Patent highlights from December 2017 to January 2018

摘要

Spinal muscular atrophy (SMA) is an umbrella term for degenerative diseases (inherited mostly through missense mutations in SMN1 but occasionally in various other genes) [1] that is characterized by progressive loss of alpha motor neurons in the spinal cord and brainstem causing muscle weakness and muscle atrophy. Nusinersen (Spinraza?), a modified antisense oligonucleotide that targets the splicing of the alternative SMN2 gene, was approved in 2016/17 as the first disease-modifying SMA therapy. Olesoxime (TRO19622), acquired by Roche in early 2015 along with its original developer Trophos, is nowhere as specific for SMA (it is a quite general neuroprotectant that increases mitochondrial membrane fluidity and has multiple molecular targets [2]), but- being a cholesterol oxime- it could certainly be cheaper by orders of magnitude. A Phase II study (NTCO1302600) in SMA type II and III patients had shown that a dose of 10 mg/kg per day was well tolerated, and demonstrated potential to maintain motor function [3]. Additional analysis revealed that the administered dose might not have exhausted the therapeutic window. The present patent application claims doses of 15-40 or 20-30 mg/kg per day to achieve maximal therapeutic effect. Data show olesoxime at 30 mg/kg/day sc. improving survival of transgenic NSE-Cre;SMNF7/F7 mice. The corresponding new dose range finding study (NCT02628743) is scheduled for completion in 2021. Earlier evidence from a Phase II/III trial in amyotrophic lateral sclerosis patients had failed to convince regulators [4]; however, SMA and ALS might have even more in common than was previously thought [5].