Ionis announces that FDA accepts New Drug Application and grants Priority Review of tofersen for a rare, genetic form of ALS

Ionis Pharmaceuticals announced that the U.S. Food and Drug Administration (FDA) has accepted a New Drug Application (NDA) for tofersen, an investigational antisense medicine for the treatment of superoxide dismutase 1 amyotrophic lateral sclerosis (SOD1-ALS). The NDA was submitted by Biogen, which licensed tofersen from Ionis in 2018. The application has been granted priority review and given a Prescription Drug User Fee Act action date of Jan. 25, 2023. The FDA has noted that it is currently planning to hold an Advisory Committee meeting for this application. The average life expectancy for people with ALS is three to five years from time of symptom onset; patients with some SOD1 mutations have an even shorter life expectancy. There is currently no treatment targeted for SOD1-ALS.

“Acceptance of the new drug application for tofersen is a monumental milestone, not just for Ionis but for all people with SOD1-ALS, their families and healthcare professionals battling this devastating disease. To them we extend our deepest gratitude. Their courage has been instrumental to the achievement of this goal,” said C. Frank Bennett, Ph.D., executive vice president, chief scientific officer and franchise leader for neurological programs at Ionis. “We also want to thank Biogen for their commitment to advancing tofersen, which, if approved, will be the first treatment that targets a genetic cause of ALS.” Dr. Bennett added, “Acceptance of the NDA for tofersen further strengthens Ionis’ platform strategy to target all forms of ALS and central nervous system disorders more broadly.”

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 has stated its commitment to ongoing data generation and finalizing the confirmatory package with the FDA.

The tofersen NDA included results from a Phase 1 study in healthy volunteers, a Phase 1/2 study evaluating ascending dose levels, the Phase 3 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 reported in October 2021, VALOR, a six-month Phase 3 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 VALOR and OLE 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 AEs were reported in 36.5 percent of participants who received tofersen in VALOR and/or the OLE and 17.3 percent of participants discontinued treatment due to an AE.

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 3 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.