Presenters at Cure SMA 2026 reviewed recent studies of apitegromab, emugrobart in combination with risdiplam, and salanersen, highlighting safety, treatment impact, population considerations, and practical issues such as infusion burden and dosing schedules. Together, these updates reflect ongoing efforts to expand treatment options for people living with spinal muscular atrophy (SMA).

Following these presentations, featured expert John Brandsema, MD, was interviewed by Conference Reporter Associate Editor-in-Chief Sandra Ramadani, PhD. Clinical perspectives from Dr Brandsema on these findings are presented here.

Care for SMA was transformed in 2016 with the US Food and Drug Administration (FDA) approval of nusinersen. We then had gene replacement therapy (GRT) with onasemnogene abeparvovec, and risdiplam came shortly thereafter. This past year, intrathecal onasemnogene abeparvovec also became available for patients aged 2 years and older.

We now have the potential to make a tremendous difference with medication for this disease, which is something that is really special to be a part of in the clinic. However, it is also getting more confusing. At Cure SMA 2026, I was a panelist for the session titled “Therapeutic Strategies in Spinal Muscular Atrophy in an Era of Multiple Options,” during which we discussed what combination therapy looks like in SMA (abstract 7). Unfortunately, there is very little to guide us, as most data are in monotherapy, and doing a direct comparison between treatments is oftentimes difficult.

One challenge is the language used in the face of multiple treatment options. Some patients receive GRT and then start an SMN2-targeted therapy—we call this “add-on therapy” since you cannot take away GRT once it is done. However, there are other patients who receive SMN2-targeted therapy before receiving GRT, as well as those who switch back and forth between SMN2 modulators. And so, how can you possibly make sense of what the optimal sequence is when there is so much heterogeneity? We have a lot to learn, but there were many great ideas presented during this session.

Aside from genetic approaches, we also have treatments that target the lower motor neurons. The one that is closest to receiving FDA approval in the United States is the myostatin inhibitor apitegromab, which works by optimizing muscle function in the context of compromised lower motor neurons.

At Cure SMA 2026, Jena M. Krueger, MD, presented a post hoc analysis of the phase 3 SAPPHIRE trial evaluating apitegromab in patients with nonambulatory type 2 or 3 SMA (abstract 26). As we saw with the results of part 1 of the phase 2/3 MANATEE trial on emugrobart in combination with risdiplam presented at Cure SMA 2026 by Laurent Servais, MD, PhD (abstract 19), getting positive trial results in a slowly progressing neuromuscular disease is hard, so the fact that the SAPPHIRE trial had statistically significant interpretable results is a big deal. Patients were already on genetically targeted treatment, so seeing a superimposed impact of augmentative therapy with myostatin inhibition on top of that was great to see. In the SAPPHIRE trial, younger patients responded the most robustly to apitegromab, but older age groups were still able to achieve minimal clinically important differences in routine functional scales such as the Hammersmith Functional Motor Scale Expanded (HFMSE).

I am hopeful that apitegromab will come into the clinic as another option based on these data. I expect that it is going to be well tolerated based on our experience thus far, but sometimes we do learn things in the clinic that were not initially appreciated in the trial. The patient population is important when you are thinking about treatment impact. For SAPPHIRE, the investigators chose to focus on nonambulatory patients, but there were stipulations regarding factors that can impact functional scales (eg, scoliosis and contracture burden), and there were minimal respiratory and nutrition support needs. We will see what the label ends up including in terms of the patient population (eg, whether apitegromab is for specific functional levels or broader in terms of including more and fewer individuals with functional impairment).

In another presentation at Cure SMA 2026, Thomas O. Crawford, MD, presented phase 1 interim results evaluating the safety, tolerability, and pharmacokinetics of salanersen for SMA in patients with a suboptimal response to GRT (abstract 21). Efficacy was also examined as an exploratory outcome. The salanersen program is intriguing, but it is very early in its development. What we are seeing are early phase 1 safety data looking at tolerability in a very small number of people. It is hard to take a lot away from the efficacy data from such a small group, but what they showed at the meeting was that salanersen does seem to be well tolerated, similar to its predecessor nusinersen.

A huge advantage of salanersen is that it only needs to be dosed once yearly, as opposed to the 3 times yearly maintenance dose for nusinersen. One question that immediately comes to mind is the wearing-off phenomenon described by patients on nusinersen, where they can feel their function worsening, usually a few weeks before 1 of the 3 doses is due. Clearly, that is not motor neurons dying and then being revived; there has to be another mechanism. My best guess is that nerve transmission and the conduction of signals along the nerve, which is somewhat dependent on SMN, may improve with more SMN and then start to wane as it wears off. Phase 2 trials of salanersen are now being designed to give us some data on efficacy and whether salanersen is comparable or superior to nusinersen or other treatment options.