Efficacy and Safety of CSF- Delivered AVXS-401 in Mice and NonHuman Primates for the Treatment of Friedreich’s Ataxia

Martin Fugere, Rajeev Sivasankaran, Susan McQuown, Chang Choi, Katrina Salvador, Shirley Phillips, Yin Gu, Binh Chu, Janet Do, Tsun-Kai Chang, Katherine Nguyen, Yanchi Li, Stephanie Solano, Natalia Teider, Colin Fennelly, Ricardo Dolmetsch, Monica Bennett, Kevin Foust, Page Bouchard; AveXis Research and Development, San Diego, CA, Novartis Institutes for Biomedical Research, Cambridge, MA

For clinical translation, we developed AVXS-401, a self-complementary adenoassociated virus (AAV9) based gene replacement therapy to provide sustained expression of FXN in key tissues relevant to FA. Toxicity studies in wildtype mice proved AVXS-401 is safe and well-tolerated. Dose ranging efficacy studies following a one-time, pre-symptomatic intracerebroventricular (ICV) administration of AVXS-401 in conditional FXN-deficient mice in the CNS (Pvalb) demonstrates amelioration of behavioral phenotypes, rescue of Purkinje neurons and cerebellar gliosis at low doses. ICV delivery of AVXS-401 in cardiac mutants (MCK) results in full recovery of cardiac functions as measured by magnetic resonance imaging (MRI), prevention of histopathological evidence of cardiomyopathy and >300% increase in median survival at efficacious doses.
Scale up of therapeutic doses to non-human primates (NHP) showed that AVXS-401 is safe and well tolerated with no aberrant behavior, clinical or anatomical pathology attributable to frataxin expression. Importantly, AVXS-401 provides durable mRNA transcription in the CNS and heart of NHP at 6 months postinjection with frataxin expression detectable above endogenous levels. Dose escalation studies by intrathecal (IT) administration in NHP show a dose correlation between mice and NHP by ddPCR quantification of vector genomes. Together these pre-clinical data show that AVXS-401 is suitable for first-inhuman studies.

Efficacy and Safety of CSF- Delivered AVXS-401 in Mice and NonHuman Primates for the Treatment of Friedreich’s Ataxia