Can Biogen rebound with ALS? Maybe so, new antisense drug data suggests

It’s no secret: Amyotrophic Lateral Sclerosis (ALS) is a nut that is difficult to crack. And no one knows that Biogen will flare up in Phase 3 when it saw its last ALS initiative, Dexpramipexole, in 2013.

“The drug focused on a rather inaccurate mechanism… and the data Pretty obviously negative“, Dr Toby Ferguson, who is in charge of Biogen’s neuromuscular development unit, told Fierce Biotech. But instead of stopping it, Biogen doubled ALS’s work and “restructured our way of thinking about ALS,” he added. In fact, that’s what Ferguson tempted the company from his post as an academic neurologist.

Big Biotech has focused on drugs that target gene mutations, rather than focusing on drugs with specific mechanisms such as anti-inflammatory drugs. Now it is unveiling The complete Phase 1/2 data emerging from this shift: Tonicene, an antisense oligonucleotide licensed from Ionis Pharmaceuticals.

Open submission

Fierce Innovation Awards: Life Sciences Edition 2020

Submit your entry to demonstrate innovative technologies and services that can have the greatest impact on biotechnology and pharmaceutical companies.

Relation: Biogen’s antisense ALS drug holds promise in early clinical trials

Tofersen is designed for patients with ALS genotype due to mutations in the SOD1 gene. About 10% of ALS cases have known genetic factors. One fifth of them are associated with SOD1 mutations. These patients produce defective SOD1 proteins that are misfolded in brain and spinal cord neurons, leading to loss of muscle control, paralysis, and ultimately death.

In this study, placebo received four doses of tofelsen in 50 patients over 3 months. Highest dose of 100 mg reduced cerebrospinal fluid (CSF) SOD1 protein levels by more than one-third (36%) in patients taking placebo, compared to only a 3% reduction I understand. The findings appear in the New England Medical Journal.

The trial was small, with 10 patients taking a dose of 100 mg and 12 patients taking placebo. [the drug] It may be clinically important. “

According to Ferguson, reduced CSF levels of SOD1 reflect similar reductions in proteins in the spinal cord and brain. “This is a hypothesis, but I think it is a valid one.”

The study also examined several exploratory clinical endpoints, including a 48-point patient score that measures ALS severity, respiration, and muscle strength. Patients taking the highest dose of Toffelsen had an average reduction of 1.2 points in the ALS Functional Rating Scale score, while the placebo group had an average increase of 5.63 points.

Relation: ALS discontinuation by gene therapy approach

“What we saw was a reduction in ALS function, breathing, and weakness that was much greater in the placebo group than in the treatment group.” “But I was critical In that case, I was able to punch holes in any of those data, but some data show that SOD1 is reduced.”

Taken together, what has to be confirmed in a Phase 3 trial of 183 patients scheduled to be wrapped in July 2021, but various parts paint a promising picture for Toffelsen.

Headaches consistent with ALS, lumbar puncture syndrome, and falls were among the most common side effects. Five tofelsen patients and two placebo patients suffered serious side effects and three died. One placebo patient and one Toffersen patient died of respiratory failure, and a second Toffersen patient died of pulmonary embolism or pulmonary artery thrombosis.

Biogen has two other ALS programs behind tofersen. It is an antisense drug for Ionis partners that targets mutations in the C9orF72 gene, and a drug that blocks the protein exportin 1 (XPO1). While 90% of ALS cases are considered “non-hereditary”, Biogen believes these patients have an underlying genetic component. Ferguson said he would like to translate the lessons learned from working with SOD1 and C9orF72 into other populations.

Next, the company is collaborating on another protein that plays a role in ALS, ataxin-2. It wants to learn more about disease biology from examining genetically defined populations, and apply those findings to a wider population.