Novartis Announces New Clinical Data Showing Zolgensma Improves Multiple Developmental Outcomes in Infants with Spinal Muscular Atrophy

On March 14, 2022, Novartis announced the latest data from clinical trials of Zolgensma (onasemnogene abeparvovec). The press release noted that Zolgensma is the first gene therapy approved for treating spinal muscular atrophy (SMA), designed to halt disease progression with a single dose. Results from a Phase 3 clinical trial showed that children with three copies of the SMN2 gene who received treatment before symptom onset achieved age-appropriate motor milestones, including standing and walking, without the need for ventilation or feeding tube support, and experienced no severe treatment-related adverse events. Additionally, descriptive post-hoc analyses of one Phase 1 clinical trial and two Phase 3 clinical trials indicated that children with Type 1 SMA achieved or maintained critical bulbar function metrics after receiving Zolgensma, including speech ability, swallowing, meeting nutritional needs, and maintaining airway protection.

Spinal Muscular Atrophy (SMA) is a rare, hereditary neuromuscular disease and also the leading genetic cause of infant mortality. The root cause of its onset lies in the absence or abnormality of a protein called Survival Motor Neuron (SMN). In the human body, there are two genes capable of producing the SMN protein: the SMN1 gene and the SMN2 gene. However, the SMN1 gene plays a dominant role, while the SMN2 gene only produces a small amount of SMN protein (about 10%). Once the function of the SMN1 gene is impaired, it can lead to insufficient production of SMN, thereby affecting the patient's movement, breathing, swallowing, as well as multiple organs such as the spleen, heart, and pancreas, and even threatening the patient’s life. Based on the degree of SMN protein deficiency, SMA can be divided into several types. Among them, patients with the most severe Type 1 SMA usually die or require permanent respiratory support by 24 months due to rapid neuronal death and muscle damage.

Zolgensma packages the transgene that expresses normal SMN protein into an AAV9 viral vector, and the transgene has been optimized to enhance its ability to produce SMN protein. Its design aims to enable long-term expression of SMN protein in cells after a single treatment, achieving a "curative" effect.

This open-label, single-arm, multi-center Phase 3 clinical trial aims to evaluate the safety and efficacy of a one-time intravenous infusion of Zolgensma in SMA patients with 2 or 3 copies of SMN2 before symptom onset, with patients aged ≤6 weeks.

Final results of the patient cohort (n=15) carrying three copies:

100% of patients (15/15) reached the primary endpoint of standing unassisted for ≥3 seconds by 24 months of age, with 14 achieving this milestone within the World Health Organization (WHO) normal developmental window.

Fourteen patients (93%) achieved independent walking, with 11 reaching this milestone within the WHO normal developmental window.

All patients (100%) were independent of nutritional and respiratory support during the trial period.

All patients experienced at least one adverse event (AE) after dosing, with eight events (53%) considered treatment-related. No serious treatment-related AEs occurred.

In addition, a post-hoc descriptive analysis evaluated pooled data from one Phase 1 and two Phase 3 clinical trials to assess bulbar function in symptomatic Type 1 SMA children treated with Zolgensma. The analysis included 65 patients who were <6 months of age at the time of Zolgensma treatment. Bulbar motor neurons control muscles required for swallowing, speaking, and chewing. Bulbar function was defined as the integrity of cranial nerves allowing the patient’s speech to be intelligible to an unfamiliar listener, ability to swallow food and liquids, and meet nutritional needs while maintaining airway protection. Overall, among patients with results for all three metrics, 80% (16/20) achieved the composite endpoint of being able to speak, swallow normally, and maintain airway protection.

References:

[1] Novartis data again demonstrate age-appropriate development when Zolgensma is used presymptomatically, and post-hoc data reveal SMA Type 1 patients could speak, swallow and maintain airway protection. Retrieved March 14, 2022, from https://www.novartis.com/news/media-releases/novartis-data-again-demonstrate-age-appropriate-development-when-zolgensma-used-presymptomatically-and-post-hoc-data-reveal-sma-type-1-patients-could-speak-swallow-and-maintain-airway-protection

(Original text has been abridged)

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