Reimagining SMA Treatment: Salanersen and the Push for Durable, Low-Frequency Therapies

This article originally appeared on NeurologyLive, a sister publication of CGTLive.

Spinal muscular atrophy (SMA) care has undergone a major transformation over the past decade, driven by therapies that restore survival motor neuron (SMN) protein and significantly alter disease trajectories. While these advances have improved survival and motor outcomes, many patients—particularly those treated later or previously exposed to gene therapy—continue to experience ongoing disease activity and incomplete functional recovery. As a result, there remains a growing focus on therapeutic strategies that can deliver more durable effects with fewer treatment interventions.

Recent data presented at the 2026 Muscular Dystrophy Association (MDA) Clinical & Scientific Conference point to salanersen (Biogen), an investigational antisense oligonucleotide, as a potential step forward in this direction. Early phase 1b findings demonstrated notable reductions in neurofilament light chain (NfL), a key marker of neuroaxonal injury, along with evidence of sustained biologic activity following a single administration. With a proposed once-yearly dosing approach, the therapy is now advancing into a global phase 3 program, reflecting continued momentum in next-generation SMA treatment development.

In a conversation with NeurologyLive, a sister brand of CGTLive®, Diana Castro, MD, founder and director of the Neurology and Neuromuscular Care Center, discussed the scientific rationale behind salanersen, the implications of emerging biomarker data, and how this therapy may fit into the broader evolution of SMA care.

Describe more about the mechanism and rationale behind salanersen - why do we believe it can be a successful agent for SMA?

Diana Castro, MD: Salanersen is a novel ASO designed to address the underlying biology of SMA by correcting splicing of the SMN2 gene.

• Like nusinersen (Spinraza; Biogen), salanersen targets SMN2 pre‑mRNA to correct splicing and increase the production of functional SMN protein.
• Salanersen incorporates a new chemical structure that dramatically increases its potency. This enhanced design offers the potential to deliver high efficacy with once-yearly dosing.
• Although advances in SMA treatment over the past decade have been transformative, there is still a need for therapies that may offer greater efficacy while also reducing treatment burden for patients and families. Salanersen has the potential to do both.
• The early Phase 1 data are encouraging and help explain why there is enough confidence to move rapidly into Phase 3 development.

The study showed about a 75% reduction in neurofilament light chain levels; how meaningful is this biomarker change for monitoring disease activity in SMA?

• Neurofilament light chain, or NfL, is a biomarker of active neurodegeneration. When neurons are damaged or die, neurofilaments are released into the cerebrospinal fluid and bloodstream, where it can be measured.
• Baseline concentrations of plasma neurofilament light chain (NfL) were elevated in 16 of 23 evaluable participants, despite many participants being one or more years post gene therapy treatment.
• The elevated baseline levels indicate ongoing neurodegeneration, which might be expected in individuals after gene therapy as aav9 gene therapies have been shown to only transduce, or treat, a portion of motor neurons. Untraduced motor neurons are untreated subject to disease progression.
• That is important because it suggests there may still be ongoing neurodegeneration in some patients after onasemnogene abeparvovec, which is biologically plausible given the AAV9-base gene therapy may not transduce all motor neurons. The approximately 75% reduction in NfL within six months of starting salanersen is therefore a meaningful signal. It was not only robust, but also sustained over the one-year follow up after a single dose.
• These neurofilament data provide clear evidence of target engagement and treatment response and are similar to what was observed in the RESPOND study of nusinersen after onasemnogene abeparvovec. The data suggest that salanersen may be treating untransduced motor neurons.
• These findings, combined with the initial efficacy signals, are encouraging and have prompted Biogen to quickly move salanersen into Phase 3 studies.

Based on these findings, where might salanersen fit for patients who continue to show clinical deficits after receiving onasemnogene abeparvovec (Zolgensma)?

• Based on encouraging Phase 1 findings, salanersen shows promise as a potential option for patients who continue to have residual disease burden following onasemnogene abeparvovec.
• That said, the Phase 3 data will be critical for defining where salanersen may fit within the evolving future treatment paradigm.
• Importantly, the Phase 3 program has been intentionally designed to evaluate salanersen both as a potential first‑line monotherapy and as an add‑on therapy following gene therapy, acknowledging that a large number of patients worldwide have already received onasemnogene abeparvovec and may still have ongoing deficits or unmet needs.
• From a broader clinical perspective, there is strong interest in understanding whether a single therapy that sufficiently restores SMN could adequately control disease, as that could have implications for patient safety, treatment burden, and healthcare resource use, while preserving flexibility for future therapies with different targets. The Phase 3 program is designed to generate the data needed to begin addressing this question, rather than assuming combination therapy is always required.

How could a once-yearly intrathecal therapy change long-term treatment planning and adherence for patients with SMA?

• The value of Salanersen is not simply that it is dosed once a year, but that it may offer high and sustained efficacy with once‑yearly administration.
• If successful, this could allow people living with SMA to focus more on their daily lives and supportive care, rather than the ongoing demands of frequent treatments.
• Fewer procedures and clinic visits may also:
  • Reduce logistical and physical burden of treatment
  • Improve long-term adherence
  • Make it easier to plan treatment around major life events (e.g., pregnancy, school schedules)
  • Reduce disruptions to daily life

Provide some background on the newly initiated phase 3 studies – describe their conduct/design and what questions they aim to answer.

• The Phase 3 program for salanersen includes three global studies, designed to evaluate the therapy across a broad range of SMA populations and treatment settings, spanning from presymptomatic infants to older adolescents and adults.
• STELLAR-1:
  • Design: STELLAR-1 is an open-label study evaluating the effects of salanersen in young (under 6 weeks old), treatment-naïve and clinically presymptomatic infants with a genetic diagnosis of SMA.
  • Key question: By initiating salanersen before symptom onset, STELLAR-1 seeks to define the best outcomes that can be achieved when treatment begins as early as possible.
• STELLAR-2:
  • Design: STELLAR-2 is a randomized, double-blind, sham-controlled study evaluating the effects of salanersen when initiated ~6 months after onasemnogene abeparvovec-xioi in infants with SMA who received presymptomatic treatment with the gene therapy at 6 weeks of age or younger. While the initial comparison period is sham‑controlled, all participants in the study will receive salanersen as part of the trial.
  • Key questions:
    • STELLAR‑2 is designed to assess the benefit of adding salanersen after gene therapy, compared with not adding salanersen.
    • When considered together, data from STELLAR‑1 and STELLAR‑2 will help inform the optimal treatment approach in presymptomatic infants (e.g., salanersen alone, gene therapy alone, or gene therapy followed by salanersen)
• SOLAR:
  • Design: SOLAR is an open-label study evaluating the effects of salanersen in teens and older adults (aged 15–60 years) with SMA who are either treatment-naïve or previously treated with risdiplam.
  • Key question: SOLAR aims to characterize the potential benefit of salanersen across the broader SMA population, including older patients and those with prior treatment exposure.