Highlights from

AAN 2019

American Academy of Neurology annual meeting

Philadelphia, USA 4-10 May 2019

Experimental oligonucleotide drug shows promising results for SOD1-ALS

In the first report on an investigational oligonucleotide therapy for ALS, it was linked to possible slower progression in people with a genetic form of the disease caused by mutations in the superoxide dismutase 1 (SOD1) gene. The authors claimed their results strongly support further investigation of this therapy’s efficacy in patients with SOD1-ALS.

Approximately 10% of ALS cases are genetic; about one fifth of these is linked to SOD1 mutations, of which over 200 have been identified thus far. The antisense oligonucleotide BIIB067 was designed to reduce production of the mutated SOD1 mRNA in SOD1-ALS patients.

The randomised placebo-controlled study that was presented evaluated safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of BIIB067. In the multiple-ascending dose part of the 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, the secondary outcome PK/PD; efficacy was evaluated in an exploratory analysis.

Most adverse events (AEs) were mild or moderate in severity. There were dose-dependent increases in BIIB067 concentrations in plasma and cerebrospinal fluid (CSF). The 100 mg dose (n=10) was associated with a statistically significant reduction of CSF SOD1 vs placebo (n=12) (P=0.002). Prof Dr Timothy Miller (Washington University School of Medicine, St. Louis, USA) said, “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 further.”

In the 100 mg cohort, CSF phosphorylated neurofilament heavy was lowered, functional decline (measured by ALS Functional Rating Scale Revised scores) was slowed, as were loss of vital capacity and muscle strength. Differences between the 100 mg and placebo groups were greater in participants with rapidly progressive SOD1 mutations.

Miller TM, et al. AAN 2019.

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