Since 2016, the FDA has approved three disease-modifying treatments for spinal muscular atrophy, with several companies—including Novartis, Scholar Rock and Biogen—progressing novel candidates through clinical trials.
The last decade has fundamentally changed how clinicians treat spinal muscular atrophy. In 2016, Biogen’s Spinraza became the FDA-approved treatment for SMA, offering new hope for patients with the rare, neuromuscular disease. Since then, two more medicines—Novartis’ gene therapy Zolgensma and Roche’s SMN2 splicing modifier Evrysdi—have hit the market, and many more are in various stages of development.
Before 2016, without treatment, many patients with the most severe form of SMA did not survive past two years of age without respiratory support, according to Biogen.
“The landscape of SMA has changed drastically for the better,” Seth Perlman, a neurologist at Seattle Children’s Hospital, told BioSpace. “It is a completely different world. We’re not expecting to see children die before age two.”
SMA is caused by a dysfunction in the survival motor neuron (SMN) protein, typically due to a mutation in the SMN1 gene. The SMN protein is critical for cell survival. It repairs DNA, manages cellular stress and preserves overall neuromuscular health. Without it, motor neurons waste away. Most investigational drugs seek to boost the amount of functional protein or deliver a functional copy of the SMN1 gene, but recent innovations in this space also target muscles directly.
Here, BioSpace looks at six SMA therapies and novel formulations to watch in 2025 and beyond.
Novartis’ IT Zolgensma (OAV101 IT)
Last week, Novartis announced positive safety and efficacy readouts for OAV101 IT, an investigational intrathecal injection of its landmark gene therapy, Zolgensma (onasemnogene abeparvovec). The only gene therapy for SMA on the U.S. market, Zolgensma is currently FDA-approved for intravenous delivery in children under 2 years of age.
Data from the Phase III STEER study, presented March 19 at the Muscular Dystrophy Association’s Clinical & Scientific Conference in Dallas, showed that treatment with OAV101 IT improves motor muscular ability in patients 2–17 years of age, potentially expanding the cohort of patients who can benefit from this therapy. OAV101 IT differs from the approved formulation of Zolgensma in that it is delivered directly into the spinal fluid, which Norman Putzki, global development head of neuroscience and gene therapy at Novartis, said allows for safer delivery of the drug in the higher doses required to effectively treat older patients.
In STEER, OAV101 IT elicited a 2.39-point improvement on the Hammersmith Functional Motor Scale Expanded (HFMSE)—a gold standard SMA assessment tool, according to Novartis’ press release—compared to 0.51 points in the control arm. “We’ve seen motor gains that are clinically meaningful,” Putzki told BioSpace. “It’s really exciting.”
Novartis plans to file for approval of OAV101 IT with regulators in the first half of 2025.
Scholar Rock’s Apitegromab
Scholar Rock’s apitegromab, a myostatin inhibitor, sailed through Phase III testing with flying colors.
In the Phase III SAPPHIRE trial, reported by Scholar Rock in October 2024, patients aged 2 to 12 years receiving apitegromab experienced clinically meaningful benefits in motor function, with the treatment group seeing at least a 1.8-point improvement on the HFMSE compared to placebo. In addition, 30% of apitegromab-treated patients saw at least a 3-point improvement in HFMSE compared to 12.5% in the placebo group.
Unlike other drugs, apitegromab directly targets muscles, selectively inhibiting the activation of myostatin. Perlman said apitegromab could be an effective “add-on” to other therapies, especially for people with SMA who may have already developed muscular weakness.
NMD Pharma’s NMD670
NMD Pharma is testing NMD670, a small molecule inhibitor of skeletal muscle-specific chloride ion channel 1 (CIC01), in a Phase II trial for SMA. The first patient in this trial, which is evaluating changes in a 6-minute walk test in ambulatory adults aged 18 to 75, dosed its first patient in late 2023, according to a company press release.
The study is estimated to wrap up in January 2026, according to ClinicalTrials.gov.
While earlier in development than other drugs on this list, NMD670 has shown promise in early-stage trials of other neuromuscular disorders. In a Phase I clinical trial, patients with myasthenia gravis experienced clinically meaningful improvements in the Quantitative Myasthenia Gravis (QMG) score—which assesses muscle control and function—and electrophysiological assessments. The drug is thought to enhance muscle excitability, amplifying responses to motor commands from the brain.
Biogen’s Higher Dose Spinraza and BIIB115
In January, the FDA accepted Biogen’s supplemental new drug application for a higher dose of its Ionis-partnered Spinraza, an antisense oligonucleotide that alters the splicing of SMN2, a “backup” gene for SMN1 that produces a truncated version of the SMN protein. The drug, which is injected into the spinal fluid, enables the SMN2 gene to make full-length SMN protein, increasing its production in patients with SMA.
The higher-dose regimen, which comprises a loading regimen of two 50-mg doses 14 days apart, followed by a 28-mg maintenance regimen every four months, could “enable meaningful clinical benefits while maintaining a safety profile broadly consistent with the approved 12-mg regimen,” Thomas Crawford, co-director of the Muscular Dystrophy Association Clinic at Johns Hopkins Medicine, said in Biogen’s acceptance announcement.
But Biogen isn’t resting on the success of Spinraza. In January 2022, the big biotech exercised an option from Ionis for an exclusive global license for another antisense oligonucleotide, BIIB115, which according to Ionis offers the potential for extended dosing intervals.
Biogen is currently testing BIIB115 in a Phase I trial intended to ascertain safety and pharmacokinetic effects in healthy adult male volunteers and pediatric SMA patients who were previously treated with Zolgensma. The study is expected to read out in November 2026, according to Clinicaltrials.gov.
Biohaven’s Taldefgrobep Alfa
Biohaven’s investigational myostatin and activin receptor blocker, taldefgrobep alfa, missed the mark in a recent Phase III trial, but the Connecticut-based biotech hasn’t given up on the drug yet. In Biohaven’s RESILIENT SMA study, taldefgrobep alfa failed to improve motor function in patients with SMA as compared with placebo, according to a November 2024 press release. Biohaven noted, however, that in Caucasian patients, the drug showed a statistically significant improvement. Patients in this subset treated with taldefgrobep alfa showed a statistically significant 2.2-point improvement in the Motor Function Measurement-32 (MFM-32) scale at 48 weeks. Non-Caucasian patients, however, showed a higher-than-average response to the placebo, Biohaven said.
The company struck an optimistic tone regarding the drug’s efficacy and plans “to engage the FDA regarding potential steps forward” for the candidate.
Biohaven also discovered that treatment with taldefgrobep alfa resulted in a reduction of body fat and improvements in lean muscle mass and bone density. Based on these findings, the company stated plans to launch a Phase II trial in obesity in Q4, 2024.
