Tofersen Early Access Program Now Open to SOD1-ALS Patients

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by Marta Figueiredo PhD |

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The first part of Biogen’s early access program for tofersen is now open to patients with the most rapidly progressing cases of familial amyotrophic lateral sclerosis (ALS), the company announced.

These patients, with familial ALS caused by mutations in the SOD1 gene, will be the first to receive the experimental therapy, which aims to slow disease progression.

The program’s first part is meant for people with very rapidly progressing SOD1-associated familial ALS — defined as a monthly decline of two or more points in the ALS Functional Rating Scale-Revised (ALSFRS-R), a measure of disability.

To gain access to the Biogen therapy for eligible patients, physicians must submit individual requests to [email protected]. Each patient’s eligibility will be confirmed by a third-party organization.

Tofersen — designed to suppress the production of SOD1, the molecule that accumulates to toxic levels in SOD1-associated ALS patients — is expected to be available as early as mid-July to patients who complete the eligibility process. The therapy is administered directly into the spinal canal.

Notably, the initiation of this program marks the completion of the six-month randomized part of VALOR, the Phase 3 portion of a pivotal global trial (NCT02623699) evaluating Tofersen’s safety, tolerability, and pharmacokinetics, or the movement of the therapy within the body. That phase involved the switch of patients originally assigned to receive a placebo to be given the experimental therapy.

In an April announcement, Biogen said it considered this to be the minimum prerequisite to fairly offer the therapy to patients outside the trial. Initially, the biotechnology company had rejected the possibility of early access until VALOR’s final data were analyzed and the therapy deemed safe and effective.

Biogen changed its position due to the many requests of patients with rapidly progressing SOD-1-associated ALS to gain early access to the promising therapy.

One such request came from Lisa Stockman-Mauriello, a wife and mother of three sons, who has one of the most rapidly progressing forms of SOD1-associated ALS. A pharmaceutical healthcare communications professional, she launched an online petition asking the company to provide her access to tofersen.

That petition was signed by more than 100,000 people.

While Stockman-Mauriello likely is eligible for the current early access program, it might just come too late.

“She has progressed dramatically over the five months that I have known her,” Neil Shneider, MD, PhD, Stockman-Mauriello’s physician and a co-investigator on the VALOR trial, said in a press release. “I think that her chances of benefiting from this are very small, even if she does get it.”

Bob Mauriello, Stockman-Mauriello’s husband of 25 years, isn’t convinced his wife will be accepted into the early access program at this point.

“I even worry that they might say ‘she doesn’t have enough functionality for it to be worth giving it to her, we don’t think it’s going to help her,’ so they might even just deny her for one reason or another, which would be one final kick in the family jewels,” Mauriello said.

VALOR — an international, placebo-controlled, pivotal Phase 1/2/3 trial — is testing tofersen in 178 adults with ALS who have SOD1 mutations.

Previous data from the Phase 1/2 portion showed that the therapy was generally safe and significantly dropped SOD1 levels in the cerebrospinal fluid (CSF), the liquid that surrounds the brain and spinal cord.

Notably, the therapy also appeared to be associated with slower disease progression, as assessed with the ALSFRS-R, but that portion of the trial was not powered to determine treatment effectiveness.

Now, the trial is evaluating both the safety and effectiveness of tofersen in 99 patients who were randomly assigned to receive eight spinal canal injections of either tofersen or a placebo over six months.

Its main goal is to assess whether the experimental therapy is superior to the placebo at slowing disease progression, using the ALSFRS-R as its measure. Secondary goals include changes in patients’ lung function and muscle strength, time to needing ventilatory support, survival, and the levels of CSF biomarkers.

VALOR is expected to finish by the end of August and final data are anticipated by this fall.

“There’s something of a proof of concept going on here,” Shneider said. He noted that if VALOR does prove that suppressing the production of a known toxic protein “has a positive effect on the disease course,” the results may be meaningful not only for other forms of familial ALS, but also sporadic ALS.

If the results demonstrate that tofersen is a safe and effective treatment for SOD1-ALS, and if no further trials are required, Biogen will open the second part of its early access program. That second phase will include all patients with ALS caused by SOD1 mutations.

It is expected to start in the fall, before the company files regulatory applications seeking tofersen’s approval.

Both parts of this access program, which will be run by the Clinigen Group, will be available only in countries where this type of program is allowed and where Biogen can ensure future access to the therapy.

Biogen also is evaluating tofersen in the ongoing ATLAS Phase 3 trial (NCT04856982). That study is evaluating whether giving tofersen to adults who do not yet show symptoms, but who carry SOD1 mutations linked to rapid ALS progression, can delay or even prevent disease onset.

Also an international, placebo-controlled trial, ATLAS seels to enroll up to 150 participants worldwide. Recruitment has started at two U.S. sites, both in Florida, with about 28 more locations expected to open. Information on contacts and locations can be found here.

Scientists are hoping the trial also may help researchers in understanding what triggers ALS in people who live with the disease-causing mutation for most of their lives without any signs or symptoms. That’s exactly what happened with Stockman-Mauriello.

“For the first 50-plus years of her life before she developed symptoms of ALS, she carried this gene mutation, but didn’t have ALS,” Shneider said.

“Something happened after her 50th birthday and she developed the disease,” he said. “The question is, what is the trigger? What initiates the process that leads to symptom development?”

That’s one of the things Biogen is trying to figure out, and something Stockman-Mauriello’s family would like to know.

“I do hope that tofersen and other things work, so even if it doesn’t benefit Lisa, it could benefit our kids,” Bob Mauriello said, referring to the couple’s three sons. “Or even if somehow none of them end up getting it, then obviously the other people who have [SOD1-ALS].”