Nusinersen versus Sham Control in Infantile-Onset Spinal Muscular Atrophy

Abstract

BACKGROUNDSpinal muscular atrophy is an autosomal recessive neuromuscular disorder that is caused by an insufficient level of survival motor neuron (SMN) protein. Nusinersen is an antisense oligonucleotide drug that modifies pre-messenger RNA splicing of the SMN2 gene and thus promotes increased production of full-length SMN protein. METHODSWe conducted a randomized, double-blind, sham-controlled, phase 3 efficacy and safety trial of nusinersen in infants with spinal muscular atrophy. The primary end points were a motor-milestone response (defined according to results on the Hammersmith Infant Neurological Examination) and event-free survival (time to death or the use of permanent assisted ventilation). Secondary end points included overall survival and subgroup analyses of event-free survival according to disease duration at screening. Only the first primary end point was tested in a prespecified interim analysis. To control the overall type I error rate at 0.05, a hierarchical testing strategy was used for the second primary end point and the secondary end points in the final analysis. RESULTSIn the interim analysis, a significantly higher percentage of infants in the nusinersen group than in the control group had a motor-milestone response (21 of 51 infants [41%] vs. 0 of 27 [0%], P<0.001), and this result prompted early termination of the trial. In the final analysis, a significantly higher percentage of infants in the nusinersen group than in the control group had a motor-milestone response (37 of 73 infants [51%] vs. 0 of 37 [0%]), and the likelihood of event-free survival was higher in the nusinersen group than in the control group (hazard ratio for death or the use of permanent assisted ventilation, 0.53; P = 0.005). The likelihood of overall survival was higher in the nusinersen group than in the control group (hazard ratio for death, 0.37; P = 0.004), and infants with a shorter disease duration at screening were more likely than those with a longer disease duration to benefit from nusinersen. The incidence and severity of adverse events were similar in the two groups. CONCLUSIONSAmong infants with spinal muscular atrophy, those who received nusinersen were more likely to be alive and have improvements in motor function than those in the control group. Early treatment may be necessary to maximize the benefit of the drug. (Funded by Biogen and Ionis Pharmaceuticals; ENDEAR ClinicalTrials.gov number, NCT02193074.)

Nusinersen for SMA: expanded access programme

“…The observed improvements in motor function are similar to previous reports, in which not all infants had a uniform response to nusinersen treatment 6 9. While the maximum and long-term response is not yet clear, at the end of the phase III randomised controlled trial on infants with symptomatic SMA type 1, 51% achieved a motor milestone response, including head control (22%), rolling over (10%), sitting independently (8%) and the ability to stand (1%) 9. Stabilisation or some improvement in motor function is considered clinically meaningful by patients and their families,19 and in this context our results suggest a shift in addressing nutritional and pulmonary issues earlier in newly diagnosed patients, and considering introducing proactive measures in the more severe phenotypes.…”

Protein production is an early biomarker for RNA‐targeted therapies

“…Our approach can be directly applied to multiple RNA‐directed strategies, such as siRNAs 31 and ASOs,32, 33 that target long‐lived proteins in neurodegeneration for clinical trials. Besides its lowered protein production readout, stable isotope labeling could be a powerful tool to examine increased protein production for therapeutic strategies such as gene therapy 34 and splicing ASO treatments 35, 36. Moreover, an understanding of protein kinetics using stable isotope labeling can also inform on assays for therapies that target protein turnover, such as approaches that activate protein clearance mechanisms 37 or promote proper protein folding 38…”

Recent therapeutic developments of spinal muscular atrophy

“…Nusinersen (Spinraza, Biogen, Cambridge, MA, USA) has shown promising results in preclinical, early phase human, and clinical trials (47,57,58). The route of administration is intrathecal due to its poor transport across the blood-brain barrier.…”

“…Based on significant interim results from two Phase 3 studies on infants and later onset SMA, the study subjects switched to active treatment (59). In the final analysis, nusinersen-treated infants were more likely to be alive and have improved motor functions compared to the control group (57). Furthermore, the results indicated that early treatment is necessary to maximize the effect of the nusinersen treatment (57).…”

“…In the final analysis, nusinersen-treated infants were more likely to be alive and have improved motor functions compared to the control group (57). Furthermore, the results indicated that early treatment is necessary to maximize the effect of the nusinersen treatment (57). A Phase 3 trial of nusinersen in later-onset patients (NCT02292537) was recently completed, whereas a Phase 2 trial is ongoing in presymptomatic (NCT02386553) patients.…”