Biogen Declines Early Access to Tofersen Until Pivotal Trial Ends

Biogen will not offer early access to tofersen, its experimental therapy for familial amyotrophic lateral sclerosis (ALS) caused by mutations in the SOD1 gene, at least until data from its pivotal clinical trial are analyzed.

Now in its Phase 3 portion, the study (NCT02623699) is testing the therapy against a placebo in ALS patients carrying SOD1 mutations and is expected to finish by the end of August.

The announcement came as a response to a recent online petition, signed by more than 98,000 people, asking the company to provide the therapy to Lisa Stockman-Mauriello — a woman with fast progressing, SOD1-associated ALS — under early access or compassionate use.

In her petition, Stockman-Mauriello says she is “losing function every week” and that her physician, who is one of the trial’s investigators, has never seen such fast progression in ALS. “Getting access now can preserve my life,” she wrote.

These access programs are intended to make investigational therapies available outside clinical trials to people with serious or life-threatening conditions who have few or no adequate treatments, and when the therapy’s potential benefit are thought outweighs its potential risks.

In the announcement, Alfred Sandrock, MD, PhD, the executive vice president of Biogen’s R&D, wrote that Biogen has had “a difficult and often disappointingly unsuccessful path” in ALS, with investigational therapies showing early promise, but failing or posing “unjustified risks” to patients in later trials.

“This is why even when a [therapy] shows early promise, it is essential to conduct confirmatory studies,” he stated.

Those patients enrolled in the current trial did so fully “acknowledging the risk that they may not receive tofersen, and with hope that tofersen could be shown to work and be approved for all patients,” he added.

Sandrock emphasized that it would not be fair to keep these people on a placebo, while offering the therapy to those outside the study.

“Providing individual access to tofersen at this time could jeopardize access to tofersen for hundreds of SOD1-ALS patients by impeding our ability to complete the study and seek subsequent regulatory approvals,” the company also stated on its access programs page, in an update addressing tofersen.

“Decisions such as these are among the most difficult and challenging we face as a company,” Sandrock wrote, adding that Biogen’s “collective conclusion is that early access to tofersen should only be provided after study participants are no longer [on a] placebo.”

Final trial data is expected by year’s end. If the results highlight a favorable benefit-risk profile for tofersen and no further controlled studies are needed, Biogen will “immediately open an Early Access Program for individuals with SOD1-ALS,” Sandrock wrote.

Initially developed by Ionis Pharmaceuticals and later acquired by Biogen, tofersen is designed to suppress the production of SOD1, a protein thought to drive ALS in people with mutations in its coding gene, SOD1.

These mutations are thought to affect the proper folding of the protein, leading to its toxic buildup. As such, by reducing SOD1 production, tofersen is expected to slow disease progression in this patient group. The therapy is administered directly into the spinal canal.

The international, placebo-controlled Phase 1/2/3 trial is testing the therapy in 178 adults with ALS and SOD1 mutations.

Single and multiple increasing doses of the therapy were previously examined in its Phase 1/2 part, which showed that tofersen was generally well-tolerated and that it significantly reduced SOD1 protein levels in the cerebrospinal fluid (CSF), the liquid that surrounds the brain and spinal cord.

There were also signs that tofersen slowed disease progression — as assessed with the ALS Functional Rating Scale (ALSFRS-R) — but that portion of the trial was not powered to test for treatment efficacy.

The safety and effectiveness of tofersen’s optimal dose, determined in the trial’s Phase 1/2 part, are now being evaluated in its Phase 3 portion, called VALOR. Here, a total of 99 patients are receiving eight spinal canal injections of either tofersen or a placebo over the course of 24 weeks (about six months).

Its main goal is to assess changes in disease progression — measured with ALSFRS-R — while secondary goals include changes in lung function and muscle strength, time to needing ventilatory support, survival, and the levels of CSF biomarkers.

Participants completing any of the trial’s phases have the option of entering an open-label extension study (NCT03070119), in which all will be treated for up to five years.