By: Amita Singh, Pharm D Candidate c/o 2025

Voxelotor, marketed under the brand name Oxbryta, was approved by the US. Food and Drug administration (FDA) under the accelerated approval pathway in 2019 for the treatment of sickle cell anemia in adults and pediatric patients 12 years of age or older. In 2021, FDA granted accelerated approval of Oxbryta for the treatment of sickle cell disease in patients 4 to 11 years of age. Recently, Pfizer Inc., the manufacturer of Oxbryta, announced on September 25th, 2024, that it is voluntarily withdrawing the drug from the market and discontinuing all ongoing active clinical trials and terminating expanded access programs worldwide.

Sickle cell disease (SCD) is a genetic disorder characterized by the production of hemoglobin (Hb) molecules that cause red blood cells to take on a crescent or sickle shape. It is caused by a mutation in the HBB gene, which encodes the beta-globin subunit of Hb, the protein that carries oxygen in red blood cells. A single nucleotide change replaces valine with glutamic acid, resulting in the formation of hemoglobin S (HbS).¹ Stressful environments such as dehydration, acidosis, or an infection triggers the sickling process or polymerization of HbS. The resulting rigid, sticky, sickle shaped red blood cells have low affinity for oxygen and adhere to vascular endothelium, triggering inflammation. This leads to blockage of small blood vessels, causing ischemia and reperfusion injury. Common consequences of these events include painful vaso-occlusive crises (VOC) as well as tissue infarctions that can be portrayed as stroke or acute chest syndrome.¹ VOCs are the most common complication of SCD and one of the more frequent reasons for emergency room visits in this population.²

Oxbryta binds reversibly to Hb, stabilizing the oxygenated Hb state and preventing HbS polymerization by increasing Hb’s affinity for oxygen.² On November 25, 2019, the FDA granted accelerated approval to Oxbryta based on the results from the HOPE trial (NCT 03036813), a phase 3, randomized, double-blind, placebo-controlled trial. The trial enrolled a total of 274 patients from 12 to 65 years of age with confirmed SCD and one vaso-occlusive episode in the past 12 months. Patients were randomized to receive Oxbryta 1500 mg, 900 mg, or placebo.³ The primary efficacy outcome measure was Hb response rate defined as an Hb increase of >1 g/dL from baseline to week 24.³ The response rate for Oxbryta was 51.1% (46/90) in the 1500 mg group, 33 % (30/92) in the 900 mg  group, compared to 6.5% (6/92) in the placebo group (p<0.0001).³ The most common adverse events with ≥10% incidence were headaches, diarrhea, nausea, arthralgia, rash, abdominal pain, and pyrexia.³  Annualized incidence rate of vaso-occlusive crisis or the number of crises per person per year on a 95% confidence interval was 2.77  in the 1500 mg group, 2.76 in the 900 mg group, and 3.19 in the placebo group.³  Following the results, the recommended dose was set at 1500 mg orally once daily with or without food.

As aforementioned, the FDA granted Oxbryta accelerated approval due to the limited treatment options available for people with sickle cell disease and the urgent need for new therapies. At the time of approval, there were no warnings of potentially life-threatening side effects. However, Pfizer was required to conduct additional clinical trials post-approval to further assess the drug’s safety profile. During post-marketing trials, it was revealed that Oxbryta posed several serious health threats, including an increased risk of vaso-occlusive crisis, organ damage, and death. Additionally, according to the FDA Adverse Events Reporting System (FAERS), sickle cell anemia crisis accounted for 10,839 cases out of a total of 21,498 reported cases, representing 50.4%.⁴

In July 2024, the European Medicines Agency (EMA), the EU equivalent of the U.S. Food and Drug Administration (FDA), launched a review of Oxbryta following concerns raised in two post-marketing clinical trials. Study GBT440-032 evaluated the impact of Oxbryta on transcranial doppler ultrasound measurements of cerebral arterial blood flow in children aged 2 to 15 years with sickle cell disease who are at high risk of stroke.⁵ The study enrolled 236 participants from Egypt, Ghana, Kenya, Nigeria, Oman, Saudi Arabia, the United States, and the United Kingdom. Among the participants, there were 8 deaths in those receiving Oxbryta compared to 2 deaths in the placebo group.⁵ Study GBT440-042 investigated the effects of Oxbryta on leg ulcers in 88 patients aged 12 years and older. Participants were recruited from Brazil, Kenya, and Nigeria. Eight deaths have been reported during the open-label phase of this study.⁵

Review of all clinical data indicate that the overall benefits of Oxbryta no longer outweigh the risks for the approved sickle cell patient population. The data revealed a concerning imbalance in the occurrence of vaso-occlusive crises and fatal events. Following the announcement, healthcare professionals were urged to cease prescribing Oxbryta, while patients and caregivers were encouraged to consult with their healthcare providers to discuss discontinuing Oxbryta and transitioning to alternative treatment options.

References:

1. Elendu C, Amaechi DC, Alakwe-Ojimba CE, et al. Understanding Sickle cell disease: Causes, symptoms, and treatment options. Medicine (Baltimore). 2023;102(38):e35237. doi:10.1097/MD.0000000000035237
2. Yenamandra A, Marjoncu D. Voxelotor: A Hemoglobin S Polymerization Inhibitor for the Treatment of Sickle Cell Disease. J Adv Pract Oncol. 2020;11(8):873-877. doi:10.6004/jadpro.2020.11.8.7
3. Vichinsky E, Hoppe CC, Ataga KI, et al. A Phase 3 Randomized Trial of Voxelotor in Sickle Cell Disease. N Engl J Med. 2019;381(6):509-519. doi:10.1056/NEJMoa1903212
4. Center for Drug Evaluation and Research. “FDA Adverse Event Reporting System (FAERS) Public Dashboard.” U.S. Food and Drug Administration, FDA, Accessed 30 Nov. 2024.  www.fda.gov/drugs/fdas-adverse-event-reporting-system-faers/fda-adverse-event-reporting-system-faers-public-dashboard.
5. European Medicines Agency, Ema Starts Review of Sickle Cell Disease Medicine Oxbryta Published 29 July 2024. Accessed November 30, 2024. www.ema.europa.eu/en/documents/referral/oxbryta-article-20-procedure-review-started_en.pdf.

Published by Rho Chi Post