Mitapivat Faces a November 1st FDA Decision for Sickle Cell Disease on the Same Kind of Evidence Oxbryta Had

On September 26, 2024, the FDA told people with sickle cell disease who were taking Oxbryta to contact their health care professional about stopping it and starting another treatment (FDA, 2024). Oxbryta had reached the market almost 5 years earlier on the strength of a single measurement, a rise in hemoglobin, and the trials that came after it showed more pain episodes and deaths in people taking it (EMA, 2025). In August 2026, Pfizer wrote that there is not a viable path to make Oxbryta available again in the U.S. (Pfizer, August 2026).

On November 1, 2026, the FDA is due to decide on mitapivat for sickle cell disease. Agios Pharmaceuticals filed it under the same accelerated approval pathway, and the main evidence is again hemoglobin. In the 207-person RISE UP Phase 3 trial, 40.6% of people taking mitapivat had a hemoglobin response compared with 2.9% on placebo. Pain crises, the trial's other main goal, ran at 2.62 a year on mitapivat and 3.05 on placebo, a difference that did not reach statistical significance (Agios, November 2025).

What the RISE UP Phase 3 Trial of Mitapivat Showed in Sickle Cell Disease

RISE UP randomly assigned 207 people aged 16 and older to mitapivat 100 mg twice a day or a matching placebo, 2 on the drug for every 1 on placebo, and kept everyone blinded for 52 weeks (Agios, July 2026). A hemoglobin response meant an average rise of at least 1.0 g/dL from week 24 through week 52. The 12-week Phase 2 part that came first enrolled people with any sickle cell genotype, a starting hemoglobin of 5.5 to 10.5 g/dL, and 2 to 10 pain crises in the year before joining; 50% of those on the 100 mg dose had a hemoglobin response against 4% on placebo (Lancet Haematology, 2025).

Some secondary numbers leaned in mitapivat's favor without counting as proof. Hospitalizations for pain crises ran at 1.56 a year on the drug and 1.81 on placebo, but the trial's testing order meant no statistical conclusion could be drawn (Agios, November 2025). At the European Hematology Association meeting in June 2026, Agios reported that 23.9% of people on mitapivat needed a blood transfusion in the trial compared with 40.6% on placebo, with 0.70 units transfused per person against 1.59, and said the difference held whether or not people also took hydroxyurea (Agios, June 2026).

Agios also split the mitapivat group by who reached a hemoglobin response. Responders averaged 2.20 pain crises a year and non-responders 2.98 (Agios, November 2025). That comparison was chosen after the results were in and looks only inside the mitapivat group, where the people who responded may have differed from the rest before they took a single dose, so it can point to a pattern without showing that the drug caused it.

““This drug is expected to help some people.” … I would want to know exactly how “some people” was determined, what exactly you used to determine who this helps.”

A participant at the FDA's 2014 patient meeting on sickle cell disease, The Voice of the Patient report

Mitapivat safety in RISE UP

Serious side effects were reported in 20.3% of people on mitapivat and 29.0% on placebo, and in 1 mitapivat patient the serious side effect was judged related to the drug. Side effects led 4.3% on mitapivat and 2.9% on placebo to stop treatment. There were 3 deaths on mitapivat, 2.2% of that group, and 2 on placebo, 2.9%, and investigators judged none of them related to treatment. Agios said liver test changes in the trial were not suggestive of drug-induced liver injury, unlike what its thalassemia trials had shown (Agios, November 2025).

The FDA granted Oxbryta (voxelotor) accelerated approval on November 25, 2019. Its HOPE trial of 274 people measured one thing as its main goal: the share whose hemoglobin rose by more than 1 g/dL at week 24, which was 51.1% on the 1,500 mg dose and 6.5% on placebo. About 65% of HOPE participants were already taking hydroxyurea, and the FDA's notice said continued approval may depend on confirmatory trials (FDA, 2019).

Hemoglobin is what the FDA calls a surrogate endpoint, a lab measurement “thought to predict clinical benefit, but is not itself a measure of clinical benefit” (FDA, accelerated approval). With Oxbryta the later evidence pointed the other way. When Europe's medicines regulator closed its review in October 2025, it wrote that the newer trials showed more sudden pain episodes and deaths, results it called “inconsistent with those of the earlier main clinical trial that supported” Oxbryta's approval, even though the final analysis of 2 patient registries did not confirm an increase in pain episodes (EMA, 2025).

Hematologists have argued about that lesson ever since. At the American Society of Hematology's annual meeting in December 2024, Harvard hematologist Maureen Achebe said the field has to wrestle with whether a rise in hemoglobin is a viable surrogate endpoint at all, and whether trials that move quickly from a short Phase 2 into Phase 3 gather enough safety data. RISE UP is that kind of combined Phase 2/3 trial. Others, like Mount Sinai's Jeffrey Glassberg, warned against overcorrecting (ASH Clinical News, February 2025).

“If you got rid of the accelerated approval process, the damage to people with SCD would be extraordinary. It's not diabetes; you can't get 50,000 patients into your study to get the data you need.”

Jeffrey Glassberg, MD, director of the Center for Sickle Cell Disease at Mount Sinai, ASH Clinical News, February 2025

Mitapivat is a different molecule aimed at a different target, and none of Oxbryta's history is evidence about it. What separates the 2 cases is trial design: Oxbryta's approval rested on hemoglobin alone, while mitapivat's Phase 3 tested pain crises as a second main goal for a full year and did not meet it, so the FDA is deciding with that result already on the table.

What the rules require of mitapivat that they did not require of Oxbryta

Congress rewrote parts of the accelerated approval rules in the Consolidated Appropriations Act, 2023, and FDA guidance now describes procedures for expedited withdrawal of an accelerated approval (FDA, accelerated approval guidance). Agios says its confirmatory trial must be underway when the FDA makes its decision, and it filed only after agreeing on that trial with the agency (Agios, May 2026). It dosed the first patient in the trial, called REIGNITE, by July 30, 2026 (Agios, July 30, 2026).

REIGNITE is testing transfusions, not pain crises, which children, parents and adults at the FDA's 2014 sickle cell patient meeting named among the most significant effects of the disease (FDA, 2014). Its main goal is the share of people who stay transfusion-free from week 4 through week 52, in about 159 people aged 12 and older given mitapivat 100 mg twice a day or placebo, 2 to 1 (Agios, July 2026). If mitapivat is approved, whether it prevents pain crises will still rest on the RISE UP result described above.

Mitapivat Is Already Sold as Pyrukynd and Aqvesme, and Aqvesme Carries a Liver Warning

Mitapivat is not new to the FDA. It was approved as Pyrukynd for pyruvate kinase deficiency on February 17, 2022, and as Aqvesme for anemia in adults with alpha- or beta-thalassemia on December 23, 2025. Aqvesme's thalassemia trial used 100 mg twice a day, the same dose tested in RISE UP (Agios, December 2025).

Aqvesme's label opens with a boxed warning that it can cause serious hepatocellular injury, meaning damage to the main cells of the liver. Liver tests are required at the start and every 4 weeks for 24 weeks, and the drug is available only through a restricted safety program called a REMS. In the thalassemia trials, 5 patients had reactions suggestive of liver injury and 2 of them were hospitalized; the problems appeared within the first 6 months and improved after the drug was stopped. Agios gave the thalassemia version its own brand name because of that REMS program (Agios, December 2025).

RISE UP did not show that pattern in sickle cell, according to Agios. Whether a sickle cell label carries the same boxed warning, the same REMS and the same brand name is one of the questions the November 1st decision will answer. Price is another. Agios put Aqvesme's U.S. list price for thalassemia at $425,000 a year and has not announced a price for sickle cell (Agios, December 2025 investor presentation).

How mitapivat works in sickle cell disease

Mitapivat switches on pyruvate kinase, an enzyme red blood cells use to make energy. That raises ATP, the cell's fuel, and lowers a molecule called 2,3-DPG. Agios says high 2,3-DPG raises the likelihood that red cells take on the sickle shape (Agios, July 2026). Lower 2,3-DPG also makes hemoglobin hold on to oxygen more tightly, and an April 2026 editorial in Annals of Translational Medicine noted the theoretical concern that this could reduce oxygen delivery to tissues and blunt the benefit. The same editorial pointed to Phase 2 data showing no rise in erythropoietin, a hormone the body makes when tissues run short of oxygen, as some reassurance (Annals of Translational Medicine, 2026).

Mitapivat vs Hydroxyurea, Gene Therapy, Etavopivat and Other Sickle Cell Treatments

Mitapivat would join a short list. Hydroxyurea remains the foundation: national guidelines recommend it for adults with 3 or more moderate to severe pain crises in a year and say to offer it to children from 9 months of age regardless of severity (NHLBI, 2014). The table below puts each option's own trial result next to its current status, and each approved option has its own page: hydroxyurea, L-glutamine, crizanlizumab, Casgevy and Lyfgenia.

Etavopivat is the closest comparison and the one to watch next. It works the same way as mitapivat, activating pyruvate kinase, and in Novo Nordisk's HIBISCUS Phase 3 trial of 385 people aged 12 and older it cut the yearly rate of pain crises by 27% compared with placebo and pushed the median time to a first crisis from 20.9 weeks to 38.4 weeks, with standard care allowed throughout (Novo Nordisk, April 2026). Its definitions differ from RISE UP's, so the 2 results cannot be lined up directly. Agios dropped its own second pyruvate kinase activator, tebapivat, from sickle cell development in July 2026 after Phase 2 results did not show a differentiated profile (Agios, July 21, 2026).

Adakveo, the crizanlizumab infusion, is still sold in the U.S., but its current label states that the efficacy of 2 doses was evaluated, but not established, in the STAND trial, and Europe revoked its authorization in 2023 (Adakveo label, 2026; EMA, 2023). For a full comparison of the 2 gene therapies, including price and eligibility, see our Casgevy vs Lyfgenia guide.

Hydroxyurea and Sickle Cell Clinical Trials: What 152 Trial Listings Say

Hydroxyurea is the standard treatment for sickle cell disease, so the rules about it decide who can join many trials. On September 29, 2026, we pulled every recruiting or not-yet-recruiting interventional study for sickle cell disease on ClinicalTrials.gov, 152 in all and 97 with a U.S. site, and read the eligibility text of each one that mentions hydroxyurea. Of those, 48 set a rule about it.

The stable-dose rule is the one most people on hydroxyurea will meet. Among the trials that name a length of time, the required time on a steady dose runs from 30 days to 6 months, and about 3 months is the most common, used by 8 of the 19. REIGNITE, mitapivat's confirmatory trial, asks for 90 days on a stable dose and a 90-day washout for anyone who stops, and it excludes people who took voxelotor, crizanlizumab or L-glutamine in the previous 90 days (ClinicalTrials.gov NCT07656415).

In most drug trials, starting hydroxyurea or changing the dose resets the stable-dose window, so a routine adjustment can push a possible trial start back by weeks or months. Mention trial plans when a dose change comes up, and see our analysis of medication rules across rare disease trials for how common this is beyond sickle cell.

Who the Mitapivat Decision Could Matter To, in 3 Situations

You were taking Oxbryta when it was withdrawn in 2024

The advice at the time came from both the company and the agency: Pfizer told patients to contact their physicians to discuss alternative treatment, and the FDA told patients and caregivers to talk with their health care professional about stopping Oxbryta and starting another option (Pfizer, 2024; FDA, 2024). Pfizer confirmed in August 2026 that Oxbryta is not coming back in the U.S. Akshat Jain, who directs the sickle cell center at Loma Linda University Health and had more than 60 patients on Oxbryta when it was pulled, told ASH Clinical News that most of them had not tolerated hydroxyurea or needed a second drug to reach their treatment goals. Bridget Reynolds, a patient in the same report who has the hemoglobin SC form of the disease and briefly took Oxbryta, said she might “wait and see” how patients do on any new sickle cell drug in the real world before trying it (ASH Clinical News, February 2025). Mitapivat reaches the FDA with a hemoglobin result of the same kind, plus a pain crisis result that fell short. If it is approved, the questions worth taking to your hematologist are what the label says it is for, whether it comes with liver monitoring, and whether your hemoglobin and crisis history look like those of the people in RISE UP.

You are 17 and weighing a daily pill against gene therapy

Casgevy has been approved for people 2 and older with recurrent pain crises since July 1, 2026, and Lyfgenia for people 12 and older (FDA, July 2026; FDA, 2023). Both start with collecting your own stem cells and end with high-dose chemotherapy before the modified cells go back in, and CMS notes that this chemotherapy typically leaves patients, male or female, infertile. In the 32 states plus Washington, D.C. and Puerto Rico that take part in the federal Cell and Gene Therapy Access Model, covering 84% of Medicaid enrollees with sickle cell disease, manufacturers must pay for fertility preservation for patients in the model, including storage for at least 5 years (CMS, CGT Access Model FAQ).

Mitapivat was studied in people 16 and older, so a 17-year-old fits the trial population, although the label will set who can get it. It would be taken every day with no chemotherapy, and it works on red cells already in circulation rather than changing the stem cells that make them. The gene therapies and mitapivat have never been compared in the same trial. The HBB gene page explains the gene behind sickle cell disease and lists trials that name it.

You take hydroxyurea and still have several pain crises a year

“We need new agents. We're down to blood transfusions and hydroxyurea because the other approved agents are being used much less frequently due to increased toxicity or limited tolerance.”

Crawford Strunk, MD, Cleveland Clinic, vice chief medical officer of the Sickle Cell Disease Association of America, ASH Clinical News, February 2025

RISE UP allowed people on a stable dose of hydroxyurea (Annals of Translational Medicine, 2026), and Agios says the lower transfusion rate held with or without it. Across the whole trial, though, mitapivat did not significantly reduce pain crises, the outcome this situation is about. Etavopivat did reduce them in its Phase 3 trial but has not been filed yet. REIGNITE and 4 etavopivat studies, 1 of them an extension for earlier participants, were recruiting when we checked ClinicalTrials.gov, and the sickle cell trial list shows those and others with their locations, with the hydroxyurea rules above as a guide to what each will ask.

What to Watch for When the FDA Decides on Mitapivat on November 1st

November 1, 2026 is the FDA's goal date under priority review. The agency can act before it, approve the drug, or send a complete response letter asking for more. If mitapivat is approved, 6 details will matter most: the exact wording of what it treats, the lowest approved age, whether it carries Aqvesme's boxed liver warning and REMS, the brand name, the confirmatory trial requirement, and the price Agios sets. The medical committee of the Sickle Cell Disease Association of America asked the FDA and drugmakers in August 2026 to look past the clinical outcomes usually measured in sickle cell studies and add patient-reported outcomes that affect quality of life (SCDAA, August 2026).