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The Roche Tower in Basel, Switzerland. The pharmaceutical company yesterday pulled the plug on a late-stage trial of a drug for Huntington disease.

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Promising drug for Huntington disease fails in major trial

An experimental therapy that generated huge excitement in the Huntington disease (HD) community 3 years ago has failed in a late-stage clinical trial, dashing hopes of a treatment for the devastating and incurable neurological disease that afflicts 30,000 people in the United States and hundreds of thousands more worldwide.

The pharmaceutical company Roche announced yesterday that it had stopped giving patients doses of the antisense drug tominersen in the pivotal clinical trial on the recommendation of an independent data monitoring board.  The company said the board based its decision on the drug’s “potential benefit/risk profile for study participants.”

“This is very unfortunate news,” said Levi Garraway, Roche’s head of global product development and chief medical officer. “We know it will be especially difficult for people with Huntington’s disease to hear.” The company revealed little else beyond saying that no new safety concerns had emerged during the international trial that completed enrollment of nearly 800 patients in April 2020. Roche said it would analyze the data behind the monitoring board’s decision and present it publicly in due course.

Tominersen is an antisense oligonucleotide (ASO)—a snippet of DNA that is intended to block production of a mutant protein, huntingtin, that causes Huntington disease. The protein, produced because of an inherited genetic mutation, causes a disorder that gradually steals patients’ control of their movements and their minds. The drug was being delivered by injection into the cerebrospinal fluid bathing participants’ spinal cords and brains. 

The trial’s halt stunned its leaders, who were blinded to the data in the ongoing study. As recently as last month, the clinical investigators said they expected the trial to run its course and produce results in 2022.  The stoppage is “unexpected and understandably heart-breaking for all of us in the HD community,” says Sarah Tabrizi, the trial’s global leader and a neurologist at University College London. “We now need to analyze the data which will take many months to really dig down properly. … At the moment my focus is on looking after my patients in the trial and supporting the HD patient and family community, who are all devastated.”

Michelle Dardengo of Coquitlam, Canada, who in 2015 became the first person to receive the drug in a human trial, learned of the stoppage through a newswire service. “I’m really upset because I don’t know what is going to be happening” after years of receiving regular injections of the drug, she says. Dardengo, who believes tominersen slowed the progression of her disease, is also troubled by the lack of information on the stoppage. “We need to know why.”

Hopes for the drug escalated in 2017, after an early human trial showed dose-dependent reductions of the mutant protein in the cerebrospinal fluid. Roche found the data promising enough that it licensed the drug for $45 million from its creator, Ionis Pharmaceuticals.

Frank Bennett, who led the development of tominersen at Ionis, says he continues to believe in the company’s technology, which has led to half a dozen ASOs now in clinical trials against Alzheimer’s disease, amytrophic lateral sclerosis, Parkinson’s, and other maladies. It also led to spinraza, which received U.S. Food and Drug Administration approval in 2017 to treat children with spinal muscular atrophy. Bennett says he isn’t giving up on Huntington: “I am committed to finding a therapy for HD patients.”  

Joel Dardengo, who inherited from his mother, Michelle, the gene that causes Huntington disease, says although he’s disappointed by the trial’s abrupt termination, he has not given up hope. “There are many different trials and drugs in the works for Huntington disease. There are other places where we can have hope. We’ll just have to put our faith there.”