A single dose of a new formulation of the gene replacement therapy intrathecal onasemnogene abeparvovec ( OAV101 IT) improved movement ability in teens and children older than 2 years with spinal muscular atrophy (SMA), new phase 3 data showed.

Improvement was also observed in upper limb function and fine motor skills in those receiving OAV101 IT vs sham treatment, but it did not reach statistical significance.

The therapy contains the same active ingredient as the first gene therapy approved for SMA, Zolgensma, which is administered intravenously by patient weight to children younger than 2 years.

This new formulation is delivered directly to the central nervous system at a smaller concentration, independent of patient weight. This opens the treatment up to older patients with SMA.

The findings, published online on December 8 in Nature Medicine, contributed to the recent FDA approval of the therapy, which is marketed as Itvisma. Both gene therapies are manufactured by Novartis.

“The efficacy and safety of OAV101 IT for SMA has been demonstrated in treatment-naive patients without the confounding effects of other therapies,” demonstrating “clinical benefits across a broad SMA population with a wide range of ages and baseline motor function,” lead author Crystal M. Proud, MD, of Children’s Hospital of The King’s Daughters in Norfolk, Virginia, and her colleagues reported.

One-Time Treatment

SMA is a rare genetic neurologic condition in which mutations in the survival motor neuron 1 (SMN1) gene cause the loss of motor neurons, resulting in progressive muscle weakness.

In addition to gene therapy, the two other therapies for SMA are nusinersen, given intermittently intravenously, or risdiplam, taken orally daily. However, both these SMN2 splicing modifiers require lifelong administration, whereas the gene therapy is a one-time treatment.

The phase 3 randomized, sham-controlled, double-blind STEER trial included 126 participants (age, 2-18 years; 50.8% female) from 29 sites in 14 countries. The mean age at SMA symptom onset was 12.7 months. Patients could sit but had never walked independently and had never received treatment for SMA. Nearly all (94%) had three SMN2 copies.

Patients received a single dose of OAV101 IT (n = 75) or a sham procedure (n = 51), with both followed for 52 weeks. The mean age at dosing was 5.88 years (range, 2.1-16.6).

At baseline, the gene therapy group had a mean Hammersmith Functional Motor Scale-Expanded (HFMSE) score of 17.97 (range, 1.0-41.0) and a mean Revised Upper Limb Module (RULM) score of 16.52 (range, 4.0-31.7). In the sham group, the mean baseline score was 18.17 (range, 2.0-42.5) for HFMSE and 17.42 (range, 4.3-31.0) for RULM.

‘Clinically Meaningful’ Benefit

Participants in the gene therapy group had a 2.39-point increase in the HFMSE score, which was significantly greater than the 0.51-point improvement in the sham group (least squares mean [LSM] difference, 1.88; P = .007). This score improvement began as early as 4 weeks after treatment and persisted throughout follow-up.

More participants receiving the treatment (39%) experienced an improvement of at least 3 points on HFMSE compared with those receiving the sham procedure (26%), but the difference did not reach significance (P = .09).

“Similarly, a greater percentage of participants in the OAV101 IT group achieved a clinically meaningful increase of ≥ 1.5 points (a minimum clinically important difference) in their HFMSE score compared to the sham group,” the authors reported.

The other secondary endpoint, improvement in the RULM score, similarly did not achieve significance. Although the treatment group’s LSM improvement of 2.44 points in the RULM score was greater than the 0.92 in the sham group (LSM difference, 1.52; P = .01), it missed significance based on the 95% CI (0.34-2.71).

The researchers also assessed improvement based on age groups and saw numerical but not statistically significant improvements within groups.

The rates of adverse events (AEs), including both serious AEs and those of special interest — such as hepatotoxicity and transient thrombocytopenia — were similar between groups.

Upper respiratory tract infections, a known comorbidity with SMA, and transient pyrexia were the most common AEs in both groups. Two participants receiving the treatment and one receiving the sham procedure developed sensory symptoms that may be suggestive of dorsal root ganglia toxicity.

The treatment group experienced more vomiting (15%) than the sham group (2%) within 72 hours of treatment administration, a known complication of lumbar puncture and possible AE of OAV101 IT. Other known complications of lumbar punctures — including nausea, procedural pain, back pain, and headache — were roughly similar between groups.

Another Option for Older Children

Commenting for Medscape Medical News, Leslie D. Delfiner, MD, director of the Muscular Dystrophy Association Care Center at the Children’s Hospital at Montefiore in Bronx, New York, said the trial’s findings contributed to the path to FDA approval for Itvisma.

Prior to this approval, older patients with SMA only had access to nusinersen and risdiplam, Delfiner said.

“We lack real, direct head-to-head comparisons of the available treatment options, but this is nonetheless an addition to the armamentarium of treatment choices,” Delfiner said. “Individuals will need to partner with their neuromuscular teams to identify the right choice for them based on the risks and benefits.”

She noted the potential for serious side effects with gene replacement therapies as well as the need for systems for monitoring and follow-up.

“Perspectives on treatment benefits and risks may evolve as longer-term data becomes available,” she added.

Michelle Allen-Sharpley, MD, PhD, an assistant professor of pediatrics, neurology, and biomedical sciences at Cedars-Sinai Guerin Children’s in Los Angeles, noted that an advantage of this mechanism of gene delivery is that it avoids intravenous/systemic delivery, thereby avoiding potential harm to other organs.

“We already know gene therapy is effective in babies with SMA, so a more tissue-targeted formulation that can expand therapy to all SMA patients is incredibly encouraging,” with this study’s findings “potentially revolutionizing treatment paradigms for SMA management,” Allen-Sharpley told Medscape Medical News.

“The authors showed improvement in motor function of SMA patients whose natural course would have been declining function,” she said. “It’s exciting that there was this increase in their motor function after only 1 year, since unlike babies being treated before symptoms emerge, these are patients whose disease was already advancing.”

It will be important to follow these patients over the years to better understand long-term benefit, she added. “My hope is that we can develop an evidence-based algorithm that matches patient-specific details to identify a tailored long-term treatment plan for each person.”

Allen-Sharpley said the remarkable advancements in SMA treatment over the past decade set a precedent for the future of neurologic disease management.

“I imagine a future where combination therapy is provided to patients across their lifetime, optimizing their health outcomes and ensuring the best quality of life,” she said.

The research was funded by Novartis. Proud reported financial disclosures with Novartis, Biogen, Sarepta, PTC, CSL Behring, Scholar Rock, and Catabasis. Five of the authors are Novartis employees, and four other authors reported having various financial disclosures, whereas the other nine authors had no conflicts of interest. Delfiner reported being an investigator on a Sarepta-funded trial for a different disease. Allen-Sharpley reported having participated on an advisory board for Scholar Rock as an SMA medical expert.

Tara Haelle is a science/health journalist based in Dallas.