Novartis will initiate SMART, a Phase 3b clinical study to evaluate the safety and efficacy of the one-time gene therapy Zolgensma (onasemnogene abeparvovec) in young children with spinal muscular atrophy (SMA) who weigh 8.5 to 21 kilograms (about 18 to 46 pounds). 

Zolgensma is approved in the U.S. to treat all types of SMA in newborns and toddlers up to age 2. However, according to the Pediatric Neuromuscular Clinical Research’s (PNCR) natural history study of SMA, most patients younger than 5 will weigh less than 21 kg, with some as old as 8 below that threshold.

The therapy has received approval to treat babies and young children up to 21 kg in the European Union and Canada. Since then, 55% of children treated in Europe range in weight between 8.5 kg and 21 kg. 

Although clinical trials evaluating Zolgensma have studied children younger than 6 months with type 1 SMA, emerging findings from the RESTORE registry (NCT04174157), a multinational, observational study following SMA patients, indicated children 6 months and older achieved a clinically meaningful benefit from Zolgensma alone, after switching to gene therapy or in combination with other SMA therapies. 

SMART (NCT04851873) will further expand clinical evidence on Zolgensma and is expected to enroll up to 24 symptomatic children with SMA (carrying any copy number of the SMN2 gene) across sites in North America, Europe, Australia, and Taiwan. 

Information about contacts and enrollment, which is anticipated to begin in September, is available here, or by emailing the Novartis Medical Information team at [email protected].

“With more than 1,000 patients treated globally to date, we have seen the transformative impact of Zolgensma and are committed to making our essential, one-time gene therapy available to all patients with SMA who may benefit,” Shephard Mpofu, MD, chief medical officer at Novartis, said in a press release. “SMART will expand the clinical evidence beyond the patient population studied in Zolgensma trials to date, and provide the SMA community valuable data on its use in children up to 21 kg.

“These data will add to the strong interest and emerging real-world use and evidence we have seen to date, with a goal of enabling confidence among caregivers, healthcare professionals, and regulatory authorities as they make informed treatment decisions,” he added. 

Zolgensma is designed to directly address the genetic root cause of the disease by replacing the non-working SMN gene, which provides instructions for making the SMN protein necessary for the survival of motor neurons — the nerve cells that control muscle contraction. 

The therapy is administered directly into the bloodstream and uses a modified and harmless virus to deliver a functional copy of the SMA gene to cells.

To date, the therapy has demonstrated significant and clinically meaningful therapeutic benefits in pre-symptomatic and symptomatic SMA. Zolgensma has prolonged event-free survival and achieved motor milestones compared to the natural history of the disease. Moreover, these benefits have been sustained for more than five years in children up to 6 years old.

SMART is a Phase 3b, open-label trial designed to evaluate the safety, tolerability, and effectiveness of a one-time infusion of Zolgensma, and will follow participants for 12 months. 

The trial is limited to 24 participants, weighing 8.5 kg to 21 kg, to provide additional evidence beyond the patient population studied so far, which will be used to inform physicians and caregivers in a timely fashion. 

The primary goal will include assessment of adverse events (side effects), laboratory data, vital signs, and cardiac safety monitoring. 

Secondary efficacy endpoints will assess changes in motor milestones according to the World Health Organization-Multicentre Growth Reference Study (WHO-MGRS), the Hammersmith Functional Motor Scale – Expanded (HFMSE), the Bayley Scales of Infant and Toddler Development-Third Edition (Bayley-III) criteria, and the Revised Upper Limb Module (RULM).

Eligible participants who complete the trial will be invited to enroll in a long-term, follow-up study to collect additional efficacy and safety data.

“SMART is a study designed to expand the clinical evidence for Zolgensma in children up to 21 kg,” said Nicole Gusset, PhD, president of SMA Europe. “We have seen the interest in Zolgensma among physicians and families across Europe, and believe this additional safety, and efficacy data will help the community better understand its potential and inform treatment decisions for young children with SMA.”

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