FDA accepts NDA for tofersen to treat for superoxide dismutase 1 amyotrophic lateral sclerosis

The application has been granted priority review and given a Prescription Drug User Fee Act action date of January 25, 2023. The FDA has noted that it is currently planning to hold an Advisory Committee meeting for this application, on a yet-to-be determined date. The average life expectancy for people with ALS is three to five years from time of symptom onset. There is currently no treatment targeted for SOD1-ALS.

Biogen is seeking approval of tofersen under the FDA’s accelerated approval pathway, based on the use of neurofilament as a surrogate biomarker that is reasonably likely to predict clinical benefit. Neurofilaments are normal proteins found in healthy neurons, that are increased in blood and cerebrospinal fluid when damage has been done to neurons or their axons and are a marker of neurodegeneration. In ALS, higher levels of neurofilaments have been found to predict more rapid decline in clinical function and shortened survival. Tofersen study results suggest reductions in neurofilament preceded and predicted slowing of decline in measures of clinical and respiratory function, strength, and quality of life. Biogen is committed to ongoing data generation and finalizing the confirmatory data package with the FDA.

“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, M.D., Ph.D., principal investigator of VALOR and ALS Center co-Director at Washington University School of Medicine, St. Louis. “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.”

The tofersen NDA included results from a Phase 1 study in healthy volunteers, a Phase 1/II study evaluating ascending dose levels, the Phase III VALOR study, and the open label extension (OLE) study. Also included are the most current 12-month integrated results from VALOR and the OLE study, recently presented at the European Network to Cure ALS (ENCALS) annual meeting.

As previously reported in October 2021, VALOR, a six-month Phase III randomized study, did not meet the primary endpoint of change from baseline to week 28 in the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale. However, trends of reduced disease progression across multiple secondary and exploratory endpoints were observed. The 12-month integrated data showed that earlier initiation of tofersen led to sustained reductions in neurofilament, a marker of neurodegeneration and slowed decline across multiple efficacy endpoints.In the 12-month data, the most common adverse events (AEs) in participants receiving tofersen in VALOR and the OLE study were headache, procedural pain, fall, back pain and pain in extremities. Most AEs in both VALOR and the OLE were mild to moderate in severity. Serious neurologic events including myelitis, radiculitis, aseptic meningitis, and papilledema, were reported in 6.7 percent of participants receiving tofersen in VALOR and its OLE.

During the FDA review period Biogen will maintain its early access program for tofersen, now with participants in over a dozen countries. The open-label extension and Phase III ATLAS study in presymptomatic individuals with a SOD1 genetic mutation remain ongoing. Biogen is actively engaging with other regulators around the world and will provide updates when appropriate.