6 Drugs Approved Despite Failed Trials or Minimal Data

FDA Entrance_iStock, Grandbrothers

Pictured: FDA headquarters/iStock, Grandbrothers

Original story posted Oct. 9:

In recent years, the FDA has granted approval to some novel drugs despite failed clinical trials or minimal evidence. Guidance issued in rare or uniformly fatal diseases like amyotrophic lateral sclerosis and the approvals of Aduhelm in Alzheimer’s and Qalsody in ALS indicate a trend toward greater regulatory flexibility.

But is the agency moving too quickly? Recent research from Stanford, Oregon State University and the McGovern School of Medicine found that the FDA is greenlighting more novel drugs based on single clinical trials, and pharmaceutical companies are only required to share the results from two trials, “leaving questions about why they chose those two for submission and what happened in the other trials,” study co-author Veronica Irvin said in Medical Xpress.

Another study published in The BMJ in July 2023 found that less than half of new drugs being approved in the U.S. and Europe are adding true therapeutic value to patients, with the largest culprit being cancer therapies.

On the other hand, cases like that of Takeda’s mobocertinib—which the Japanese pharma pulled from U.S. and global markets last week following discussions with the FDA after it failed to meet the primary endpoint in a confirmatory trial—and Covis Pharma’s preterm birth drug Makena, for which the FDA withdrew approval in April, point to an effort by the regulator to clamp down on ineffective medicines.

BioSpace looks at half a dozen therapies approved by the FDA during the past seven years despite failure to meet Phase III endpoints or provide consistent proof of efficacy. 

Ipsen’s Sohonos

Most recently, on August 16, the FDA granted approval to Ipsen’s Sohonos (palovarotene) for the ultra-rare genetic disease fibrodysplasia ossificans progressive (FOP) after the agency noted the drug “crossed the prespecified futility boundary” in a Phase III trial. 

The approval is the culmination of a long and winding path for Ipsen. The FDA rejected palovarotene’s first New Drug Application in December 2022 due to a previous request for additional clinical trial data. The agency accepted Ipsen’s resubmitted NDA in March of this year.

Ipsen has maintained that the Phase III result was due to statistical discrepancies and the biases that come with using historical controls. In briefing documents released ahead of a June advisory committee meeting, the FDA appeared to agree, stating, “We think it is reasonable to consider alternative, more appropriate analyses to assess evidence of efficacy.” So did the external advisers, who voted 11-3 that palovarotene’s benefits outweighed its associated risks. 

Sarepta’s Elevidys

In June, the FDA approved Sarepta’s Elevidys as the first gene therapy for Duchenne muscular dystrophy (DMD) even though the medicine failed to meet the primary functional endpoint in a randomized trial. Elevidys won accelerated approval based on data showing it increased the expression of the micro-dystrophin protein—a biomarker the agency determined is “reasonably likely to predict clinical benefit” in DMD patients four to five years of age.

As a condition of the approval, the FDA is requiring Sarepta to complete a study to confirm Elevidys’ clinical benefit. ClinicalTrials.gov lists a Phase III study, Embark, intended to evaluate the therapy’s safety and efficacy. The study is expected to read out before the end of this year. 

Biogen’s Qalsody

In April, Biogen won FDA approval for Qalsody (tofersen) to treat patients with superoxide dismutase 1 (SOD1)-ALS, a rare subtype of the fatal neurodegenerative disease. Like Elevidys, Qalsody went through the FDA’s accelerated approval pathway, which gives the regulator license to grant approval when there is an unmet medical need and a drug is shown to have an effect on a surrogate endpoint. In the case of Qalsody, this endpoint was neurofilament light chain (NfL).

Biogen sought approval of Qalsody based on NfL after the drug failed to meet the primary endpoint of a statistically significant change from baseline to week 28 on the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) in the Phase III VALOR study. The company did publish combined analyses of 12-month VALOR data and the accompanying open-label extension study showing that earlier initiation of Qalsody slowed decline in function and strength in SOD1-ALS patients.

Biogen and Eisai’s Aduhelm

One of the most controversial FDA approvals in recent history, Biogen and Eisai got the nod for Aduhelm (aducanumab) in June 2021, setting off a firestorm of commentary in both scientific and mainstream publications about the drug’s relative merits. In March 2019, Biogen and Eisai had announced they would abandon aducanumab after a futility analysis suggested it was unlikely to work. A few months later, the partners did an about-face, saying a thorough data analysis found that the Phase III EMERGE trial hit the primary endpoint in a subpopulation at the highest dose.

In its approval announcement, the FDA noted that “patients receiving [Aduhelm] had significant dose-and time-dependent reduction of amyloid beta plaque,” a well-known Alzheimer’s biomarker, while patients in the control arm of Biogen’s three studies had no reduction of these plaques. 

The FDA granted Aduhelm approval even after a near-unanimous vote by its Peripheral and Central Nervous System Drugs Advisory Committee that there was insufficient evidence to demonstrate the drug slowed cognitive decline. Three committee members ultimately resigned over the decision.

Jazz Pharmaceuticals and PharmaMar’s Zepzelca

While Zepzelca (lurbinectedin) showed enough efficacy in an open-label monotherapy study to win accelerated FDA approval in small cell lung cancer (SCLC) that had progressed on or after platinum-based chemotherapy, it failed to meet the endpoint in a much larger Phase III trial just six months later.

In June 2020, Jazz Pharmaceuticals and partner PharmaMar secured approval for Zepzelca based on an overall response rate of 35% and duration of response of 5.3 months in a trial of 105 patients. However, in December of the same year, Zepzelca combined with doxorubicin was found to make no significant difference to overall survival when the same combination was compared with the physician’s choice of topotecan or cyclophosphamide/doxorubicin/vincristine in a trial of 613 patients. Zepzelca remains on the market and earned Jazz $70.3 million in sales in the second quarter of this year.

Acadia’s Nuplazid

An early example of the trend toward greater regulatory flexibility came in 2016 when the FDA approved Acadia Pharmaceuticals’ Nuplazid (pimavanserin) to treat hallucinations and delusions associated with psychosis in Parkinson’s disease. The first approved medicine for this indication, Nuplazid got the FDA’s nod based on efficacy shown in a six-week clinical trial of 199 participants, although it failed two other trials, PBS reported.

An atypical antipsychotic, Nuplazid’s label came with a boxed warning due to an increased risk of death associated with this drug class in older people with dementia-related psychosis. The regulator noted at the time that no atypical antipsychotic was approved for this patient population.

Two years later, CNN reported that the FDA was taking another look at Nuplazid’s safety profile after monitoring showed it was associated with more than 700 deaths. The FDA's analysis ultimately found no new or unexpected safety risks associated with Nuplazid. “After a thorough review, FDA’s conclusion remains unchanged that the drug’s benefits outweigh its risks for patients with hallucinations and delusions of Parkinson’s disease psychosis,” the regulator noted in a 2018 press release

In August 2022, the FDA rejected a supplemental New Drug Application for pimavanserin for hallucinations linked to Alzheimer's disease psychosis due to “interpretability” issues with the study data.

Heather McKenzie is a senior editor at BioSpace. You can reach her at heather.mckenzie@biospace.com. Follow her on LinkedIn and X @chicat08.

Clarification, Oct. 10: This story has been updated from its original version to clarify that in 2018, an FDA analysis found no new or unexpected safety risks associated with Acadia's Nuplazid. 

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