A drug lowers Huntington’s disease protein for the first time

UCL scientists have successfully completed the first human trial of the drug that targets the cause of Huntington’s disease. After over a decade in pre-clinical development, this first human trial of huntingtin-lowering drug began in late 2015 and was led by Professor Sarah Tabrizi of UCL
Institute of Neurology and was sponsored by Ionis Pharmaceuticals.

The trial involved enrolling 46 patients with early Huntington’s disease at nine study centres in the UK, Germany and Canada. Each patient received four doses of either IONIS-HTTRx or placebo, given by injection
into the spinal fluid to enable it to reach the brain. As the phase 1/2a trial progressed, the dose of IONIS-HTTRx was increased several times according to the ascending-dose trial design. 

Patient safety was monitored throughout the study by an independent safety committee. Announcement of completion of the trial confirmed that IONIS-HTTRx was well-tolerated by the trial participants and its safety profile supported further testing in patients.

"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. The key now is to move quickly to a larger trial to test whether the drug slows disease progression," said Professor Tabrizi, Director of the UCL Huntington’s Disease Centre and IONIS-HTTRx Global Chief Investigator in a press release.

A major unknown was whether the trial would show that IONIS-HTTRx could lower the level of mutant huntingtin protein in the nervous system. Using an ultra-sensitive assay, concentrations of the protein were measured in each patient’s spinal fluid before and after treatment.

As hoped, IONIS-HTTRx produced significant, dose-dependent lowering of the level of mutant huntingtin. This is the first time the protein known to cause Huntington’s has been lowered in the nervous system of patients.

As a result of these successful outcomes, Ionis’ partner, Roche, has exercised its option to license IONIS-HTTRx and assumes responsibility for further development, regulatory activities and commercialization activities.   Meanwhile, Ionis announced in June that all patients in the completed trial would be offered a place in an open-label extension to
receive IONIS-HTTRx.

The research is supported by The National Institute for Health Research (NIHR) University College London Hospitals Biomedical Research Centre. The center is a partnership between UCL and University College London Hospitals NHS Foundation Trust funded by the NIHR to translate scientific breakthroughs into better patient treatments.