Pfizer’s sudden market withdrawal of sickle cell therapy Oxbryta, which some analysts predicted would reach $750 million in sales by the end of the decade, has left patients and healthcare providers with few options, while investors question the pharma giant’s dealmaking prowess.
Pfizer’s decision this week to withdraw sickle cell medicine Oxbryta from the market has left patients and advocates around the world scrambling for information. This marks the second time in two years that a newer medicine has come under scrutiny, stoking concerns yet again from a patient population that has long been underserved.
BMO Capital Markets analyst Evan David Seigerman called the withdrawal a “significant blow” for the sickle cell community. He noted that the news was communicated “in the strongest of terms,” with all lots globally being pulled and clinical trials and expanded access programs shut down. The therapy was approved in 2019 for patients 12 years and older, then expanded in 2021 for patients four years and older.
Pfizer made the move Wednesday evening, hours after the European Medicines Agency (EMA) revealed a review of the product over an observed imbalance of fatalities. The review initially focused on concerns about infection and malaria risk but expanded to examine increased cases of vaso-occlusive crisis in patients taking Oxbryta.
Pfizer paused two ongoing clinical trials of Oxbryta in May over concerns about a higher rate of deaths in patients taking the treatment compared to placebo seen in the GBT-440-032 study. In the other study, GBT440- 042, the total number of deaths was higher than anticipated. Eight out of the nine deaths were recorded in an open-label expansion of GBT440- 042.
The EMA reviewers recommended that Oxbryta be withdrawn due to emerging safety data that patients had higher rates of vaso-occlusive crisis while taking the medication than they had before starting. Before the agency had a chance, however, Pfizer did so voluntarily.
Meanwhile in the U.S., the FDA took the unusual step of warning patients and healthcare providers about the withdrawal and advised providers to stop prescribing the medication. Patients already taking it should reach out to their healthcare provider to talk about another treatment option. The agency had been undergoing a safety review of the post-marketing data prior to Pfizer’s withdrawal of the drug.
No Warning
The sudden withdrawal leaves providers with one fewer option to treat the disease, which causes the blood cells to form into a sickle shape. Patients experience painful attacks called vaso-occlusive events when the sickled cells obstruct the blood vessels.
“We were given no warning,” wrote the U.K.’s Sickle Cell Society in a Thursday statement. “It is inexcusable that the doctors and nurses who treat people with sickle cell every day have woken to this sudden, demoralising news.”
The Sickle Cell Disease Association of America issued a brief statement promising to gather more information and urging patients to contact their healthcare providers.
In recent years, biopharma has turned back to the disorder, cranking out new medicines that finally gave the patient population hope. Last year, the FDA approved two gene therapies for the condition, bluebird bio’s Lyfgenia and Vertex Pharmaceuticals and CRISPR Therapeutics’ Casgevy. The roll out of these complex therapies has been slow, with the first patients just beginning to receive infusions.
Vertex/CRISPR and bluebird’s products have been limited to the sickest patients, so those taking Oxbryta are unlikely to immediately look to gene therapy, Leerink Partners analysts stated. Options for this milder population include Novartis’ Adakveo and Emmaus Medical’s Endari.
Adakveo, however, has also come under scrutiny in Europe. The therapy missed the primary endpoint of a Phase III trial, which was a reduction in pain crises that lead to a healthcare visit. Patients taking Adakveo had an average of 2.5 events, compared to 2.3 for those taking placebo.
The EMA recommended revoking a conditional marketing authorization for Adakveo in May 2023, which was accepted by the European Commission three months later. Novartis pulled the treatment from the European market, however it remains available in the U.S.
Analysts Question Pfizer’s Dealmaking, Business Outlook
Oxbryta was acquired through the $5.4 billion buy out of Global Blood Therapeutics in 2022. Pfizer recorded global sales of $328 million for the therapy in 2023. BMO had expected about $400 million in annual revenue from Oxbryta, while Guggenheim said sales could eventually exceed $750 million by the end of the decade.
With the key treatment from the deal now defunct, Pfizer’s dealmaking prowess has come into question. The pharma giant does not expect a material impact to fiscal year 2024 guidance, however BMO wrote that “sentiment could suffer” given the billions spent on the biotech.
Shares of Pfizer, a company with a $164 billion market cap, dipped briefly after the withdrawal was announced but have since recovered to around $29 apiece. Guggenheim clocked a 1.93% drop on Wednesday, linking the decline to news from the European Medicines Agency that Oxbryta was coming under review due to an imbalance in fatalities.
“Overall, we think the financial impact of today’s news is somewhat modest for a company of Pfizer’s size,” Guggenheim analysts wrote in a note to investors. “But, it will likely increase investor frustrations with Pfizer’s business development track record given Oxbryta and GBT-601 were key drivers of the company’s decision to acquire Global Blood Therapeutics for $5.4Bn in 2022.”
Analysts also wondered about the prospects of Pfizer’s other Global Blood assets, including GBT-601, which is currently in Phase III. The company previously delayed primary completion from 2026 to 2028. Pfizer had predicted that Oxbryta and GBT-601 could combine for $3 billion in worldwide peak sales.
A Phase II study of GBT-601 raised safety concerns for this drug as well, according to Leerink Partners. Treatment-emergent adverse events were seen in eight out of 35 patients, including headache, abdominal discomfort, suspected seizure, sickle cell anemia with crisis and upper abdominal pain. There was one death that was deemed unrelated to the treatment.
Another therapy from the deal is osivelotor, also in Phase III. Leerink Partners noted that the ClinicalTrials.gov record had recently been updated by the investigator,moving the primary completion from October 2026 to October 2028. Six new trial sites were also added.
Finally, investors will also likely wonder about Pfizer’s ability to grow the business over the next five years, as multiple patent expirations will dent sales, Guggenheim said. The company is also struggling now that the COVID-19 pandemic has turned endemic, plummeting demand for its vaccines and antivirals.
Spotlight Shifts to Other Drugs in Development
While Leerink Partners does not see much cross-over or benefit for Vertex/CRISPR or bluebird in light of Oxbryta’s withdrawal, the analyst firm did point to Agios Pharmaceuticals as a company that could benefit from “one less competitor.”
However, Leerink Partners analysts wrote, “we have concerns that similar physiological effects could be seen with both Oxbryta and AGIO’s mitapivat.” The company is testing mitapivat, approved as Pyrukynd for hemolytic anemia, in a Phase III study of sickle cell called RISE UP. That study is expected to read out next year, with the company targeting a label expansion into this indication in 2026.
Oxbryta and mitapivat have different mechanisms of action, but both increase hemoglobin levels, and both have shown a trend toward improving vaso-occlusive crises, though Agios’ data so far shows lower rates of these events. In the Phase III trial that underpinned Oxbryta’s accelerated approval, the annualized rate of crises were 2.77 in patients taking the study drug and 3.19 in the placebo group, while Agios’ therapy had a rate of 0.51 compared to 1.71 for placebo in the Phase II portion of the RISE UP program.
“We think concerns that mitapivat may have a risk for a similar outcome may remain a significant overhang for AGIO shares until the RISE UP trial releases data,” Leerink Partners said.
The Oxbryta withdrawal could also impact the regulatory path for Agios, Leerink Partners noted. The firm expects revenues of $521 million for Agios by 2030 thanks to the sickle cell disease product, if approved.
“Given the Oxbryta withdrawal, we think the regulatory agencies may become more vigilant about the need to demonstrate a [vaso-occlusive crisis ] benefit or strong trend in pivotal trials,” Leerink Partners said.
Another biotech that could benefit is Fulcrum, which is currently running a Phase Ib trial of pociredir called PIONEER with a population similar to Oxbryta’s. The company could see a bump in enrollment interest from patients who need to find a new treatment option, Leerink Partners said.
Enrollment has been a challenge for Fulcrum, which is speeding towards a 2025 readout. Pociredir was placed on a full clinical hold due to incidences of hematological malignancies observed in the class of medications called polycomb repressive complex 2 inhibitors. The hold was lifted in August 2023 with a protocol amendment.
But with this latest blow to the already underserved patient population, the Sickle Cell Society lamented the loss of 20 years of progress in drug development.
The fight for new treatment options goes back to the drawing board, the society wrote. “For many, voxelotor (OXBRYTA) offered hope. The sudden loss of this option leaves us, once again, in a position of having to fight for better care and treatment options for our community.”
