The accelerated approval of voxelotor, sold under the brand name Oxbryta, in 2019 was seen as a significant advance in expanding treatment options for patients with sickle cell disease (SCD) and was the first therapy to target the root cause of the condition by inhibiting deoxygenated sickle hemoglobin polymerization.1 Just five years later, clinicians and patients were shocked to hear that the drug was being withdrawn from the market because of safety concerns.
“We were taken by surprise because we had not observed any life-threatening clinical toxicity since 2019 when we started prescribing this medication,” said Akshat Jain, MD, MPH, medical director of the Sickle Cell Center of Excellence at Loma Linda University Health in California, who had more than 60 patients taking voxelotor at the time of the withdrawal.
“These patients came to depend on that therapy option. These were patients who had not tolerated hydroxyurea or who needed a second-line agent to meet their treatment goals, so the only option left for them was this medication. It was shocking to hear that option was being pulled out with no forewarning,” he added.
On September 25, 2024, Pfizer announced the voluntary withdrawal of voxelotor from the global market for adults and pediatric patients 4 years of age and older based on clinical data indicating that the overall benefit of the drug no longer outweighed the risks.2
“The data suggest an imbalance in vaso-occlusive crises and fatal events, which require further assessment. Consequently, Pfizer is voluntarily withdrawing the product from the market at this time. Pfizer is also discontinuing all ongoing Oxbryta studies and early access programs,” the company said in a letter to health care providers that was dated one day after the public announcement.3
There were reports of deaths in two clinical studies being conducted outside of the U.S. In a study of 236 children with SCD and a higher risk of stroke in Africa, the Middle East, and the United Kingdom, there were eight deaths in the voxelotor group, mainly related to malaria or sepsis. A separate study of 88 adolescents and adults in Brazil, Kenya, and Nigeria who had SCD and leg ulcers saw eight deaths occur in the voxelotor group, with malaria being identified as a cause or a factor in some of those cases.4
ASH Clinical News spoke with clinicians who treat SCD and individuals with the disease about the effects of this announcement, the role of voxelotor in the disease armamentarium, and rebuilding trust within the patient community.
More Questions than Answers
Aside from the surprising nature of the announcement, many clinicians were also grappling with the lack of details Pfizer released. Specifically, the letter noted that the decision was based on the “totality of clinical data” but did not provide any details on adverse events (AEs) in the U.S. or explain if any specific patient populations were most at risk.
“I’m not really sure if the safety signal is real or not because there’s been so little detail about what really happened,” said Charles Abrams, MD, the Francis C. Wood professor of medicine at the University of Pennsylvania School of Medicine and chair of the SCD Program for the American Society of Hematology (ASH) Research Collaborative.
Jeffrey Glassberg, MD, professor and director of the Center for Sickle Cell Disease at the Icahn School of Medicine at Mount Sinai in New York, sees the voxelotor risk-benefit picture as being more nuanced than the abrupt global withdrawal of the drug suggests.
Over the last five years, he has treated more than 100 patients with voxelotor. He first noticed that patients who missed doses or abruptly terminated the drug sometimes became critically ill, prompting him to recommend that patients stockpile medication. He also observed that patients with severe anemia had little benefit, while patients with mild-to-moderate anemia experienced significant increases in their hemoglobin levels, he explained.
In patients with poor red cell drive, voxelotor could be harmful. But a combination of voxelotor, erythropoietin, and hydroxyurea produced significant improvement for many of those patients. “In some cases, it was really the only option left,” Dr. Glassberg said.
Given the learning curve involved with prescribing voxelotor and identifying patients most likely to benefit, Dr. Glassberg said some AEs could be the result of physicians prescribing voxelotor to patients with poor red cell drive without modifications to the regimen. But that is not clear because Pfizer has not released full details about the safety concerns, he said.
Tapering or Cold Turkey
Even as questions linger about the safety signal, hematologists say they were left on their own when it came to counseling patients about the withdrawal. Pfizer’s letter stated that patients should no longer be prescribed voxelotor but did not provide guidance on whether to taper the medication or how to do it. “Complications when treatment is interrupted abruptly cannot be excluded, but neither efficacy nor a dose for gradual discontinuation have been established,” the company wrote.
Some clinicians chose to taper patients off the medication over a period of about two weeks. Payal Desai, MD, director of the Sickle Cell Enterprise at Atrium Health Levine Cancer Institute in Charlotte, North Carolina, said that immediately following the withdrawal announcement, academic hematologists across North Carolina convened to develop a strategy for patients who had been taking voxelotor.
The group drafted a working document that outlined a taper strategy. Based on emerging research and the drug’s mechanism of action, they concluded that there was a potential risk for blood breakdown and a drop in hemoglobin, especially for patients who had experienced a robust response to voxelotor. “We were the most worried, as a whole group, about patients who, for example, have an inability to transfuse. They were on voxelotor because they didn’t have a transfusion option due to having too many red cell antibodies,” Dr. Desai said.
But not all patients were tapered off voxelotor, either because they didn’t have enough leftover medication to perform a taper or because they were concerned about the safety of continuing voxelotor, even temporarily. Dr. Jain said a sizeable number of patients with SCD who stopped the medication “cold turkey” suffered rebound pain, and a few needed inpatient care due to severe vaso-occlusive events.
Debating Accelerated Approval
Voxelotor was introduced to the U.S. market through a process known as accelerated approval. The pathway was created by the U.S. Food and Drug Administration (FDA) in 1992 to expedite therapies during the AIDS epidemic and was later codified to accelerate the approval process for treatments for other serious or life-threatening conditions. The program uses the same standard of evidence as regular approval but allows drug companies to submit evidence on a surrogate endpoint that is reasonably likely to predict clinical benefit, rather than waiting for definitive evidence like mortality data.5
To gain full approval for a drug, companies must conduct confirmatory trials to show a clinical benefit beyond the surrogate endpoint. If the confirmatory trial fails, the FDA has a process that could lead to the drug’s withdrawal from the market.6
In the case of voxelotor, the FDA based its initial 2019 accelerated approval on the results of the pivotal phase III HOPE trial, where the primary efficacy outcome was hemoglobin response rate, defined as an increase of more than 1 g/dL in hemoglobin from baseline to week 24. Overall, the response rate was 51% for patients receiving voxelotor compared with 7% for patients receiving placebo. In 2021, the FDA expanded the voxelotor approval to include pediatric patients as young as 4 years old. At the time of the voxelotor withdrawal, additional studies were underway to provide confirmatory data in both adult and pediatric populations.7,8
“[Accelerated approval] has always been a double-edged sword. Certainly, it accomplished the idea of getting drugs out there and utilized more quickly. But some drugs that have been approved through this pathway have later been proved to be ineffective and sometimes even unsafe for patients,” Dr. Abrams said. “It’s had this scrutiny and debate over the years, particularly with regard to the level of trust it engenders among health care professionals, patients, and the general public.”
Crawford Strunk, MD, co-director of the Lifespan Sickle Cell Program at the Cleveland Clinic and vice chief medical officer of the Sickle Cell Disease Association of America, Inc., said that Pfizer, as well as other pharmaceutical companies, should develop a plan going forward to make the process more transparent so clinicians, researchers, and patients can get the data they need to assess risks and benefits.
But Dr. Glassberg is concerned that if the voxelotor withdrawal damages the credibility of the accelerated approval process, it could limit access to therapies for patients with SCD.
“If you got rid of the accelerated approval process, the damage to people with SCD would be extraordinary,” he said. “It’s not diabetes; you can’t get 50,000 patients into your study to get the data you need. Rare disease management means living with incomplete knowledge. To hold yourself to similar standards as common diseases is just absurd.”
Remaining Options Are Limited
The voxelotor withdrawal emphasizes the need for continued research into new treatment options for patients with SCD.
“We need new agents,” Dr. Strunk said. “We’re down to blood transfusions and hydroxyurea because the other approved agents are being used much less frequently due to increased toxicity or limited tolerance.”
The three disease-modifying agents approved in the U.S. are hydroxyurea, glutamine, and crizanlizumab (which has been withdrawn in Europe).9 Two new gene therapy options — exagamglogene autotemcel and lovotibeglogene autotemcel — were approved in December 2023. Blood transfusions are an option for some patients, especially if stroke is a concern. Additionally, hematopoietic cell transplant is a curative option but requires a donor.
Dr. Glassberg said he has been using more erythropoietin and hydroxyurea since the withdrawal of voxelotor and is seeking to enroll patients into clinical trials for sickle cell drugs that work by other mechanisms to increase hemoglobin. But even clinical trials aren’t a great fix, he said, because some patients will get placebo.
Dr. Desai said she hopes the voxelotor withdrawal doesn’t put a chill on interest in developing sickle cell therapies. “One of the biggest concerns in the field now is that people on the pharma side will see sickle cell as hard to treat. I think that would be the most devasting blow to the field,” she said.
The voxelotor experience raises questions about how best to design SCD clinical trials moving forward, according to Maureen Achebe, MD, MPH, associate professor at Harvard University who treats patients with SCD and was part of a session on the clinical care and research implications of voxelotor’s withdrawal at the 66th ASH Annual Meeting and Exposition in December.10 For instance, Dr. Achebe said it’s important to wrestle with whether an increase in hemoglobin is a viable surrogate trial endpoint, as well as whether a phase II/III design provides a rigorous safety assessment for sickle cell drug candidates.
“Is it sufficient for us to have a phase II trial of 12 to 24 weeks, choose a dose, and then move straight to phase III trials? Are they equivalent to having a phase II trial first and then going to phase III? We know that they’re equivalent for efficacy, but are they equivalent for safety data?” she said during the session.
Another question going forward is whether SCD trials in low- and middle-income countries should be identical to high-income countries and if there should be different strategies and support for managing AEs in low- and middle-income settings, she said.
“Our current situation provides an opportunity to address these questions and apply what we’ve learned to further drug discovery in SCD,” Dr. Achebe said at the ASH annual meeting.
Rebuilding Trust
Clinicians who spoke with ASH Clinical News said the loss of patient trust was also a major worry following the voxelotor withdrawal. “This has always been a disenfranchised group, and trust is utmost,” Dr. Abrams said. “Things like this don’t help. It wasn’t done maliciously, but when you have a community that might be a little wary to begin with, this doesn’t help the situation.”
Bridget Reynolds, a patient with the hemoglobin SC form of SCD, was briefly on voxelotor when it was first approved but experienced severe heart palpitations with the drug so opted to continue treatment with hydroxyurea alone. Ms. Reynolds said she suspects the recently approved drug did not work for her because it was not designed for patients with the hemoglobin SC form of SCD.11
Even though voxelotor didn’t work for her, Ms. Reynolds said she was disappointed when she heard the news of the withdrawal and questioned why the safety issues weren’t brought to light earlier.
Going forward, she said she is unsure how she would react to the approval of a new sickle cell therapy and might want to “wait and see” how patients respond to the drug in the real-world setting. At the same time, she said she’s concerned that the voxelotor withdrawal will make the FDA think twice before fast tracking a sickle cell drug.
Dr. Jain said one way to earn back patients’ trust is by sharing more information. He urged the FDA and Pfizer to release data so clinicians can answer patients’ questions about why they had to stop a medication that was working for them. He also urged the FDA to use public service announcement channels in the future to communicate withdrawals clearly, especially when the drug affects an underserved community.
“Patients are looking at us as the gatekeepers of the health care enterprise, and this experience has put the trust we built with the community over decades on shaky ground,” he said. “They are seeing this not as a fault of the FDA, not as a fault of the drug manufacturer, but as a failing of the health care system that put them on this medication.”
Dr. Desai said she is hopeful that the long-term relationships she and her team have built with patients will help to rebuild some of the trust lost by the voxelotor withdrawal. When the news came out about the withdrawal, the team called each patient personally to try to prevent them from hearing it first in the media.
“The idea that we’re in it together goes a long way to support patients and families,” she said. “Patients are looking to us for not just treatment but also hope.”
The sickle cell community has weathered worse storms, Dr. Jain said, and he believes all is not lost. “This gives a renewed opportunity to rebuild trust with these patients and prepare the ground for plentiful therapeutic offerings in the pipeline that are around the corner,” he said.
References
- U.S. Food and Drug Administration. FDA approves novel treatment to target abnormality in sickle cell disease. November 25, 2019. Accessed November 22, 2024. https://www.fda.gov/news-events/press-announcements/fda-approves-novel-treatment-target-abnormality-sickle-cell-disease.
- Pfizer voluntarily withdraws all lots of sickle cell disease treatment OXBRYTA (voxelotor) from worldwide markets. September 25, 2024. Accessed November 22, 2024. https://www.pfizer.com/news/press-release/press-release-detail/pfizer-voluntarily-withdraws-all-lots-sickle-cell-disease.
- Pfizer voluntarily withdraws OXBRYTA (voxelotor) from the market for the treatment of sickle cell disease in adults and pediatric patients 4 years of age and older. September 26, 2024. Accessed November 22, 2024. https://webfiles.pfizer.com/dear-hcp-letter-oxbryta-us-final-092524.
- Sickle Cell Disease Association of America. MARAC statement: Pfizer’s voxelotor (Oxbryta) withdrawal. September 30, 2024. Accessed November 22, 2024. https://www.sicklecelldisease.org/2024/09/28/marac-statement-oxbryta/.
- Beakes-Read G, Neisser M, Frey P, et al. Analysis of FDA’s accelerated approval program performance December 1992-December 2021. Ther Innov Regul Sci. 2022;56(5):698-703.
- U.S. Food and Drug Administration. Accelerated approval program. February 22, 2024. Accessed November 22, 2024. https://www.fda.gov/drugs/nda-and-bla-approvals/accelerated-approval-program.
- 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.
- U.S. Food and Drug Administration. FDA approves drug to treat sickle cell disease in patients aged 4 up to 11 years. December 17, 2021. Accessed November 22, 2024. https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-drug-treat-sickle-cell-disease-patients-aged-4-11-years.
- European Commission (EC) adopts decision endorsing CHMP recommendation to revoke the conditional marketing authorization for Adakveo (crizanlizumab). August 4, 2023. Accessed November 22, 2024. https://www.novartis.com/news/european-commission-ec-adopts-decision-endorsing-chmp-recommendation-revoke-conditional-marketing-authorization-adakveo-crizanlizumab.
- Achebe MO. Implications for ongoing clinical research in SCD and drug development. Special Interest Session. Presented at the 66th American Society of Hematology Annual Meeting and Exposition; December 9, 2024; San Diego, California.
- Nelson M, Noisette L, Pugh N, et al. The clinical spectrum of HbSC sickle cell disease-not a benign condition. Br J Haematol. 2024;205(2):653-663.