Biogen and Ionis have taken a significant step forward in receiving accelerated approval of tofersen for treating superoxide dismutase 1 (SOD1) ALS following a unanimous vote of 9-0 from the FDA’s Peripheral and Central Nervous System Drugs Advisory Committee, indicating that the drug’s effect on neurofilament light chain (NfL) could be an effective predictor of clinical benefit.
In a close vote, a panel of external experts decided by a 5-3 margin (with one abstention) that the data presented on the candidate medication tofersen was not sufficient to conclusively demonstrate its efficacy in the indicated area.
The FDA is not obligated to heed the advice of its advisory committee, but it usually does. On April 25, the organization will make a decision on Tofersen’s target action date. Stay tuned to find out what they decide!
Tofersen, an investigational antisense oligonucleotide, was licensed from Ionis in 2018 with the aim of targeting the mutant SOD1 mRNA and reducing the amount of faulty protein in the body. By doing so, it offers a potential new approach for treating a range of diseases and disorders that are caused by this faulty protein.
In July 2022, the FDA accepted Biogen’s New Drug Application (NDA) for tofersen, based largely on NfL as a biomarker that could predict clinical benefit. Despite the Phase III VALOR study failing to meet its primary endpoint, Biogen’s application was accepted and is now under review for approval.
The candidate’s trial failed to demonstrate any substantial improvement in patients’ scores on the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) when compared to the placebo group. Despite their efforts, it appears the candidate’s proposed treatment did not yield the desired results.
Tofersen has been found to make a remarkable difference in the fight against ALS, as evidenced by its ability to reduce levels of the SOD1 protein and NfL, a biomarker of neurodegeneration and axonal damage associated with the disease. This is a major breakthrough in the search for a potential treatment or cure for ALS.
The FDA expressed doubts about relying on biomarker data in a set of briefing documents ahead of an advisory committee meeting. They noted that the connection between changes in NfL levels and ALSFRS-R scores was weak and could be affected by analytic decisions.
The panelists had differing opinions regarding the use of biomarker data. Klaus Romero, M.D., Chief Scientific Officer of the Critical Path Institute, highlighted that the issue at hand was not whether NfL was a fully validated surrogate, but rather whether it was a reasonably likely predictor of clinical benefit.
Romero emphasized the need to carefully weigh the importance of gaining knowledge against ethical considerations when it comes to treating rare diseases. She pointed out that while it can be difficult to perform a placebo-controlled study in this indication, the epistemic needs should never override ethical considerations.
Romero asserts that all existing evidence points to NfL as a potentially effective indicator of clinical benefit. This promising marker could lead to enhanced patient care and improved outcomes.
Biogen is hoping to receive accelerated approval of their new medicine, tofersen, and have proposed that their ongoing ATLAS study, which studies tofersen in pre-symptomatic patients, can be used to validate the clinical efficacy of the drug. If approved, Biogen will need to continue their efforts to keep tofersen on the market: the ATLAS study is expected to deliver data in 2027.