Experimental drug may benefit some patients with rare form of ALS

When Columbia neurologist and scientist Neil Shneider speaks to his ALS patients who volunteer for experimental therapies, he’s unwaveringly honest. “Patients always ask me, ‘What can I hope to get out of this?”‘ Shneider says. “And I always say, in most clinical trials, our hope is that we can slow the disease or maybe even halt progression.”

So it was a big surprise when some of the patients treated with an experimental drug—a therapy that emerged from Shneider’s research efforts—showed improvements.

“When testing new drugs for ALS, we do not expect to see clinical improvement,” Shneider says. “What we’ve seen in one patient is really unprecedented functional recovery. It’s surprising and deeply motivating for us, the ALS research community, but also the community of ALS patients.”

Remarkable success stories

Data from 12 patients—all treated with the novel therapy for a rare form of ALS caused by a genetic mutation in a gene called FUS—were presented in a case series published by Shneider online in The Lancet.

Though these gene mutations are responsible for only 1–2% of ALS cases, they cause some of the most aggressive forms of ALS that begin in adolescents and young adults. In patients with these mutations, toxic FUS proteins accumulate in the motor neurons that control the patient’s muscles, eventually killing the neurons.

Two of the patients in the published case series showed a remarkable response to the experimental therapy, ulefnersen (previously known as jacifusen), developed by Shneider in collaboration with Ionis Pharmaceuticals.

One young woman, who has received injections of the therapy since late 2020, recovered the ability to walk unaided and to breathe without the use of a ventilator, both previously lost to ALS. She has lived longer with this disease than any other known patient with this juvenile-onset form of FUS ALS.

The second patient, a man in his mid-30s, was asymptomatic when he began treatment, but tests of electrical activity in his muscles indicated that symptoms would likely emerge soon. In three years of continuous treatment with the experimental drug, the man has yet to develop any symptoms of FUS-ALS and the abnormal electrical activity in his muscles has improved.

Overall, after six months of treatment, patients in the series experienced up to an 83% decrease in a protein called neurofilament light, a biomarker of nerve damage.

“These responses show that if we intervene early enough and go after the right target at the right time in the course of disease, it’s possible to not only slow disease progression, but actually reverse some of the functional losses,” Shneider says. “It’s also a wonderful example of precision medicine and therapeutic development based on science and an understanding of the biology of disease.”

Though most of the other symptomatic patients in the series did not survive their aggressive disease, Shneider says “several apparently benefited from the treatment. The progression of their disease slowed, and they lived a longer life as a consequence.”

The case series also showed that the drug is safe and well tolerated, with no serious adverse events related to the drug.

Following the results from the first of these patients, a global clinical trial of the drug is now in progress.

“Now we are eagerly awaiting those results, which we hope will lead to the approval of ulefnersen,” Shneider said.

The story behind ulefnersen

The development of ulefnersen began as an effort to help a single patient and has grown into a full-scale clinical trial that could help many patients with this aggressive form of ALS.

Shneider first tested the therapy six years ago in a patient from Iowa, Jaci Hermstad, whose identical twin had died from the disease years earlier. Shneider worked with Ionis Pharmaceuticals to develop a drug, never tested in people, that might slow the progression of Jaci’s symptoms.

He had good reason to believe the drug might work. Just a few years earlier, his research in mice revealed that the FUS mutations cause cells to make proteins that are toxic to motor neurons. The results suggested that reducing levels of toxic FUS proteins could prevent or delay onset and progression of ALS.

Shneider believed the drug might be a powerful way to reduce FUS proteins. The drug belongs to an emerging and highly promising class that uses short pieces of DNA, called antisense oligonucleotides, or ASOs, to silence specific genes and halt the production of the proteins they encode.

Ulefnersen was designed to silence the FUS gene and reduce the production of toxic and normal FUS proteins. “Because we also found that mature neurons tolerate a reduction of normal FUS protein, our studies provided the rationale for treating FUS-ALS patients with this drug,” Shneider says.

In 2019, Shneider requested permission from the FDA to administer ulefnersen to Jaci through its expanded access program, sometimes called “compassionate use.”

Since then, at least 25 patients have been treated with ulefnersen (originally named jacifusen for Jaci Hermstad) around the world in expanded access programs, including the dozen patients described in The Lancet article.