An Overview of the SMA Treatment Landscape

Over the last five years, significant progress has been made to treat children born with spinal muscular atrophy (SMA), a rare, genetic disease that affects the central nervous system, peripheral nervous system and muscle movement.

The FDA has approved three novel, targeted therapies that offer hope to affected children and their families, but the treatments have a high price tag, and investigators say none of are cures.

The three therapies — Novartis’ Zolgensma (onasemnogene abeparvovec-xioi), Biogen/Ionis’ Spinraza (nusinersen), and Roche’s Evrysdi (risdiplam) — have mechanisms of action involving the survival motor neuron (SMN) gene that is mutated in those with SMA. The authors of a review published in Cell Reports Medicine in July 2021 noted that each has its own limitations, and the long-term effects of all them are unknown. What’s more, no treatment guidelines exist, and comparisons are difficult because of the different inclusion criteria and outcomes measures in the clinical trials.

• Dec. 23, 2016. FDA approves Spinraza (nusinersen)

• May 24, 2019. FDA approves Zolgensma (onasemnogene abeparvovec-xioi
• August 7, 2020. FDA approves Evrysdi (risdiplam)

Spinraza was approved in December 2016. It is an antisense oligonucleotide that targets SMN2 and aims to increase production of the full-length SMN protein. A trial of 28 children found that after treatment resulted in motor function improvements and stabilization of the disease. Spinraza is priced at about $125,00 per dose.

Zolgensma, approved by the FDA May 2019, is an adeno-associated virus vector-based gene therapy that provides an functional copy of the SMN gene in a single, one-time infusion. In a phase 3 trial of 22 patients with type 1 SMA, 13 infants were sitting independently at 18 months of age. But liver toxicity is an adverse event that led to a temporary pause in this trial. Zolgensma also has the highest price tag, at $2.1 million for a single injection.

A report from the Institute for Clinical and Economic Review (ICER) issued in May 2019 found that to reach a common cost-effectiveness threshold between of $100,000 and $150,000 per quality-adjusted life year gained, Zolgensma would need to be priced at between $1.1 million to $1.9 million per treatment.

A more recent study published in the Journal of Market Access & Health Policy that was that funded Novartis found that Zolgensma was cost effective in comparison to Spinraza but not to best supportive care. In that analysis, survival was predicted to be 37.6 years for patients treated with Zolgensma, compared with 12.1 years for Spinraza and 7.3 years for best supportive care.

Evrysdi is an oral medication that was approved August 2020. Like Spinraza, this small molecule binds to SMN2 and promotes the production of the full-length SMN protein. In a study of 21 infants, investigators found that treatment with Evrysdi increased levels of functional SMN protein in the blood. After 12 months of treatment, 41% of patients were able to sit independently for more than five seconds, and after 23 or more months of treatment and 81% of patients were alive without permanent ventilation. Phase 3 clinical trials of Evrysdi are ongoing. Evrysdi costs up to $340,000 a year, but dosing is calibrated to weight and therefore may be less in younger patients.

Novartis is also developing branaplam, another oral therapy that targets SMN2 as a treatment for both SMA and Huntington’s disease, but the company executives have suggested they don’t see a big opportunity in SMA.