AGIO mitapivat

Sickle cell disease · Agios · sNDA

Of 100 applications in this same position, about 87 get approved.

Until the FDA deadline27d

Base rate95%

Gap−8pts

PDUFA target date 2026-11-01the FDA may act earlier or later

Summary

We put approval of Agios's mitapivat for sickle cell disease at 87%, below the ~95% base rate for supplements. The Phase 3 RISE UP trial met its hemoglobin endpoint (40.6% vs 2.9%) but missed its pain-crisis co-primary. The filing relies on hemoglobin as an accelerated-approval surrogate, the same surrogate that failed with voxelotor. In its favour: the FDA itself recommended the accelerated-approval route after seeing the data, agreed a confirmatory trial that is now running, and granted priority review. Safety in sickle cell is clean, with fewer serious adverse events than placebo, no liver injury signal and fewer transfusions. Manufacturing risk is minimal. Confidence is medium.

Recorded 2026-10-04 19:58 UTC · v1Proof ↓

Evidence · 5 items

Why 87%, not 95%

Indication

Sickle cell disease (RISE UP population: age >=16), filed under the accelerated approval pathway with hemoglobin response as the surrogate endpoint; REIGNITE is the confirmatory Phase 3 trial

95% of comparable applications were approved in the past: the opponent every forecast has to beat. Below are the reasons this forecast differs.

▲ supports approval, ▼ counts against it. More squares, more weight.

01▼ AgainstLarge Mixed pivotal trial: the hemoglobin surrogate was met but the pain-crisis co-primary endpoint was not, in a disease where the Hb surrogate has been discredited

In RISE UP Phase 3 (n=207, 2:1), hemoglobin response was 40.6% vs 2.9% (p<0.0001). The annualized sickle-cell pain crisis rate was 2.62 vs 3.05 (p=0.12, not significant), and the PROMIS-Fatigue key secondary endpoint also missed. Accelerated approval needs the Hb rise to be 'reasonably likely' to predict clinical benefit. Voxelotor's 2019 accelerated approval rested on the same >=1 g/dL Hb endpoint and was withdrawn in 2024 after imbalances in deaths and pain crises. This is a supplement, so the 95% base rate assumes routine efficacy; this file is closer to a contested new-indication review.

Source: Agios press release 2025-11-19 (RISE UP topline); Am J Hematol 2025 voxelotor withdrawal analysis; HCPLive sNDA coverage
02▲ SupportsMedium The FDA itself steered Agios toward accelerated approval, agreed a confirmatory trial and granted priority review

Agios had the full RISE UP results in hand at its Q1 2026 pre-sNDA meeting, where 'the FDA recommended submission of a proposal for a confirmatory clinical trial to support U.S. accelerated approval'. REIGNITE (about 159 patients, 2:1, primary endpoint transfusion-free status from week 4 to week 52) has dosed its first patient, which meets the FDORA requirement that the confirmatory trial be under way. The sNDA was submitted in May 2026 and accepted with priority review. The PDUFA date of 1 November 2026 was assigned by the FDA.

Source: Agios press release 2026-03-31 (pre-sNDA meeting); Agios press release 2026-07-07 (priority review); SEC 10-Q filed 2026-07-30
03▲ SupportsSmall Safety in sickle cell disease is clean and the clinical signals point in the right direction, unlike voxelotor

Serious TEAEs were 20.3% on mitapivat vs 29.0% on placebo, and there were no treatment-related deaths. Coverage of the EHA plenary reports deaths of 3 (2.2%) vs 2 (2.9%). Management says the liver injury seen in thalassemia, which carries a boxed warning and REMS there, was not seen in the sickle cell trials. Patients on mitapivat needed transfusions less often (23.9% vs 40.6%) and received fewer RBC units (0.70 vs 1.59). The pain-crisis rate trended lower, and Hb responders had fewer pain crises, ER visits and hospitalizations, though those responder analyses are not randomized comparisons.

Source: Agios EHA 2026 plenary release 2026-06-13; EMJ EHA 2026 coverage; Agios Q2 2026 earnings call (MarketBeat/TradingView summary)
04▲ SupportsSmall The drug is already approved and made at commercial scale, so CMC risk is minimal

Mitapivat has been approved since 2022 (PK deficiency) and was approved for thalassemia in December 2025. The SCD dose (100 mg twice daily) matches the thalassemia dose, so no new formulation or facility should be needed.

Source: Drugs@FDA NDA216196; SEC 10-Q filed 2026-07-30
05▼ AgainstSmall No advisory committee called, but the FDA's view of accelerated approval is unsettled

About four weeks before the PDUFA date, no hematology advisory committee has been scheduled, which suggests the division does not see a need for outside input. On the other side, FDA leadership turned over through 2026, and the agency has become more sceptical of surrogate-based approvals. A late change of position cannot be ruled out. Agios's own follow-on PK activator, tebapivat, failed in its SCD Phase 2 in July 2026 (Hb response 29-47% vs 33% on placebo). The FDA could read that as a reason for caution about the class's Hb effect.

Source: FDA advisory committee calendar search 2026-10-04; Agios press release 2026-07-21 (tebapivat)

What would change this forecast

01
The FDA calls an advisory committee, or Agios discloses a major amendment or a 3-month extension (the extension changes only the date)
02
The FDA signals that hemoglobin is not an acceptable surrogate in SCD, or requires more confirmatory evidence before approval
03
New safety information from the RISE UP open-label extension or REIGNITE (deaths, pain-crisis or liver events)
04
Disclosure of label negotiations or a REMS decision (up)

Any change is published as a new version; earlier versions stay exactly as they were.

Confidence

Medium

Manufacturing and inspection risk

Low

This is a supplement for a commercially manufactured small-molecule tablet that has already passed FDA review twice (2022, 2025). No new facility or formulation is expected.

Record · version 1

Written on 2026-10-04, 28 days before the PDUFA target date.

Timeline

Versions

v1 2026-10-04 19:58 UTC 87% Current version JSON ↓.ots ↓ ○ Timestamp submitted, awaiting block confirmation

Fingerprint

SHA-256f7326be3c648721b0a95ced373f5fc7da1a097a08e8f35abd05f1cb29ebda6bf

The fingerprint of the v1 file. It is what the timestamp commits to: change one character of the file and the fingerprint no longer matches.

Verify it yourself

Download the JSON file above and the .ots file of the same name into one folder.
Compute the SHA-256 of the file. It should match the fingerprint above.
Verify with OpenTimestamps. Once the timestamp is in a Bitcoin block, ots verify reports the block time if you run a Bitcoin node; without one, drop both files on the verifier at opentimestamps.org, or run ots info to see the block height and look it up in any block explorer. If the block time is before the FDA’s decision, the file cannot have been written afterwards.

pip install opentimestamps-client
shasum -a 256 v1_20261004T195804Z.json
ots verify v1_20261004T195804Z.json.ots
ots info v1_20261004T195804Z.json.ots

Scoring rule

What is scored is the last version recorded at least 2 days before the PDUFA target date; if the FDA decides early, only versions recorded before the day of its decision count. For this forecast the cutoff is 2026-10-30. Its error (also called the Brier score) is the squared distance between the forecast and the outcome, set against the error of quoting the base rate only.