New Biogen/Ionis Data Suggests ALS Drug Effective Upon Earlier Initiation

Biogen_John Tlumacki/The Boston Globe via Getty

John Tlumacki/The Boston Globe via Getty

Biogen and Ionis Pharmaceuticals have announced results from the Phase III VALOR trial and an open-label extension (OLE) trial of amyotrophic lateral sclerosis (ALS) hopeful tofersen. This data suggests that earlier initiation of the drug compared to delayed initiation decreased declines in clinical function, respiratory function, muscle strength and quality of life.

Because the majority of patients in the trial survived without permanent ventilation (PV), neither PV nor median time to death could be estimated. But they argue early survival data hints at a lower risk of death or PV with earlier initiation of the drug.

In October 2021, Biogen put a positive spin on the failure of the VALOR trial. Although the drug missed the primary endpoint, the company emphasized favorable trends in multiple secondary and exploratory markers. Biogen is partnered with Ionis on the drug.

At the time, many analysts and skeptics wondered if Biogen was re-visiting its strategy for the controversial Alzheimer’s drug Aduhelm (aducanumab). When that drug failed clinical trials, the company revived it after an analysis of subgroups of the studies and evidence that it cleared amyloid plaque in the brain of Alzheimer’s patients, even if the clinical improvements weren’t as convincing. Aduhelm was approved under an accelerated approval pathway that depends upon surrogate biomarkers instead of clinical improvement.

Biogen’s announcement seemed to suggest that tofersen had positive effects on superoxide dismutase 1 (SOD1) levels in SOD1 ALS, even though it failed to hit the primary endpoint.

SOD1-ALS is a rare, progressive and fatal genetic form of ALS and affects about 2% of ALS patients. ALS, also known as Lou Gehrig's disease, is a fatal, progressive neurodegenerative disease with an average survival of three to five years, typically ending in respiratory failure.

Toferson is an antisense drug that binds to SOD1 messenger RNA (mRNA), helping it degrade by RNase-H, which decreases the synthesis of SOD1 protein production.

Biogen and Ionis presented their latest findings at the European Network to Cure ALS (ENCALS) meeting held in Edinburgh, Scotland.

“We are very pleased with these new 12-month data, which show that tofersen slowed disease progression and lowered neurofilament levels,” C. Frank Bennett, Ph.D., executive vice president, chief scientific officer and franchise leader for neurological programs at Ionis said. “Together, these results offer compelling evidence of tofersen’s potential to provide meaningful clinical benefit to people living with SOD1-ALS.”

The 12-month data compared initiation of tofersen at the start of VALOR to delayed initiation of the drug six months later in the OLE part of the study. Clinical function as measured by ALSFRS-R had a difference of 3.5 points; respiratory function measured by slow vital capacity had a difference of 9.2%-predicted; muscle strength as measured by the handheld dynamometry megascore had a difference of 0.28 and quality of life as measured by the 5-item ALS assessment questionnaire (ALSAQ-5) demonstrated a difference of 10.3 points.

For biomarkers, tofersen decreased CSF SOD1 protein levels by 33% in the early-start and 21% in the delayed-start group. The drug decreased plasma neurofilament levels, a marker of neuron injury, by 51% in the early-start cohort and 41% in the delayed-start cohort.

The most common side effects were headache, procedural pain, fall, back pain and pain in the extremities. Usually, they were mild to moderate. However, 36.5% reported serious adverse events in VALOR and/or the OLE and 17.3% of participants discontinued treatment because of them. Serious neurologic events included myelitis, radiculitis, aseptic meningitis and papilledema, which were reported in 6.7% of patients receiving toferson in VALOR and its OLE. There were also 14 reported deaths in patients receiving the drug in the studies, although none have been determined to be related to the drug.

ALS is a tough nut to crack and is a serious unmet medical need. In March, Biogen and Ionis reported another of their drugs for ALS, BIIB078, failed a Phase I trial in C9orf72-associated ALS. The drug was generally well tolerated but did not meet any secondary endpoints and didn’t show any clinical benefit. They discontinued that program.

It’s not all bad news, though. Just this week, Eledon Pharmaceuticals announced positive topline data from its Phase IIa trial of tegoprubart for ALS. The drug is a humanized monoclonal antibody that inhibits CD40 Ligand (CD40L). It hit the primary endpoints of safety and tolerability. Target engagement was seen at the 4 and 8 mg/kg dosing levels using CD40L and CXCL13 biomarkers related to T cell and B cell function, respectively, and a pro-inflammatory ALS signature was identified. Again, this is promising biomarker data, but not necessarily a definitive indication of clinical benefit, although Eledon hopes it is.

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