The ALS Association submitted comments today to the FDA’s Central and Peripheral Nervous System Advisory Committee, urging it to recommend approval of tofersen for people with ALS linked to a SOD1 gene mutation. The committee will meet virtually on March 22 to review data associated with Biogen’s new drug application.
Biogen is seeking approval of tofersen, an antisense oligonucleotide (ASO) drug, through the FDA’s Accelerated Approval Program. According to the FDA, this program was instituted “to allow for earlier approval of drugs that treat serious conditions, and fill an unmet medical need based on a surrogate endpoint.”
Tofersen is designed to block neurons from turning the flawed instructions found in mutated SOD1 genes into toxic proteins implicated in ALS development. Mutations in the SOD1 gene appear in about 12-20% of people with familial ALS, and 1-2% of people with ALS who have no family history. The most common SOD1 gene mutations in North America are associated with younger age of onset and shorter survival.
SOD1-linked ALS is a particularly rare and aggressive form of an already rare and devastating disease. Knowing the urgent need for new ALS treatments and based on the data available at this stage, we believe tofersen meets all the conditions required for accelerated approval: treating a serious condition, providing a meaningful advantage over existing therapies and demonstrating an effect on a surrogate marker that is reasonably likely to predict clinical benefit.”
Dr. Neil Thakur
Chief Mission Officer, The ALS Association
While the phase 3 VALOR trial did not meet its predetermined primary endpoint – a change in the ALS functional rating scale (ALSFRS-R) after 28 weeks – tofersen reduced SOD1 protein levels in cerebrospinal fluid by 35% as early as eight weeks after participants began receiving the therapy and further reduced neurofilament light (NfL) levels in blood by 50% within 12-16 weeks, indicating a substantial reduction in the rate of neurodegeneration. High levels of NfL reflect neuron damage, and research has demonstrated a strong link between NfL levels and the risk of ALS development and progression.
The VALOR results suggest that the 28 weeks allotted for the initial blinded phase of the trial were not long enough to demonstrate clinical benefit but were long enough to show biological effects of reducing SOD1 and NfL levels. These reductions translated into a clinical benefit by 52 weeks during the open label extension. Participants who began receiving tofersen during the initial phase 3 trial had a 3.5-point slower decline (on average) in clinical function as measured by ALSFRS-R than those who were initially on placebo and began taking tofersen 6 months later. Tofersen also significantly reduced decline in respiratory function, muscle strength and quality of life.
The ALS Association only makes recommendations on drug approvals after seeking an independent peer review. Specifically, we ask sponsors to share data that will be submitted to the FDA and engage the recommendations of external experts who are not conflicted in any way with the program or the sponsor. Consistent with our policy, we consulted with independent experts to conclude that the safety and efficacy evidence in the context of NfL are sufficient for approval of tofersen through the accelerated approval pathway.
“We recognize that the FDA has a tough decision to make. The VALOR trial did not meet its primary endpoint,” Thakur said. “However, drugs granted accelerated approval are often required to confirm anticipated clinical benefits through post-marketing trials. Given that SOD1-linked ALS impacts about 2% of people diagnosed with the disease and the heterogeneity within this population, it would not be ethically or operationally possible to run a new larger and longer randomized trial. Fortunately, Biogen’s ongoing ATLAS prevention trial could serve as a confirmatory trial.”
ATLAS is a randomized, double-blind, placebo-controlled trial of tofersen in people who have specific SOD1 gene mutations but do not have any signs or symptoms of ALS. The researchers are trying to determine whether tofersen can delay the onset of signs or symptoms of ALS and/or slow declines in function once signs or symptoms appear. This trial is projected to be completed in 2027.
Calaneet Balas, president and CEO of The ALS Association, will provide oral testimony at the advisory committee meeting along with board member Larry Falivena. A decision on tofersen’s new drug application is expected by April 25.