Novartis today announced that the U.S. Food and Drug Administration (FDA) has accepted the company’s Biologics License Application (BLA) for AVXS-101, now known as ZOLGENSMA® (onasemnogene abeparvovec-xxxx)1, an investigational gene replacement therapy for the treatment of spinal muscular atrophy (SMA) Type 1. ZOLGENSMA is designed to address the genetic root cause of SMA Type 1, a deadly neuromuscular disease with limited treatment options. ZOLGENSMA previously received Breakthrough Therapy designation and has been granted Priority Review by the FDA, with regulatory action anticipated in May 2019.
This first filing is for intravenous (IV) delivery of gene therapy. Based on typical practices, the expectation is that the FDA approval for IV delivery will closely match the IV clinical trial participants, who were SMA type I infants under nine months of age.
SMA is caused by a defective or missing SMN1 gene. Without a functional SMN1 gene, infants with SMA Type 1 rapidly lose the motor neurons responsible for muscle functions such as breathing, swallowing, speaking and walking. Left untreated, a baby’s muscles become progressively weaker eventually leading to paralysis or death, in most cases by his or her second birthday. Delivered as a single, one-time infusion, this breakthrough technology works by replacing the missing or defective SMN1 gene with a functional copy that makes SMN protein, thereby improving motor neuron function and survival.
“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, president of AveXis. “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. Novartis and AveXis are proud to lead the way toward a modern healthcare system built on the tremendous value of truly innovative and transformative medicines that could bend the curve of life. We are committed to flexibly partnering with healthcare stakeholders to ensure appropriate access to our medicines.”
In the START trial, all 15 patients infused with ZOLGENSMA were alive and without the need for permanent ventilation* at 24 months. Ninety-two percent (11/12) of patients who received the proposed therapeutic dose of ZOLGENSMA could sit unassisted for ≥5 seconds, a milestone never achieved in the natural history of SMA Type 1. Natural history indicates that more than 90 percent of untreated patients with SMA Type 1 will die or require permanent ventilation by 24 months of age.5 Patients who voluntarily enrolled in an ongoing observational long-term follow-up of the START trial have maintained their developmental motor milestones – including patients who are four years post infusion – with some achieving additional motor milestones. The most commonly observed side effect in the ZOLGENSMA clinical trial was elevated liver enzymes.
In Japan, where ZOLGENSMA has SAKIGAKE Designation, a decision by regulators on the New Drug Application (J-NDA) is expected in the first half of 2019. In Europe, where ZOLGENSMA has PRIME (PRIority MEdicines) designation, a decision by regulators on the Marketing Authorization Application (MAA) is expected in mid-2019. The SAKIGAKE and PRIME designations are comparable to the FDA’s Breakthrough Therapy designation. These regulatory applications are based primarily on data from the START trial.
Priority Review designation means the FDA’s goal is to take action on an application within six months, compared to 10 months under standard review.
Cure SMA Supports Multiple Gene Therapy Approaches
Beginning in 2010, Cure SMA made a series of grants to Nationwide Children’s Hospital to study gene therapy, also called gene transfer. Spinal muscular atrophy (SMA) is caused by a mutation in the survival motor neuron 1 gene (SMN1). Because of this mutation, the individual does not produce enough survival motor neuron (SMN) protein.
Gene transfer may increase SMN levels by using a virus, called a vector, to deliver the SMN1 gene to affected cells. Adeno-associated virus serotype 9 (AAV9) has the unique ability to cross the blood brain barrier and the Blood-Cerebrospinal Fluid Barrier (CSF).
Currently, two approaches are being studied: an injection into a vein, known as IV delivery, and injection directly into the CSF, a process known as IT delivery. The IV delivery approach is currently under review for approval by the FDA.
IT delivery of gene therapy has shown promise for reducing the amount of drug required for larger and older patients. This could eventually make the treatment accessible to a wider population. IT delivery of gene therapy is currently being tested in clinical trials.