New Drug a 'Ground-Breaking' Advance in Huntington's Disease

Megan Brooks

December 11, 2017

In the first human trial, an experimental antisense drug (Ionis-HTTRx, Ionis Pharmaceuticals) successfully lowered the level of mutant huntingtin protein (mHTT) in spinal fluid of patients with Huntington's disease, researchers reported today.

"The results of this trial are of ground-breaking importance for Huntington's disease patients and families. For the first time a drug has lowered the level of the toxic disease-causing protein in the nervous system, and the drug was safe and well-tolerated," Sarah Tabrizi, MD, PhD, director of the University College London Huntington's Disease Centre and global chief investigator of the phase 1/2a study of the drug, said in a statement issued by the university. 

"The key now is to move quickly to a larger trial to test whether the drug slows disease progression," said Dr Tabrizi.

"This is very big news for the HD [Huntington's disease] community," George Yohrling, PhD, senior director, mission and scientific affairs for the Huntington's Disease Society of America (HDSA), told Medscape Medical News.

The trial enrolled 46 patients with early Huntington's disease at nine study centers in the United Kingdom, Germany, and Canada. Each patient received four doses of Ionis-HTTRx or placebo, given by injection into the spinal fluid. According to the ascending-dose trial design, the dose of Ionis-HTTRx was increased several times during the trial.

Treatment with Ionis-HTTRx led to significant, dose-dependent reductions in mHTT — the first time the protein known to cause Huntington's disease has been lowered in the nervous system of patients.

The drug was safe and well tolerated, as judged by an independent safety committee, which "supports continued development," Ionis said in a news release. An open-label extension study for patients who completed the phase 1/2a study is underway.

"Historic Moment"

"We are encouraged by the performance of Ionis-HTTRx in the Phase 1/2a clinical study. The dose-dependent reductions of mHTT we observed in the study substantially exceeded our expectations and we were equally encouraged by the safety profile of the drug," C. Frank Bennett, PhD, senior vice president of research at Ionis Pharmaceuticals said in the release.

"The fact that levels of mutant huntingtin were reduced in correlation to the dose of Ionis-HTTRx that was given is significant, and the fact that participants in this first Phase 1/2a study are able to continue on the drug through open label extension gives us optimism regarding its safety," HDSA President and CEO Louise Vetter said in a statement.

"Ionis' announcement of the completion of the Phase 1/2a study of IONIS-HTTRx is a historic moment in the fight against HD as it represents the successful completion of the first trial to treat the underlying cause of Huntington's disease, the genetic mutation itself," said Vetter.

David Russell, MD, PhD, from the Institute for Neurodegenerative Disorders in New Haven, Connecticut, is equally excited about the study results.

 "This trial builds on concepts from trials for a number of other neurodegenerative diseases to directly target the known 'bad player' proteins in those diseases," he told Medscape Medical News.

 For HD, "now we are seeing some evidence for being able to directly target the mutant Huntingtin (mHTT) allele. This is a direct and intuitive approach to a genetic disease that is all the more exciting in light of the long string of failed trials based on less direct hypotheses of mHTT toxicity mechanisms," said Dr Russell.

 "So, in short," said Dr Russell, "I find the UCL and Ionis' announcement exciting and hopeful, and it appeals to my view that direct approaches that make intuitive sense always have the greater chance of success. HD is a terrible disease, but genetic tools such as this are powerful weapons against genetic diseases, so I am very hopeful that meaningful therapy against HD is on the near horizon."

Ionis and its development partner Roche will present results from this study at medical conferences in the first half of 2018 and plan to submit the study results for publication in a peer-reviewed medical journal.

Ionis-HTTRx is designed to reduce the production of all forms of the huntingtin (HTT) protein, which in its mutated variant is responsible for Huntington's disease. "As such, Ionis-HTTRx offers a unique approach to treat all patients with Huntington's disease, irrespective of their individual HTT mutation," Ionis notes in the release.

Ionis-HTTRx has been granted orphan drug designation by the US Food and Drug Administration and by the European Medicines Agency.

Roche has exercised its option to license Ionis-HTTRx and will assume responsibility for further development, regulatory activities, and commercialization activities for the drug.

Huntington's disease is a rare, genetic, progressive neurodegenerative disease resulting in deterioration in mental abilities and physical control. In the United States, roughly 30,000 individuals have symptomatic Huntington's disease and more than 200,000 people are at risk for inherited Huntington's disease.

The study was sponsored by Ionis Pharmaceuticals, with additional support from the National Institute for Health Research University College London Hospitals Biomedical Research Center.

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