— Increased event-free survival, muscle function scores and achievement of new motor milestones observed —
— Favorable safety and tolerability profile observed —
Positive clinical results from the ongoing Phase 2 open-label study evaluating SPINRAZATM (nusinersen) in patients with infantile-onset spinal muscular atrophy (SMA) were recently published in The Lancet. The paper titled “Treatment of infantile-onset spinal muscular atrophy with nusinersen: a phase 2, open-label, dose-escalation study” (1), reported positive results across multiple efficacy endpoints, including event-free survival, motor function endpoints, electrophysiological measurements and developmental milestones. SPINRAZA demonstrated a favorable safety and tolerability profile in the study.
The Phase 2 open-label study is evaluating multiple doses of SPINRAZA in patients with infantile-onset SMA. A Kaplan-Meier event-free survival analysis of infants treated with SPINRAZA for 18 months or longer shows an increase in event-free survival as demonstrated by a substantial separation between treated infants and published natural history data (1). This analysis also shows that a median age for death or permanent ventilation has not been reached in the SPINRAZA-treated infants. In addition, in contrast to the known natural history of this disease, infants treated with SPINRAZA achieved new motor milestones and increases in the compound muscle action potential (CMAP) amplitude of ulnar and peroneal nerves compared to baseline. Analysis of spinal cord and brain tissue from treated patients showed drug uptake into the motor neurons and other cell types throughout the spinal cord, brain stem and other brain regions. In addition, SMN2 mRNA exon 7 inclusion and SMN protein levels were increased in the spinal cord following treatment.
SMA is a devastating disease that places an extreme burden on both patients and their caregivers. It is characterized by severe and progressive muscular atrophy and weakness. SMA is one of the leading genetic causes of death in infants. Mutations in or loss of the survival of motor neuron 1 (SMN1) gene results in a substantial decrease in SMN protein and loss of motor neurons in the spinal cord and lower brain stem. In its most severe form, Type 1 SMA, the median time to death or permanent ventilation is approximately 6.1 to 10.5 months (2, 3). Currently, there is no approved treatment for SMA (4-7).
According to the authors of the manuscript, the results from this study demonstrate the potential for SPINRAZA to profoundly change the course of infantile-onset SMA. These data are further confirmed by the positive results from an interim analysis of the registrational Phase 3 ENDEAR study in patients with infantile-onset SMA.
The totality of these results, coupled with positive data from open-label studies and an interim analysis of the Phase 3 CHERISH study in patients with later-onset SMA, reinforce the potential of SPINRAZA as a treatment for a broad range of SMA patients.
Regulatory submissions for SPINRAZA for the treatment of SMA are currently under review in both the U.S. and E.U. The U.S. Food and Drug Administration granted Priority Review and the European Medicines Agency’s Committee for Medicinal Products for Human Use granted Accelerated Assessment status to SPINRAZA. Biogen is preparing for the potential launch of SPINRAZA in the U.S., possibly as early as the end of 2016 or the first quarter of 2017.
SPINRAZATM is a trademark of Biogen.
- Finkel et al., Lancet, Advanced Online Publication, December 6, 2016 (link: http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)31408-8/fulltext)
- Finkel, R.S. et al. (2014) Observational study of spinal muscular atrophy type I and implications for clinical trials. Neurology. 83, 810-817.
- Rudnik-Schoneborn, S. et al. (2009) Genotype-phenotype studies in infantile spinal muscular atrophy (SMA) type I in Germany: implications for clinical trials and genetic counselling. Clinical Genetics. 76, 168-178.
- Darras B, Markowitz J, Monani U, De Vivo D. Chapter 8 – Spinal Muscular Atrophies. In: Vivo BTD, ed. Neuromuscular Disorders of Infancy, Childhood, and Adolescence (Second Edition). San Diego: Academic Press; 2015:117-145.
- Lefebvre S, Burglen L, Reboullet S, et al. Identification and characterization of a spinal muscular atrophy-determining gene. Cell. 1995; 80(1):155-165.
- Mailman MD, Heinz JW, Papp AC, et al. Molecular analysis of spinal muscular atrophy and modification of the phenotype by SMN2. Genet Med. 2002; 4(1):20-26.
- Monani UR, Lorson CL, Parsons DW, et al. A single nucleotide difference that alters splicing patterns distinguishes the SMA gene SMN1 from the copy gene SMN2. Hum Mol Genet. 1999; 8(7):1177-1183.
- Peeters K, Chamova T, Jordanova A. Clinical and genetic diversity of SMN1-negative proximal spinal muscular atrophies. Brain. 2014;137(Pt 11):2879-2896.