Oxbryta Withdrawal by Pfizer Causes Turmoil in Sickle Cell Community and Disarray Among Investors
This week, Pfizer’s announcement to withdraw its sickle cell drug Oxbryta from the market has sent shockwaves through the patient community and advocates globally. This incident is the second of its kind within a two-year timeframe, amplifying worries among a historically neglected patient demographic.
According to analyst Evan David Seigerman of BMO Capital Markets, this withdrawal represents a “significant blow” to patients suffering from sickle cell disease. He emphasized that the communication surrounding this decision was particularly forceful, as all global lots were withdrawn and clinical trials alongside expanded access programs were halted. Oxbryta was initially approved in 2019 for individuals aged 12 and older, with an extension of approval for those four years and above in 2021.
The decision from Pfizer came shortly after the European Medicines Agency (EMA) announced a review of Oxbryta related to an observed disparity in death rates. Initially focused on infection and malaria risks, the investigation expanded to cover increased instances of vaso-occlusive crises in patients using Oxbryta.
This past May, Pfizer had already suspended two ongoing clinical trials concerning the drug due to heightened mortality rates compared to a placebo observed in the GBT-440-032 study, with eight out of nine deaths occurring in a separate open-label expansion of the GBT440-042 study.
In light of emerging safety data, EMA reviewers suggested that Oxbryta be withdrawn because of increased risks of vaso-occlusive crises while on the medication, prompting Pfizer to act voluntarily.
Simultaneously, in the U.S., the FDA took the rare step of alerting both patients and healthcare professionals regarding the withdrawal, advising providers to cease prescribing the medication and for patients to consult their healthcare providers about alternative treatments.
No Warning
This abrupt decision leaves healthcare providers with a diminished arsenal against the disease characterized by sickle-shaped blood cells, which can cause painful vaso-occlusive events when obstructing blood vessels.
The U.K.’s Sickle Cell Society expressed its outrage in a Thursday statement, stating, “We were given no warning,” and calling it inexcusable that healthcare providers were blindsided by this news.
The Sickle Cell Disease Association of America has also released a statement indicating they are working to gather additional information and advising patients to connect with their healthcare providers.
In light of recent advancements in biopharma targeting sickle cell disease, the last couple of years had seen renewed hope with the FDA approving two gene therapies: bluebird bio’s Lyfgenia and a collaboration between Vertex Pharmaceuticals and CRISPR Therapeutics known as Casgevy. However, the rollout of these complex therapies has been sluggish, with the first patients only recently beginning treatment.
Analysts from Leerink Partners caution that patients currently taking Oxbryta may not readily transition to gene therapies, as these products have so far been limited to the most serious cases. Alternative options for the milder patient population include treatments from Novartis like Adakveo and Emmaus Medical’s Endari. However, Adakveo has also faced challenges, as the therapy was reported to miss its primary endpoint in a Phase III trial focused on reducing pain crises.
The EMA recommended revocation of Adakveo’s conditional marketing authorization in May 2023, accepted by the European Commission shortly after. While Novartis has withdrawn the therapy from the European market, it remains available in the U.S.
Analysts Question Pfizer’s Dealmaking, Business Outlook
Oxbryta was acquired as part of Pfizer’s .4 billion deal for Global Blood Therapeutics in 2022, generating global sales of 8 million for the drug in 2023. BMO had anticipated approximately 0 million in yearly revenue from Oxbryta, while Guggenheim speculated that sales may eventually reach over 0 million by decade’s end.
With this major therapeutic option from the acquisition now unavailable, questions regarding Pfizer’s dealmaking strategy have surfaced. Despite the setback, the pharma giant asserts that this will not significantly affect its fiscal year 2024 forecasts. Nonetheless, BMO indicated that “sentiment could suffer” due to the substantial investment made in the biotech.
Following the withdrawal announcement, Pfizer shares, which have a market cap of 4 billion, briefly dipped before stabilizing around each. Guggenheim analysts attributed a 1.93% drop on Wednesday’s trading to the EMA’s review announcement regarding Oxbryta’s fatality imbalances.
“In sum, we believe the financial consequences of this announcement are relatively minor for Pfizer. Still, it might amplify investor concerns regarding the company’s track record with business development,” noted Guggenheim analysts.
Questions remain about other Global Blood Therapeutics assets, including GBT-601, now in Phase III trials. The company had previously pushed the primary completion date from 2026 to 2028. Pfizer had initially estimated that both Oxbryta and GBT-601 could yield combined peak sales of billion globally.
A Phase II trial of GBT-601 exhibited safety concerns as well, with treatment-emergent adverse events recorded in eight out of 35 subjects, including headaches, abdominal issues, and instances of sickle cell crises. One death was reported but was ruled unrelated to the treatment.
Osivelotor, another asset in Phase III from the same acquisition, recently had its ClinicalTrials.gov file updated, moving its primary completion date from October 2026 to October 2028, with six new trial sites added.
Finally, analysts will likely scrutinize Pfizer’s growth strategy over the next five years, especially considering multiple patent expirations expected to erode sales. They also face challenges now that the COVID-19 pandemic ceases to be a public health emergency, leading to a sharp decline in demand for their vaccines and antivirals.
Spotlight Shifts to Other Drugs in Development
Leerink Partners noted that while Vertex/CRISPR or bluebird may not see benefits from Oxbryta’s withdrawal, Agios Pharmaceuticals could gain from one less competitor. However, concerns linger about similar physiological outcomes with both Oxbryta and AGIO’s mitapivat. Agios is conducting a Phase III study of mitapivat, previously known as Pyrukynd, for sickle cell disease, with expectations for label expansion by 2026.
Both Oxbryta and mitapivat aim to increase hemoglobin levels and have shown trends toward reducing vaso-occlusive crises, although Agios’ data thus far show lower crisis rates. In the Phase III trial leading to Oxbryta’s accelerated approval, the annualized crisis rates were 2.77 for the drug users and 3.19 for those on the placebo, while mitapivat reported rates of 0.51 compared to 1.71 in a Phase II analysis.
“Concerns about potential risks of mitapivat continuing to pose a similar outcome may linger as a significant ulterior risk for AGIO shares until the RISE UP trial’s data emerges,” Leerink Partners commented.
The withdrawal of Oxbryta might also alter regulatory landscapes for Agios. The firm estimates potential revenues of 1 million for Agios by 2030, contingent upon the approval of its sickle cell treatment.
“The withdrawal of Oxbryta could heighten regulatory scrutiny over demonstrating substantial benefits regarding vaso-occlusive crises in pivotal trials,” Leerink Partners stated.
Another potential beneficiary is Fulcrum, which is presently conducting a Phase Ib trial of pociredir called PIONEER, targeting a similar patient demographic as that of Oxbryta. The trial could see increased enrollment interest from patients seeking new therapy options. Enrollment had previously posed challenges for Fulcrum, which is embarking on a 2025 data release.
Although pociredir faced a full clinical hold due to safety issues regarding hematological malignancies, the hold was lifted in August 2023 following protocol amendments.
With the latest setback impacting an already vulnerable patient demographic, the Sickle Cell Society expressed concern over a regression of 20 years in drug development progress. They concluded, “For many, voxelotor (Oxbryta) represented hope. Its sudden disappearance places us back in a position to advocate for enhanced care and treatment alternatives for our community.”