FDA Accepts Filing for Zolgensma for Spinal Muscular Atrophy Type 1

The US Food and Drug Administration (FDA) has accepted a Biologics License Application (BLA) as well as granted Priority Review for AVXS-101, now onasemnogene abeparvovec (Zolgensma), a therapy for spinal muscular atrophy Type 1.

Spinal muscular atrophy (SMA) Type 1 is a devastating progressive neuromuscular disease that affects infants with a defective or missing SMN1 gene. These infants lose motor neurons necessary for functions including breathing, swallowing, speaking, and walking. Untreated, SMA Type 1 leads to paralysis or death, generally by the child’s second birthday.

Novartis’ gene replacement therapy is a one-time infusion that replaces the defective or missing SMN1 gene with a functional copy that can create SMN protein and prevent the loss of motor neurons.

"This important step by the FDA brings us ever closer to delivering Zolgensma to patients with SMA Type 1. Babies affected by this rare disease are currently faced with debilitating disease progression and lifelong invasive chronic treatment. As a one-time infusion that addresses the genetic root cause of SMA without the need for repeat dosing, Zolgensma represents a potentially significant therapeutic advance for these patients and their families," said David Lennon, PhD, president of AveXis, a Novartis company.

The onasemnogene abeparvovec BLA is supported by data from the START trial. The phase 1 trial included 15 patients infused with the therapy between .9 to 7.9 months of age. Cohort 1 (n = 3) received a low dose and Cohort 2 (n = 12) received a high dose. While 90% of patients with untreated SMA Type 1 die or require permanent ventilation by 24 months of age, at a 24-month follow up all 15 patients (100%) were event-free.

Among Cohort 2 participants at the 24-month follow up, 11 patients (91.7%) were able to hold their head erect for ≥3 seconds and sit without support for ≥5 seconds; 10 patients (83.3%) were able to sit unsupported for ≥10 seconds; 9 patients (75.0%) were able to sit unsupported for ≥30 seconds; and 2 patients (16.7%) were able to stand and walk alone.

The most common side effect of Zolgensma in the trial was elevated liver enzymes.

Presentations given at the 70^th American Academy of Neurology Annual Meeting highlighted the exceptional progress of children in the trial, especially those dosed at younger ages.

“Everyone we treated improved, but we know that treating early is more likely to give us a more rapid and improved outcome,” said Linda Lowes, PhD, a researcher at the Center for Gene Therapy, Nationwide Children’s Hospital, Columbus, Ohio, who presented the data in April 2018.

The improvement was such that investigators called for an update to the standard Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) scale that is used to measure motor function loss or gain in children with SMA Type 1.

"The introduction of one-time, potentially curative therapies will require rethinking how our healthcare system manages diagnosis, treatment, care and associated costs for patients with genetic disease,” said Lennon.

The gene therapy has previously been granted Breakthrough Therapy designation, and with the recent Priority Review the company anticipates regulatory action in May 2019.