Results provide Class IV evidence that nusinersen is safe and efficient on motor symptoms in patients older than 7 months of age.
Laurent Servais, MD, PhD
A new study evaluated the safety and clinical efficacy of nusinersen in patients with spinal muscular atrophy type 1 older than 7 months of age, concluding that nusinersen may be effective for muscle control even when treatment is started at a later stage of disease.
Nusinersen, first approved by the FDA in December 2016, is the first and only approved treatment for all types of spinal muscular atrophy. Data aligns with the results from the phase III study evaluating nusinersen in patients with spinal muscular atrophy type 1 treated prior to 7 months of age. The study provides Class IV evidence that nusinersen is beneficial for those with spinal muscular atrophy type 1 between 7—113 months of age.
“They [clinicians/researchers] can learn that even if phase III study was not conducted in patients older than 7 months, for obvious safety and methodological reasons, it does not mean that it is a non-sense treating patients older than 7 months,” study author Laurent Servais, MD, PhD, Pitié-Salpêtrière Hospital in Paris, France, and Citadelle Hospital in Liège, Belgium, told NeurologyLive.
Researchers treated 33 children with spinal muscular atrophy type 1 ranging in age from 8.3 to 113.1 months between December 2016—May 2017 with nusinersen by intrathecal injections, as part of the Expanded Access Program.
Researchers categorized patient respiratory status as no support, support for <16 h/d, or permanent support, and nutritional status as no support, nasogastric tube or gastrostomy. The Hammersmith Infant Neurologic Examination Part 2 (HINE-2) evaluated moto milestones. Physiotherapists performed Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) in all participants younger than 2 years old and the Motor Function Measure (MFM) 20 was performed in all participants 2—5 years of age and MFM 32 in those >5 years of age. Researchers analyzed changes over time with the Friedman and McNemar tests for quantitative and qualitative variables, respectively. Researchers assessed the differences between 2 and 3 survival moto neuron 2 (SMN2) copies with Mann-Whitney and x2 tests for quantitative and qualitative variables, respectively. Negative results were confirmed with a parametric t test and analysis of variance.
Participants were evaluated prior to treatment initiation (M0), at 2 months (M2) and at 6 months (M6) after treatment initiation. Data was collected about survival, breathing, need for feeding help and participants’ ability to move.
Six months after treatment, all participants were alive and continuing treatment and no safety concerns were reported, however, the need for ventilatory support significantly increased over time. Researchers reported 8 patients to have a worsened respiratory status at M6 versus M0.
There were no statistically significant differences between patients presenting with 2 and those with 3 copies of the SMN2 gene. Two patients with 2 SMN2 copies started noninvasive ventilation between M0 and M2 but presented motor-milestones response between M2 and M6. No significant change in nutritional support was reported. SMN2 copy number did not influence the need for ventilatory or nutritional support.
The median progress on the modified HINE-2 was 1.5 points after 6 months of treatment (P <.001), regardless of the SMN2 copies number. Even though patients who scored ≥2 points on the modified HINE-2 at baseline presented with an improvement 2 times higher than patients scoring <2, the difference was not statistically significant. Five participants (16.6%, 5 of 30) ranging from 18 months to 4 years old acquired a stable (>30 seconds), support-free sitting position. On the CHOP INTEND scale (n = 17), the median progress was 4 points at M6.
There were 17 hospitalizations concerning 9 patients recorded; 13 due to respiratory events and 3 that resulted in respiratory failure. The remaining hospitalizations were caused by fever, vomiting, gastroenteritis and gastrostomy insertion. There were no other major events or lab abnormalities reported.
In the cohort, motor function improved after 6 months of treatment with nusinersen. Treatment response was highly variable, but new motor acquisitions were attained even by 8-year-old participant. The results reported were comparable to that in the previously studied younger population. The increase in respiratory support was in some cases a result of a more proactive approach motivated by participation in the Expanded Access Program, and in other participants respiratory worsening was observed despite motor improvement, which might suggest that nusinersen is slower to act on respiratory symptoms and possible intercurrent infections destabilizing weak participants.
In the study researchers noted that several parents reported improvements during treatment with nusinersen not captured through the measures used and that were not predefined in data collection like louder voice, better endurance and more efficient coughing, concluding that better definition of these outcomes is useful for long-term follow-up of participants.
“Obviously, we need longer term data. We need data in even more specific population, like adults, patients on permanent ventilation, patients after spinal fusion. We also need to know what are the predictive factors of being a good responder,” Servais concluded. “We plan to try to assess these different questions. In addition, we are interested in the other spectrum of the disease: patients treated very early, which means before the onset of treatment. We have started the newborn screening in Belgium. You can follow the adventure of the project on Facebook: sunmayariseonsma.”
Aragon-Gawinska K, Seferian A, Daron A, et al. Nusinersen in spinal muscular atrophy type 1 patients older than 7 months. Neurology. 2018;91:1-7.