On average, younger and older participants who were unable to sit without support improved from baseline on CHOP-INTEND scores over a 183-day period.
Newly released interim data from the ongoing, phase 4 RESPOND study (NCT04488133) revealed that treatment with nusinersen (Spinraza; Biogen) following onasemnogene abeparvovec (Zolgensma; Novartis) may improve motor function in patients with spinal muscular atrophy (SMA). Presented at the 2023 SMA Research & Clinical Care Meeting, some individuals saw positive impacts on respiratory function, swallowing/feeding ability, and the ability to sit without support.
RESPOND is an open-label study assessing the clinical and safety outcomes of treatment with nusinersen, an antisense oligonucleotide that became the first FDA-approved treatment for SMA in 2016, and Zolgensma, the only FDA-approved gene therapy for the condition. As of the cutoff date (November 15, 2022), 29 children comprised the interim set and 38 made up the safety set. The majority of the cohort (26 of 29) had 2 SMN2 copies, and slightly more than half (n = 15) were at least 9 months of age at first nusinersen dose. Of note, the only 3 individuals with 3 SMN2 copies were at least 9 months of age at first dose.
At day 183 of treatment, most participants with investigator-reported suboptimal motor function showed improvements. This included 12 of 13 individuals with 2 SMN2 copies who received their first nusinersen dose less than 9 months after birth. Of note, all 3 individuals with 3 SMN2 copies showed improvements in motor function. After 183 days, the majority of participants with suboptimal swallowing/feeding ability or respiratory function at baseline had no changes, with some showing improvements. Among the 15 individuals with data, 6 improved their swallowing or feeding ability and 9 remained stable.
"We are learning that gene therapy may not be treating all motor neurons leaving the potential for disease progression,” Crystal Proud, MD, pediatric neurologist, Children’s Hospital of the King’s Daughters, said in a statement.1 "The RESPOND study has begun to characterize remaining unmet need in some SMA patients treated with Zolgensma whose outcomes have not met clinical expectations. These interim results provide the community with the first clinical study data evaluating SPINRAZA treatment following Zolgensma and suggest there may be potential for additional benefit with SPINRAZA treatment."
On caregiver-reported assessments, most participants with suboptimal motor function showed improvements while the majority with suboptimal respiratory function at baseline had no changes. Of note, 1 individual with 2 SMN2 copes who was less than 9 months at their first nusinersen dose had motor function changes that were considered “fully resolved.” In addition, in the same group, 2 individuals showed fully resolved status of swallowing or feeding ability and 1 participant had fully resolved respiratory function.
Participants with 2 SMN2 copies (n = 24) improved by a mean of over 5 points on Hammersmith Infant Neurological Examination (HINE-2), with minimal differences regardless of age at first nusinersen dose (≤9 mo: 5.4 [SD, 2.62] vs > 9 mo: 5.2 [SD, 2.74]). Of note, all 3 participants with 3 SMN2 copies improved; however, mean changes were not calculated due to sample size.
On Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND), those with 2 SMN2 copies who were less than 9 months at first nusinersen dose showed mean changes of 6.7 (SD, 6.76) from baseline, whereas those older than 9 months showed only changes of 0.6 (SD, 5.50). Mean changes were no calculated for participants with 3 copies of SMN2 due to small sample size. Among those who were unable to sit without support at screening, the younger cohort showed mean changes of 6.7 (SD, 6.76) on CHOP-INTEND while the older cohort showed mean changes of 3.6 (SD, 3.91).
In terms of safety, no emerging concerns were identified at the time of the data cutoff. In the safety cohort (n = 38), infections and infestations were the most common adverse event (AE 63.2%) by system organ class, followed by respiratory, thoracic, and mediastinal disorders (26.3%). AEs were found in 81.6% (n = 31) of the cohort, with 2 AEs that were considered related to the study drug. Serious AEs were observed in 34.2% (n = 13) of the population, with no AEs that led to study or drug withdrawal.