Experimental drug for genetic form of ALS improves molecular signs of disease – Washington University School of Medicine in St. Louis

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Prolonged use of tofersen can help stabilize muscle strength, control

Huy Mach

An experimental drug developed to treat a rare inherited form of amyotrophic lateral sclerosis (ALS) reduced the molecular signs of the fatal and paralyzing disease and curbed neurodegeneration, but at six months the drug did not improve motor control and muscle strength. according to the results of a phase 3 clinical trial conducted by researchers at Washington University School of Medicine in St. Louis.

However, the researchers found evidence that long-term use of the drug can help stabilize muscle strength and control, a finding the researchers called encouraging. The trial was sponsored by the pharmaceutical company Biogen, the manufacturer of the investigational drug. The data is published on September 22 in the New England Journal of Medicine.

Study participants carry mutations in a gene called SOD1 which create a misfolded version of a protein of the same name, which leads to ALS, also known as Lou Gehrig’s disease.

The study showed that the drug, known as tofersen, reduces SOD1 levels and also the light neurofilament protein, a molecular marker of neurological damage. At the end of the placebo-controlled part of the study, participants were offered the option to receive tofersen as part of an open-label extension that will last up to 4.5 years. The establishment of the open label extension created two groups of participants: those who had taken tofersen from the start and those who had received a placebo for six months before starting the tofersen. An interim analysis six months into the extension revealed a significant difference in motor function between early and late. After a year of taking the drug, some participants showed stabilization of muscle strength and control, a notable finding for a disease characterized by relentless decline, the researchers said.

The open label extension is ongoing and researchers continue to monitor participants’ motor function. In July, the Food and Drug Administration accepted Biogen’s new drug application for tofersen as a treatment for ALS related to SOD1 mutations.

“This is an exciting and promising step towards finding a therapy for SOD1-related ALS,” said principal investigator Timothy M. Miller, MD, PhD, David Clayson Professor of Neurology at Washington University and co-director of School of Medicine’s ALS Center. “We see strong evidence that the drug slows the trigger – a SOD1 mutation – as well as the process of neurodegenerative disease. We haven’t seen substantial clinical improvement at six months, but stabilization of function and strength over longer moments suggests it may take some time for people to heal from the damage that has already been caused. The vast majority of people living with ALS experience an inexorably progressive downhill path, so the stabilization of function during open extension is truly remarkable. “

About 20,000 people in the United States are living with ALS. The deadly disease kills the nerve cells that control walking, eating and breathing. Few people survive more than five years after being diagnosed.

About 2% of ALS cases are caused by mutations SOD1. Tofersen is an antisense oligonucleotide, a DNA-based molecule that interferes with the genetic instructions for building proteins. The molecule is designed to block the production of the SOD1 protein.

The phase 3 study was conducted at 32 sites in 10 countries and included 108 patients with ALS SOD1 mutations. Two-thirds (72) of the participants were randomly assigned to receive eight doses of tofersen over a 24-week period, administered directly into the fluid surrounding the spinal cord. The remaining 36 people received eight doses of a placebo. All participants underwent assessments at enrollment and at 28 weeks to measure motor function in four areas: swallowing and speaking; breathing; excellent motor skills; and gross motor skills. They also provided spinal fluid samples so that the researchers could measure the levels of proteins associated with ALS.

At the end of the trial, 95 of the participants continued the open label extension. All extension participants receive tofers. Neither the extension participants nor the researchers know who received tofersen or a placebo during the study.

“The data published in the NEJM gives the ALS community great enthusiasm and hope for treatments that can slow or stop the progression of the disease,” said co-researcher Merit Cudkowicz, MD, director of the Sean M. Healey & AMG Center for ALS. at Massachusetts General Hospital. “The drug has the potential to improve the quality of life of people living with SOD1-ALS by stabilizing muscle function with long-term use, which is an extremely promising development.”

Robert Bucelli, MD, PhD, a professor of neurology at Washington University, is co-director of the university’s ALS Center. As the leader of Washington University’s clinical trial site, he cared for 10 participants.

“Most of the participants at our site have regained and / or maintained some of their daily living activities, and our tests and strength measurements confirm their history of improvement, stabilization or both,” Bucelli said. “As a neuromuscular physician, the privilege of witnessing this firsthand has changed the way I think about this and other related devastating neurodegenerative disorders.”

Although the findings of this study only apply to people with ALS caused by mutations in SOD1they could inform research that it could benefit people with other forms of the disease.

“I’ve always believed that ALS is a treatable disease,” Miller said. “This is the basis of my entire career, the assumption that neurodegenerative diseases, including ALS, don’t have to be fatal. If you look at later time points in this study, they show a substantial slowing of neurodegeneration in people with SOD1-SELF. I think this is promising news for people with any form of ALS. He tells me that if we find the right therapy, we can change the course of the disease. We just have to find the right therapy. “

Miller TM, Cudkowicz ME, Genge A, Shaw PJ, Sobue G, Bucelli RC, Chio A, Van Damme P, Ludolph AC, Glass JD, Andrews JA, Babu S, Benatar M, McDermott CJ, Cochrane T, Chary S, Chew S, Zhu H, Wu F, Nestorov I, Graham D, Sun P, McNeill M, Fanning L, Ferguson TA, Fradette S and the VALOR working group. Tofersen antisense oligonucleotide test for SOD1 ALS. The New England Journal of Medicine. September 22, 2022. DOI: 10.1056 / NEJMoa2204705

This study was supported by Biogen.

Timothy Miller serves on an advisory board for Biogen. Robert Bucelli served on an advisory board and worked as a paid consultant for Biogen. Washington University has no financial interest in the tofers.

Information on the University of Washington School of Medicine

WashU Medicine is a global leader in academic medicine, including biomedical research, patient care, and educational programs with 2,700 faculty members. Its National Institutes of Health (NIH) research funding portfolio is the fourth largest among medical schools in the United States, has grown 54% over the past five years, and along with institutional investments, WashU Medicine commits beyond $ 1 billion annually in basic research and clinical innovation and education. Its faculty practice is consistently in the top five in the country, with more than 1,790 faculty physicians practicing in over 60 locations and who are also the medical staff at BJC HealthCare’s Barnes-Jewish and St. Louis Children’s hospitals. WashU Medicine has a legendary history in MD / PhD training, recently dedicated $ 100 million in scholarship and curriculum renewal for its medical students, and is home to world-class training programs in every medical subspecialty as well as therapy physics, occupational therapy and audiology and communication sciences.

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