FDA Reviewing Tofersen for SOD1-ALS; Decision Expected in January

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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The U.S. Food and Drug Administration (FDA) has agreed to review an application from Biogen for approval of the company’s experimental therapy tofersen to treat amyotrophic lateral sclerosis (ALS) associated with mutations in the SOD1 gene.

The FDA has granted the application accelerated review and a decision is expected by Jan. 25, 2023. The regulatory agency plans to hold an advisory committee meeting to discuss the application, but has not set a date for that meeting, according to Biogen.

“If approved, tofersen will be the first treatment to target a genetic cause of ALS and we hope this will pave the way for further advances in this relentless disease,” Priya Singhal, MD, head of global safety and regulatory sciences and interim head of R&D at Biogen, said in a company press release.

Biogen is pursuing approval of tofersen under the FDA’s accelerated approval pathway, which allows the agency to give conditional approval to a therapy based on early clinical data that suggest it’s probably effective. In this case, Biogen is basing its application off of early data from clinical trials showing tofersen reduced levels of a marker of nerve cell damage called neurofilament light chain (NfL).

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If tofersen is granted accelerated approval, Biogen would be required to conduct additional testing to prove the therapy’s effectiveness on clinical outcomes.

“The available data show that tofersen has the potential to make a meaningful difference for people with SOD1-ALS. Pursuing the FDA’s accelerated approval pathway offers the potential to make tofersen available to people living with this fatal, neurodegenerative disease as quickly as possible,” Singhal said.

Tofersen is an RNA-based therapy designed to lower production of the abnormal and toxic SOD1 protein, which is made when the SOD1 gene is mutated. Mutations in this gene are found in up to 20% of people with familial ALS, and up to 2% of those with sporadic disease.

In addition to a Phase 1 trial in healthy volunteers (NCT03764488), Biogen’s application is based on data from the Phase 1/2/3 VALOR trial (NCT02623699) and its open-label extension (OLE) (NCT03070119).

VALOR’s Phase 1/2 portion investigated single- and multiple-ascending doses of tofersen in people with ALS and indicated that it was generally well tolerated and reduced toxic SOD1 levels as intended.

The Phase 3 part enrolled 108 patients who were randomly assigned to receive eight spinal canal injections of either 100 mg of tofersen (72 patients) or a placebo (36 patients) over six months.

After completing this part, 95 participants chose to join the trial’s OLE, where all will continue to receive treatment for up to seven years.

Top-line data from the trial showed it failed to meet its primary goal of significantly slowing disability progression, as measured by changes in the ALS Functional Rating Scale-Revised (ALSFRS-R).

However, one-year data spanning VALOR and its OLE showed that patients originally assigned to tofersen in the Phase 3 trial had greater reductions in NfL levels compared with those who first received a placebo and started the treatment six months later.

Those who started the treatment earlier also had significantly slower declines in a number of clinical measures, including the ability to perform day-to-day functions (ALSFRS-R), muscle strength, lung function, general health, and patient-reported quality of life.

The most recent data also suggested that early starters had a 73% reduction in the risk of death compared with when the treatment was delayed.

The most common side effects reported in those given tofersen in VALOR and its extension trial were headache, fall, pain in the back or extremities, or pain related to the therapy’s administration.

Serious neurologic events, including spinal cord inflammation, inflammation in the nerve roots, inflammation in the brain’s meninges, and swelling of the optic nerve (which conveys information from the eyeballs to the brain), were reported in 6.7% of patients on the experimental therapy.

“The 12-month results showed that individuals with SOD1-ALS who started tofersen earlier experienced a slower rate of decline in clinical and respiratory function, strength and quality of life. These are critical measures for people living with this devastating disease,” said Timothy Miller, MD, PhD, of Washington University School of Medicine and the principal investigator for the VALOR trial.

“For people in my clinic living with SOD1-ALS, tofersen may meaningfully slow the rapid progression of their disease and the impact it has on their lives,” Miller said.

While the FDA conducts its application review, SOD1-ALS patients may access tofersen as part of Biogen’s early access program (NCT04972487).

The company also is running a Phase 3 trial called ATLAS (NCT04856982) to test the therapy in people with ALS-causing SOD1 mutations who have elevated NfL levels, indicating nerve damage, but have not yet developed ALS symptoms. The study is actively recruiting up to 150 participants at more than two dozen sites around the globe.