Intrathecal Zolgensma Meets Primary End Point in Phase 3 STEER Study of Spinal Muscular Atrophy

Shreeram Aradhye, MD

In newly announced data from the phase 3 STEER study (NCT05089656), results revealed that OAV101IT (Novartis), an intrathecal (IT) investigational formulation of an approved gene therapy for spinal muscular atrophy (SMA), met its primary end point among treatment-naïve patients with the disease. Novartis plans to share these results with regulatory agencies with the goal of bringing this IT formulation to market.¹

In STEER, more than 100 patients with SMA Type 2 were randomly assigned to receive OAV101 by IT injection or to receive a sham procedure for a 52-week period, followed by a crossover phase. All told, treatment with the agent met its primary end point, demonstrating enhancements in total Hammersmith Functional Motor Scale-Expanded (HFMSE) scores, considered a gold standard for SMA-specific assessment of motor ability and disease progression. OAV101 IT demonstrated a favorable safety profile, with similar rates of adverse and serious adverse events between arms, and the most common events being upper respiratory tract infection, pyrexia, and vomiting.

OAV101IT is a new formulation of onasemnogene abeparvovec (Zolgensma), the first and only approved gene therapy for SMA, which came into market in 2019. Zolgensma, an adeno-associated, virus vector-based, one-time treatment, was first approved in an intravenous infusion for patients less than 2 years of age with mutations in the SMN1 gene. In addition to STEER, OAV101IT has been testes in the phase 1/2 STRONG study (NCT03381729) and the phase 3b STRENTH study.

"Many patients with SMA currently rely on chronic treatments to manage their disease. These positive topline results from the STEER trial underscore the efficacy, safety and tolerability of OAV101 IT in patients with SMA aged two and above,” Shreeram Aradhye, MD, president, development and chief medical officer at Novartis, said in a statement.¹ "The totality of evidence clearly supports a positive risk benefit profile of OAV101 which is expected to support registration covering a broad range of SMA patients. We remain committed to leading innovation in SMA treatment through our one-time gene therapies, uniquely designed to replace the function of the missing or defective SMN1 gene."

STRONG, a previously completed study, included 23 sitting, nonambulatory patients with SMA who received a single dose of OAV101IT. Patients were enrolled sequentially into 1 of 3 (low, medium, and high) dose cohorts and stratified into 2 groups by age at dosing: younger (6-<24 months) and older (24-<60 months). After 12 months of treatment, those in the older group on the medium level dose (1.2 x 10¹⁴ vg) demonstrated a significant improvement in HFMSE from baseline in comparison with the SMA historic control population that was approximately twice the 3-point difference accepted as minimal clinically meaningful change (P <.01).²

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Additional data from STRONG showed that OAV101IT was safe, with no deaths reported in the study. All patients had at least 1 treatment-emergent adverse event (TEAE), the most common being upper respiratory tract infection (62.5%), pyrexia (56.3%), cough (34.4%), vomiting (31.3%), and constipation (21.9%). While younger patients did not meet the primary or secondary endpoints of standing or walking independently, improvements in Bayley-III gross and fine motor subtest scores were observed, though the absence of natural history data for children with SMA type 2 makes it unclear if these gains are due to developmental maturation or drug response.

Crystal Proud, MD

STRENGTH, an ongoing phase 3 trial of OAV101IT, tests the safety, tolerability, and efficacy of the agent in patients with SMA who discontinued previously approved treatments nusinersen (Spinraza; Biogen) or risdiplam (Evrysdi; Genentech). This open-label, single-arm multicenter study includes approximately 28 participants aged 2 to 18 years who undergo a screening period, a 1-time treatment, and a 52-week follow-up. STRENGTH excludes those with elevated AAV9 antibodies, significant test abnormalities, or contraindications for lumbar puncture. Additional exclusions apply for recent nusinersen/risdiplam use, vaccinations, pulmonary or nutritional hospitalizations, infections, or the need for invasive ventilation.³

"Maintaining motor function is a key goal for many older patients with SMA. This may allow them the capacity to continue to propel their electric wheelchair, feed themselves with intact hand to mouth function, and perform other activities of daily living as independently as possible," Crystal Proud, MD, a pediatric neurologist and principal investigator at Children’s Hospital of the King’s Daughters, said in a statement.¹ "OAV101 IT administration has not only been demonstrated to maintain motor function, but also increased it in indicating the impact a one-time therapy could have."

REFERENCES
1. Novartis intrathecal onasemnogene abeparvovec Phase III study meets primary endpoint in children and young adults with SMA. News release. Novartis. December 30, 2024. Accessed January 2, 2024. https://www.novartis.com/news/media-releases/novartis-intrathecal-onasemnogene-abeparvovec-phase-iii-study-meets-primary-endpoint-children-and-young-adults-sma
2. Finkel RS, Darras BT, Mendell JR, et al. Intrathecal Onasemnogene Abeparvovec for Sitting, Nonambulatory Patients with Spinal Muscular Atrophy: Phase I Ascending-Dose Study (STRONG). J Neuromuscul Dis. 2023;10(3):389-404. doi:10.3233/JND-221560
3. Phase IIIb, Open-label, Multi-center Study to Evaluate Safety, Tolerability and Efficacy of OAV101 Administered Intrathecally to Participants With SMA Who Discontinued Treatment With Nusinersen or Risdiplam (STRENGTH). Clinicaltrials.gov. Accessed January 2, 2025. https://ctv.veeva.com/study/phase-iiib-open-label-multi-center-study-to-evaluate-safety-tolerability-and-efficacy-of-oav101-a