Biogen ALS Drug Misses Endpoint in Late-Stage Study

Biogen said that topline results from its pivotal phase 3 VALOR study of tofersen, an experimental antisense drug being evaluated for people with a rare, genetic form of amyotrophic lateral sclerosis or ALS, failed to meet the primary endpoint in the study, although there were positive secondary and exploratory measures of biologic activity and clinical function.

Photo: Alfred Sandrock, head of Research and Development at Biogen

The company said it is engaging with regulators, the medical community, patient advocacy groups, and other key stakeholders around the world to determine potential next steps.

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 2 percent of the estimated 168,000 people who have the disease globally. Currently, there are no genetically targeted treatment options for ALS.

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 under a collaborative development and license agreement.

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.

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 in adults with ALS associated with a SOD1 mutation. In total, 108 participants were randomized in VALOR. 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”).

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.  

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 percent and 26 percent in the faster- and slower-progressing populations, respectively.

On the second key secondary endpoint of change from baseline in plasma neurofilament light chain, a potential marker of neuronal degeneration, differences were observed between the tofersen and placebo groups of 67 percent and 48 percent in the faster- and slower-progressing populations, respectively. 

In the faster-progressing population, trends favored tofersen on measures of respiratory function and muscle strength. 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 in participants receiving tofersen in the VALOR study were procedural pain, headache, pain in extremity, fall and back pain. Most adverse events in both VALOR and the OLE were mild to moderate in severity.

In VALOR, serious adverse events were reported in 18.1 percent of participants receiving tofersen and 13.9 percent of those receiving placebo. In the tofersen group, 5.6 percent of participants discontinued treatment due to an adverse events. There were no discontinuations due to adverse events in the placebo group. Serious neurologic events were reported in 4.8 percent of patients receiving tofersen in VALOR and its OLE, including 2 cases of myelitis (2.0 percent). There was one death reported in the tofersen-treated group in VALOR, which was determined not to be related to tofersen.

Biogen said it 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.

“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, 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.”

Author: Rare Daily Staff