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

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

New Capabilities

FDA moves its mitapivat decision to February 2027 as it weighs a safety programme

October 30th, 2026: FDA extends mitapivat decision to February 1, 2027

Overview

Updated Nov 2

The FDA pushed its decision on mitapivat for sickle cell disease from November 1, 2026 to February 1, 2027. On October 9 the agency asked whether the drug needs a risk plan, known as a REMS, to manage safety. Agios sent nine months of extra safety data on October 19; the FDA called that a major amendment on October 28 and added three months to the review.

The RISE UP trial, published in The Lancet on October 24, raised hemoglobin by at least 1 g/dL in 40.6% of patients versus 2.9% on placebo. It did not significantly cut pain crises: 2.6 a year against 3.1 (p=0.12). France's HAS refused early access on October 1 over that uncertainty. Agios says the new data show no liver injury of the kind seen in its thalassemia trials, and its confirmatory REIGNITE trial is running.

Why it matters

A February 1 FDA decision will settle whether US regulators approve a sickle cell drug that raises hemoglobin without proven pain relief.

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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.
Feb 1, 2027
FDA decision deadline (PDUFA)
Moved from November 1, 2026 after the FDA called Agios's extra safety submission a major amendment.
18%
Agios share drop
Fall in Agios stock on Friday October 30, 2026, from $37.23 to $30.55, after the delay was disclosed.

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People Involved

Biree Andemariam
Biree Andemariam
Lead author of the RISE UP trial publication
Hematologist and sickle cell disease researcher

Organizations Involved

Agios Pharmaceuticals
Agios Pharmaceuticals
Biopharmaceutical company
Awaiting an FDA decision on mitapivat for sickle cell disease, now due February 1, 2027

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

2026 October 2026

7 events Latest: October 30th, 2026 · 1 week ago
Tap a bar to jump to that date

  1. FDA extends mitapivat decision to February 1, 2027

    Latest Regulatory decision

    The FDA moved the PDUFA goal date for mitapivat in sickle cell disease from November 1, 2026 to February 1, 2027 after Agios's October 19 response to a request about a possible REMS was classed as a major amendment. Agios shares fell nearly 18%.

  2. The Lancet publishes RISE UP phase 3 results

    Publication

    The Lancet published the full RISE UP results, confirming the 40.6% hemoglobin response rate against 2.9% on placebo and reporting that the pain crisis endpoint did not reach statistical significance (p=0.1213).

  3. France's HAS refuses early access to mitapivat in sickle cell disease

    Regulatory decision

    The French National Authority for Health refused early access to Pyrukynd (mitapivat) for adults with haemolytic anaemia linked to sickle cell disease, publishing its decision on 6 October 2026. It said the RISE UP package did not meet the evidence threshold for early access because the painful-crisis result retained statistical uncertainty.

  4. First patient dosed in REIGNITE confirmatory trial

    Clinical trial

    Agios said the first participant was dosed in REIGNITE (NCT07656415), a phase 3 trial of about 159 patients aged 12 and older. The trial tests whether mitapivat beats placebo at reducing transfusions, and the FDA required it for accelerated approval.

  5. FDA grants priority review to mitapivat sNDA in sickle cell disease

    Regulatory filing

    Agios said the FDA granted priority review to its supplemental application for mitapivat in sickle cell disease. Priority review shortens the standard review period from 10 months to six.

  6. RISE UP results presented at EHA 2026

    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.

  7. FDA accepts Agios application, sets November 1 decision date

    Regulatory filing

    The FDA accepted Agios's application for mitapivat in sickle cell disease and granted priority review, with a decision date of November 1, 2026. Agios has said it sought accelerated approval based on the RISE UP and earlier phase 2 data.

Scenarios

1

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.

2

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.

3

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.

4

European regulators follow France and limit mitapivat access

Possible Resolves by Q2 2027

Discussed by: French National Authority for Health (HAS)

HAS refused early access in October 2026, saying the RISE UP evidence fell short because the pain crisis endpoint kept statistical uncertainty. If other European assessors read the hemoglobin-only result the same way, access there would stay narrow even with a marketing authorisation.

5

FDA approves mitapivat with a REMS

Possible Resolves by Feb 1, 2027

Discussed by: Agios Pharmaceuticals and regulatory analysts

Agios said it is in labeling talks with the FDA that include elements of a possible REMS for sickle cell disease. If the agency approves by February 1, 2027, the drug would carry restrictions on prescribing or monitoring tied to liver safety.

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 - September 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.

Sources

(13)
+7
The Lancet Agios Pharmaceuticals (EHA 2026 presentation) Agios Pharmaceuticals Sickle Cell Anemia News EMJ Reviews AbangeLabs Editorial AdiaMed Lonevi GEN Genetic Engineering & Biotechnology News TIKR Agios Pharmaceuticals Sickle Cell Anemia News Agios Pharmaceuticals