Ionis Pharmaceuticals, Inc. (Nasdaq: IONS) partner Biogen today announced results from the Phase 3 VALOR study and its open-label extension (OLE) of tofersen, an investigational antisense medicine being evaluated for people with superoxide dismutase 1 (SOD1) amyotrophic lateral sclerosis (ALS). The data show that earlier initiation of tofersen, compared to delayed initiation, slowed declines in clinical function, respiratory function, muscle strength and quality of life. At the time of the analysis, because the majority of participants survived without permanent ventilation (PV), the median time to death or PV could not be estimated. However, early survival data suggest a lower risk of death or PV with earlier initiation of tofersen. These results are based on new integrated data from the VALOR pivotal study and its OLE study.
The results were presented at the European Network to Cure ALS (ENCALS) meeting in Edinburgh, Scotland. An archived version of the presentation will be available on the Investors section of Biogen’s website at investors.biogen.com.
“We are very pleased with these new 12-month data, which show that tofersen slowed disease progression and lowered neurofilament levels. Together, these results offer compelling evidence of tofersen’s potential to provide meaningful clinical benefit to people living with SOD1-ALS,” said C. Frank Bennett, Ph.D., executive vice president, chief scientific officer and franchise leader for neurological programs at Ionis.
Clinical Results
As previously reported in October 2021, VALOR, a six-month Phase 3 randomized study, did not meet the primary endpoint of change from baseline to week 28 in the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R). However, trends of reduced disease progression across multiple secondary and exploratory endpoints were observed. The new 12-month data further build on the results previously observed in the initial readout.
The 12-month data compare early initiation of tofersen (at the start of VALOR) to delayed initiation of tofersen (six months later, in the OLE). Over 12 months in the overall study population, results favored earlier start tofersen on measures of:
- Clinical function as measured by ALSFRS-R (difference of 3.5 points; 95% confidence interval [CI]: 0.4, 6.7)
- Respiratory function as measured by slow vital capacity (difference of 9.2 percent-predicted; 95% CI: 1.7, 16.6)
- Muscle strength as measured by the handheld dynamometry megascore (difference of 0.28; 95% CI: 0.05, 0.52)
- Quality of life as measured by the 5-item amyotrophic lateral sclerosis assessment questionnaire (ALSAQ-5) (difference of 10.3 points; 95% CI: -17.3, -3.2)
At the time of the analysis, because the majority of participants survived without permanent ventilation (PV), the median time to death or PV and median time to death, could not be estimated. However, early survival data suggest a lower risk of death or PV (Hazard ratio [HR] 0.36; 95% CI: 0.137, 0.941) and death (HR 0.27; 95% CI: 0.084, 0.890) with earlier initiation of tofersen.
Biomarker Results
The latest 12-month results show that reductions in total SOD1 protein (a marker of target engagement) and neurofilament (a marker of axonal injury and neurodegeneration) were sustained over time.
Tofersen reduced total CSF SOD1 protein and plasma neurofilament levels in both early- and delayed-start groups as follows:
- 33 percent and 21 percent reduction in SOD1 protein, the intended target for tofersen, respectively
- 51 percent and 41 percent reduction in plasma neurofilament, a marker of neuron injury, respectively
Safety Results
The most common adverse events (AEs) in participants receiving tofersen in VALOR and the OLE study were headache, procedural pain, fall, back pain and pain in extremity. Most AEs in both VALOR and the OLE were mild to moderate in severity. Serious AEs were reported in 36.5 percent of participants who received tofersen in VALOR and/or the OLE and 17.3 percent of participants discontinued treatment due to an AE. Serious neurologic events including myelitis, radiculitis, aseptic meningitis, and papilledema, were reported in 6.7 percent of participants receiving tofersen in VALOR and its OLE. There were 14 deaths reported in tofersen-treated participants in VALOR and the OLE, all of which were determined not to be related to tofersen.
