Phase 3 Antisense Medicine Trial Examines Leading Cause of Juvenile ALS


Antisense-mediated reduction of mutant FUS protein previously showed prevention of motor neuron loss in an FUS-ALS mouse model.

C Frank Bennett, PhD

C Frank Bennett, PhD

Ionis Pharmaceuticals recently announced the initiation of its phase 3 clinical trial (NCT04768972) of ION363, its investigational antisense medicine, in patients with amyotrophic lateral sclerosis (ALS) with mutations in the fused in sarcoma gene (FUS).1

Patients with a mutation in the FUS gene develop a rare form of ALS called FUS-ALS, which is the most common cause of juvenile-onset ALS. The phase 3 trial of ION363 is a global, multi-center study that will enroll up to 64 patients.

The trial is split into 2 parts, the first consisting of patients who will be randomized to receive a multi-dose regimen of ION363 or placebo for 29 weeks. Part 2 is an open-label period that follows part 1, in which all the patients in the trial will receive the medicine for 73 weeks.

"There is an urgent need for novel treatments for all forms of ALS, a devastating disease that affects far too many patients and their families. Advancement of ION363 to a pivotal trial is the latest example of the power of Ionis' antisense technology to potentially target the root causes of neurological diseases," C Frank Bennett, PhD, chief scientific officer and franchise leader for neurological problems, Ionis, said in a statement.1

According to, the primary outcome measure will be change from day 1 to day 253 in part 1 in functional impairment. This will be measured by a joint rank analysis of the combined assessment of in-clinic Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) total score, time of rescue or discontinuation from part 1 and entering part 2 due to a deterioration in function, and Ventilation Assistance-free survival (VAFS).2

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Mutant FUS causes motor neuron degeneration through a toxic gain of function mechanism. A study published in 2016 characterized a series of transgenic FUS mouse lines that manifest progressive, mutant-dependent motor neuron degeneration preceded by early, structural and functional abnormalities at the neuromuscular junction.3

The findings from the study demonstrated that FUS-dependent motor degeneration is not due to loss of FUS function, but to the gain of toxic properties conferred by ALS mutations. Neil Shneider, MD, PhD, director, Eleanor and Lou Gehrig ALS Center, Columbia University, was the senior author on that trial, and will lead the new phase 3 study of ION363.1

Ionis began collaborating with Shneider when the company learned of his efforts to develop a treatment for Jaci Hermstad, an Iowa woman living with FUS-ALS. They then shared their research, which resulted in the experimental treatment ION363 to be specifically designed for Hermstad.

The antisense medicine is also known as Jacifusen (not an official United States Adopted Name) in honor of Hermsted. Since then, several patients with FUS-ALS have received treatment with ION363 under Shneider’s investigator-initiated study through the FDA’s expanded access pathway.

"FUS-ALS is an atypically aggressive form of the disease, involving the youngest of ALS patients. Building on our expanded access program, a controlled clinical trial is the best way to demonstrate the efficacy of ION363 and to make this therapeutic available to all patients who could potentially benefit from it,” Shneider said in a statement.

1. Ionis initiates phase 3 trial of novel antisense medicine to treat leading cause of juvenile-onset ALS. News release. April 5, 2021. Published April 8, 2021.
2. A study to evaluate the efficacy, safety, pharmacokinetics and pharmacodynamics of ION363 in amyotrophic lateral sclerosis participants with fused in sarcoma mutations. Updated April 8, 2021. Accessed April 8, 2021.
3. Sharma A, Lyashchenko AK, Lu L, et al. ALS-associated mutant FUS induces selective motor neuron degeneration through toxic gain of function. Nat Commun. Published online February 4, 2016. doi: 10.1038/ncomms10465
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