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Biogen Announces Topline Results from the Tofersen Phase 3 Study

  • In the Phase 3 VALOR study, the primary endpoint as measured by the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) did not reach statistical significance; however, signs of reduced disease progression across multiple secondary and exploratory endpoints were observed.
  • The totality of evidence from VALOR and its ongoing open-label extension showed that participants who started tofersen earlier experienced better outcomes, further suggesting a positive clinical effect.
  • Given the high unmet medical need, Biogen will expand its ongoing early access program (EAP) to the broader SOD1-ALS population

Biogen Inc. today announced topline results from its pivotal Phase 3 VALOR study of tofersen (BIIB067), an investigational antisense drug being evaluated for people with superoxide dismutase 1 (SOD1) amyotrophic lateral sclerosis (ALS). While tofersen did not meet the primary endpoint of change from baseline to week 28 in the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R), trends favoring tofersen were seen across multiple secondary and exploratory measures of biologic activity and clinical function.

In addition, a pre-specified integration of data from VALOR and its ongoing open-label extension study (OLE) reinforced these findings and showed that early tofersen initiation led to less decline across multiple measures of motor function, respiratory function, muscle strength, and quality of life in people with SOD1-ALS. Most adverse events in both VALOR and OLE were mild to moderate in severity, including procedural pain, headache, pain in extremity, fall and back pain.

Biogen is actively engaging with regulators, the medical community, patient advocacy groups and other key stakeholders around the world to determine potential next steps.

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“The results from the VALOR study are encouraging as they show reduction of SOD1 protein, reduction of neurofilament, a potential biomarker for neurodegenerative disease, and positive signals across multiple key endpoints including measures of important aspects of the daily lives of SOD1-ALS patients,” said Timothy Miller, M.D., Ph.D., principal investigator of VALOR and ALS Center Director at Washington University School of Medicine, St. Louis. “The wait for new options has been long and difficult for the ALS community, and we welcome this important research advancement in this difficult to treat disease space.”

“Data from the tofersen Phase 3 study and its open-label extension showed signs of slowing disease progression in people with SOD1-ALS, a rare, devastating disease that leads to loss of everyday functions and ultimately death,” said Alfred Sandrock, Jr., M.D., Ph.D., Head of Research and Development at Biogen. “Following discussions with investigators, bioethicists, and having listened to the voice of patient advocacy groups, we will broaden early access to tofersen to all eligible SOD1-ALS patients through our already established expanded access program. We are grateful for the courageous efforts of patients, families, advocates, and the scientific community who have contributed to this important research.”

ALS is a progressive neurodegenerative disease that is uniformly fatal with an average survival of three to five years. The most common cause of death is respiratory failure. SOD1-ALS is a rare, genetic form of ALS that accounts for approximately two percent of the estimated 168,000 people who have the disease globally. Currently, there are no genetically targeted treatment options for ALS.

In light of the critical unmet need, Biogen will expand eligibility for its ongoing early access program (EAP) to all people with SOD1-ALS, in countries where such programs are permitted by local regulations and future access may be secured. EAP programs enable patients to gain access to a medicine free of charge before the treatment is licensed commercially. If a clear path forward for tofersen is not established, or if another controlled trial is required by regulators, Biogen may revise or discontinue the EAP.

The VALOR and Open-Label Extension Studies
VALOR was a 28-week Phase 3, randomized, double-blind, placebo-controlled study to evaluate the efficacy, safety and tolerability, pharmacodynamic, and biomarker 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). Sixty of these participants met the study’s protocol-defined enrichment criteria for rapid disease progression, comprising the primary analysis population (“faster progressing”). Forty-eight participants did not meet these prognostic enrichment criteria (“slower progressing”).

The open-label extension study is an ongoing Phase 3 study for participants who completed VALOR. Of the 108 participants in VALOR, 95 enrolled in the OLE.

Topline Results
In VALOR the primary efficacy endpoint of change from baseline to week 28 in the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) total score in the primary analysis (faster-progressing) population did not reach statistical significance as measured by a joint-rank analysis (difference of 1.2; p=0.97).   

Trends favoring tofersen were seen across multiple secondary and exploratory measures of biologic activity and clinical function, including motor function, respiratory function, and quality of life. On the first key secondary endpoint of change from baseline in total CSF SOD1 protein, a marker of target engagement, differences were observed between the tofersen and placebo groups of 38% and 26% in the faster- and slower-progressing populations, respectively. On the second key secondary endpoint of change from baseline in plasma neurofilament light chain (NfL), a potential marker of neuronal degeneration, differences were observed between the tofersen and placebo groups of 67% and 48% in the faster- and slower-progressing populations, respectively.  

In the faster-progressing population, trends favored tofersen on measures of respiratory function (Slow Vital Capacity (SVC); difference of 7.9 percent-predicted) and muscle strength (Hand-held dynamometer (HHD); difference of 0.02). Similar trends were observed across multiple exploratory patient-reported outcome measures of disease severity, quality of life, and fatigue. Median time to event could not be estimated for survival analyses due to the low number of events over the 28-week period.

In addition, with longer-term follow up in the OLE, earlier tofersen initiation consistently led to a reduction in decline in measures of clinical function across the population.

The most common adverse events (AEs) in participants receiving tofersen in the VALOR study were procedural pain, headache, pain in extremity, fall and back pain. Most AEs in both VALOR and the OLE were mild to moderate in severity. In VALOR, serious AEs were reported in 18.1% of participants receiving tofersen and 13.9% of those receiving placebo. In the tofersen group, 5.6% of participants discontinued treatment due to an AE. There were no discontinuations due to AEs in the placebo group. Serious neurologic events were reported in 4.8% of patients receiving tofersen in VALOR and its OLE, including 2 cases of myelitis (2.0%). There was one death reported in the tofersen-treated group in VALOR, which was determined not to be related to tofersen.

American Neurological Association (ANA) Annual Meeting Presentation Details
Results from VALOR and the OLE are being presented at the ANA Annual Meeting.

Sunday, October 17, 2021, 4:20 p.m. ET – Results from the Phase 3 VALOR study and its open-label extension: evaluating the clinical efficacy and safety of tofersen in adults with ALS and confirmed SOD1 mutation, presented by Timothy Miller, M.D., Ph.D., principal investigator of VALOR and ALS Center Director at Washington University School of Medicine, St. Louis.

To access the presentation, please go to the Investors section of Biogen’s website at investors.biogen.com. Following the event, an archived version will be available on the website.

Biogen’s Commitment to ALS
For over a decade, Biogen has been committed to advancing ALS research to provide a deeper understanding 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 broad 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 broad pipeline of investigational drugs being evaluated in ALS.

About Tofersen
Tofersen is an antisense drug being evaluated for the potential treatment of SOD1-ALS. Tofersen binds to SOD1 mRNA, allowing for its degradation by RNase-H in an effort to reduce synthesis of SOD1 protein production. Tofersen is also being studied in the Phase 3 ATLAS study, which is designed to evaluate the ability of tofersen to 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 the Phase 3 VALOR Study (NCT02623699)
VALOR was a Phase 3, randomized, double-blind, placebo-controlled study to evaluate the efficacy, safety, tolerability and pharmacodynamic effects of tofersen 100 mg in adults with ALS and a confirmed SOD1 mutation. Subjects were randomized to receive tofersen or placebo. In total, 108 participants were randomized in VALOR (n=72 to tofersen 100 mg and n=36 to placebo). Sixty of these participants met the study’s prognostic enrichment criteria for rapid disease progression based on SOD1 mutation type and pre-randomization ALSFRS-R slope decline and comprised the primary analysis population (“faster-progressing population”). Forty-eight participants did not meet these prognostic enrichment criteria (“slower-progressing population”). 

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. Life expectancy for people with ALS is 3-5 years from time of symptom onset. Multiple genes have been implicated in ALS. Mutations in the SOD1 gene are responsible for approximately two percent of all ALS cases (SOD1-ALS). SOD1-ALS can occur in patients with or without a family history of ALS. Genetic testing may help determine if a person’s ALS is associated with a genetic mutation, even in individuals without a family history of the disease.

Source: Biogen
Date: Oct 17, 2021


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