Biogen's antisense ALS drug shows promise in early clinical trial

biogen
Detailed results from a phase 1 study of Biogen's anti-SOD1 ALS therapy tofersen (BIIB067) showed early promise in slowing clinical decline. (Biogen)

Biogen is still reeling from the pivotal failure of aducanumab in Alzheimer’s disease, but it is celebrating some positive news from another pipeline asset in neurology.

Preliminary results from a phase 1 trial showed that tofersen (BIIB067), which Biogen in licensed from Ionis Pharmaceuticals, was well tolerated in amyotrophic lateral sclerosis (ALS) patients. The results suggest the drug could slow the progression of the disease in people with a mutant SOD1 gene.

Mutations in SOD1 can cause the protein the gene expresses to misfold in ways that are toxic nerve cells in the brain and the spinal cord, leading to loss of control over muscles, then paralysis and eventually death. About 10% of all ALS cases emerge from inherited gene mutations, and among these familial cases, around 20% are caused by the SOD1 gene.

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Tofersen is an antisense oligonucleotide that aims to reduce production of the toxic protein. It works by binding to and inhibiting the SOD1 mRNA, which turns off the malfunctioning gene.

During the phase 1 trial, 50 SOD1-mutated ALS patients received either 20 mg, 40 mg, 60 mg or 100 mg of tofersen or placebo via a lumbar puncture over about three months. Investigators found that the 10 people who got the highest dose of tofersen experienced a 37% reduction of the SOD1 protein in their spinal fluid when compared to 12 people who received placebo, according to a study presented at the American Academy of Neurology’s 71st annual meeting in Philadelphia.

“Lower concentrations of the protein in the spinal fluid suggest that there were 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,” the study’s senior author, Timothy Miller of Washington University in St. Louis, said in a statement.

What’s more, patients on the 100 mg dose performed better on tests that measure clinical decline in ALS, including breathing capacity, muscle strength and other body functions. On a score of 48, patients on 100 mg tofersen experienced an average decline of 1.1 points, while those on placebo suffered an average 5.3-point drop, according to Miller’s team.

RELATED: Neurimmune’s anti-SOD1 antibody shows promise in ALS mouse studies

The drivers behind most ALS cases are unknown, so targeting SOD1, a known cause of the familial form of the disease, offers a clear strategy for researchers. Swiss biotech Neurimmune used healthy elderly people’s memory B cells as the basis to develop a recombinant antibody targeting SOD1. (The company had previously used the same technology to discover aducanumab before licensing it to Biogen.) Neurimmune's drug, called α-miSOD1, recently showed promise in postmortem spinal cord samples from ALS patients and in mouse models with SOD1 mutations.

A team of scientists at the Umeå University in Sweden has been analyzing the SOD1 clumps found in ALS, providing a roadmap for researchers developing drugs that target the gene mutation.

The phase 1 trial of Biogen's tofersen offers a proof of concept, and based on a positive analysis first disclosed last December, the company has exercised its option to obtain full control of the antisense drug from Ionis. Biogen is now advancing the drug into pivotal trials, with the goal of proving it works in larger groups of patients over longer periods of time.

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