A Biogen drug that addresses a subset of amyotrophic lateral sclerosis patients who have a particular genetic mutation has fallen short of the main goals of a pivotal study. Despite that clinical trial failure, Cambridge, Massachusetts-based Biogen points to encouraging data from other measures taken during the study, and it’s on that basis that the company plans to talk with the FDA to try and find a path forward for the drug.

The Phase 3 results for the drug, tofersen, were presented Sunday during the annual meeting of the American Neurological Association.

More than 20 genes have been identified as causing or contributing to ALS. The Biogen drug was designed to address SOD1, an enzyme that is highly expressed in the central nervous system. Research has shown that mutations to the SOD1 gene lead to SOD1 protein that is prone to misfolding. It’s believed that this mutant protein leads to motor neuron dysfunction and cell death, causing a progression of the disease.

Tofersen is an antisense oligonucleotide, a type of drug consisting of genetic material that binds to specific molecules of RNA, blocking its ability to make a protein. The Biogen ALS drug, which is given as an injection into the spinal canal, is intended to reduce the synthesis of SOD1 protein.

Biogen tested tofersen in a placebo-controlled Phase 3 study enrolling 108 participants with muscle weakness attributed to ALS and a confirmed SOD1 mutation. The patients assigned to receive the study drug were further divided into two subgroups: 60 whose disease was faster progressing and 48 who were slower progressing. The main goal was to measure a change according to a scale used to score ALS patients on various functions. After 28 weeks, the scores in the tofersen groups were better than the placebo group scores, but not by enough to show statistical significance.

Despite missing the study’s main goal, Timothy Miller, a Washington University professor of neurology and the principal investigator of the tofersen study, pointed to more encouraging data according to secondary and exploratory goals of the clinical trial. On secondary goals measuring breathing and muscle strength, the study showed trends favoring the drug, according to Miller’s presentation. Those encouraging trends were observed across other exploratory measures that include disease severity, quality of life, and fatigue.

Miller also noted that those treated with tofersen showed a reduction of SOD1 protein as well as reduction of neurofilaments, which are filaments found in the cytoplasm of neurons. These filaments considered a potential biological indicator of neurodegenerative disease. The reductions suggest a slowing in neuron degeneration, the presentation stated.

The study was not able to estimate time to death due to the low number of such events reported over the course of the clinical trial’s 28 weeks. According to Biogen, most of adverse events in both the Phase 3 study and the open-label extension study were mild to moderate in severity, and included pain associated with the intrathecal injection, headache, and pain in the extremities.

In its announcement of the Phase 3 results, Biogen said it is “actively engaging with regulators,” as well as the medical community, patient advocacy groups, and others to determine the next steps for the drug. The company did not specify whether those steps include seeking accelerated approval, which requires less evidence than a standard drug review but requires a company to conduct post-marketing studies to confirm a drug’s benefit. Biogen’s Alzheimer’s disease drug Aduhelm, which produced mixed results in its two Phase 3 clinical trials, was approved in June under the accelerated approval pathway.

In the meantime, Biogen said it will expand eligibility for the ongoing early access program to include all people who have the SOD1 mutation. This program provides patients with free access to tofersen. But Biogen added that if no a clear path forward for the drug emerges, or if regulators require another clinical trial, Biogen may revise or discontinue the early access program.

The FDA’s views on experimental ALS drugs may be evolving. Amylyx Pharma’s experimental ALS drug, AMX0035, met the goals of a Phase 2 study, yet the agency earlier this year told the company that it needed to conduct a larger Phase 3 test to support a regulatory application. In September, the Cambridge-based biotech announced it planned to file for approval, a course change that followed discussions with the FDA.

Meanwhile, Brainstorm Cell Therapeutics is still assessing how to proceed with its experimental ALS treatment, Nurown. The stem cell therapy failed to achieve primary or secondary goals of a Phase 3 clinical trial last year. But the company has pointed to clinical improvement in a subgroup of patients. In its report of second quarter 2021 financial results, New York-based Brainstorm said it is “evaluating next steps based on emerging scientific insights and the rapidly changing regulatory landscape for [Alzheimer’s disease] following the recent FDA decision on Aducanumab.”

Tofersen was discovered by Ionis Pharmaceuticals. Biogen entered a multi-disease research partnership with Ionis in 2018, paying $1 billion in cash and the purchase of Ionis stock. The deal built on earlier alliance on Spinraza, which in 2016 became the first FDA-approved drug for the rare disease spinal muscular atrophy. Biogen paid $35 million to license tofersen in 2018, taking over responsibility for the drug’s development.

Tofersen is not the first Biogen drug to fall short in a Phase 3 test in ALS. In 2012, the company’s drug dexpramipexole failed to show efficacy against primary and secondary goals. Based on those results, the company stopped the drug’s development.

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