Sustained Long-Term Benefit of Gene Therapy for SMA

Megan Brooks

May 20, 2021

For children with spinal muscular atrophy (SMA), gene therapy with onasemnogene abeparvovec (Zolgensma, Novartis) provides long-lasting benefits with a favorable safety profile, new long-term follow-up data show.

At a median of 5.2 years since receiving the approved therapeutic dose, onasemnogene abeparvovec provided "sustained, durable efficacy, with all patients alive and without the need for permanent ventilation," report Jerry Mendell, MD, with the Center for Gene Therapy, Nationwide Children's Hospital, Columbus, Ohio, and colleagues.

The study was published online May 17 in JAMA Neurology.

Single Infusion

SMA is a rare genetic disease that can lead to paralysis, breathing difficulty, and death. The disorder is caused by a mutation in the survival motor neuron 1 (SMN1) gene, which encodes the SMN protein critical for maintenance and function of motor neurons.

In 2019, Zolgensma was approved in the United States for children younger than age 2 years with SMA.

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.

In the phase 1 START study, 15 infants with SMA type 1 were treated with either a low or therapeutic dose of Zolgensma at Nationwide Children's Hospital in Columbus, Ohio, between 2014 and 2017.

The START long-term follow-up study (START LTFU) is an ongoing, observational study assessing safety and durability of response over 15 years in 13 of the infants; 3 infants received the low dose and 10 received the approved high dose.

Prior to baseline, four patients (40%) in the therapeutic dose cohort required noninvasive ventilatory support, and six (60%) did not require regular ventilatory support, which did not change in long-term follow-up.

All 10 patients who received the therapeutic dose remained alive and without the need for permanent ventilation up to 6.2 years after dosing, Mendell and colleagues report.

These patients also maintained previously acquired motor milestones. Two patients attained the new milestone of "standing with assistance" without the use of nusinersen (Spinraza, Biogen). 

Serious adverse events occurred in eight patients (62%), none of which resulted in study discontinuation or death.

The most common serious adverse events were related to the underlying SMA disease process and included acute respiratory failure (31%), pneumonia (31%), dehydration (23%), respiratory distress (15%), and bronchiolitis (15%).

Importantly, the investigators note, no new safety signals or "adverse events of special interest" emerged during follow-up, including liver function enzyme elevations, new incidences of malignancy or hematologic disorders, and new incidences or exacerbations of existing neurologic or autoimmune disorders.

The investigators acknowledge that this follow-up study is limited by the small sample size of the patient population and confounded by treatment with nusinersen in several patients.

"However, given that the two patients who acquired the new motor milestone of standing with assistance did not receive nusinersen at any time, this benefit can be attributed solely to onasemnogene abeparvovec," Mendell and colleagues say. 

The study was supported by Novartis Gene Therapies. Mendell and several co-investigators have disclosed financial relationships with the company.

JAMA Neurol. Published online May 17, 2021. Full text

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