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An FDA meeting this week will focus on whether an investigative treatment for an ultra-rare and fatal neurovisceral genetic disorder is truly efficacious.

On Friday, the Genetic Metabolic Diseases Advisory Committee will vote on whether the data supporting arimoclomol shows efficacy for adults and children ages 2 years and older with Niemann-Pick disease type C, FDA staff said in a .

Arimoclomol was initially rejected for approval by the FDA after it was submitted by its previous sponsor Orphazyme in July 2020, despite a pivotal of 50 patients that met its primary endpoint.

With an estimated prevalence of one to three cases per million in the U.S., Niemann-Pick disease type C is a progressive and autosomal recessive lysosomal storage disorder caused by bi-allelic mutations in the NPC1 and NPC2 genes.

Not to be debated at the advisory committee meeting is the glaring unmet need for this debilitating disease that causes progressive encephalopathy from neuronal death. Currently, there are no FDA-approved therapies for Niemann-Pick disease type C.

The treatment landscape only consists of symptom management therapies, such as anti-seizure medications. Following uncontrolled seizures, patients typically progress to paralysis, lose the ability to communicate, and develop fatal dementia or die from other comorbidities like aspiration pneumonia.

A synthetic pyridine derivative, arimoclomol doesn't belong to any specific drug class but is thought to affect certain biochemical mechanisms like activation of transcription factors E3 and EB, leading to nuclear translocation and enhanced binding of transcription factor EB3 to target gene promoters like NPC1 and NPC2.

During arimoclomol's first time under review, the FDA had raised concerns about the appropriateness of the "hypothetical estimand" used for the primary efficacy analysis in the randomized trial, as well as the validity and reliability of the scoring instruments used for the primary endpoint.

When the investigational agent was picked up by current sponsor Zevra Denmark in 2022, a 4-year open-label extension of the original phase II/III trial was carried out. These data were included in the resubmission, along with eight additional in vitro studies and three more in vivo studies.

The new sponsor also took the recommendations of the FDA to re-score the primary endpoint, which will be one of the first discussion items on the docket for the advisory committee.

While the main trial results used the 5-Domain Niemann-Pick disease type C Clinical Severity Scale (NPCCSS), the resubmission used the 4-Domain NPCCSS -- which includes ambulation, fine motor skills, speech, and an updated swallow domain, but not the cognitive domain included in the previous scale -- based on FDA recommendations.

"This ... was in response to the Agency noting that the cognition domain ratings relied on the patient environment (e.g., access to services) and may not be adequately evaluated within the 12-month trial by a severity scale," FDA staff wrote in the briefing document.

Other points of discussion at Friday's meeting will include if the assessment of the swallow domain "was an adequate assessment of swallow function." The FDA said it did not agree with the proposal to re-score the swallowing domain, "citing lack of evidence, protocols, and supporting materials establishing how the scores were initially assigned," agency staff wrote.

In the 12-month phase II/III 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).

Using the original 5-Domain NPCCSS score, there was a treatment difference of -1.40 in favor of arimoclomol (95% CI -2.76 to -0.03, P=0.0456), corresponding to a 65% reduction in annual disease progression.

The committee will also likely discuss the role of miglustat (Zavesca), which 78% of patients were also taking in the pivotal trial. This drug is only approved in the U.S. for patients with Gaucher disease, but is approved in the European Union, Canada, and Japan for Niemann-Pick disease type C.

In the subgroup of patients who didn't take miglustat in the pivotal trial, the estimated treatment difference numerically favored the placebo arm but it is "difficult to interpret ... given the small sample size," FDA staff wrote.

Other clinical and nonclinical data will also be discussed, including concerns about the consistency of the survival benefit when arimoclomol was administered in animals.

While the FDA isn't required to follow the advisory committee's recommendations, it typically does.

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