Regulatory Decision Summary for Spinraza

Spinal muscular atrophy (SMA) is a rare autosomal recessive neuromuscular disease characterized by degeneration of motor neurons resulting in atrophy of the voluntary muscles of the limbs and trunk and respiratory insufficiency. SMA is the most common genetic cause of infant mortality, primarily due to pulmonary disease secondary to neuromuscular weakness, and a major cause of childhood morbidity. There are no approved therapies for the treatment of SMA and standard of care is supportive and includes respiratory, nutritional and musculoskeletal support.

Spinraza (nusinersen) is an antisense oligonucleotide that is designed specifically to treat SMA by targeting the survival motor neuron-2 (SMN-2) gene. Data from 7 clinical trials have provided evidence of clinically meaningful treatment effects with nusinersen for the treatment of 5q SMA, across all age ranges (newborn to 15 years at treatment onset) and SMA subtypes [infantile onset (Type 1), later onset (Type 2, Type 3), presymptomatic genetically diagnosed] that were included in the studies. Spinraza is administered intrathecally via lumbar puncture.

The pivotal efficacy data were from a planned interim analysis of a Phase 3 randomized, double-blind, sham procedure controlled clinical trial that included patients with infantile onset SMA (30 to 262 days old at first dose). The primary endpoint of the study was the proportion of patients that could be considered motor milestone responders based on the protocol-specified level of achievement of developmental motor milestones assessed by the Hammersmith Infant Neurological Examination. A greater proportion of patients in the Spinraza group (41%) compared to the sham-control group (0%) were motor milestone responders and the difference between groups was statistically significant (p<0.0001). The largest proportion of patients that were motor milestone responders had improvements in head control, sitting and rolling and achieved motor milestones were sustained with continued treatment. Any motor milestones achieved by patients that received the sham control were less advanced and less likely to be sustained. These findings were supported by interim data from an ongoing open label clinical trial with a longer treatment and observation period, also conducted in patients with infantile onset SMA, in which the largest proportion of motor milestone responders had improvements in head control, rolling, sitting and touching toes; several patients also achieved a level of standing and 2 patients were able to walk. Patients in both studies treated with nusinersen also showed clinically meaningful improvements in other assessments of motor function for infants with SMA, and event-free survival (death or need for permanent ventilation or tracheostomy) was increased in patients treated with nusinersen. In the pivotal study, there was a 29% reduction in the risk of death or need for permanent ventilation or tracheostomy and the total daily time on ventilation support was also shown to be less in patients that received nusinersen compared to the patients that had sham control procedures. In an ongoing open label clinical trial, infants with presymptomatic, genetically diagnosed SMA, who are expected to develop Type 1, Type 2 or Type 3 SMA (8 to 42 days old at first dose), are being treated with nusinersen. At the interim analysis patients in this study were achieving developmental motor milestones and gains in motor function at ages that are expected for normal healthy infants, at an age when most of these patients would be expected to manifest symptoms of SMA. In 4 open label clinical trials in which children with later onset SMA (2 to 15 years old at first dose) were treated with nusinersen, there were clinically meaningful improvements in motor function, including upper body strength in non-ambulatory patients and walking ability in ambulatory patients.

The observed developmental motor milestones achievements and improvements motor function in patients with infantile onset SMA and presymptomatic genetically diagnosed SMA were inconsistent with the natural history of Type 1 SMA and beyond what has been observed in symptomatic patients that have received standard of care in natural history studies. The effects of treatment on motor milestones and motor function appeared to be sustained and little or no regression was observed with continued treatment. Similarly, the improvements observed in patients with later onset SMA were maintained over time with continued treatment and, therefore, also inconsistent with the natural history of Type 2 and Type 3 SMA, because these patients normally show gradual loss of functions that were acquired earlier in development.

Nusinersen was a well-tolerated treatment across all age groups studied and across the different SMA subtypes. The non-serious and serious treatment emergent adverse events (TEAEs) that occurred in the clinical trials were largely related to the known complications of SMA or the lumbar puncture procedure. The only reported deaths in clinical trials occurred in the two studies with patients with infantile onset SMA and most/all were the fatal outcomes of serious respiratory events or complications from respiratory infections. Other than the patients that died, there were no patients that discontinued treatment or were withdrawn from any of the clinical trials due to TEAEs. There has been a postmarketing report of meningitis associated with the lumbar puncture procedure used for nusinersen administration.

Safety concerns that were associated with the use of nusinersen included transient mild reductions in platelet count, transient mild elevated urine protein and rashes (red macular lesions), all of which may be potential indicators of toxicities (thrombocytopenia, nephrotoxicity, vasculitis) that have occurred to varying degrees when other antisense oligonucleotides in the same class as nusinersen were administered intravenously or subcutaneously in non-clinical and clinical studies. Therefore, these effects are not specific to the sequence of the antisense oligonucleotide, but rather are class-related effects. In the pivotal clinical trial in patients with infantile onset SMA, the reductions in platelet count, elevated urine protein and rashes were observed more frequently in patients that received nusinersen than in the sham control group. None of the occurrences of platelet count reductions or elevated urine protein were considered TEAEs and none were associated with relevant clinical symptoms or changes in other relevant clinical laboratory parameters. The rashes appeared to resolve despite continued treatment, although recurred in 1 of the 2 patients. The clinical significance of the observed platelet count reductions, elevated urine protein and rashes is not known, because these effects were not seen consistently across studies (platelet count reductions, elevated urine protein were seen in some patients in open label studies). Although nusinersen is administered by the intrathecal route, there is nonetheless some systemic exposure with nusinersen and its half-life is long. In addition, similar to other antisense oligonucleotides, the kidney is a target organ where the highest concentrations of nusinersen are observed (i.e., higher than in the central nervous system). In view of all of these factors and the limited characterization of long-term safety, the relationship between nusinersen and these identified safety concerns is uncertain. Therefore, disclosing these findings in the labelling with monitoring recommendations (platelets, coagulation, urine protein) is considered warranted at this time.

An additional safety concern with nusinersen relates to the potential neurotoxicity observed in repeat-dose toxicity studies in juvenile monkeys that showed time and concentration dependent hippocampal histopathology (neuronal vacuolation and neuronal and glial necrosis/cellular debris). One of the studies also suggested there were potential learning deficits in the animals. Because the concentrations at which the observed hippocampal histopathology and potential learning deficits occurred were within the recommended clinical dose range and the long-term safety of nusinersen has not been fully elucidated, the clinical relevance of the hippocampal histopathology and potential learning deficits in monkeys is not known. These findings have been described in the labelling.

Current medical care for SMA is supportive and focused on respiratory, nutritional and musculoskeletal support and there is a need for an effective treatment of SMA. The available data indicate that Spinraza could provide an effective treatment with an acceptable safety profile for patients with 5q SMA. At this time, when used under the conditions described in the approved Spinraza Product Monograph, the benefit-harm-uncertainty for Spinraza can be considered acceptable for the treatment of patients with 5q SMA.

The Sponsor proposed related substance impurities limits, though slightly higher than what would be considered qualified from a nonclinical toxicology perspective, are nonetheless acceptable considering Spinrazas indication and dosing.

In conclusion, it was determined that the available clinical data supports the issuance of a Notice of Compliance (NOC) for Spinraza for the treatment of 5q SMA.