The Genetic Metabolic Diseases Advisory Committee will meet on Friday to discuss Zevra’s modified scale to describe the efficacy of its drug candidate for the treatment of Niemann-Pick disease type C.
Ahead of Friday’s advisory committee meeting, the FDA has raised concerns about Zevra Therapeutics’ investigational oral drug arimoclomol, which the biotech is proposing for the treatment of Niemann-Pick disease type C.
The regulator’s internal reviewers flagged “uncertainties” in Zevra’s efficacy assessment for arimoclomol, particularly the use of a rescored NPC Clinical Severity Scale (NPCCSS) to evaluate treatment effect. The FDA also raised questions regarding additional clinical and non-clinical data as confirmatory evidence for arimoclomol’s benefit.
“A drug’s effectiveness must be established by substantial evidence,” the FDA’s staffers wrote in its briefing document, adding that this requirement has typically been satisfied by two “adequate and well-controlled clinical investigations to establish effectiveness.”
However, in some cases, the regulator can consider data from just one study—plus confirmatory evidence—provided that these findings “are sufficient to establish effectiveness.” Companies focused the rare diseases market, where enrollment presents a significant challenge and where it is infeasible to run multiple trials, typically prefer this approach.
Zevra chose to use this pathway for arimoclomol by presenting data from the NPC-002 trial, a 12-month, randomized, placebo-controlled and double-blinded study. In the biotech’s original application, it used the 12-month change in the NPCCSS score which measured disease activity according to five domains: swallowing, speech, fine motor, ambulatory and cognitive function.
In June 2021, the FDA rejected arimoclomol citing “concerns with the interpretability” with the five-domain NPCCSS score, especially in its swallow and cognition scales, according to Wednesday’s briefing document. The regulator also flagged the “weak and contradictory confirmatory evidence of effectiveness” for arimoclomol.
In its resubmission, Zevra employed a rescored four-domain NPCCSS tool which did away with the cognition domain and used a modified swallow domain. The FDA is asking the newly formed Genetic Metabolic Diseases Advisory Committee on Friday to determine whether Zevra’s reanalysis was adequate. The regulator is also asking the panel of external experts to review the totality of evidence and decide whether this supports the efficacy of arimoclomol.
Nieman-Pick disease type C (NPC) is an ultra-rare neurodegenerative disorder that manifests as severe cognitive and physical impairments, affecting speech, motor and swallowing functions. The disease is caused by mutations in the NPC1 or NPC2 genes, which affect the clearance and transport of cholesterol and other lipids inside the cell, leading to the toxic accumulation of these compounds in various organs such as the brain.
Arimoclomol seeks to addresses a central disease pathway in NPC by crossing the blood-brain barrier and helping cells resist stress, preventing their destruction despite lipid build-up.
