ALS: Treatment for One Opens Door for Others

What started as a one-time request to use an experimental therapy for a young woman with ALS has evolved into a multicenter clinical trial led by Neil Shneider, MD, PhD, director of the Eleanor and Lou Gehrig ALS Center and the Claire Tow Associate Professor of Motor Neuron Disorders in the Department of Neurology at VP&S.

The trial involves jacifusen, an investigational therapy designed specifically for ALS patients with mutations in a gene called FUS. Such gene mutations cause some of the most aggressive forms of ALS, including a type that begins in adolescents and young adults.

Jacifusen is named for Jaci Hermstad, a 26-year-old Iowa woman who spurred its rapid development after she was diagnosed with FUS-ALS in February 2019. Dr. Shneider met Jaci, whose identical twin had died from the disease years earlier, at a Project ALS support group before she began showing symptoms. When he learned of Jaci’s diagnosis, Dr. Shneider thought a compound never before tested in people might slow the progression of Jaci’s symptoms.

Dr. Shneider had good reason to believe the compound—an antisense oligonucleotide (ASO)—might work because the short, synthetic, single-stranded pieces of DNA can stop the production of a specific protein by binding to the protein’s messenger RNA. And just a few years earlier, Dr. Shneider found that in mice carrying FUS mutations, mutant FUS is toxic to motor neurons in a way that suggests that reducing levels of the toxic protein would prevent or delay onset and progression of ALS.

“Because we also found that mature neurons could tolerate a reduction of normal FUS protein, these studies provided the rationale for a strategy to treat ALS patients with FUS mutations by lowering the levels of FUS—both toxic and normal versions—in the central nervous system,” says Dr. Shneider.

Ionis Pharmaceuticals had created an ASO that reduces all FUS proteins, but it had never been tested in humans. Dr. Shneider requested permission from the FDA to administer the ASO to Jaci through its expanded access program, sometimes called “compassionate use.”

In record time, additional preclinical studies requested by the FDA were completed, and Jaci received her first dose of the ASO named jacifusen in June 2019.

By February of this year, Dr. Shneider had received permission to administer the drug to several other ALS patients with FUS mutations; funding was provided by the ALS Association and Project ALS.

Jaci died May 1, 2020, but Dr. Shneider saw encouraging signs that the drug was doing what it was designed to do.

As word of jacifusen spread, more patients reached out to Dr. Shneider, and he requested additional permission from the FDA to treat more patients. The FDA initially rejected the request but created an opening for Dr. Shneider to begin a multicenter clinical trial instead. Building on Dr. Shneider’s expanded access program, Ionis Pharmaceuticals has committed to sponsor a global early phase clinical trial of jacifusen and is working with the ALS Center team at Columbia to design this study.

“The FDA provided a regulatory path to continue our investigation of this promising, experimental therapeutic. They made the targets very clear, and that was very motivating to Ionis,” says Dr. Shneider, “and with the resources that Ionis is able to commit to this study, we will be able to determine whether we are having an impact on the lives of patients with ALS caused by mutant FUS.”

The opening of the trial will allow patients to receive jacifusen at other centers around the world while investigators collect the data needed to determine if jacifusen can slow the disease. “This began as an effort to help a single patient and has grown into a full scale clinical trial that could help many patients like Jaci,” says Dr. Shneider. “It’s a wonderful example of precision medicine and of therapeutic development based on an understanding of the biology of disease.”

The Eleanor and Lou Gehrig ALS Center can be reached at 212-305-6788.