O.11 Personalized therapy in Duchenne muscular dystrophy: An integrated approach

Abstract

Exon skipping, a promising new approach for the treatment for Duchenne muscular dystrophy (DMD), relies on the systemic administration of exon-specific antisense oligonucleotides (AONs) to reframe genetic mutations. As the targeted exon is relevant to specific subpopulations of patients with DMD, a number of AONs targeting increasingly smaller patient populations are required. Orphan drug designation and development is ongoing for six compounds, and a comprehensive development program is underway for the most prevalent subpopulation, representing approximately 13% of patients with DMD. Such a program is not feasible for less prevalent groups. Discussions with regulators, clinicians, and scientists are underway to find appropriate ways to develop these compounds, building on information gained from the lead molecule. Concepts such as abrogated preclinical development packages, manufacturing design space, and seamless trial designs may facilitate this process. Central to this theme is the patient’s perception of risk, which is being pursued independently by patient advocacy groups. Here we will discuss the seamless design accepted by the EMA and FDA for two exon skipping programs targeting sub-populations too limited to carry out fully powered, placebo-controlled pivotal Phase III studies and how future programs may be further accelerated in the ‘ultra-orphan’ DMD space.