Researchers are set to carry out a large-scale, global study of a ground-breaking Huntington’s disease drug which is the first in the world to lower the level of the harmful huntingtin protein which causes Huntington’s.
Full results of the first human trial of the drug involving 46 patients led by UCL/UCLH researcher Prof Sarah Tabrizi have been published in the New England Journal of Medicine and showed that the drug – IONIS-HTTRx (now RG6042) – is safe and well tolerated and successfully lowered levels of the harmful protein.
Researchers will now move on to a global ‘phase III’ study in 660 patients. It means the first disease-modifying treatment may possibly be one step closer.
Huntington’s disease is a neurodegenerative disease caused by a mutation to the huntingtin gene (HTT) resulting in the production of a toxic mutant protein (mHTT). The drug trialled is an antisense oligonucleotide (ASO) discovered and developed by Ionis Pharmaceuticals to inhibit the huntingtin messenger RNA and thereby reduce the levels of mHTT. This is the first study to show a toxic protein can be suppressed by an ASO in the brains of adult patients.
For the Huntingtin Lowering Antisense Oligonecleotides Trial, participants received the drug or placebo (3:1) every four weeks for four doses.
The drug treatment resulted in an average lowering of 40% in mHTT levels for the higher dose groups – with some patients seeing a 60% lowering – and no serious adverse events were recorded.
Prof Sarah Tabrizi said: ‘’I am so pleased now that the full trial results including critical pre-clinical data are now published in the New England Journal of Medicine. We are excited to be moving forward to a global phase III trial sponsored by F. Hoffmann-La Roche, which licensed the medicine, to see if regular intrathecal [injection into the spinal canal] antisense treatment slows clinical progression of the disease. This is an important time in clinical research for patients and families in Huntington’s disease and we are working together with the global community to help enable this trial.’’
“Peer-reviewed publication of these exciting results from the first successful huntingtin-lowering trial is a crucial step that lets us update and call upon the combined expertise of the global community of HD researchers’,’ said Dr Ed Wild, Associate Director, UCL Huntington’s Disease Centre and manuscript co-author.
Prof Michael Hanna (Director of the Queen Square UCL Institute of Neurology) said ‘’this pioneering trial is of ground-breaking importance in to neurodegenerative research and I am proud that it was led from the UCL Queen Square Institute of Neurology, the UCLH National Hospital for Neurology and the Leonard Wolfson Experimental Neurology Centre where first active dosing was given. Huntington’s disease is a terrible disorder, and therapeutics that target the cause of the disease genetically are those most likely to make a difference. Importantly, the publication of these results has relevance for all neurodegenerative diseases with ASO therapies now being taken forward for trials in Alzheimer’s, Parkinson’s and Motor neuron disease.”
Read the paper: https://www.nejm.org/doi/full/10.1056/NEJMoa1900907
