The European Medicines Agency (EMA) has confirmed a suspension notice for Oxbryta (voxelotor, Pfizer), which is used to treat sickle cell disease (SCD). The medicines regulator said that a higher rate of death and disease complications in recent trials meant the benefit-risk balance was “no longer favorable.”

The move follows a review initiated in May 2024 after the sponsor paused two ongoing global clinical trials due to safety concerns. 

Prevalence Increasing Across Europe 

SCD is an autosomal recessive inherited hemoglobinopathy in which abnormal hemoglobin S (HbS) causes red blood cell lysis, hemolytic anemia, and recurrent occlusion of small vessels with consequent ischemia. These vaso-occlusive events cause acute and chronic pain, vasculopathy, and a wide range of progressive organ-specific clinical complications.

The disease is most common in people of Black African, Caribbean, Middle Eastern, and South Asian heritage. It is rare in Europe but prevalence is increasing, predominantly among migrants from sub-Saharan Africa and parts of the Middle East and particularly in France and the UK, which have higher immigrant populations from these regions.

SCD had few treatment options available prior to Oxbryta, which was initially authorized in 2022 to treat hemolytic anemia in SCD patients aged 12 years and older. 

The drug is an HbS polymerization inhibitor that increases the affinity of hemoglobin for oxygen, improving sickling and red blood cell deformability. It was hoped that the drug would reduce the need of SCD patients for blood transfusions.

Increased Deaths in Trials

The first trial that was paused was a pediatric trial in London assessing the efficacy of voxelotor in increasing red blood cell counts and reducing the severity of symptoms of SCD. It was paused when an imbalance in the number of deaths became apparent, with eight deaths in the voxelotor vs two in the placebo group. 

The other was a trial assessing the effect of voxelotor in healing leg ulcers, a known complication of SCD. This resulted in a higher than anticipated number of deaths in the voxelotor group. In the first 12 weeks, one person died in the voxelotor group, with no deaths in the placebo group. In the following 12 weeks, when all patients received voxelotor, eight additional deaths were reported. 

More Occlusive Episodes on the Active Drug

The EMA said that the studies also showed a higher number of episodes of sudden severe pain, including vaso-occlusive crises, among patients treated with the active drug. Further data from registry-based studies confirmed a higher frequency of such episodes after starting the drug. In September 2024, the EMA temporarily suspended the drug pending a safety review and advised healthcare professionals to switch patients to an alternative treatment.

The EMA’s Committee for Medicinal Products for Human Use (CHMP) has now recommended that Oxbryta’s marketing authorization remain suspended. Although there is no clear explanation for the increased risks, the committee could not identify measures that might effectively minimize them nor distinguish any subgroup of patients for whom the drug’s benefits would outweigh its risks.

The CHMP opinion will now be forwarded to the European Commission, which will issue a final legally binding decision applicable in all EU Member States.