Insufficient evidence of clinical benefit from surrogate marker
Severity: majorThe observed increase in truncated dystrophin (0.92 ± 1.01 percent of normal) is considered too small (9 parts per thousand) to reasonably predict a meaningful clinical benefit. Furthermore, there is no correlation between the maintenance of physical performance and the magnitude of truncated dystrophin production.
Recommended response: Conduct further clinical studies to demonstrate a more substantial and clinically meaningful increase in dystrophin or direct clinical benefit, and establish a clear correlation between the surrogate marker and clinical outcomes.
Cited: section 506(c) of the FD&C Act, 21 CFR part 314, subpart H
Significant risk of serious infections associated with drug delivery
Severity: criticalPostmarketing data from eteplirsen (a similar drug) showed a 2.3% or greater risk of serious infections (bacteremia, sepsis, septic shock, deaths) related to central venous access ports, which are necessary for drug administration. This risk is directly applicable to golodirsen, and the lack of such events in the golodirsen development program is attributed to the small sample size and specialized centers, not a true absence of risk.
Recommended response: Develop a comprehensive risk evaluation and mitigation strategy (REMS) to address the risk of serious infections, including enhanced monitoring, patient education, and clear labeling instructions for managing central venous access ports. Explore alternative administration methods if feasible.
Evidence of significant renal toxicity from nonclinical studies
Severity: criticalNonclinical studies showed significant renal toxicity, including severe renal impairment and irreversible renal damage in juvenile animals, with a small safety margin. This is a known class effect for antisense oligonucleotides. The agency notes the difficulty or impossibility of monitoring renal function in these patients, making adequate labeling challenging.
Recommended response: Conduct further nonclinical and clinical studies to fully characterize the renal toxicity profile, identify appropriate monitoring parameters, and develop strategies to mitigate this risk. Provide clear and actionable instructions for renal monitoring and management in the labeling.
Inability to provide adequate instructions for use in labeling
Severity: majorDue to the unmitigated risks of serious infections and renal toxicity, and the difficulty in monitoring these conditions, the agency determined that adequate instructions for use cannot be provided in the labeling to ensure safe and effective use of the product.
Recommended response: Address the underlying safety concerns (infections and renal toxicity) to a degree that allows for the development of comprehensive and adequate labeling instructions, including risk mitigation strategies and monitoring guidelines.
