Despite Limited Literature, Combination Therapy Occurring in Spinal Muscular Atrophy


Comprised of more than 400 patients with SMA, results showed that wanting to be treated with all possible DMTs was the most common reason for combination therapy.

Lisa Belter, director of research analytics at Cure SMA

Lisa Belter

In the 2023 Cure SMA community update survey, investigators observed that combination therapy was used by several individuals with spinal muscular atrophy (SMA) despite the limited evidence on the efficacy and safety of this approach. Although combination therapy was used less than a sequential therapy method, the study authors concluded that these data emphasize a call to action to recognize combination treatment and collect more data to further validate efficacy and safety.1

Presented at the 2024 Muscular Dystrophy Association (MDA) Clinical and Scientific Conference, held March 3-6, in Orlando, Florida, the final sample included 215 children and 222 adults with SMA after excluding non-US residents (n = 87), those with missing information (n = 157) and birthdays (n = 1), and duplicate surveys (n = 17). The majority (58%; n = 255) of affected individuals were treated with monotherapy, followed by sequential therapy (29.3%; n = 128) and then combination therapy (12.4%; n = 54). Of note, those treated with combo therapy (mean age, 6.8 years) were younger than those treated with sequential therapy (mean age, 24.7 years).

The 3 approved therapies for SMA include nusinersen (Spinraza; Biogen), risdiplam (Evrysdi; Genentech), and onasemnogene abeparvovec (Zolgensma; Novartis). Led by Lisa Belter, director of research analytics at Cure SMA, combination therapy was defined as use of nusinersen and/or risdiplam after Zolgensma administration, whereas sequential therapy was defined as a discontinuation of either nusinersen or risdiplam prior to starting an additional SMA disease-modifying therapy (DMT). Sequential approaches may include bridge therapies, where a patient is treated with nusinersen or risdiplam for a short time before starting Zolgensma.

When looking at the survey results, the most common reason (82%; 37 of 45) for being treated with combination therapy was wanting to be treated with all possible DMTs while trying a different DMT was the most common reason (73%; 37 of 51) for sequential treatment. Physician recommendation was the second most common reason for trying combination therapy (78%), followed by the inability to gain function (48%). Only a handful of patients claimed that the loss of function was the reason behind wanting to switch to combination therapy (14%) or sequential therapy (12%).

Additional findings from the study showed that the most common reason (88%; 66 of 75) for being treated with sequential therapy was wanting to try a different DMT. Other reasons included “wanted to be treated with all possible DMTs” (35%), “was losing function” (27%), “wasn’t gaining function” (31%), and “physician recommendation” (18%).

READ MORE: Marlin Study Aims to Assess Fertility Outcomes in Risdiplam-Treated Males With Spinal Muscular Atrophy

Increasing the amount of survival motor neuron (SMN) protein in the body is not the only way to treat SMA. The lost of SMN protein also impacts other systems, pathways, and processes, and other SMA treatments target these systems. Many in the field believe that it will take a combination of SMN-based and non-SMN treatments to provide the most benefit for those with SMA. In the conclusion of the analysis, investigators claimed that future studies will need to evaluate if adverse events, method of administration, efficacy, and insurance coverage impact treatment patterns.

To date, no systematic approach has been proposed to classify the various combination treatment scenarios for patients with SMA who receive DMTs and to facilitate analyses that will clarify potential benefit-risk differences between treatment regimens, including regimens incorporating one-time gene replacement therapy. The currently ongoing phase 4 RESPOND study (NCT0448133), a notable trial in the field, assesses nusinersen in individuals with SMA who were previously on Zolgensma and had suboptimal clinical status as determined by an investigator.

Led by Crystal Proud, MD, director of neurology and neuromuscular medicine at the Children’s Hospital of the King’s Daughter in Norfolk, Virginia, the study featured 60 individuals with SMA who have at least 1 SMN2 copy and were less than 36 months after first nusinersen dose. Presented at the 2023 Cure SMA Clinical & Scientific Conference, most participants demonstrated improvements in motor function at day 183 of treatment. This included 12 of 13 individuals with 2 SMN2 copies who received their first nusinersen dose less than 9 months after birth. In addition, a majority of patients with suboptimal swallowing/feeding ability or respiratory function at baseline had no changes, with some showing improvements.2

Click here for more MDA 2024 coverage.

1. Belter L, Curry M, Schroth M. 2023 Cure SMA community update survey: patient and caregiver reported rationale for combination and sequential therapy. Presented at: MDA Clinical and Scientific Conference; March 3-6, 2024; POSTER T389
2. Proud C, Parsons JA, Kuntz NL, et al. Interim results from the ongoing RESPOND study evaluating nusinersen in children with spinal muscular atrophy previously treated with onasemnogene abeparvovec. Presented at: 2023 Cure SMA Research & Clinical Care; June 28-30; Orlando, FL.
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