Lydia Edelman

Lydia Edelman asked about the regulatory bar for the Angelman study, given the use of Bayley cognition as a primary endpoint versus Ionis's expressive communication, and the company's confidence in the established bar.

Answer

Emil Kakkis, Chief Executive Officer and President, clarified that the regulatory bar is defined by a randomized sham-controlled trial with continuous variable analysis of Bayley cognition, for which they expect a statistically significant, clinically meaningful change. He noted the FDA appreciates the magnitude of clinical benefit (around 5-6 points) and that the Multi-Domain Responder Index, with alpha allocation, provides a broader view of the disease. Discussions with the agency are ongoing to set and validate the minimally important difference for the MDRI.

Lydia Edelman asked about the regulatory bar for GTX-102 (Angelman), specifically concerning the use of different endpoints like Bayley cognition and the Multidomain Responder Index, and the company's confidence in establishing this bar.

Answer

CEO Emil Kakkis clarified that while primary and secondary endpoints differ, the commercial future will consider all data. He explained that the regulatory bar for the Bayley cognition primary endpoint is a continuous variable analysis in a randomized sham-controlled trial, with an expectation of demonstrating a statistically significant, clinically meaningful change. Kakkis noted that the Multidomain Responder Index (MDRI) is a broader, new type of endpoint analysis for heterogeneous diseases, which the FDA has allowed with alpha allocation. He stated that discussions with the agency are ongoing to set and understand the minimally important difference-driven changes for the MDRI, with validation data from Phase 3 to substantiate the regulatory bar.