FDA OKs First Gene Therapy for Spinal Muscular Atrophy

Megan Brooks

May 24, 2019

The US Food and Drug Administration (FDA) has approved onasemnogene abeparvovec-xioi (Zolgensma, AveXis Inc, a Novartis company), the first gene therapy for children younger than age 2 with spinal muscular atrophy (SMA).

A one-time infusion, though, will cost more than $2 million, making it the world's most expensive drug. According to the company, the annualized cost of Zolgensma is $425,000 per year for 5 years. The company said it is working closely with payers to create 5-year outcomes-based agreements and novel pay-over-time options. 

SMA is a rare genetic disease that can lead to paralysis, breathing difficulty, and death. It is the leading genetic cause of death in infants.

"Children with SMA experience difficulty performing essential functions of life. Most children with this disease do not survive past early childhood due to respiratory failure" Peter Marks, MD, PhD, director of the FDA's Center for Biologics Evaluation and Research, said in a news release.

"Patients with SMA now have another treatment option to minimize the progression of SMA and improve survival. This approval demonstrates the continued momentum of this promising new area of medicine and the FDA's commitment to supporting and helping expedite the development of these products," said Marks.

SMA is caused by a mutation in the survival motor neuron 1 (SMN1 ) gene. The gene encodes the SMN protein critical for the maintenance and function of motor neurons. 

Zolgensma is an adeno-associated virus vector-based gene therapy that addresses the genetic root cause of SMA by replacing the defective or missing SMN1  gene to halt disease progression.  A single, one-time intravenous infusion results in expression of the SMN protein motor neurons, which improves muscle movement and function, and survival. Dosing is weight-based.

In the phase 3 STR1VE trial, Zolgensma was associated with prolonged event-free survival, increases in motor function, and significant milestone achievement in patients with SMA type 1 (acute infantile form).

In the START trial, patients treated with Zolgensma met motor milestones never seen in the natural history of the disease, including sitting, talking, and some patients walking, with no waning of effect nearly 4 years post-dosing, according to a company news release.

"In the START clinical trial we conducted with Zolgensma, all children were alive at the conclusion of the study and many were able to sit, roll, crawl, play and some could walk," Jerry Mendell, MD, of the Center for Gene Therapy at The Abigail Wexner Research Institute of Nationwide Children's Hospital in Columbus, Ohio, said in the release. 

"This level of efficacy, delivered as a single, one-time therapy, is truly remarkable and provides a level of unprecedented hope for families battling SMA Type 1. We now have data 4 years out from the trial, and we see the durability of this gene therapy," said Mendell.

The most common side effects with Zolgensma are elevated liver enzymes and vomiting. Zolgensma has a boxed warning that acute serious liver injury can occur. Patients with preexisting liver impairment may be at higher risk of experiencing serious liver injury. Clinical examination and laboratory tests to assess liver function should be performed prior to treatment with Zolgensma, and patients' liver function should be monitored for at least 3 months after Zolgensma administration.

Certain vaccines are contraindicated for patients on a substantially immunosuppressive steroid dose. Therefore, caregivers should consult with their healthcare professional to determine if adjustments to the patient's vaccination schedule are necessary to accommodate concomitant corticosteroid administration, the FDA said.

The FDA granted the Zolgensma application fast track, breakthrough therapy, and priority review designations, as well as orphan drug designation. The FDA also awarded the manufacturer a rare pediatric disease priority review voucher under a program intended to encourage the development of new drugs and biological products for the prevention and treatment of certain rare pediatric diseases.

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