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The U.S. Food and Drug Administration (FDA) has announced an advisory committee meeting seeking advice on whether to approve <a href="https://www.biogen.com/">Biogen</a>&#8216;s investigational therapy <a href="https://alsnewstoday.com/ionis-sod1-rx-biib067/">tofersen</a> for the treatment of <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS) caused by SOD1 gene mutations.
The public meeting, to be <a href="https://www.federalregister.gov/documents/2023/01/24/2023-01216/peripheral-and-central-nervous-system-drugs-advisory-committee-notice-of-meeting-establishment-of-a">held online March 22</a>, by the FDA’s Peripheral and Central Nervous System Drugs Advisory Committee, will determine whether tofersen can be approved based on the strength of biomarker data from the <a href="https://clinicaltrials.gov/ct2/show/NCT02623699">VALOR Phase 1/2/3 trial (NCT02623699)</a>.
The FDA <a href="https://alsnewstoday.com/news/fda-expected-decide-tofersen-approval-sod1-als-january/">began reviewing the treatment</a> in June under its accelerated approval pathway, which allows a therapy to receive conditional approval based on early clinical data suggesting it likely is effective.
A decision initially was expected by Jan. 25, but the submission of additional data requested by the agency was <a href="https://alsnewstoday.com/news/decision-delayed-proposed-als-therapy-tofersen-until-april-2023/">deemed a major amendment to the application</a>, extending the review time by three months. The FDA’s new decision date now is April 25.
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<a href="https://alsnewstoday.com/als-and-genetics/">SOD1 gene mutations</a> are found in up to 20% of people with <a href="https://alsnewstoday.com/forms-of-als/familial-als/">familial ALS</a> and up to 2% of <a href="https://alsnewstoday.com/forms-of-als/sporadic-als/">sporadic ALS</a> cases. Such mutations produce a toxic form of the SOD1 enzyme that builds up to harmful levels and is prone to forming clumps in nerve cells, disrupting their function.
Tofersen, administered by intrathecal injection (into the spinal canal), is an RNA-based therapy designed to reduce toxic SOD1 protein and preserve cell function. It does so by binding to SOD1 mRNA molecules, which are produced from the gene and used as a template for protein production, and targeting them for degradation.
The experimental therapy was investigated in the VALOR trial, which was conducted in three parts. Its Phase 1/2 portion found that tofersen, given in single and multiple ascending doses, is generally well-tolerated and able to lower SOD1 levels in the cerebrospinal fluid (CSF, the liquid that surrounds the brain and spinal cord).
The randomized Phase 3 part was designed to assess the safety and efficacy of tofersen in 108 patients, 60 of whom had rapidly progressing disease. Participants were assigned randomly to take tofersen or a placebo, given in eight intrathecal injections over six months.
<h3>Mixed results</h3>
This part <a href="https://alsnewstoday.com/news/phase-3-tofersen-trial-fails-slow-sod1-als-trends-hopeful-valor-trial/">failed to meet its primary goal</a> of showing that tofersen could significantly slow disease progression in fast-progressing ALS patients. However, the therapy did lead to a sustained decrease in toxic SOD1 protein and neurofilament light chain (NfL), a marker of nerve cell damage, compared with a placebo.
A total of 95 participants who completed VALOR&#8217;s Phase 3 portion chose to join an <a href="https://clinicaltrials.gov/ct2/show/NCT03070119">open-label extension study (NCT03070119)</a>, where all receive tofersen for up to seven years.
Data spanning the placebo-controlled part and the open-label extension suggested that long-term treatment with tofersen <a href="https://alsnewstoday.com/news/early-tofersen-treatment-may-slow-sod1-progression-valor-study/">can slow ALS progression</a> in a significant and clinically meaningful manner.
After one year, patients who started on tofersen in the Phase 3 part experienced a six-point decline in their ALS Functional Rating Scale-Revised (ALSFRS-R) scores, compared with a decline of 9.5 points among those who were first given a placebo and started on tofersen six months later. Significant differences in early starters versus late starters also were observed in measures of lung function and muscle strength.
<div class="code-block code-block-6">Additional analyses suggested that early declines in NfL after treatment may <a href="https://alsnewstoday.com/news/tofersen-clinical-benefits-linked-nfl-levels-trial-data/">predict a slower disease progression over time</a>.</div>
The FDA advisory committee meeting will determine whether tofersen’s approval can rest solely on changes in NfL biomarker levels as an indicator of disease progression. Presentations by Biogen and others will be viewed, captioned, and recorded via an online platform.
Tofersen also is <a href="https://alsnewstoday.com/news/tofersen-to-treat-sod1-als-under-review-for-european-union/">under review</a> in the European Union.
Meanwhile, Biogen continues to evaluate tofersen in the ongoing <a href="https://clinicaltrials.gov/ct2/show/NCT04856982">Phase 3 ATLAS study (NCT04856982)</a> in up to 150 people with SOD1 mutations. Eligible participants are those who show elevated NfL levels, indicating nerve damage, but have not yet developed ALS symptoms.
The trial will measure how many participants will develop symptoms of ALS after one year of tofersen versus a placebo. Along with safety, the study will assess disease progression, NfL levels, lung function, and survival.

Tag: VALOR clinical trial

FDA Seeks Input on Tofersen’s Approval for ALS