders across measures of sickle cell pain crises, pain, sleep, and physical function compared with non-responders. Together, these data reinforce the potential for mitapivat to improve the relentless physical toll that comes with living with sickle cell disease.”