Since its inception in 1992, the FDA’s accelerated approval pathway has helped shepherd nearly 300 new drugs to the market. However, recent years have seen a number of high-profile market withdrawals and failed confirmatory trials.
When Pfizer pulled its sickle cell disease therapy Oxbryta from the worldwide market last month, it became part of a growing trend: drugs approved under the FDA’s accelerated approval pathway that have later disappointed, sometimes being withdrawn from the market.
Oxbryta follows Biogen and Eisai’s first Alzheimer’s drug Aduhelm, which Biogen discontinued in January after a controversial approval and inauspicious rollout, and other recent market withdrawals of drugs that came through the accelerated pathway. High-profile about-faces such as these have raised concerns about the pathway’s value.
Implemented in 1992 in response to the HIV/AIDS epidemic, accelerated approval enables drugs to be approved based on a surrogate endpoint that is reasonably likely to predict clinical benefit. Pharmaceutical companies are allowed to begin selling the drug on the condition that they conduct a confirmatory trial. Since its inception, the pathway has helped bring nearly 300 new drugs to the market, many for conditions with high unmet need.
Peter Marks, director of the FDA’s Center for Biologics Evaluation and Research (CBER), has been a staunch proponent of the approval mechanism, saying at the American Society of Gene & Cell Therapy conference in May that in the case of rare diseases, “[being able to] use a biomarker or intermediate endpoint is a powerful way to get over the finish line initially.”
But the pathway has come under scrutiny of late. The 2021 accelerated approval of Aduhelm in particular sparked questions after the FDA went against its own advisory committee, which voted overwhelmingly against the treatment. Concern has also been raised over delays in the completion of confirmatory trials, spurring the FDA to require these studies to already be underway before granting accelerated approval.
In the early days of the program, the majority of accelerated approvals were in the oncology space. Joseph Ross, a professor of medicine and public health at Yale School of Medicine, expressed concern to BioSpace that other FDA divisions are not benefiting from this division’s hard-won knowledge: “We are essentially being forced to relearn the lessons that the Oncology Group learned over the past 25 years.”
These lessons include the need to avoid confirmatory trial delays and to focus on clinical outcomes. “Surrogate markers do not work as well as people thought they did as proxies for important clinical outcomes,” Ross said.
“It is discouraging to see the director of CBER come out and make very bold statements of how accelerated approval is going to be leveraged to bring new gene therapies to market for rare diseases without seemingly accounting for the challenges that have been experienced for decades in oncology,” he continued.
Here, BioSpace looks at five drugs that have won accelerated approval but were later withdrawn from the market.
Pfizer’s Oxbryta
Approved: November 2019
Withdrawn: September 2024
A hemoglobin polymerization inhibitor, Oxbryta won accelerated approval in November 2019 as the first medicine to specifically target the root cause of sickle cell disease (SCD). The drug was originally developed by Global Blood Therapeutics, which was acquired by Pfizer in 2022 for $5.4 billion, and was approved three months ahead of its target action date.
Nearly five years later, Pfizer withdrew the drug from all global markets after new data showed a higher risk of deaths and complications in treated patients. According to the company, new safety data for Oxbryta pointed to an “imbalance” of vaso-occlusive crises and mortality events in patients “which require further assessment.” Pfizer ultimately determined that Oxbryta’s overall benefit “no longer outweighs the risk” in patients with SCD.
The sudden withdrawal left providers and patients scrambling, particularly given the lack of available options for SCD, with the Sickle Cell Society lamenting the loss of 20 years of progress in drug development.
Biogen and Eisai’s Aduhelm
Approved: June 2021
Discontinued: January 2024
One of the most controversial approvals in recent history, Aduhelm was greenlit by the FDA in June 2021 as the first Alzheimer’s drug to treat an underlying cause of the disease. In granting the approval, the FDA went against its Peripheral and Central Nervous System Drugs Advisory Committee, which resoundingly recommended the drug’s rejection, voting that the evidence from the Phase III EMERGE and ENGAGE trials was insufficient to establish its efficacy.
Biogen and Eisai initially abandoned Aduhelm in March 2019 after a futility analysis showed the drug would not meet its endpoints. However, six months later, in October 2019, the development partners announced they would file for regulatory approval after the treatment hit the EMERGE trial’s primary endpoint.
“We decided that the accelerated approval pathway fits well here,” Patrizia Cavazzoni, director of the FDA’s Center for Drug Evaluation and Research, told Reuters at the time, adding that it “allows for there being some residual uncertainty on the drug’s clinical benefits while making the drug available to patients rather than having to wait.”
Others disagreed. Three members of the aforementioned advisory committee resigned in protest over the approval, and Aduhelm struggled to gain traction in the market. In January 2024, Biogen—by then solely in charge of marketing the medicine—discontinued all development and commercialization activities in order to focus its attention on Leqembi, which in July 2023 became the first anti–amyloid beta treatment to receive traditional FDA approval.
Takeda’s Exkivity
Approved: September 2021
Withdrawn: October 2023
The oncology space, in particular, has leveraged accelerated approval, with more than half of all cancer drugs approved in 2022 coming via this pathway.
The previous year, Takeda won accelerated approval for Exkivity in non-small cell lung cancer (NSCLC) after the tyrosine kinase inhibitor elicited an overall response rate of 28% and a median overall survival of 24 months. However, the company voluntarily withdrew Exkivity from the market in October 2023 after the Exclaim-2 trial failed to confirm these results.
Exkivity was specifically approved to treat patients with NSCLC with epidermal growth factor receptor (EGFR) exon 20 mutations. It was the only approved oral therapy for this type of mutation.
TG Therapeutics’ Ukoniq
Approved: February 2021
Withdrawn: June 2022
Also in the oncology space, TG Therapeutics’ Ukoniq met a similar fate as Pfizer’s Oxbryta. After getting the green light under the accelerated approval pathway in February 2021 to treat lymphoma, the FDA pulled that approval in June 2022 after updated data showed a possible increased risk of death in patients being treated with the PI3K inhibitor.
Ukoniq’s approval for marginal zone lymphoma and follicular lymphoma was based on overall response rate data from the Phase II UNITY-NHL trial. But in February 2022, the FDA launched a safety investigation after clinical data assessing Ukoniq in a related type of cancer revealed a “possible increased risk of death in patients taking the medicine.” The UNITY-CLL study, which had been assessing Ukoniq in patients with chronic lymphocytic leukemia, raised alarm due to an increase of reported serious adverse events.
Gilead Sciences’ Zydelig
Approved: July 2014
Withdrawn: January 2022
The withdrawal of Ukoniq followed that of another PI3K inhibitor, Gilead Sciences’ Zydelig, which the company pulled from the relapsed follicular B-cell non-Hodgkin lymphoma (FL) and relapsed small lymphocytic lymphoma (SLL) markets in January 2022 after failing to complete follow-up clinical trials to confirm efficacy and safety.
Zydelig received accelerated approval in 2014 for the third-line treatment of patients with FL and SLL. In FL, the approval was backed by data showing an overall response rate (ORR) of 54%. Duration of response (DOR) was not evaluable. In SLL, the ORR was 58%, with a DOR of 11.9 months.
In its withdrawal announcement, Gilead said it had been difficult to complete enrollment in the confirmatory studies as “the treatment landscape for FL and SLL has evolved.”
A Notable Exception: Sarepta’s Elevidys
Other times, a drug might fail to meet the primary endpoint in a confirmatory study, but the sponsor and/or the FDA make the decision to keep it on the market due to other considerations. This was the case with Sarepta Therapeutics’ Elevidys, which won accelerated approval in June 2023 as the first gene therapy for Duchenne muscular dystrophy (DMD).
The approval, for ambulatory children four to five years of age, was supported by data showing that the therapy increased the expression of Elevidys’ micro-dystrophin protein, which was considered a surrogate endpoint reasonably likely to predict clinical benefit in this population. However, just four months later, Elevidys missed the primary efficacy endpoint in the Phase III EMBARK study, failing to significantly improve functional mobility versus placebo.
Despite this, Sarepta plowed ahead with a filing for a label expansion based on what it called “robust evidence” of “clinically meaningful treatment benefit” across all of the pre-specified key functional secondary endpoints. This decision paid off as Elevidys secured full approval and a label expansion in June 2024 to treat DMD patients who are at least 4 years old, regardless of whether they can walk. Accelerated approval was granted for non-ambulatory patients contingent upon the results of an ongoing Phase III study.
