Familial amyotrophic lateral sclerosis Trials in Disease

Study of Tofersen for Adults with Presymptomatic Amyotrophic Lateral Sclerosis (ALS) Due to SOD1 Gene Mutation

This trial is investigating a treatment called tofersen for adults who carry a specific genetic change known as the SOD1 mutation but do not yet show any symptoms of amyotrophic lateral sclerosis. The SOD1 gene mutation is associated with familial ALS, a rare condition that affects nerve cells responsible for controlling voluntary muscle movement.

Main inclusion criteria:

• Participants must be adults aged 18 years or older
• They must have a confirmed SOD1 gene mutation, specifically a rapidly progressive type
• Their plasma neurofilament light chain (NfL) levels must be below a certain threshold. NfL is a protein that, when elevated in the blood, can indicate nerve cell damage
• Participants must not show any symptoms of ALS at the time of enrollment

Main exclusion criteria:

• Individuals who do not carry the SOD1 gene mutation
• Those who already show symptoms of ALS
• People who are younger than 18 years old

Focus and goal of the trial:

The study aims to evaluate whether tofersen can delay or prevent the onset of clinically manifest ALS in people who carry the SOD1 mutation. The trial has several phases. Initially, participants undergo a period where their natural health progression is observed to establish baseline measurements. These measurements include assessments of physical function using the ALS Functional Rating Scale, which evaluates respiratory function, bulbar function (related to speech and swallowing), and both fine and gross motor skills, as well as measurements of slow vital capacity and plasma NfL concentrations.

After the observation period, participants are randomly assigned to receive either tofersen or a placebo. The placebo looks like the actual treatment but does not contain the active substance, allowing researchers to compare the effects of tofersen against no active treatment. Participants are closely monitored for up to 24 months to see if they develop symptoms of ALS and to assess any changes in their health status.

Following this initial phase, there is an open-label extension where all participants have the opportunity to receive tofersen. The study includes long-term follow-up extending up to 5.6 years to assess the time until emergence of clinically manifest ALS and other important health indicators. Researchers also monitor changes in cerebrospinal fluid SOD1 concentrations and track any adverse events or serious adverse events.

Investigational drug:

Tofersen is the medication being tested in this trial. It is an antisense oligonucleotide, a type of drug designed to interfere with the genetic instructions for producing specific proteins. Tofersen works by targeting and reducing the production of the SOD1 protein, which is believed to contribute to the progression of ALS. The medication is administered through an injection into the spinal canal, a method known as intrathecal administration, where the solution is injected into the space around the spinal cord.

The study is expected to conclude by October 2027, and researchers hope the results will provide valuable insights into whether tofersen can benefit individuals at genetic risk of developing ALS due to the SOD1 mutation.