The first human drug trial targeting the cause of Huntington’s disease was safe, well-tolerated and successfully lowered the level of the harmful huntingtin protein in the nervous system, report University College London scientists. Professor John Hardy, Breakthrough Prize winner for his work on Alzheimer’s and not involved in the study, said: “This is, potentially, the biggest breakthrough in neuro-degenerative disease in the past 50 years.”
After over a decade in pre-clinical development, this first human trial of huntingtin-lowering drug began in late 2015, led by Professor Sarah Tabrizi (UCL Institute of Neurology) and 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. The announcement at completion of the trial confirms that IONIS-HTTRx was well-tolerated by the trial participants and its safety profile supports further testing in patients.
Professor Tabrizi, Director of the UCL Huntington’s Disease Centre and IONIS-HTTRx global chief investigator, said: “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.”
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 – 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 commercialisation 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 results of the trial and plans for the ongoing IONIS-HTTRx programme will be presented in detail at forthcoming scientific meetings and prepared for peer-reviewed publication.
The research is supported by The National Institute for Health Research (NIHR), University College London Hospitals Biomedical Research Centre. The centre 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.
Doctors are not calling this a cure. BBC News reports that they still need vital long-term data to show whether lowering levels of huntingtin will change the course of the disease. The animal research suggests it would. Some motor function even recovered in those experiments.
Professor John Hardy, who was awarded the Breakthrough Prize for his work on Alzheimer’s, is quoted in the report as saying: “I really think this is, potentially, the biggest breakthrough in neuro-degenerative disease in the past 50 years. That sounds like hyperbole – in a year I might be embarrassed by saying that – but that’s how I feel at the moment.”
The UCL scientist, who was not involved in the research, says the same approach might be possible in other neuro-degenerative diseases that feature the build-up of toxic proteins in the brain. The protein synuclein is implicated in Parkinson’s while amyloid and tau seem to have a role in dementias.
The report says off the back of this research, trials are planned using gene-silencing to lower the levels of tau.
Professor Giovanna Mallucci, who discovered the first chemical to prevent the death of brain tissue in any neuro-degenerative disease, said the trial was a “tremendous step forward” for patients and there was now “real room for optimism”.
But, the report says, Mallucci, who is the associate director of UK Dementia Research Institute at the University of Cambridge, cautioned it was still a big leap to expect gene-silencing to work in other neuro-degenerative diseases.
She said: “The case for these is not as clear-cut as for Huntington’s disease, they are more complex and less well understood. But the principle that a gene, any gene affecting disease progression and susceptibility, can be safely modified in this way in humans is very exciting and builds momentum and confidence in pursuing these avenues for potential treatments.”