Starting Tofersen Early Slows ALS Progression Better: Trial Data

Marta Figueiredo, PhD avatar

by Marta Figueiredo, PhD |

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Early use of Biogen’s tofersen significantly slows disability progression, as well as a decline in lung function, muscle strength, and quality of life in amyotrophic lateral sclerosis (ALS) patients with mutations in the SOD1 gene, compared with a six-month delay in starting treatment.

These benefits were accompanied by pronounced and sustained reductions in neurofilament light chain (NfL), a marker of nerve cell damage.

These are the findings of updated, one-year analyses of the VALOR Phase 3 trial (NCT02623699) and its open-label extension (OLE) study (NCT03070119), whose previous results only suggested possible trends that favored tofersen.

“The initial six-month and now 12-month results show that tofersen had an impact on important measures critical to people with SOD1-ALS,” Timothy Miller, MD, PhD, VALOR’s principal investigator, said in a press release. Miller is the co-director of the ALS Center at Washington University School of Medicine, in St. Louis.

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“These new 12-month data showed tofersen consistently slowed disease progression across endpoints and, if approved, may meaningfully change the lives of people living with SOD1-ALS,” Miller said.

“For more than a decade Biogen has pursued new medicines for ALS. These additional data further reinforce our belief in tofersen and we will continue to follow the science to change the course of this cruel and deadly disease,” Toby Ferguson, MD, PhD, the vice president and head of Biogen’s neuromuscular development unit, said.

“Biogen is engaging with [the U.S. Food and Drug Administration] and regulators around the world, the medical community and patient advocacy groups and will provide updates on next steps when appropriate,” Ferguson said.

The updated results were shared by Miller in an oral presentation, titled “Evaluating Efficacy and Safety of Tofersen in Adults with SOD1-ALS: Results from the Phase 3 VALOR Trial and Open-Label Extension,” at the 2022 European Network to Cure ALS annual meeting, held in Edinburgh, Scotland, June 1–3.

It’s estimated that up to 20% of people with familial ALS and up to 2% of those with sporadic ALS carry mutations in the SOD1 gene, which provides instructions to produce an antioxidant enzyme. These mutations lead to producing a mutant SOD1 protein that’s prone to misfolding and forming clumps, thought to interfere with various cellular processes to drive the disease.

Administered directly into the spinal canal, tofersen is an RNA-based medication designed to reduce production of the abnormal SOD1 protein.

The international, placebo-controlled VALOR Phase 1/2/3 trial tested tofersen in 178 adults with ALS associated with SOD1 mutations.

In its single- and multiple-ascending dose Phase 1/2 portion, the therapy was found to be generally safe, to significantly reduce SOD1 levels in the cerebrospinal fluid (CSF), and to be linked to a trend toward slower disease progression. The CSF is the liquid that surrounds the brain and spinal cord.

VALOR’s Phase 3 part enrolled 108 patients, who were randomly assigned to receive eight spinal canal injections of either 100 mg of tofersen (72 patients) or a placebo (36 patients) over six months. Among the participants, 60 had rapidly progressing disease, while the disease was progressing slower in the remaining 48.

After completing this part, 95 (88%) participants decided to move into the trial’s OLE study, where all are receiving the experimental therapy for up to seven years.

Top-line, six-month results showed tofersen was not significantly superior to a placebo at slowing disability progression, as assessed with the ALS Functional Rating Scale-Revised (ALSFRS-R), failing to meet its main goal.

However, tofersen-treated patients showed positive trends for some secondary measures, including lung function, muscle strength, and patient-reported disease severity, quality of life, and fatigue.

Biogen also stated that early data analyses from VALOR and its extension study (minimum follow-up of six months) suggested that those who started on tofersen earlier tended to have better long-term outcomes.

Newly presented results combined data from VALOR and OLE, with participants having at least one year of follow-up and being exposed to the therapy for about 20 months (range: 1–34 months). Analyses compared early tofersen initiation, at the start of VALOR, to treatment initiation six months later in the OLE.

Results showed that, in the patients starting tofersen in VALOR, CSF SOD1 levels were robustly and sustainably reduced as early as three months and blood NfL levels progressively dropped up to about six months, after which they remained stable through one year.

While similar SOD1 and NfL reductions were observed after patients on a placebo switched to tofersen, these were less pronounced at one year compared with those reported for patients always on tofersen (21% vs. 33% for SOD1 and 41% vs. 51% for NfL).

Initiating tofersen early was associated with a significantly slower decline in disability (ALSFRS-R), lung function, muscle strength, and patient-reported quality of life and general health, relative to delayed initiation.

As most patients were still free from permanent ventilation (PV) at the time of the analysis, the median time to death and to death or permanent ventilation could not be estimated.

However, data suggested that patients starting tofersen in the randomized part of VALOR had a lower risk of both death (by 73%) and death or PV (by 64%) compared with those initiating the therapy six months later in the OLE study.

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Tofersen was generally well tolerated, with most side effects being mild to moderate and most commonly including headache, procedural pain, fall, back pain, and pain in an extremity.

Among tofersen-exposed participants, 36.5% reported serious side effects, 6.7% experienced serious neurologic events, and 17.3% discontinued treatment due to side effects. A total of 14 patients given tofersen died, but their deaths were deemed unrelated to the therapy.

“The combination of these biomarker results and the clinical outcomes data provide additional evidence of tofersen’s potential to effectively slow the relentless progression of SOD1-ALS,” Merit Cudkowicz, MD, VALOR’s co-principal investigator, said. Cudkowicz is the chief of the neurology department and the director of MGH’s Sean M. Healey & AMG Center for ALS at Massachusetts General Hospital. She is also the co-founder of the Northeast ALS Consortium and is the Julieanne Dorn professor of neurology at Harvard Medical School.

A Phase 3 trial called ATLAS (NCT04856982) is also testing tofersen in up to 150 adults with SOD1 mutations who have not yet developed ALS but show elevated NfL levels. Participants are actively being recruited at sites in the U.S., Canada, Europe, Asia, Brazil, and Australia.

Biogen is also providing SOD1-ALS patients access to tofersen before its approval as part of its early access program in countries where such programs are allowed and access to the medication can be ensured.