Background

ION363 is an antisense oligonucleotide designed to reduce the production of a mutated, neurotoxic form of the Fused in Sarcoma (FUS) protein. FUS mutations have been identified as a cause of familial ALS and frontotemporal lobar degeneration. ION363 is delivered by intrathecal injection.

One study has implicated FUS mutations in Alzheimer’s disease. In a study of familial AD in China, an FUS variant was associated with cases in families with no other known dementia-causing genes (Zhang et al., 2020). FUS was also identified as a gene involved in mRNA splicing errors that occur in AD brain (Oct 2018 news).

Findings

No Phase 1 or 2 trials are registered for this therapy.

In 2019, Ionis and Columbia University Medical Center sought permission from the U.S. FDA for compassionate use of ION363 in Jaci Hermstad, a 26-year-old woman with ALS caused by the P525L FUS mutation. P525L causes an aggressive and rapidly fatal form of ALS that begins in childhood or early adulthood (Conte et al., 2012), and Hermstad’s identical twin had earlier died of the disease (Nature Medicine news report). That led the U.S. House of Representatives to pass Jaci’s Bill, which allowed doctors to administer the ASO before completing toxicology testing in rodents. According to her obituary, Hermstad received 12 injections of the drug, named Jacifusen, between June 2019 and March 2020 before dying from ALS on May 1, 2020. Clinical details were later published (Korobeynikov et al., 2022). At the start of the trial, Hermstad was unable to move around on her own and needed assistance breathing. ION363 dosing started at 20 mg, and reached a maximum of 120 mg monthly, with no adverse events. Through the course of injections, her rate of decline on the ALS-Functional Rating Score slowed. At autopsy, ION363 was detected widely throughout brain and spinal cord tissue, two months after the last infusion. Normal and P525L FUS protein levels were reduced compared to normal control tissue, to nearly undetectable levels. Pathological hallmarks of P525L FUS-ALS were likewise reduced, including FUS-positive neuronal cytoplasmic inclusions, insoluble aggregates of FUS and other RNA binding proteins, and nuclear FUS localization.

As of February 2020, two more patients had received ION363 at Columbia through compassionate use protocols. In March 2020, the same investigators received funding from the ALS Association and Project ALS to treat eight more patients (ALS Association news).

In June 2021, Ionis began a Phase 3 trial called FUSION, to treat up to 77 patients worldwide. Participants are age 11 and older, have ALS caused by a confirmed pathogenic mutation in FUS, and must not be on permanent ventilation at the time of enrollment. They receive spinal injections of ION363 or placebo every twelve weeks, after a loading dose at four weeks, for 61 weeks, followed by an 85-week open-label extension. Patients who have completed this course can receive ION363 for another three years, in hopes that this second extension will bridge the time until the drug is commercially available. The primary outcome is functional change in the revised ALS-Functional Rating Scale, and time to live free of ventilation. Secondary outcomes include quality of life, lung and muscle function, survival, and changes in the CSF biomarker neurofilament light chain. Conducted at 24 sites in North America, Europe, the United Kingdom, Taiwan, and Korea, the trial is expected to run through June 2026.

For details on ION363 trials, see clinicaltrials.gov.