SCDAA Medical and Research Advisory Committee (MARAC) Statement: Pfizer’s Voxelotor (Oxbryta®) Withdrawal

9/27/24

What is the news?

Pfizer announced the withdrawal of voxelotor (Oxbryta®) from national and global markets on September 25, 2024.  Clinical research was also stopped. “Pfizer’s decision is based on the totality of clinical data that now indicate the overall benefit of OXBRYTA no longer outweighs the risk in the approved sickle cell patient population. The data suggest an imbalance in vaso-occlusive crises and fatal events, which require further assessment.” [1].

What is the reason?

The Pfizer statement mentions that worrisome new information came from three reports that link voxelotor with more pain and deaths:

  1. A clinical research study of children with sickle cell disease and with higher risk of stroke (GBT440-032) had eight deaths in the voxelotor group compared to two deaths in the group without voxelotor. The study recruited 236 children (2y-15y) from Egypt, Ghana, Kenya, Nigeria, Oman, Saudi Arabia, USA and the United Kingdom.
  2. Another clinical research study of adolescents and adults with sickle cell disease and leg ulcers (GBT440-042) had eight deaths on voxelotor. Eighty-eight patients at least 12 years of age were enrolled in Brazil, Kenya and Nigeria.
  3. Monitoring reports from people taking voxelotor as a prescribed medication, not on a clinical research study. No numbers were listed.

Following standard rules when new risks are found, Pfizer voluntarily withdrew voxelotor from use worldwide, while further investigation is conducted. Pfizer also reports that they are halting manufacturing production and clinical research.

What if I have been doing well on voxelotor (Oxbryta®)?

The FDA has received questions about whether to allow some individuals living with sickle cell disease to continue voxelotor on a “compassionate use” basis. However, for now we cannot assume that “compassionate use” will be allowed.

Do I just throw away the voxelotor?

For people with sickle cell disease who have been on voxelotor and doing well, MARAC does not have evidence on what will happen when you stop taking the medication. There is a report that going from full-dose voxelotor to completely stopping taking the drug led to intense hemolysis (breakdown of red blood cells) and severe sickle cell problems within three days that injured the kidneys and other organs and required hospital care. Thus, many doctors are suggesting that people taper off voxelotor over a period of about two weeks. However, tapering is optional and not based on strong clinical evidence. We strongly urge individuals to discuss their options and next steps with their sickle cell health care professional.

What if I have unusual problems as I discontinue voxelotor?

Contact your sickle cell health care provider. Voxelotor acts by slowing down the breakage of red blood cells (hemolysis) and blocking the red cells from changing to the sickle shape. A possible problem is that if the hemolysis suddenly increases it may damage the kidneys. Your eyes will probably become more yellow (jaundiced), and your urine will be darker yellow-orange. Tell your doctor if you have brown urine (the color of cola). You will probably need to come in for lab tests and treatment. Immediately seek medical attention if you stop making urine even when you are drinking a lot of water. Comprehensive sickle cell centers and sickle cell health care providers are collecting reports from patients about any new problems experienced when they come off voxelotor.

What about my other sickle cell medicines?

This news is only about voxelotor.  Continue taking other medications as prescribed.

What are the alternatives to voxelotor?

In the USA, sickle cell disease severity can be reduced by three other medications approved by FDA:

  • hydroxyurea (Droxia®, Siklos®),
  • glutamine (Endari®), and
  • crizanlizumab (Adakveo®)

Blood transfusions are used for selected problems in sickle cell disease, especially to prevent stroke.

  • “top-off transfusions” or simple transfusions
  • “exchange transfusions” or erythrocytapheresis

Hematopoietic stem cell transplant (also known as bone marrow transplant) is a cure that requires an:

  • HLA-identical (fully-matched) sibling donor, or
  • haploidentical (half-matched) related donor, or
  • unrelated HLA-matched donor

Two gene therapy approaches can potentially cure sickle cell disease without having to find a donor.

  • CasgevyTM (CRISPR/Vertex) or
  • LyfgeniaTM (bluebird bio)

MARAC recommends making an appointment to discuss your sickle cell treatment plan with your sickle cell health care provider.

Is this the first time a medication has been withdrawn?

No. Other situations of medication withdrawal from the market have occurred.

  • 2004: Merck withdrew rofecoxib (Vioxx) as an arthritis drug.
  • 1997: FDA ordered Wyeth to remove the weight-loss medications fenfluramine (Pondimin) and a related drug, dexfenfluramine (Redux) from the market.
  • 1961: Chemie withdrew thalidomide as an antinausea drug. 2006 thalidomide was approved for the treatment of plasma cell myeloma.

When will there be more updates?

We do not know. MARAC is following the news as it unfolds. The U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) regulations control some of the timing for release of information. SCDAA MARAC is continuing to monitor the situation and will update the community as soon as new information is released.

Additional Information — 9/30/24 Update

What details are publicly available about the deaths?
A document posted online by the European Medicines Agency has the most details that MARAC was able to find. “Notification to the CHMP/EMA Secretariat of a referral under Article 20 of Regulation (EC) 726/2004” electronically signed July 30, 2024, accessed Sept. 29, 2024. https://www.ema.europa.eu/en/documents/referral/oxbryta-article-20-procedure-notification_en.pdf The rules of EMA and FDA control release of information.

  • Of the 8 deaths in the GBT440-032 randomized study of children with abnormal stroke risk: “Most of the fatal cases in the voxelotor group describe incidence of infection, including 3/8 who developed fatal malaria and 2/8 patients with sepsis.”
  • Of the 8 deaths in the open-label GBT440-042 of voxelotor for leg ulcers: “In 4 cases, malaria was identified either the cause or contributing factor.”
  • “The investigator and sponsor considered that none of the fatal cases were related to voxelotor in these studies.”

What information is still missing?
Quoting from the same EMA document from July 30, 2024:

  • Some of the “case narratives” from GBT440-032 and GBT440-042 “are still not available, … and overall information provided to date is limited. However, given the fact that concerns due to possible immunosuppressive effects of voxelotor were raised at the time of the MA (with immunosuppressive effects observed in animal studies and decrease in WBC in clinical studies), and the study population in those studies partially overlap with the intended population based on the authorized indication, the findings from these emerging safety data need to be further reviewed, taking into account all available data, to determine whether there is an impact on the benefit-risk balance of Oxbryta in the authorized indication.”
  • It is unclear how these deaths compare with the known vulnerability to infection and early death of sickle cell disease without treatment.

References

Pfizer statement, 9/25/24: https://www.pfizer.com/news/press-release/press-release-detail/pfizer-voluntarily-withdraws-all-lots-sickle-cell-disease

Pfizer letter to Health Care Providers, 9/26/24: https://webfiles.pfizer.com/dear-hcp-letter-oxbryta-us-final-092524?cmp=US-21234&campaign=US-21234&identitytype=account&tpn=1532773&LNK=GL_BD3-C2&mkt_tok=MTk1LVVMQy0yMDAAAAGV1F26wnPvgN6fKRyyOgU-kt_3Pa-xaL9I_wa6yP1ROToTo85YnZaSQ98g2cAj9j-cf9xvsubH4Rvs50AWKcAMrA4qw1nLMAsCEbu8-c6PeXuPhg

European Medicines Agency, July 2024: https://www.ema.europa.eu/en/medicines/human/referrals/oxbryta

FDA statement, 9/26/24: https://www.fda.gov/drugs/drug-safety-and-availability/fda-alerting-patients-and-health-care-professionals-about-voluntary-withdrawal-oxbryta-market-due