The global recall of voxelotor (Oxbryta, Pfizer) has left clinicians treating sickle cell disease (SCD) with the urgent task of reaching patients taking the drug while trying to understand why it was withdrawn from the market.

The National Association of Sickle Cell Centers issued a statement urging patients not to suddenly stop using the voxelotor. Instead, they should work with their doctors and medical teams to develop plans for weaning plans.

“Don’t lose faith. This is a step back, but we will remain on the path to better outcomes for all,” the alliance said in a statement to patients and clinicians.

On September 25, Pfizer stated that it would recall all batches of voxelotor in all markets where it is approved. The New York-based drugmaker also said it was discontinuing all clinical trials of active voxelotors and expanding access programs globally. This was due to data suggesting “an imbalance in vascular occlusive crises and fatal events that require further evaluation.”

Pfizer said Medscape Medical News in the email that he is focused on data analytics and will provide future updates on presentations or publications on this topic.

The withdrawal took place due to increased control of the drug by the European Medicines Agency (EMA). In July, the EMA began assessing voxelotor after data from a clinical trial showed that the drug had more deaths compared to placebo, and another study showed that the total number of deaths was higher than expected.

On September 26, EMA’s committee for human medicines recommended suspending voxelotor’s marketing authorization, citing new safety data that emerged during the review. The agency said the drug received marketing authorization in the European Union in 2022.

The US Food and Drug Administration (FDA), which first approved voxelotor for sale in 2019, also said it was assessing the drug’s safety. The agency continues to analyze data from postmarketing clinical trials of voxelotor, real-world registry studies, and data from the FDA’s Adverse Event Reporting System. The agency said that once the review is completed, the FDA will communicate any additional findings, if necessary.

The FDA stated that in postmarketing clinical trials, more deaths and higher rates of vascular crisis were observed in patients taking voxelotor compared to placebo.

“In two real-world registry studies, Pfizer observed a higher incidence of vaso-occlusive crisis in patients with sickle cell disease receiving Oxbryta,” the FDA said. “Based on the totality of the clinical data, Pfizer has concluded that Oxbryta’s benefits do not outweigh its risks.”

Gene therapy, tried and true hydroxyurea (HU)

As a field, SCD has received increased attention in recent years, and significant progress has been made recently in cutting-edge designs.

In December, the FDA approved two gene-editing methods for patients 12 years of age and older. They are considered “treatment milestones” for the devastating and potentially life-threatening blood disease that affects about 100,000 people in the United States. Exagamglogene autotemcel (Casgevy, Vertex Pharmaceuticals and CRISPR Therapeutics) is the first to use the CRISPR gene editing tool. In contrast, lovotibeglogene autotemcel (Lyfgenia, bluebird bio) uses a different gene editing tool called a lentiviral vector.

These advances have been widely covered in the media but are not expected to be widely available, and the cost of these broad-based therapies is estimated at approximately $2 million to $3 million per patient.

“Gene therapy is amazing because it can provide a cure, but it is very expensive and not all patients are suitable for it. Some people have such severe organ damage that it’s not an option for them,” said Dr. John Wood, M.D., director of cardiovascular MRI at Children’s Hospital Los Angeles, Los Angeles, who conducts SCD research.

“So it’s a really great treatment for very few people,” he said in an interview.

The mainstay of treatment for SCD remains what Lydia Pecker, MD, a pediatric hematologist at Johns Hopkins University in Baltimore, describes as “the first, oldest and best”: HU.

The FDA approved it in 1998 for use in SCD. It reduces the frequency of painful crises and acute chest syndromes and other complications of SCD that could otherwise be serious or even fatal, Pecker said.

“Senior physicians can say that what they experienced in sickle cell hospitals has completely changed because of the high use of the drug,” she said, adding that it has caused a “profound” change. “We simply don’t have data on any other agent doing something similar.”

Pecker noted that voxelotor was a good second drug to add in some patients in addition to HU and blood transfusions. It was a first-line drug for those for whom transfusion and HU were not an option, which is a relatively small number of patients, she added.

“So over the last five years, we felt more hopeful because we had something different to offer,” she said.

Alexis A. Thompson, MD, MPH, chief of the Department of Hematology at the Children’s Hospital of Philadelphia, said Medscape Medical News that her organization also included patients who appeared to benefit from voxelotor, some of whom were involved in clinical trials.

Thompson, a leading researcher involved in gene therapy research, urged companies to continue trying to expand options for people with SCD, even after the voxelotor failure.

“I hope there is recognition of the need for further investment in this very serious disease for which there are insufficient treatment options,” Thompon said. “If we are to expect progress, continued investment is really needed.”

Pecker disclosed ties to Novartis, Afimmune, the American Society of Hematology and the National Institutes of Health. Thompson reported affiliations with bluebird bio, Beam, Editas, Novartis and Novo Nordisk.

Kerry Dooley Young is a freelance journalist based in Washington, DC. You can follow her further LinkedIn.