Experimental drug shows promise for SOD1-ALS

An investigational therapy for ALS, the antisense oligonucleotide BIIB067, was linked to possible slower progression in people with a genetic form caused by mutations in the superoxide dismutase 1 (SOD1) gene [1].

Approximately 10% of ALS cases are genetic; about one fifth of these is linked to SOD1 mutations. BIIB067 was designed to reduce production of the mutated SOD1 mRNA in SOD1-ALS patients. In the multiple-ascending dose part of a study, 50 patients with SOD1 mutation were randomised 3:1 to BIIB067 or placebo for 12 weeks. BIIB067 groups received 20, 40, 60, or 100 mg, respectively. The primary outcome was safety.

Most adverse events were mild or moderate in severity. There were dose-dependent increases in BIIB067 concentrations in plasma and CSF. The 100 mg dose was associated with a statistically significant reduction of CSF SOD1 versus placebo (P=0.002). Prof. Timothy Miller (Washington University School of Medicine, St. Louis, USA) noted: “Lower concentrations of the protein in the CSF suggest that there are also lower concentrations in the brain and spinal cord. Such reductions could lead to preservation of motor neurons and slow progression of the disease, but more study is needed to examine this.” In the 100 mg cohort, CSF phosphorylated neurofilament heavy was also lowered, functional decline as measured by ALS Functional Rating Scale Revised (ALS-FRS-R) scores was slowed, and there was loss of vital capacity and muscle strength. Differences between the 100 mg and placebo groups were greater in participants with rapidly progressive SOD1 mutations. Prof Miller said these results strongly support further investigation of BIIB067's efficacy in patients with SOD1-ALS.

In a review, Prof. Jinsy Andrews (Columbia University, New York, USA) said the pipeline for new ALS therapies is loaded, which is why trial designs must become more efficient. She shared the following thoughts about the future of ALS, saying there is a need to increase the depth of our understanding of the biology of the disease (which will decrease the need for placebo in trials); to develop innovative trial designs; incorporate biomarkers, technology and novel outcome measures in clinical trials; develop our understanding of the natural history of ALS; improve access to new treatments pre- and post-approval; and put patients at the centre to improve our understanding of ALS and improve therapy development.

1. Miller TM, et al. AAN 2019, emerging science 007.



Posted on 30 July, 201922 February, 2024