-- If approved, tofersen will be the first treatment targeting a genetic cause of ALS and the next marketed Ionis-discovered antisense medicine

-- FDA decision expected by April 25, 2023

Ionis (Nasdaq: IONS) today announced the outcome of the U.S. Food and Drug Administration's (FDA) Peripheral and Central Nervous System Drugs Advisory Committee meeting on tofersen, an investigational antisense medicine for the treatment of people with superoxide dismutase 1 (SOD1) amyotrophic lateral sclerosis (ALS). SOD1-ALS is a rare genetic form of ALS that leads to the loss of everyday functions and ultimately death.

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On the question, "Is the available evidence sufficient to conclude that a reduction in plasma neurofilament light chain (NfL) concentration in tofersen-treated patients is reasonably likely to predict clinical benefit of tofersen for treatment of patients with SOD1-ALS?", the committee voted unanimously yes (9 yes to 0 no) for consideration of a potential accelerated approval. On the second question, "Does the clinical data from the placebo-controlled study and available long-term extension study results, with additional supporting results from the effects on relevant biomarkers (i.e., changes in plasma NfL concentration and/or reductions in SOD1), provide substantial evidence of the effectiveness of tofersen in the treatment of patients with SOD1-ALS?", the committee voted 3 (yes), 5 (no) and 1 (abstain) for consideration of a potential traditional approval.

Additionally, the committee discussed both of these topics and reached consensus that the benefit-risk profile was favorable based on the review of the totality of data for tofersen in people with SOD1-ALS.

"We are encouraged by the outcome of today's advisory committee meeting. If approved, tofersen would be the first medicine targeting a known cause of familial ALS, a devastating neurodegenerative disease that diminishes motor function and leads to death within two to five years of diagnosis," said C. Frank Bennett, Ph.D., executive vice president and chief scientific officer at Ionis. "Tofersen is the lead investigational medicine from our innovative pipeline of neurological therapies designed to target the root cause of intractable diseases. We are diligently advancing these programs to potentially benefit patients in need."

Advisory Committees provide non-binding recommendations for consideration by the FDA. The New Drug Application for tofersen for the treatment of SOD1-ALS was submitted to the FDA for consideration under accelerated approval. The FDA is continuing its review of tofersen with a Prescription Drug User Fee Act (PDUFA) action date of April 25, 2023.

About Tofersen

Tofersen is an investigational antisense medicine being evaluated as a treatment for SOD1-ALS. In people with this form of the disease, mutations in their SOD1 gene cause their bodies to create a toxic form of SOD1 protein. This toxic protein causes motor neurons to degenerate, resulting in progressive muscle weakness. Tofersen is designed to bind to SOD1 mRNA and reduce SOD1 protein production.

In addition to the ongoing open label extension of the Phase 3 VALOR study, tofersen is being studied in the Phase 3 ATLAS study designed to evaluate whether tofersen can delay clinical onset when initiated in presymptomatic individuals with a SOD1 genetic mutation and biomarker evidence of disease activity. Biogen licensed tofersen from Ionis under a collaborative development and license agreement.