Biogen announces topline results from the tofersen phase III VALOR study and its open-label extension in SOD1-ALS study.

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.

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 III, 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 III 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.

Results from VALOR and the OLE are being presented at the ANA Annual Meeting.