Orphazyme A/S – FDA CRL

The U.S. Food and Drug Administration (FDA) issued a Complete Response Letter (CRL) to Orphazyme A/S for its New Drug Application (NDA 214927) for arimoclomol capsules, submitted on July 17, 2020. The FDA determined that the application, seeking approval for Niemann-Pick disease Type C (NPC), could not be approved in its current form due to a lack of substantial evidence of effectiveness. The primary concerns revolved around the pivotal 12-month clinical trial, specifically the 5-domain NPC Clinical Severity Scale (5DNPCCSS) used as the primary efficacy endpoint. The FDA found the company's primary efficacy analysis, which utilized a "hypothetical estimand," to be problematic, yielding a borderline statistically significant result (p=0.046). The agency's own analysis, employing a "while-on-treatment estimand," showed a numerically small and statistically non-significant treatment effect (p=0.12). Throughout the investigational new drug (IND) phase, the FDA had repeatedly advised Orphazyme that the 5DNPCCSS lacked adequate definition and reliability. Specific issues included unstandardized domain measurements and a lack of data comparing the scale to objective, performance-based assessments. Significant validity concerns were also identified with the swallow domain, which is a major component of the overall score, questioning its ability to accurately reflect disease progression or treatment impact. Furthermore, the confirmatory in vitro, animal, and clinical pharmacology data were deemed weak and contradictory. To address these deficiencies, Orphazyme must provide substantial evidence of effectiveness. This would entail resolving the issues with the 5DNPCCSS, including demonstrating its validity, standardization, and reliability through objective measures, and addressing the specific concerns regarding the swallow domain's scoring to accurately reflect clinical changes.