AAV8 for X-Linked Myotubular Myopathy

A Phase 2 Single Arm, Open Label, Clinical Study to Evaluate the Safety and Efficacy of AAV8 Delivered Gene Therapy Delivered to Children with X-Linked Myotubular Myopathy (XLMTM)

Suyash Prasad MD
Audentes Therapeutics, Inc, San Francisco, USA

26th October 2014

TACT reviewed an application from Audentes Therapeutics (http://www.audentestx.com/) who are developing an adeno-associated viral vector (AAV8.Des.MTM1) for use in X-linked myotubular myopathy (XLMTM) patients. Audentes Therapeutics plan to use AAV8.Des.MTM1 in a Phase-2, single-arm, open-label study in male XLMTM children.  TACT was asked to provide input regarding the appropriateness of a variety of secondary outcome measures, including both motor functional and ventilatory (e.g., ventilator-free survival). Overall, there was a great deal of enthusiasm for this application for several reasons. First, the preclinical efficacy data including both the Mtm1 knockout mouse and the XLMTM dog model (with a missense mutation), were promising.  Second, the proposal makes use of AAV8, a serotype that has been used clinically in man (haemophilia), with a good safety profile. Third, this is a devastating disorder, for which no other therapy is available.  Fourth, significant preclinical data suggesting safety has already been generated, and pre-IND interactions with the FDA have occurred, outlining an acceptable approach to development. The limitations of the proposal were largely recognized by the applicants themselves and are generally consistent with the challenges of drug development in an ultra-rare disease. These include a limited understanding of the natural history of the disease, limited understanding or availability of outcome measures to support determination of clinical efficacy, the lack of a non-invasive biomarker, and the lack of a concurrent control and blinding of trial which will confound the interpretation of some of the functional efficacy outcomes.

12 Apr 2017