FDA Extends Tofersen Review Period to April 2023

Delay happened after Biogen submitted more information to the agency

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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The U.S. Food and Drug Administration (FDA) is extending by three months its review of tofersen, Biogen’s investigational treatment for forms of amyotrophic lateral sclerosis (ALS) caused by mutations in the SOD1 gene.

Earlier this summer, the FDA granted the application priority review, with a decision expected no later than Jan. 25, 2023. The extension will push that date to April 25, 2023.

The extension is the result of Biogen’s submission of additional requested information, which the agency considers a major amendment to the application, thereby requiring extra time to complete the review.

“We are committed to providing any details the agency needs to complete the review of tofersen,” Priya Singhal, MD, head of global safety and regulatory sciences and interim head of R&D at Biogen, said in a company press release. “As the review continues, Biogen will maintain the early access program for tofersen.”

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The program (NCT04972487), meant to allow access to the therapy ahead of its potential approval, is now open to all people with ALS caused by SOD1 mutations.

About 20% of patients with familial ALS and 2% with sporadic ALS have SOD1 mutations that lead to the production and accumulation of a toxic form of the SOD1 protein in nerve cells.

An antisense oligonucleotide, Tofersen is a small strand of DNA designed to block toxic SOD1 production, slowing disease progression. It does this by binding to SOD1’s messenger RNA — the intermediate molecule derived from DNA that guides protein production — and marking it for degradation.

Biogen is seeking approval of tofersen under the accelerated approval pathway. This means the FDA can grant conditional acceptance to the therapy based on existing clinical data that suggests its effectiveness, which would have to be confirmed in additional trials.

The application for tofersen was backed in part by data from the Phase 1/2/3 VALOR trial (NCT02623699) and its open-label extension study (NCT03070119), which are testing it in ALS patients with a documented SOD1 mutation.

VALOR’s Phase 1/2 portion evaluated single and multiple ascending doses of tofersen, administered directly into the spinal canal, and found the treatment to be generally well tolerated with an ability to reduce toxic SOD1 levels.

The Phase 3 part enrolled 108 patients, 60 of whom were predicted to have fast progressing disease. Participants were randomly assigned to receive either 100 mg of tofersen (72 people) or a placebo (36 people) eight times over six months.

Most then chose to enter the extension study, wherein all are receiving tofersen for up to seven years.

Tofersen shows disease slowing, SOD1 decreases

VALOR’s data showed the trial failed to meet its main goal with tofersen not significantly slowing disease progression, as measured by the ALS Functional Rating Scale-Revised (ALSFRS-R), in the 60 fast-progressing patients after six months.

However, it did lead to sustained decreases in the levels of SOD1 and neurofilament light chain (NfL), a marker of nerve cell damage, compared with the placebo group.

As of January, 67 patients were still being treated in the open-label extension study. After a year of treatment, patients originally assigned to the therapy in VALOR had slower functional declines than those who’d started on placebo and switched to tofersen six months later.

ALSFRS-R scores declined by 6 points in the early start group, compared with 9.5 points in the late group. Early starters also had significantly slower lung function and muscle strength declines.

While median survival could not be estimated since most patients were still alive, available data suggested the risk of death or permanent ventilation were reduced by more than 60% among those who started early treatment.

Tofersen was generally well-tolerated, with common side effects including headache, procedural pain, and pain in the limbs and back. About 7% of tofersen-treated patients had serious neurological side effects such as spinal cord inflammation.

Also, a Phase 3 trial called ATLAS (NCT04856982) is testing the therapy in people with SOD1 mutations who have not yet developed ALS but show higher-than-normal NfL levels. The study is recruiting up to 150 adult participants at more than two dozen sites globally.

ATLAS aims to assess how many participants develop clinical ALS after a year of tofersen versus a placebo. Changes in ALSFRS-R scores, lung function, NfL levels, and survival, as well as safety measures, will also be assessed.