Mitapivat trial meets anemia endpoint, misses pain crisis target in sickle cell disease

Overview

Updated 1 hour ago

A global phase 3 trial published in The Lancet found that mitapivat, an oral pyruvate kinase activator, raised hemoglobin in 41% of sickle cell disease patients, versus 3% on placebo. The drug missed its other primary endpoint: annualized pain crises fell from 3.1 to 2.6 per year, a gap that did not reach statistical significance.

The split result lands as sickle cell treatment options are shrinking. Two other drugs, voxelotor and crizanlizumab, were withdrawn in 2024, leaving hydroxyurea and transfusions as the main options. Mitapivat's hemoglobin gains, comparable to monthly transfusions, could fill that gap if regulators accept an anemia endpoint without a proven pain crisis benefit.

Why it matters

If approved, mitapivat would give sickle cell patients a convenient oral option that improves anemia—but the missed pain crisis endpoint may slow that path.

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Key Indicators

40.6%

Hemoglobin response rate (mitapivat)

Patients with ≥1.0 g/dL hemoglobin increase from week 24 to 52, vs 2.9% on placebo (p<0.0001).

2.6 vs 3.1

Annualized pain crisis rate

Mitapivat vs placebo; p=0.1213, not statistically significant.

41.1%

Relative reduction in transfusions

23.9% of mitapivat patients transfused vs 40.6% on placebo.

1.6 g/dL

Mean hemoglobin increase among responders

Average change from baseline among the 56 mitapivat responders, durable for a median of 50 weeks.

Voices

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People Involved

Biree Andemariam

Lead author of the RISE UP trial publication

Hematologist and sickle cell disease researcher

Organizations Involved

Agios Pharmaceuticals

Biopharmaceutical company

Developer of mitapivat and sponsor of the RISE UP trial

Biopharmaceutical company that developed mitapivat, an oral allosteric activator of pyruvate kinase.

The Lancet

Medical journal

Publisher of the RISE UP phase 3 results

Peer-reviewed medical journal that published the RISE UP phase 3 trial results on October 24, 2026.

Timeline

June 2026 October 2026

2 events Latest: June 2026

October 2026
The Lancet publishes RISE UP phase 3 results
Upcoming Publication

The Lancet published the full RISE UP results, confirming the hemoglobin response and reporting that the pain crisis endpoint did not reach statistical significance (p=0.1213).
Tomorrow
June 2026
RISE UP results presented at EHA 2026
Latest Conference presentation

Agios presented the phase 3 RISE UP results at the European Hematology Association congress, showing a 40.6% hemoglobin response rate versus 2.9% on placebo.
June 2026

Scenarios

FDA approves mitapivat for sickle cell disease

Possible Resolves by End of 2028

Discussed by: Agios Pharmaceuticals and analysts covering the company

Agios submits a new drug application citing the hemoglobin response and transfusion reduction data. The FDA accepts hemoglobin as a clinically meaningful endpoint despite the missed pain crisis target, and approves mitapivat as the first oral disease-modifying treatment for sickle cell disease.

FDA requires a confirmatory trial before approval

Possible Resolves by End of 2028

Discussed by: Regulatory analysts and hematology researchers

The missed pain crisis primary endpoint leads the FDA to require a confirmatory trial focused on clinical outcomes. Agios continues the open-label extension while designing the new study, delaying any approval to the late 2020s.

Open-label extension data strengthen the approval case

Likely Resolves by End of 2027

Discussed by: Trial investigators

The ongoing open-label extension shows durable hemoglobin response and reduced pain crises over longer follow-up, particularly among responders. This data supports the regulatory submission and may address the pain crisis concern.

Historical Context

3 moments from history that rhyme with this story — and how they unfolded.

1998

Hydroxyurea approval (1998)

The FDA approved hydroxyurea for adults with sickle cell disease after the Multicenter Study of Hydroxyurea in Sickle Cell Anemia showed it reduced pain crises by nearly half. It was the first disease-modifying therapy for the condition.

Then

Hydroxyurea became the standard of care, reducing hospitalizations and transfusions for many patients.

Now

Nearly three decades later, hydroxyurea remains the primary disease-modifying option for sickle cell disease, though many patients do not respond fully or tolerate it.

Why this matters now

Hydroxyurea set the precedent that reducing pain crises, not just improving lab values, is the benchmark for sickle cell treatments. Mitapivat's missed pain crisis endpoint raises the question of whether regulators will accept anemia improvement alone.

November 2019 - February 2024

Voxelotor (Oxbryta) approval and withdrawal (2019-2024)

The FDA approved voxelotor in 2019 to reduce hemolysis in sickle cell disease, based on hemoglobin improvement. Pfizer voluntarily withdrew it in February 2024 after a post-marketing study showed a higher rate of deaths and vaso-occlusive events in treated patients.

Then

The withdrawal removed one of the few oral options for sickle cell disease and triggered scrutiny of drugs approved on surrogate endpoints.

Now

The episode made regulators and clinicians more cautious about approving sickle cell drugs based on hemoglobin alone without demonstrated clinical benefit.

Why this matters now

Voxelotor's withdrawal is the cautionary tale for mitapivat. Both drugs improve hemoglobin, but voxelotor's failure to show clinical benefit and its safety signal led to its removal. Mitapivat's missed pain crisis endpoint invites the same scrutiny.

November 2019 - September 2024

Crizanlizumab (Adakveo) approval and withdrawal (2019-2024)

The FDA approved crizanlizumab in 2019 to reduce vaso-occlusive crises in sickle cell disease. Novartis withdrew it in September 2024 after a confirmatory trial failed to show benefit over placebo.

Then

The withdrawal left sickle cell disease with fewer treatment options and raised the bar for confirmatory evidence.

Now

Regulators now expect post-approval confirmatory trials to show real clinical benefit, not just surrogate improvements.

Why this matters now

Crizanlizumab's withdrawal shows the risk of approving a sickle cell drug before confirmatory data is solid. Mitapivat's strong hemoglobin data but weak pain crisis signal puts it in a similar position.