Phase 3 trial of tofersen shows benefits in treating rare form of ALS

A phase 3 trial that evaluated the safety and efficacy of the intrathecally administered antisense oligonucleotide tofersen reduced concentrations of superoxide dismutase 1 protein in patients with ALS who had mutations in the gene.

Approximately 2% of ALS cases are associated with mutations in the gene encoding superoxide dismutase 1 (SOD1), Timothy M. Miller, MD, PhD, codirector of the ALS Center at Washington University School of Medicine in St. Louis, and colleagues wrote in the New England Journal of Medicine.

Miller and colleagues randomly assigned adults with SOD1 ALS in a 2:1 ratio to receive either eight doses of tofersen (100 mg) or placebo over a period of 24 weeks.

Primary endpoints were calculated by scores on the ALS Functional Rating Scale (ALSFRS) from baseline to week 28. Secondary endpoints included changes in the total concentration of SOD1 protein in cerebrospinal fluid, neurofilament light chains in plasma and in handheld dynamometry in 16 muscles.

Seventy-two patients received tofersen (39 predicted to have faster disease progression), and 36 received placebo (21 to have faster progression). In the faster progression subgroup, the change to week 28 in ALSFRS scores was –6.98 in the tofersen group and –8.14 in the placebo group — a difference of 1.2 points; 95% CI, –3.2 to 5.5).

Additionally, tofersen led to greater reductions in concentrations of SOD1 in cerebrospinal fluid and of neurofilament light chains compared with placebo.

“I see three key take home points from these data. First, tofersen clearly leads to lowering of SOD1 protein, as would be expected. Second, there is substantial lowering of neurofilament levels, which I interpret as potentially slowing the underlying disease process. And, third, there is a meaningful clinical benefit when looking at the later time points in the open label extension,” Miller said in a press release from Biogen, manufacturer of the drug.

According to the study, most common adverse events included procedural pain, headache, pain in the arms or legs, falls and back pain. The incidence of procedural pain and headache was similar between the two groups, whereas pain in the arm and legs and back pain were more common in those who received tofersen.

Seven total patients had serious neurological adverse events, including myelitis, chemical or aseptic meningitis, lumbar radiculopathy, increased intracranial pressure and papilledema.

Reference:

The New England Journal of Medicine publishes pivotal tofersen data that show benefits in rare, genetic form of ALS. https://investors.biogen.com/news-releases/news-release-details/new-england-journal-medicine-publishes-pivotal-tofersen-data. Published Sept. 21, 2022. Accessed Sept. 22, 2022.