Tofersen Safe, Appears to Slow Disease Progression in SOD1 ALS Patients, Phase 1/2 Trial Shows

Tofersen, Biogen’s investigational therapy for people with familial amyotrophic lateral sclerosis (ALS) caused by SOD1 gene mutations, was safe and generally well-tolerated over three months, and appeared to lower SOD1 protein levels in the central nervous system, a Phase 1/2 clinical trial has found.

There also were signs that tofersen (BIIB067) slowed disease progression in patients, though the trial was not powered to test for the treatment’s efficacy. The trial’s (NCT02623699) Phase 3 portion is now underway to confirm the safety and effectiveness of tofersen in patients with SOD1-related inherited ALS. The trial is recruiting at sites in the U.S., Canada, Europe, and Japan.

The study, “Phase 1–2 Trial of Antisense Oligonucleotide Tofersen for SOD1 ALS,” was published in The New England Journal of Medicine.

Mutations in the SOD1 gene account for 12–20% of familial ALS cases, and 1–2% of sporadic ALS cases. Though the mechanisms linking SOD1 mutations to ALS are not fully understood, scientists believe the SOD1 protein becomes overly active, and that reducing this protein in the brain might help patients with these mutations.

Tofersen, initially developed by Ionis Pharmaceuticals and acquired by Biogen in 2018, is an experimental antisense oligonucleotide (ASO) designed to reduce that protein in people with ALS caused by SOD1 mutations.

The treatment is a DNA-based molecule that binds the SOD1 mRNA — a blueprint of the gene that leaves the nucleus and is read by the cell’s protein-making machinery to make SOD1 protein — blocking the production of this protein. It is administered as an injection directly into the spinal canal, also known as an intrathecal injection.

The therapy has shown promise in rat models of ALS carrying SOD1 mutations, preventing nerve cell loss and preserving the connections between motor nerve cells and muscles, and ultimately helping the animals live longer.

The therapy’s safety and efficacy is being examined in a three-part study for people with SOD1 ALS. Parts A and B both have been completed and tested  using single and multiple ascending doses of tofersen, respectively.

This report focused on data from 50 participants included in Part B, who were assigned randomly to one of four tofersen doses — 20, 40, 60, or 100 mg — or a placebo for 12 weeks. For each patient receiving placebo, three were given five intrathecal injections of the experimental agent. Participants were  followed for an additional 12 weeks after completing their treatment.

The main goal of this Phase 1/2 portion was to determine the safety of tofersen, assessed via incidence of adverse events (side effects) and changes in lab tests, vital signs, and other measures. A secondary objective was to explore whether tofersen lowered SOD1 protein levels in the cerebrospinal fluid (CSF,  the colorless liquid surrounding the brain and spinal cord).

Exploratory measures sought to address changes in clinical function (assessed via the ALS Functional Rating Scale–Revised, or ALSFRS-R score), respiratory function (measured with the percent predicted slow vital capacity), and muscle strength (as assessed by the handheld dynamometry megascore) over the 24 weeks.

During the study, all participants reported at least one adverse event. These included headaches, falls, pain, and post lumbar puncture syndrome, most of which were attributable to the spinal tap required for treatment administration.

Serious adverse events were reported in five patients on tofersen and two on placebo. Also, two patients died due to pulmonary embolism and respiratory failure during the follow-up period, and one patient on placebo died of respiratory failure caused by ALS progression during the intervention part.

As expected, tofersen reached the highest concentration in the blood and CSF in patients receiving the 100 mg dose. These patients also experienced the greatest improvements in disease markers.

In fact, while the 20 mg dose was not more effective than placebo at lowering SOD1 protein levels over the 12-week period, protein concentrations dropped 25% more with the 40 mg dose than with a placebo, 19% more with the 60 mg dose, and 33% more with the 100 mg dose. During the 12 weeks after treatment completion, however, SOD1 levels rose in all groups, suggesting that treatment must be continued to provide lasting benefits.

“In adults with ALS due to SOD1 mutations, CSF SOD1 concentrations decreased at the highest concentration of tofersen administered intrathecally over a period of 12 weeks,” the researchers wrote.

The trial was not powered to detect significant changes in clinical function, respiratory function, and in muscle strength, but evidence suggested that tofersen slowed disease progression in these patients.

Researchers compared patients receiving the 100 mg dose with those on a placebo, as these two groups had similar disease progression scores before entering the trial. Results demonstrated that patients on placebo deteriorated by an average of 5.6 points in their ALSFRS-R scores, 14.5 points in their lung function scores, and 0.26 points in the muscle function scores during the 12 weeks of treatment.

Those on tofersen, however, lost only 1.2 points on their ALSFRS-R scores, 7.1 points on lung function scores, and 0.03 points on the muscle strength scores.

A slower disease progression was notably evident in a subgroup of patients whose SOD1 mutations are associated with fast-progressing disease. As an example, these patients experienced an improvement in clinical function by 0.84 points when given tofersen, compared to a deterioration of 16.7 points for fast progressors on placebo.

Researchers also found that tofersen lowered the levels of phosphorylated neurofilament heavy chains and neurofilament light chains in the blood and CSF in all patients receiving the 100 mg dose, while none receiving a placebo experienced such decreases in disease biomarkers.

“This trial indicated that tofersen shows evidence of safety that warrants further investigation and that the dose we used lowers clinical markers of disease. There are even some signs that it slowed clinical progression of ALS, although the study was not designed to evaluate effectiveness at treating the disease, so we can’t say anything definitive,” Timothy M. Miller, MD, PhD, said in a press release. Miller is a professor of neurology at Washington University School of Medicine in St. Louis, and director of the ALS Center there.

“While this investigational drug is aimed at only a small percentage of people with ALS, the same approach — blocking the production of specific proteins at the root of the illness — may help people with other forms of the illness,” Miller said.

The third portion of this trial is ongoing to confirm the safety of tofersen and determine its superiority over a placebo at slowing disease progression. Called VALOR, the Phase 3 trial will enroll 99 participants and assign them randomly to tofersen or a placebo.

Patients will receive eight doses of the experimental treatment over the course of 24 weeks. Those who conclude the Phase 3 trial, like patients in the initial Phase 1/2 portion, then are eligible for an open-label extension study (NCT03070119) that will continue to assess the safety of this treatment in the long-term.