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The New England Journal of Medicine Publishes Pivotal Tofersen Data that Show Benefits in Rare, Genetic Form of ALS

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Biogen Inc. (Nasdaq: BIIB) today announced that The New England Journal of Medicine (NEJM) has published detailed results from the Phase 3 VALOR study and the combined analysis of VALOR and its open label extension (OLE) study evaluating tofersen for the treatment of superoxide dismutase 1 (SOD1) amyotrophic lateral sclerosis (ALS). There is currently no treatment targeted for SOD1-ALS.

“I see three key take home points from these data. First, tofersen clearly leads to lowering of SOD1 protein, as would be expected. Second there is substantial lowering of neurofilament levels, which I interpret as potentially slowing the underlying disease process. And third, there is a meaningful clinical benefit when looking at the later time points in the open label extension,” said Timothy Miller, M.D., Ph.D., principal investigator of VALOR and ALS Center co-Director at Washington University School of Medicine, St. Louis. “We are grateful to the dedication from participants, their families, and the sites for taking part in this important study.”

Data from the combined analysis were previously presented at the European Network to Cure ALS (ENCALS) annual meeting and included within Biogen’s New Drug Application for tofersen that was recently accepted for priority review by the U.S. Food and Drug Administration. The application was given a Prescription Drug User Fee Act action date of January 25, 2023.

“The ALS community has been actively pursuing new medicines for decades. To have data like these published in NEJM gives us energy and hope. We are now seeing in the data what we suspected about tofersen for a long time – that it has the potential to make a clinical difference for people living with SOD1-ALS,” said Merit Cudkowicz, M.D., co-principal investigator of the VALOR trial and co-founder of the Northeast ALS Consortium, Director of the Healey & AMG Center for ALS and Chair of Neurology at Massachusetts General Hospital and the Julieanne Dorn Professor of Neurology at Harvard Medical School. “The lowering of neurofilament, a marker of axonal injury and neurodegeneration along with the clinical data, highlights the potential of tofersen.”

About VALOR and the OLE
VALOR was a six-month Phase 3, randomized, double-blind, placebo-controlled study to evaluate the effects of tofersen 100 mg in adults with ALS associated with a SOD1 mutation. In total, 108 participants were randomized in VALOR (n=72 to tofersen 100 mg and n=36 to placebo). Of these participants, 95 enrolled in the ongoing OLE. At the time of the analysis all participants had an opportunity for at least 12 months of follow-up, with a median exposure to tofersen of approximately 20 months (range: 1 – 34 months).

The primary endpoint of VALOR was change from baseline to week 28 in ALS Functional Rating Scale-Revised (ALSFRS-R) total score. Secondary endpoints included changes in total cerebrospinal fluid SOD1 protein concentration, plasma neurofilament light chain (NfL), slow vital capacity and handheld dynamometry in 16 muscles.

As previously reported in October 2021, VALOR did not meet the primary endpoint. However, trends of reduced disease progression across multiple secondary and exploratory endpoints were observed. The combined VALOR and OLE 12-month data, in which the clinical analyses adjusted for neurofilament levels as a marker of the disease progression rate at baseline, showed sustained reductions in SOD1 protein (a marker of target engagement) and neurofilament (a marker of neurodegeneration) and slowed decline in clinical function, respiratory function, strength, and quality of life with earlier initiation of tofersen.

In the 12-month data, the most common adverse events (AEs) in participants receiving tofersen in VALOR and the OLE study were procedural pain, headache, pain in the arms or legs, falls, and back pain. Most AEs in both VALOR and the OLE were mild to moderate in severity. Serious neurologic events including myelitis, chemical or aseptic meningitis, radiculitis, increased intracranial pressure and papilledema, were reported in 6.7 percent of participants receiving tofersen in VALOR and its OLE.

About Tofersen
Tofersen is an antisense drug being evaluated for the potential treatment of SOD1-ALS. Tofersen binds and degrades SOD1 mRNA to reduce synthesis of SOD1 protein production. In addition to the ongoing open label extension of VALOR, 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 Pharmaceuticals, Inc. under a collaborative development and license agreement.

About Amyotrophic Lateral Sclerosis and SOD1-ALS
Amyotrophic lateral sclerosis (ALS) is a rare, progressive and fatal neurodegenerative disease that results in the loss of motor neurons in the brain and the spinal cord that are responsible for controlling voluntary muscle movement. People with ALS experience muscle weakness and atrophy, causing them to lose independence as they steadily lose the ability to move, speak, eat, and eventually breathe. Average life expectancy for people with ALS is three to five years from time of symptom onset.1

Multiple genes have been implicated in ALS. Genetic testing helps determine if a person’s ALS is associated with a genetic mutation, even in individuals without a family history of the disease. Currently, there are no genetically targeted treatment options for ALS. Mutations in the SOD1 gene are responsible for approximately 2 percent of the estimated 168,000 people who have ALS globally (SOD1-ALS).2 Life expectancy in SOD1-ALS varies widely with some patients surviving less than a year.3

Biogen’s Continuous Commitment to ALS
For over a decade, Biogen has been committed to advancing ALS research to provide a deeper understanding of all forms of the disease. The company has continued to invest in and pioneer research despite making the difficult decision to discontinue a late-stage ALS asset in 2013. Biogen has applied important learnings to its portfolio of assets for genetic and other forms of ALS, with the goal of increasing the probability of bringing a potential therapy to patients in need. These applied learnings include evaluating genetically validated targets in defined patient populations, pursuing the most appropriate modality for each target and employing sensitive clinical endpoints. Today, the company has a pipeline of investigational drugs being evaluated in ALS, including tofersen and BIIB105.

References:

  1. Brown RH, Al-Chalabi A. Amyotrophic Lateral Sclerosis. N Engl J Med. 2017 Jul 13.
  2. Brown CA, Lally C, Kupelian V, Flanders WD. Estimated Prevalence and Incidence of Amyotrophic Lateral Sclerosis and SOD1 and C9orf72 Genetic Variants. Neuroepidemiology. 2021.
  3. Brown CA, Lally C, Kupelian V, Flanders WD. Estimated Prevalence and Incidence of Amyotrophic Lateral Sclerosis and SOD1 and C9orf72 Genetic Variants. Neuroepidemiology. 2021.

 

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