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A majority of were on the same page regarding the efficacy of an investigative treatment for an ultra-rare and fatal neurovisceral genetic disorder, but some still had concerns.

In an 11-5 vote Friday, the Genetic Metabolic Diseases Advisory Committee said the totality of clinical, nonclinical data, and favorable safety profile underpinning arimoclomol for adults and children ages 2 years and older with Niemann-Pick disease type C was reasonable enough for approval.

If the FDA follows this recommendation, arimoclomol would be the first treatment indicated for Niemann-Pick disease type C. The treatment landscape only consists of symptom management therapies, such as antiseizure medications, and miglustat (Zavesca) indicated for Gaucher disease, which 78% of patients were also taking in a pivotal trial.

"I thought the clinical trial was reasonable. I wouldn't call it compelling, but it was reasonable," said Richard Kryscio, PhD, of the University of Kentucky in Lexington, who voted in favor of the drug.

"I thought the [effect] size to be small and the strength to be weak but overall, the bulk of the data favored a slightly positive effect," added Jonathan Mink, MD, PhD, a private consultant in Pittsford, New York, who voted "a very reluctant" yes. "I think the unmet need is very clear. I'm not sure that this meets that need. But again, on balance, I voted yes."

The supporting data in question was a successful 50-patient . The primary endpoint was re-scored based on FDA recommendations following arimoclomol's initial rejection in July 2020 with previous sponsor Orphazyme. After arimoclomol was picked up by current sponsor Zevra Denmark, the primary endpoint used a 4-Domain scale that included ambulation, fine motor skills, speech, and an updated swallow domain (4-Domain NPCCSS), but not the cognitive domain included in the previous 5-Domain scale.

In the 12-month trial, the arimoclomol group had a significantly slower rate of disease progression even though this group included more patients with severe disease at baseline. The average change in clinician-reported re-scored 4-Domain NPCCSS from baseline was 0.62 compared with 2.12 with placebo (mean treatment difference -1.51, 95% CI -2.95 to -0.06, P=0.0413).

In its submission, Zevra Denmark also included data from a 4-year open-label extension of the original phase II/III trial, plus eight additional in vitro studies and three more in vivo studies. But panel members weren't quite convinced by the mixed bag of data, including a mouse study that showed an inconsistent survival benefit. For some, this was enough to vote against approval.

"I think the nonclinical data was really the linchpin for me," said Kiera Berggren, MA, MS, of Virginia Commonwealth University in Richmond, who voted "no."

"The clinical data is interesting and looks compelling with small values, but I think on nonclinical data -- not knowing the mechanism of action, not knowing how the mice were dosed -- things like that were big questions in my mind," Berggren said.

Other "no" voters also cited arimoclomol's mechanism of action as a concern. While arimoclomol doesn't belong to any specific drug class, the synthetic pyridine derivative is thought to affect certain biochemical mechanisms like activation of transcription factors E3 and EB, which leads to nuclear translocation and enhanced binding of transcription factor EB3 to target gene promoters, such as NPC1 and NPC2.

While most panel members mentioned the shortcomings of the nonclinical data, many said they relied more heavily on the pivotal trial data.

"The nonclinical data, I didn't rely on at all," said Jean-Baptiste Le Pichon, MD, PhD, of the University of Missouri Kansas City, who voted in favor of approval. "Maybe I didn't follow directives... but this is where my clinical intuition was, and I am a clinician at heart."

Several panel members were also positively swayed by the drug's the favorable safety profile. Arimoclomol was well-tolerated and only two treatment-related serious adverse events (AEs) occurred in the pivotal trial, including urticaria and angioedema. Fewer patients on arimoclomol than placebo also experienced serious AEs (14.7% vs 31.3%).

"In rare disease, patients and their families are often asked to take on a large burden of safety or treatment burden. The fact that this does show efficacy without side effects that largely impacted life was significant," said consumer representative Sarah Chamberlin of Montclair, New Jersey, who also voted "yes."

While the FDA isn't required to follow the advisory committee's recommendations, it typically does. A final decision from the FDA is expected on or before Sept. 21, 2024.

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