Tofersen has EC marketing approval

Biogen Inc. (Nasdaq: BIIB) announced that the European Commission (EC) has granted marketing authorization in exceptional circumstances for tofersen for the treatment of adults with amyotrophic lateral sclerosis (ALS) associated with a mutation in the superoxide dismutase 1(SOD1-ALS) gene, while maintaining orphan drug status for the therapy. Tofersen is the first therapy approved in the European Union to target the genetic cause of ALS, which is also known as motor neuron disease (MND).

"The European Commission's approval of tofersen is a testament to the unwavering dedication of the ALS community - people living with the disease and their loved ones, researchers, clinicians and advocates - who have worked together over the past two decades to bring this important new therapy to the community of ALS patients with mutations in the SOD1gene," - said Dr. Stephanie Fradette, head of Neuromuscular Development at Biogen. "We are working with the medical community and local authorities to make the treatment available as soon as possible to people in the region living with amyotrophic lateral sclerosis (ALS) with a mutation in the SOD1 gene."

The marketing authorization for tofersen has been granted under an approval procedure in exceptional circumstances. The use of such a procedure is recommended when the benefit-risk assessment of a treatment is determined to be favorable, but due to the rarity of the disease it is unlikely that comprehensive data can be obtained under normal conditions of use. The European Medicines Agency (EMA) has recommended maintaining orphan drug status for tofersen for the treatment of amyotrophic lateral sclerosis (ALS).

"The approval of tofersen represents a paradigm shift in the treatment of ALS with a mutation in the SOD1 gene, giving hope to patients and their loved ones who have long been waiting for a breakthrough," said Dr. Philip Van Damme, professor of neurology and director of the Reference Center for Neuromuscular Diseases at Leuven University Hospital in Belgium. "The European Academy of Neurology has confirmed new guidelines for the treatment of ALS, which say that tofersen should be used as a first-line drug in ALS patients with mutations in the SOD1gene."

The approval of tofersen is based on the totality of the evidence, including the targeted mechanism of action, biomarkers and clinical data. In the randomized, double-blind, placebo-controlled Phase 3 VALOR study (n=108), patients were randomized in a 2:1 ratio to treatment with tofersen 100 mg (n=72) or placebo (n=36) for 24 weeks. The primary efficacy endpoint was the change in ALS Functional Ratings Scale-Revised total score from baseline to week 28. Numerically, the results of the study were clearly in favor of tofersen, but were not statistically significant (ITT population: adjusted mean tofersen-placebo difference [95 percent CI]: 1,4 [-1,3, 4,1]). At week 28, mean plasma levels of neurofilament light chain (NfL), a marker of axonal damage and neurodegeneration, decreased by 55 percent (geometric mean from baseline) in tofersen-treated (ITT) participants, compared to a 12 percent increase for the placebo group (difference in geometric means for tofersen and placebo): 60 percent (95 percent CI: 51 percent, 67 percent)). Very common side effects (possibly affecting more than 1 in 10 people) reported in participants treated with tofersen were pain (back pain, arm or leg pain), fatigue, muscle and joint pain, fever, and an increase in protein levels and/or the number of white blood cells found in the fluid surrounding the brain and spinal cord.

"We at EUpALS are excited that ALS patients with the SOD1 mutation in Europe will have access to tofersen, the first drug to target the genetic cause of ALS. This is a milestone for the ALS community, demonstrating that amyotrophic lateral sclerosis is a disease that can be treated." - said Evy Reviers, president of the European Organization for Professionals and People living with ALS (EUpALS). "As a representative of the European community, I am very pleased to enter a new phase in the common fight against ALS. We thank Biogen for the many years of pioneering scientific and clinical efforts that have led to this medical success."

Biogen is committed to working closely with all stakeholders to make this treatment available to eligible patients in Europe. Through Biogen's early access program, some 330 ALS patients with the SOD1 mutation have received treatment in 18 European Union countries. Tofersen is also approved for use in the United States, and Biogen is working with regulators in other regions of the world.

What is tofersen?

Tofersen is an antisense oligonucleotide (ASO) designed to bind to the mRNA of the SOD1 gene to reduce the production of SOD1 protein. The U.S. Food and Drug Administration (FDA) has approved tofersen in an accelerated regimen for the treatment of amyotrophic lateral sclerosis (ALS) in adults who have a mutation in the superoxide dismutase 1(SOD1) gene. This indication was approved under fast-track registration based on the reduction in plasma neurofilament light chain levels observed in patients treated with tofersen. Further approval steps for this indication may depend on verification of clinical benefit in confirmatory studies.2 The European Commission granted marketing authorization under exceptional circumstances and orphan drug status for tofersen.

Biogen has repurchased the license for tofersen from Ionis Pharmaceuticals under a cooperative development and licensing agreement. Tofersen was discovered by Ionis.

In addition to the ongoing open-label (OLE) phase 3 VALOR trial, tofersen is being studied in the randomized, placebo-controlled phase 3 ATLAS trial to evaluate whether tofersen can delay the onset of clinical symptoms in presymptomatic patients with mutations in the SOD1 gene and biomarkers indicative of disease activity (elevated plasma NfL levels). More details on the ATLAS trial (NCT04856982) can be found at clinicaltrials.gov.

About amyotrophic lateral sclerosis (ALS) and SOD1-ALS

Amyotrophic lateral sclerosis (ALS) is a rare, progressive and fatal neurodegenerative disease that causes the loss of motor neurons in the brain and spinal cord that are responsible for controlling voluntary muscle movements. People with ALS experience muscle weakness and atrophy, causing them to lose their independence as they gradually lose the ability to move, speak, eat and eventually breathe. The average life expectancy for people with ALS is three to five years after the onset of symptoms.3

Many genes are associated with ALS. Genetic testing helps determine whether a person's ALS is associated with a genetic mutation, even if there are no known cases of the disease in their family. Mutations in the SOD1 gene are responsible for about 2 percent of the approximately 168,000 people who have ALS worldwide(SOD1-ALS). 1 More than 15 percent of people with ALS have the genetic form of the disease;4 even though there may not have been a family history of the disease, however. 1

In ALS patients with a mutation in the SOD1 gene, the body produces a toxic, abnormally folded form of the SOD1 protein. The toxic protein causes degeneration of motor neurons, leading to progressive muscle weakness, loss of function and eventually death.

Biogen's continued commitment to fight ALS

For more than a decade, Biogen has been committed to advancing ALS research to provide a deeper understanding of all forms of the disease. Biogen continues to make pioneering investments in research, despite the difficult decision to discontinue late-stage ALS drug development in 2013. Biogen has implemented important lessons from the effort into its portfolio of assets to treat genetic and other forms of ALS in order to increase the likelihood of bringing a potential therapy to patients who need it. These include genetic evaluations to confirm the therapeutic target in specific patient populations, the search for the most appropriate treatments for each target and the use of sensitive clinical endpoints. In addition to tofersen, the company has a number of drugs under investigation, including an effort to target therapies for proteinopathy associated with the TDP43 protein, dedicated to a broad population of ALS patients. TDP43 protein dysfunction affects 97 percent of ALS patients and is considered a symptom of amyotrophic lateral sclerosis.

Biogen's Safe Harbor declaration

This press release contains forward-looking statements regarding the potential clinical effects of tofersen; the potential benefits, safety and efficacy of tofersen; tofersen's clinical development program; the identification and treatment of ALS; our research and development program for the treatment of ALS; the potential of our commercial activities and therapeutic programs under development, including tofersen; and the risks and uncertainties associated with the development and commercialization of therapies. Forward-looking statements may be accompanied by words such as "aim," "anticipate," "believe," "may," "estimate," "expect," "forecast," "intend," "may," "plan," "potential," "possible," "will," "would" and other words and terms with similar meanings. The process of drug development and commercialization involves a high degree of risk - only a small number of studies and drug development programs result in the commercial launch of a product. The results from the early stages of a clinical trial may not completely overlap with the full results or the results from later stages or other studies of a broader scope - such results are insufficient to obtain marketing authorization for a drug. Do not place undue reliance on our forward-looking statements.

These statements involve risks and uncertainties that could cause actual results to differ materially from those reflected in such statements, including, but not limited to, with the uncertainty of success in the development and potential commercialization of tofersen; with the risk that we may not recruit an adequate number of patients to our clinical trials or that recruitment will take longer than anticipated; with unexpected uncertainties that may arise from additional data, analyses or results obtained during our clinical trials; with the fact that regulatory authorities may require additional information or further studies, or may not approve or refuse to approve our proposed drugs, including tofersen; with the occurrence of adverse safety events; the risk of other unexpected obstacles, costs or delays; the failure to protect and enforce our data, intellectual property and other proprietary rights and the uncertainty associated with intellectual property claims and challenges; product liability claims; operating results and financial condition. The above are many factors, but not all, that could cause actual results to differ from our expectations in forward-looking statements. Investors should heed these warnings and the risk factors listed in our most recent annual and quarterly reports sent to the U.S. Securities and Exchange Commission. These statements apply only as of the date of this press release.

References:

1. Brown CA, Lally C, Kupelian V, Flanders WD. Estimated Prevalence and Incidence of Amyotrophic Lateral Sclerosis and SOD1 and C9orf72 Genetic Variants. Neuroepidemiology 2021;55(5), pp. 342-353. DOI: 10.1159/000516752. Epub 2021 Jul 9.
2. QALSODY Prescribing Information, Cambridge, MA: Biogen.
3. National Institute of Neurological Disorders and Stroke. Amyotrophic Lateral Sclerosis (ALS)Available at: https://www.ninds.nih.gov/health-information/disorders/amyotrophic-lateral-sclerosis-als accessed April 2024.

Akcimen F, Lopez E.R., Landers J.E., et al. Amyotrophic lateral sclerosis: translating genetic discoveries into therapies, Nat Rev Genet, 2023. https://doi.org/10.1038/s41576-023-00592-y