On September 25, 2024, a major chapter in sickle cell treatment came to an abrupt close. Voxelotor, granted accelerated approval by the U.S. Food and Drug Administration (FDA) in November 2019, was celebrated as the first therapy to target the underlying pathophysiology of sickle cell disease (SCD). By stabilizing sickle hemoglobin in its oxygenated state, voxelotor reduced red cell sickling and its complications. The phase III HOPE trial, which showed a 44% hemoglobin response rate compared to placebo, served as the foundation for its approval. Yet, less than five years later, voxelotor was withdrawn globally following reports of increased rates of vaso-occlusive crises and mortality among treated patients.
Tomorrow, the Special Interest Session Clinical Care and Research Implications Following Voxelotor Withdrawal (10:30 a.m. – 12:00 p.m., Convention Center, Room 33) will examine how the unexpected decision impacted the sickle cell community and treatment transitions, as well as the impact on future drug development.
John J. Strouse, MD, PhD, director of the Adult Sickle Cell Program at Duke University, describes the confusion that followed. “We were blindsided,” he said. “How I learned about this was I got an email from one of my colleagues who said, ‘Did you hear that voxelotor was pulled off the market?’ And I had just seen it on a pharmaceutical industry email.”
For Alexis A. Thompson, MD, MPH, chief of hematology at Children’s Hospital of Philadelphia, the withdrawal underscores both the progress and challenges in sickle cell therapy. “We’ve come so far since the first approval of hydroxyurea,” she said. “But this withdrawal is a reminder of how fragile that progress can feel for patients.”
The Immediate Fallout
The discontinuation of voxelotor posed significant challenges for continuity of care. “Patients who tolerated voxelotor poorly or had minimal response could stop it without much disruption,” said Dr. Strouse. “But for those who had significant hemoglobin improvements, it was a different story. We offered to taper them over time … then other therapies and monitoring, as necessary.” However, the lack of exceptions in the withdrawal policy left patients and providers with limited options.
Patient Reactions: Disappointment and Determination
“Patients were deeply disappointed, some even angry,” Dr. Strouse recalled. “While they didn’t blame their providers, they felt their options had been abruptly narrowed.” Dr. Thompson emphasized the need to balance acknowledgment of this distress with optimism. “This was the first rationally designed drug for SCD,” she said. “The fact that it reached approval shows what’s possible. There’s still a robust pipeline of therapies being developed.”
Research Implications The withdrawal has sparked discussions about the future of SCD drug development and clinical trial design. Dr. Maureen Okam Achebe, MD, MPH, will explore how the withdrawal influences research priorities and trial methodologies. One key issue is the use of hemoglobin as a surrogate endpoint. “Hemoglobin increases drove voxelotor’s accelerated approval,” explained Dr. Strouse. “But that metric alone may not be sufficient in future trials.”
Dr. Achebe’s session will also address global disparities in drug development. “Most of the mortality data prompting voxelotor’s withdrawal came from trials in sub-Saharan Africa,” Dr. Strouse noted. “This raises complex questions about how regional differences in care infrastructure influence trial outcomes. For instance, malaria-associated mortality in Africa wouldn’t affect U.S. patients but has significant implications for global drug approvals.”
Dr. Thompson underscored the importance of maintaining global engagement. “The burden of SCD is highest in low-resource settings,” she said. “If we retreat from drug development in these areas, we risk delaying access to lifesaving therapies.”
Navigating the Future
Despite the setback, innovation in disease-modifying therapies shows no signs of slowing. Dr. Thompson will highlight the wave of innovative approaches in the pipeline, including hemoglobin oxygen affinity drugs, hemoglobin F inducers, and pyruvate kinase activators.
Regarding the currently approved gene editing therapies and stem cell transplants, Dr. Thompson cautioned that patient eligibility and tolerability of myeloablative chemotherapy, as well as socioeconomic and caregiver considerations, remain significant limitations. “Gene therapy and transplants are not without risk,” she said. “They demand significant preparation and recovery, and long-term monitoring is essential. These are deeply personal decisions that need to be tailored to each patient.”
Keeping Patients at the Center
Voxelotor’s withdrawal underscores the need for a patient-centered approach to drug development and regulatory decisions. Dr. Strouse emphasized the importance of listening to patients. “Patients are the most important stakeholders in this process,” he said. “Their experiences should guide our next steps.”
Dr. Thompson urged continued community engagement. “This is a moment to pivot and say what’s next,” she said. “We must advocate for inclusive drug development, expand access to approved therapies, and support patients in exploring all available options.”
Tomorrow’s special interest session will emphasize that the withdrawal of voxelotor is not an endpoint but part of a larger journey toward better care for SCD.
