Sickle cell tablet lifts blood counts but pain crises barely move

A twice-daily tablet raised haemoglobin in four in ten people with sickle cell disease in a year-long phase 3 trial, but it didn't significantly reduce the painful crises that define life with the condition. The full results of RISE UP, testing mitapivat, were published online in The Lancet on 22 October 2026, The first author is Biree Andemariam of UConn Health in the US.

In the trial, 40.6% of people given mitapivat had a meaningful rise in haemoglobin, against 2.9% of those given placebo. Pain crises fell from 3.05 a year on placebo to 2.62 on mitapivat, a difference that could have arisen by chance. The study was funded by Agios Pharmaceuticals, which makes the drug.

That split result is at the heart of the debate about where mitapivat fits. Agios is seeking accelerated approval in the US on the strength of the haemoglobin findings. The FDA had been due to decide by 1 November 2026, but in October it extended the review to 1 February 2027 while it considers whether a formal safety programme is needed.

What sickle cell disease is

Sickle cell disease is an inherited blood disorder caused by a change in the gene for beta globin, part of haemoglobin, the oxygen-carrying protein in red blood cells. People with the disease make an abnormal form called haemoglobin S. When it gives up its oxygen, haemoglobin S clumps into long fibres that distort red cells into a stiff crescent or sickle shape, as shown in the illustration above.

Sickled cells cause two main problems. They break down early, so people have chronic anaemia (haemolytic anaemia) and tiredness. And they block small blood vessels, starving tissues of oxygen. This causes sudden, severe pain known as vaso-occlusive crises, or sickle cell crises, as well as damage over time to organs including the brain, lungs, kidneys and eyes. Life expectancy remains shorter than average, even in countries with good care.

The disease is most common in people with African, Caribbean, Middle Eastern, Indian and Mediterranean heritage. In the UK, an estimated 15,000 to 17,000 people are thought to live with it, and around 100,000 in the US. Worldwide, millions are affected, mostly in sub-Saharan Africa and India.

Treatments include hydroxyurea (hydroxycarbamide), regular blood transfusions, pain relief, and, for a small number of people, stem cell transplants or newer gene therapies. Two drugs approved in recent years were withdrawn or restricted: voxelotor (Oxbryta) was pulled worldwide in 2024 over safety concerns, and crizanlizumab (Adakveo) lost its conditional marketing authorisation in Europe after a confirmatory trial failed. That leaves a real need for oral medicines that are safe to take for years.

How mitapivat works

Mitapivat activates pyruvate kinase, an enzyme that red cells use to make energy. Boosting it has two effects relevant to sickle cell disease. It increases the cell's supply of ATP, the molecule cells use for energy, which may help red cells survive longer. And it lowers levels of a molecule called 2,3-DPG, which normally encourages haemoglobin to release oxygen. With less 2,3-DPG, haemoglobin S holds on to oxygen a little longer, and deoxygenated haemoglobin S is what forms the damaging fibres.

Mitapivat is already approved in several countries as Pyrukynd for pyruvate kinase deficiency, a rare inherited anaemia, and as Aqvesme for alpha and beta thalassaemia. RISE UP tests whether the same mechanism helps in sickle cell disease.

Who took part

RISE UP (NCT05031780) was a phase 3, double-blind trial at 69 sites in 15 countries. It enrolled 207 people aged 16 and over with sickle cell disease of any genotype who had a haemoglobin level between 5.5 and 10.5 g/dL and between two and ten sickle cell pain crises in the previous year. Hydroxyurea was allowed if the dose was stable.

People were randomly assigned in a 2:1 ratio to mitapivat 100 mg twice daily (138 people) or placebo (69 people) for 52 weeks. The median age was 25, and 57.5% were women.

The results

The trial had two primary endpoints, and success on either one would count as a positive outcome for the trial design.

Haemoglobin

A haemoglobin response was defined as an average rise of at least 1.0 g/dL from the start, measured between weeks 24 and 52. That threshold was met by 56 of 138 people on mitapivat (40.6%) and 2 of 69 on placebo (2.9%), a difference that was highly statistically significant (p<0.0001).

Across all participants, average haemoglobin rose by 7.69 g/L on mitapivat and 0.26 g/L on placebo. For readers used to UK lab reports, which use g/L, that's a rise of nearly 8 g/L against virtually none.

Signs of red cell breakdown also fell. Indirect bilirubin, a by-product of haemolysis that causes yellowing of the eyes, dropped by 16.03 µmol/L on mitapivat and rose by 0.88 µmol/L on placebo.

Pain crises

The annual rate of sickle cell pain crises was 2.62 on mitapivat and 3.05 on placebo. That's roughly 14% fewer crises, but the result wasn't statistically significant (p=0.1213), so the trial didn't show a benefit on this endpoint.

Other outcomes

• Fatigue. Scores on a standard patient-reported fatigue scale (PROMIS) improved by 2.72 points on mitapivat and 2.25 on placebo. This difference didn't meet its target.
• Hospital stays. Sickle cell-related hospital admissions ran at 1.56 a year on mitapivat and 1.81 on placebo. This is a nominal difference only.
• Transfusions. 23.9% of people on mitapivat needed a transfusion during the trial, against 40.6% on placebo, and the average number of units given was 0.7 against 1.59.

People who responded

In an analysis decided after the results were known, the researchers compared people on mitapivat whose haemoglobin responded with those whose didn't. Responders had 2.20 crises a year, against 2.98 in non-responders, a rate ratio of 0.74. Hospitalisations were also lower (rate ratio 0.66), and fatigue scores improved more (5.19 points). This hints that a bigger haemoglobin rise may bring clinical benefit, but responders may differ from non-responders in other ways, so it can't prove cause and effect.

Safety

Side effects were reported by 97.1% of people on mitapivat and 98.6% on placebo, which reflects how often people with sickle cell disease have health problems of some kind. Serious side effects were less common on mitapivat (20.3%) than placebo (29.0%), and one serious event on mitapivat was judged related to the drug. Treatment was stopped because of side effects by 4.3% on mitapivat and 2.9% on placebo.

Three people on mitapivat and two on placebo died during the trial. None of the deaths was considered related to treatment.

Liver injury has been a concern with mitapivat. In the thalassaemia programme, cases of liver damage led to monitoring requirements. In RISE UP, the authors reported no signal of drug-induced liver injury. The FDA's question about whether a risk evaluation and mitigation strategy (REMS) is needed suggests regulators are still weighing liver safety across the drug's uses.

Of the 176 people who completed the 52 weeks, 174 chose to join the open-label extension, where everyone receives mitapivat.

What the experts say

In an accompanying Lancet comment, Jennifer Knight-Madden and a co-author described mitapivat as a possible new therapy for sickle cell disease, while noting that the trial didn't show fewer pain crises. Independent coverage has made the same point. Haemoglobin is a laboratory marker. Patients and doctors care most about pain, hospital stays, organ damage and survival, and RISE UP wasn't large or long enough to show changes in the last two.

There's also history behind the caution. Voxelotor raised haemoglobin and was approved on that basis in 2019, then withdrawn in 2024 after more deaths and pain crises were seen in later studies. Regulators will be wary of approving another drug on a haemoglobin rise alone, which is one reason accelerated approval would come with a requirement to confirm benefit.

Limitations

• Pain endpoint not met. The trial didn't show a significant reduction in sickle cell crises.
• One year of follow-up. Longer-term effects on organs and survival are unknown.
• Post hoc subgroups. The more striking responder findings come from analyses chosen after the data were seen.
• Funding. Agios funded the trial and was involved in its design and analysis.
• Population. People had frequent crises and low haemoglobin at the start; results may differ in people with milder or more severe disease, and children under 16 weren't included.

Where things stand

Mitapivat isn't approved for sickle cell disease anywhere. The FDA's new decision date is 1 February 2027. No applications in the UK or Europe for this use have been announced.

For people living with sickle cell disease, RISE UP offers a cautiously positive signal: a tablet that lifts haemoglobin, reduces red cell breakdown and lowers the need for transfusions, with a safety profile in this trial that looks acceptable. What it hasn't yet shown is that those changes translate into fewer painful crises. Anyone interested in mitapivat should talk to their haematologist about whether a clinical trial or the extension study might be an option.