The U.S. Food and Drug Administration has place a partial hold on Novartis subsidiary AveXis’ trials for intrathecal administration of AVXS-101, the injection of the gene therapy, also known as Zolgensma, directly into the spinal fluid.
The partial hold comes while AveXis and Novartis are still under a cloud from an FDA investigation for withholding findings of manipulated data that could impact the accuracy of certain animal data submitted in their biologics license application until a month after the agency approved the drug.
The announcement of the hold is based on a communication from Novartis subsidiary AveXis to health authorities and clinical trial investigators based on findings from a small, AveXis-initiated pre-clinical study in which animal findings showed dorsal root ganglia (DRG) mononuclear cell inflammation, sometimes accompanied by neuronal cell body degeneration or loss.
This partial hold by the FDA does not impact marketed Zolgensma or AVXS-101 intravenous clinical trials. The FDA approved Zolgensma in May, first gene therapy to treat children less than two years of age with the most severe form of spinal muscular atrophy (SMA) with bi-allelic mutations in the SMN1 gene, and a leading genetic cause of infant death. It was approved as an intravenously administered treatment.
AveXis is currently studying AVXS-101 intrathecal administration in patients with spinal muscular atrophy (SMA) type 2. The partial hold impacts enrollment in the high dose cohort of the STRONG trial, an ongoing, open-label, dose-comparison, multi-center trial designed to evaluate the efficacy, safety and tolerability of one-time intrathecal administration of AVXS-101. The low and mid dose cohort enrollment has previously been completed and interim results have been presented.
According to the company, the clinical significance of the DRG inflammation observed in this pre-clinical animal study is not known and was not seen in prior animal studies with AVXS-101. DRG inflammation can be associated with sensory effects. After reviewing human safety data from all available sources to date, they found no adverse effects related to sensory changes in AVXS-101 intrathecal or Zolgensma. Novartis said it is working with health authorities to confirm further guidance to clinical investigators.
SMA is a rare genetic disease caused by a mutation in the SMN1 gene, which encodes the protein critical for the maintenance and function of specialized nerve cells called motor neurons. If there is not enough functional SMN protein, then the motor neurons die, leading to debilitating and often fatal muscle weakness. Infantile-onset SMA is the most severe and most common subtype of SMA. Children with this condition have problems holding their head up, swallowing and breathing. These symptoms may be present at birth or may present by the age of six months.
Zolgensma is the first approved gene therapy for SMA and it carries a boxed warning for acute serious liver injury.