Zevra Therapeutics’ rare disease drug seems to be on the path to approval this fall after gaining the backing of an FDA advisory committee, although the experts were split, with some voting yes simply to address an unmet need.
The agency’s Genetic Metabolic Diseases Advisory Committee voted 11 to 5 in favor of arimoclomol on a questions of whether the evidence supports the drug’s efficacy to treat patients with Niemann-Pick disease type C at the Friday meeting. The rare, genetic lysosomal storage disease prevents the body from moving and using cholesterol and other lipids in cells. This leads to a build-up of cholesterol and other lipids in the liver, spleen or lungs.
There are no approved treatments for the disease, according to the FDA. Patients typically receive anti-seizure medicine and other supportive care.
The FDA is set to decide on the drug’s approval by September 21. While the agency does not have to do exactly as the committee suggested, it does typically heed the advice of its expert panels.
Arimoclomol was originally submitted to the FDA in July 2020 but was rejected almost a year later because the agency questioned aspects of the single clinical trial used to support the application. While the FDA can approve a drug based on evidence from just one trial, the applicant must show that the test meets the bar of being considered a “single adequate and well-controlled clinical trial.”
Zevra submitted data from a 12-month, randomized double-blind, placebo-controlled study called CT-ORZYNPC-002. The main goal was a measure of disease severity called the 5-domain NPC Clinical Severity Scale (5DNPCCSS), which assesses clinical outcomes for the disease, including swallowing, speech, fine motor, ambulatory, and cognitive functioning.
In the complete response letter from 2021, the FDA questioned the interpretability of the 5DNPCCSS, specifically its validity and reliability. There were also concerns with the prespecified primary analysis of the 5DNPCCSS endpoint and lack of statistical significance in the FDA’s own post hoc analyses of the 5DNPCCSS endpoint. And finally, the agency flagged “weak and contradictory confirmatory evidence of effectiveness,” specifically inconsistent results in mouse studies.
Zevra was asked to address the swallow scores and whether a rescoring of the scale or alignment with a National Institutes of Health measure of swallowing would be better. The company was also directed to produce more evidence to support the interpretation and use of the 5DNPCCSS score, check whether evidence from the existing clinical trial would be good enough to support a re-application and “bolster the confirmatory evidence.”
With that long to-do list, Zevra returned to the FDA in December 2023 with a rescored scale and more results from the study, including data from an open-label expansion phase. Zevra also submitted a natural history comparison of the disease from the NIH and more preclinical evidence.
At the advisory committee meeting, the FDA wanted the experts to consider the validity of the new four-point scale and the post-hoc exploratory revision of the primary efficacy endpoint. The committee was also tasked with considering the uncertainty of the estimated treatment effect on the revised primary endpoint; adequacy of the additional clinical and nonclinical evidence; and the strength of the overall evidence to support the efficacy of arimoclomol.
After the vote, many of the panel members said they were torn on the efficacy package, but ultimately Zevra's therapy passed.
“I voted yes but it was a very reluctant yes. I found the effect size to be small and the strength of the data to be weak, but overall the bulk of the data favored a slightly positive effect,” said Jonathan Mink, M.D., Ph.D., a private consultant. “I think the unmet need is very clear. I’m not sure this meets that need, but again on balance I voted yes.”
Priya Kishnani, M.D., also voted yes, noting the clinical unmet need, very good safety profile and trends toward efficacy. Kishnani is a professor of pediatrics at the Duke University Medical Center.
Jean Baptiste Le Pichon, M.D., Ph.D., voted yes as well, but said he did not rely on the nonclinical data that was submitted to make his decision. Le Pichon, a professor of pediatrics and the associate director for the Division of Neurology at Children's Mercy Kansas City and the University of Missouri Kansas City, said that the data were “not convincing.”
When looking at the clinical data, however, Le Pichon was convinced that there was enough of an effect to recommend approval of arimoclomol.
“It was not an enormous effect but it was an effect that was clinically significant,” Le Pichon said.
He acknowledged that he may have broken the rules of the vote by ignoring the preclinical evidence. But the clinical data was what mattered the most to him.
“If I was forced to vote no just because the non-clinical data was not convincing then I went against the rules but this is where my clinical intuition was and I am a clinical at heart,” Le Pichon said.
Gerard Berry, M.D., professor of pediatrics at Harvard Medical School, voted yes, noting that the testimony of the families that arimoclomol led to a beneficial effect was moving.
“Taking all data together it made sense that this is having a beneficial effect,” Berry said.
Kenneth Fischbeck, M.D., who voted no, was not convinced that the new data helped the re-application, calling it “problematic.”
“I think it could be done better. I think there’s a real unmet need in this space. And I think this drug or one like it could be effective but I haven’t seen the data yet to make a convincing case,” Fischbeck said in explaining his vote.
Like Berry, Robert Alexander, M.D., was moved by the patient testimony, but said it was not enough to convince him that the trial showed benefit. He “had to rely on the data from the controlled trial and I didn’t feel like it really rose to the level of substantial evidence of efficacy on its own.” Alexander is the chief scientific officer for the Alzheimer’s Prevention Initiative at the Banner Alzheimer’s Institute and a research professor at the University of Arizona College of Medicine.