FDA Accepts NDA for Therapy for Genetic Form of ALS


If approved, tofersen will be the first treatment that targets a genetic cause of ALS. The FDA assigned a Prescription Drug User Fee Act action date of Jan. 25, 2023, but said it will hold an advisory committee meeting for this application.

The FDA has accepted a new drug Application (NDA) for tofersen to treat patients with superoxide dismutase 1 amyotrophic lateral sclerosis (SOD1-ALS), a rare, genetic form of the disease. The agency has granted the application priority review and given a Prescription Drug User Fee Act action date of Jan. 25, 2023. The FDA indicated that it is planning to hold an advisory committee meeting for this application.

Developed by Ionis Pharmaceuticals and licensed to Biogen, toferson is an antisense drug that binds to SODI mRNA, which leads to its degradation.

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 under the accelerated approval pathway and based on the use of a neurofilament as a surrogate biomarker. Neurofilaments are normal proteins found in healthy neurons; they 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.

The application is based the phase 3 VALOR trial and an open-label extension study, as well as integrated 12-month results from both of these studies.

The six-month VALOR study did not meet the primary endpoint of change from baseline to week 28 in the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale. But 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 and slowed decline across multiple efficacy endpoints.

Timothy Miller, M.D., Ph.D.

Timothy Miller, M.D., Ph.D.

In VALOR and the open-label study, the most common adverse events were headache, procedural pain, fall, back pain and pain in extremities. Most of these were mild to moderate in severity. Serious neurologic events including myelitis, radiculitis, aseptic meningitis, and papilledema, were reported in 6.7% of participants receiving tofersen in integrated 12 month data.

“The results from the VALOR study are encouraging as they show reduction of SOD1 protein, reduction of neurofilament, a potential biomarker for neurodegenerative disease, and positive signals across multiple key endpoints including measures of important aspects of the daily lives of SOD1-ALS patients,” Timothy Miller, M.D., Ph.D., principal investigator of VALOR and ALS Center Director at Washington University School of Medicine, St. Louis, said in a press when the results were presented in October 2021. “The wait for new options has been long and difficult for the ALS community, and we welcome this important research advancement in this difficult to treat disease space.”

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