What Salanersen's FDA Breakthrough Designation Means for Spinal Muscular Atrophy

In early June, Biogen announced that the FDA granted Breakthrough Therapy Designation for salanersen for the treatment of spinal muscular atrophy (SMA), based on Phase 1b data showing clinically meaningful improvements in motor function and reductions in neurofilament light chain levels in children who had a suboptimal response to prior gene therapy. The designation is designed to expedite the development and review of drugs intended to treat serious conditions where preliminary clinical evidence suggests substantial improvement over available therapy. For context, salanersen is an investigational antisense oligonucleotide with a novel chemical backbone designed to increase potency and enable high efficacy with once-yearly dosing.

The Phase 1b findings drew particular attention for what was observed in children who had previously received gene therapy but clinically plateaued. Of 24 children treated with salanersen, all experienced improvement on at least one endpoint, 12 achieved at least one new WHO motor milestone, and those with elevated baseline neurofilament levels saw a 75% reduction within six months that was sustained through follow-up. Three Phase 3 studies, STELLAR-1, STELLAR-2, and SOLAR, are now underway or expected to begin recruitment imminently.

In this Q&A, Stephanie Fradette, PhD, Senior Vice President, Head of Rare Neurology Development Unit at Biogen, discusses what the Breakthrough Therapy Designation signals about remaining unmet needs in SMA and how clinicians should interpret the motor gains observed in children after prior gene therapy. The conversation also covers what the neurofilament data suggest about salanersen's biological impact, how once-yearly dosing could reshape treatment burden, and what the Phase 3 program is designed to answer about the drug's future role in SMA.

NeurologyLive: What does the FDA's Breakthrough Therapy designation for salanersen signal about the current treatment landscape in SMA and the unmet needs that still remain for patients?

Stephanie Fradette, PhD: Receiving this designation is a significant milestone for Biogen and reflects the FDA’s determination that preliminary clinical evidence indicates salanersen has the potential to offer substantial improvement over available therapies.

This reinforces the very reason salanersen was developed – to address these critical unmet needs of the community.

Salanersen is an investigational antisense oligonucleotide (ASO) designed with a novel chemical backbone intended to increase potency to enable high efficacy with once-yearly dosing.

With encouraging preliminary Phase 1b data and the BTD in hand, we are working with urgency to advance our Phase 3 program, designed to establish the role of salanersen in the SMA treatment landscape.

One of the more notable findings from the phase 1b study was the observation of motor gains in children who had previously received gene therapy but were considered to have a suboptimal clinical status. How should clinicians interpret these findings, and what do they suggest about the potential for further functional improvement after initial treatment?

In SMA, early intervention remains critical, as motor neuron loss is irreversible and begins before symptoms may be observed. Over time, our understanding of SMA treatment has evolved, with growing evidence suggesting that gene therapy may not transduce all motor neurons, leaving some motor neurons susceptible to ongoing disease-related neurodegeneration. As a result, there is increasing interest in whether additional treatment could address residual disease in individuals with suboptimal response to gene therapy.

In the open-label segment of the Phase 1b study of salanersen, all 24 children treated with salanersen (after gene therapy) experienced improvement from baseline on one or more endpoints. The children in this study had clinically plateaued for extended periods following prior treatment, making the observed improvements unexpected. At the time of this interim analysis, with follow-up ranging from 1 to 2 years, 12 of the 24 participants achieved at least one new WHO motor milestone, such as walking, crawling, standing or sitting. Achievement of these milestones is a high bar, as it requires strength and coordination across multiple muscle groups. Some participants achieved multiple milestones, and all participants maintained the motor milestones documented at their baseline. Improvements were also observed across the motor function scales evaluated in the study.

The majority (70%) of participants had elevated baseline concentrations of neurofilament light chain (NfL), a marker of active neurodegeneration, despite prior treatment. In these participants, NfL levels decreased by 75% over 6 months and remained reduced throughout follow-up. Elevated baseline NfL concentrations are consistent with persistent disease activity and participants’ suboptimal clinical status, while the sustained reduction observed after salanersen supports an impact on the underlying disease biology.

Overall, the magnitude and consistency of changes observed across NfL and efficacy outcomes suggest that salanersen may be having a clinically relevant impact in individuals who continue to experience disease burden despite prior treatment with gene therapy.

The salanersen results build on observations from the RESPOND study, where participants with suboptimal clinical status after gene therapy were treated with nusinersen and also experienced improvements on clinical outcome measures and reductions in NfL.

Taken together, these data suggest that more may be possible for some people living with SMA after gene therapy. By addressing persistent disease activity, additional therapeutic approaches may have the potential to further impact disease biology and clinical outcomes.

The study also reported reductions in neurofilament levels following treatment with salanersen. From a clinical perspective, how meaningful is this biomarker in SMA, and what might these findings tell us about the drug's potential impact on underlying disease biology?

Neurofilaments are a marker of axonal injury and neurodegeneration. Biologically it makes sense that neurofilament would be a clinically relevant biomarker in SMA, a disease characterized by degeneration and loss of motor neurons in the spinal cord. In motor neuron diseases such as ALS and SMA, higher levels of neurofilament are seen in more severe phenotype patients with more quickly progressing disease.

From a clinical perspective, neurofilament levels offer a window into the underlying disease biology of SMA. Elevated levels indicate active neurodegeneration that we need to slow down as quickly as possible, recognizing that we only get one motor neuron pool and we can’t bring a motor neuron back once it dies. Changes in neurofilament can provide early insight into whether a therapy is having the intended effect.

In the salanersen Phase 1b study, most participants had elevated levels of neurofilament when they enrolled. It is hypothesized that this persistent neurodegeneration may be attributable to incomplete motor neuron transduction with gene therapy. When salanersen was initiated, levels of neurofilament, in this case, neurofilament light chain (NfL), were meaningfully and rapidly reduced, suggesting a slowing of that neurodegeneration.

The role of neurofilament as a biomarker in SMA is further substantiated by observations in trials of nusinersen where we have observed rapid and sustained lowering of neurofilament in treatment-naïve and gene-therapy-treated patients. Here again, these changes in neurofilament preceded measurable improvements in clinical or functional measures. Taken together, these data give confidence that neurofilament can and will play an increasingly important role in SMA research and clinical practice, in combination with more traditional electrophysiologic and functional outcome measures.

Salanersen is being developed as a once-yearly antisense oligonucleotide. How could this dosing approach influence long-term disease management, treatment burden, and decision-making for patients, families, and providers?

While efficacy and safety remain the most important factors when investigating a new medicine, patient experience is also an important consideration. For individuals with SMA, reducing the logistical demands associated with ongoing care may help lessen the time and planning spent on treatment.

A once-yearly treatment option could offer greater flexibility in long-term disease management plans without compromising efficacy or safety.

With the STELLAR-1, STELLAR-2, and SOLAR phase 3 studies now underway, what key questions do you hope these trials will answer, and what data will be most important in determining salanersen's future role within the SMA treatment paradigm?

Together with the SMA community, we have designed the salanersen Phase 3 program to answer the most relevant questions for the field and establish salanersen’s role in the future treatment landscape.

The STELLAR trials are complementary and designed to compare multiple early treatment strategies in presymptomatic newborns – salanersen alone, gene therapy alone, and salanersen as an add-on to gene therapy – to inform future treatment approaches in SMA. SOLAR will evaluate the effects of salanersen in teens and older adults with SMA who are either treatment-naïve or previously treated with risdiplam.

Collectively, these studies are intended to answer not only whether salanersen can improve clinical outcomes across a broad range of patients with SMA, but also how salanersen may fit alongside existing therapies to further improve outcomes for people living with SMA.