Experimental ALS drug shows unprecedented recovery in some patients

Experimental ALS drug shows unprecedented recovery in some patients

When Columbia neurologist and scientist Neil Shreider speaks to his ALS patients who are coming forward for experimental therapies, he is unflinchingly honest. “Patients always ask me, ‘What can I hope to get out of this? Shreider says. And I always say in most clinical trials that we can slow the disease or maybe even stop the progression. “

So it came as a big surprise when some of the patients were treated with an experimental Drug A therapy that resulted from Shreider's research efforts.

When testing new drugs for ALS, we do not expect clinical improvement. What we have seen in one patient is a truly unprecedented functional recovery. It is surprising and deeply motivating for us, the ALS research community, but also the community of ALS patients. “

Neil Shreider, neurologist and Columbia scientist

Remarkable success stories

Data from 12 patients treated with the novel therapy for a rare form of ALS caused by a genetic mutation in a geneFuss-were presented in a case series published online by Shreiderthe Lancet.

Although these gene mutations account for only 1% to 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, controlling the patient's muscles and eventually killing the neurons.

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

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

The second patient, a man in his mid-30s, was asymptomatic when treatment began, but tests of electrical activity in his muscles showed symptoms were likely to appear 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, patients in the series experienced up to 83% decreases in a protein called neurofilament light, a biomarker of nerve damage, after six months of treatment.

“These answers show that if we intervene early enough and pursue the right target at the right time, it is possible to not only slow the progression of the disease but also reverse some of the functional losses,” says Shreider. “It is also a wonderful example of precision medicine and therapeutic development based on science and an understanding of the biology of the disease.”

Although most of the other symptomatic patients in the series did not survive their aggressive disease, Shineider said, "Some appeared to benefit from the treatment. The progression of their disease slowed and they lived longer lives as a result."

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

After seeing results from the first of these patients, Ionis Pharmaceuticals committed to sponsoring a global clinical trial of the drug, led by Shreider and now underway.

“Now we eagerly await these results, which we hope will lead to the approval of Ulefnersen,” Shreider said.

The story behind Ulefnersen

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

Shreider first tested the therapy six years ago on an Iowa patient, Jaci Hermstad, whose identical twin had died of the disease years before. Shreider worked with Ionis Pharmaceuticals to develop a drug, never tested in humans, that could 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 showed that the FUS mutations cause cells to produce proteins that are toxic to motor neurons. The results suggest that reducing levels of toxic FUS proteins may prevent or delay the onset and progression of ALS.

Shreider believed the drug could be a powerful way to reduce FUS proteins. The drug is part of an emerging and highly promising class that uses short pieces of DNA called antisense oligonucleotides, or ASOS, to silence specific genes and stop production of the proteins they encode.

Ulefnersen is 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 in normal FUS protein, our studies provided the rationale for treating FUS-ALS patients with this drug,” says Shreider.

In 2019, Shreider asked the FDA for permission to administer Ulefnersen Jaci through the expanded access program, sometimes called “compassionate use.”

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

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