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

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Prolonged use of Tofersen can help stabilize muscle strength and control

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An investigational drug developed to treat a rare, inherited form of amyotrophic lateral sclerosis (ALS) reduced the molecular signs of the deadly, debilitating disease and curbed neurodegeneration — but after six months, the drug was not improving motor control and muscle strength. according to results of a phase 3 clinical trial led by researchers at Washington University School of Medicine in St. Louis.

However, the researchers found evidence that longer-term use of the drug may help stabilize muscle strength and control, a finding the researchers said was encouraging. The study was sponsored by the pharmaceutical company Biogen, which makes the experimental drug. The data will be published September 22 in the New England Journal of Medicine.

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

The study showed that the drug known as Tofersen reduced levels of SOD1 and also neurofilament light protein, a molecular marker of neurological damage. At the end of the placebo-controlled portion of the study, participants were offered the option of receiving Tofersen through an open-label extension that will last up to 4½ years. The establishment of the open-label extension created two groups of participants: those who had received Tofersen from the start and those who had received a placebo for six months before starting Tofersen. An interim analysis six months after the extension showed a significant difference in motor skills between the early and late starters. After a year of taking the drug, some participants showed stabilization in muscle strength and control, a remarkable finding for a disease characterized by unrelenting decline, the researchers said.

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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 regulatory submission for Tofersen for the treatment of ALS-related SOD1 mutations.

“This is an exciting and hopeful step towards finding a therapy for SOD1-related ALS,” said principal investigator Dr. Timothy M. Miller, David Clayson Professor of Neurology at Washington University and Co-Director of the School of Medicine’s ALS Center. “We see clear evidence that the drug slows down the triggering factor – a SOD1 mutation – as well as the neurodegenerative disease process. We haven’t seen any significant clinical improvement after six months, but the stabilization of function and strength over longer periods suggests that it may take time for people to heal from the damage already done. The vast majority of people living with ALS experience a relentlessly progressive downhill course, so the stabilization of function during open-label 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 diagnosis.

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

The Phase 3 study was conducted at 32 sites in 10 countries and included 108 ALS patients SOD1 mutations. Two-thirds (72) of the participants were randomly assigned to receive eight doses of Tofersen administered directly into the fluid surrounding their spinal cord over a 24-week period. The remaining 36 people received eight doses of a placebo. All participants were assessed at enrollment and at 28 weeks to measure motor skills in four domains: swallowing and speaking; Breathing; fine motor skills; and gross motor skills. They also gave samples of spinal fluid so researchers could measure levels of ALS-associated proteins.

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When the study ended, 95 of the participants continued on the open-label extension. All participants in the overtime will receive Tofersen. 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 excitement and hope for treatments that may slow or stop disease progression,” said fellow investigator 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 with SOD1-ALS by stabilizing muscle function with long-term use, which is an extremely promising development.”

Robert Bucelli, MD, PhD, Professor of Neurology at Washington University, is Co-Director of the University’s ALS Center. As Washington University site manager for the clinical study, he oversaw 10 participants.

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

Although the results of this study apply only to people with ALS caused by mutations in SOD1could they inform research that could benefit people with other forms of the disease.

“I’ve always believed that ALS was a treatable disease,” Miller said. “That’s the foundation of my entire career, the assumption that neurodegenerative diseases, including ALS, don’t have to be fatal. If you look at the later time points in this study, they show a significant slowdown in neurodegeneration in people with SOD1-AS. I think this is hopeful news for people with any form of ALS. It 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.”

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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., H. Zhu, F. Wu, I. Nestorov, D. Graham, P. Sun, M. McNeill, L. Fanning, TA Ferguson, S. Fradette and the VALOR working group. Experiment with antisense oligonucleotide Tofersen for SOD1 ALS. The New England Journal of Medicine. 22 Sept 2022. DOI: 10.1056/NEJMoa2204705

This study was supported by Biogen.

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

About the Washington University School of Medicine

WashU Medicine is a global leader in academic medicine, including biomedical research, patient care and educational programs with 2,700 faculty. The National Institutes of Health’s (NIH) research funding portfolio is the fourth-largest among medical schools in the United States, has grown 54% over the past five years, and combined with institutional investments, WashU Medicine provides well over $1 billion annually for basic research and clinical research ready innovation and education. Its faculty practice is consistently ranked in the top 5 in the country with more than 1,790 faculty physicians practicing at over 60 locations who are also the medical staff at BJC HealthCare’s Barnes-Jewish and St. Louis Children’s Hospitals. WashU Medicine has a strong history in MD/PhD education, recently providing $100 million in grants and curriculum renewals for its medical students, and hosting world-class training programs in all medical specialties, as well as physical therapy, occupational therapy, and audiology and communication sciences.

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