PHILADELPHIA — An antisense oligonucleotide in development successfully reduced levels of a harmful mutant protein in the cerebral spinal fluid of people with early Huntington's disease (HD), opening the door to an era where HD therapy could transition from symptom control to disease modifying.
Researchers led by Sarah Tabrizi, MD, PhD, director of the University College London Huntington's Disease Centre, reported a phase 1/2a trial of IONIS-HTTRx (Ionis/Hoffman-La Roche), also known as RG6042, an antisense oligonucleotide designed to inhibit huntingtin (HTT) protein messenger RNA. They showed treatment was safe and reduced levels of mutant HTT protein believed to cause the disease.
The trial was published online May 6 in The New England Journal of Medicine and coincided with presentation of a dose-ranging, translational study supporting the safety and optimal dosing of RG6042 here at the American Academy of Neurology 2019 Annual Meeting.
"We did something that we could easily not have achieved. We've lowered for the first time in humans the concentration of the known cause of a neurodegenerative brain disease," study co-author Edward Wild, MA, MB, BChir, FRCP, PhD, a consultant neurologist at the National Hospital for Neurology and Neurosurgery in London, told Medscape Medical News. "And there were so many ways that might not have happened. That used to keep me awake at night.
"This is not a cure for Huntington's disease or a treatment we know is clinically effective at the moment, but we are working on that," he added.
HD is an autosomal dominant inherited condition that typically manifests in midlife. The disease is monogenic — associated with a mutation in one gene — making it a good candidate for targeted therapy. Despite discovery of the HTT gene in 1993, the only available therapies remain focused on symptoms.
Researchers hope RG6042 may change all that. The agent targets the mRNA of the mutant HTT gene and prevents it from producing the mutant HTT protein.
The phase 1/2a study of 46 people with early stage HD demonstrated that the agent decreased CSF levels of the mutant HTT protein by 40% among those who received four 90 mg doses every 4 weeks vs placebo.
In addition, researchers reported a 60% decrease in mutant HTT among others who received 120 mg RG6042 in the same regimen of four lumbar intrathecal injections, in line with previous preclinical studies. Other participants were randomly assigned to lower doses or placebo.
Honing in on Human Dosing
In the related study presented by Wild here at the AAN 2019 Annual Meeting, Wild and colleagues examined different animal models and calculated the optimal levels for CSF in humans, keeping both safety and efficacy in mind. They correlated the RG6042 mg dosing and the percentage decrease in huntingtin.
As the first-in-human research of this agent in HD, safety and proper informed consent were critical, Wild said in an interview with Medscape Medical News here at the meeting.
They compared 4 weekly and 8 weekly injections of RG6042 based on phase 1 study results. "The information we got from the phase 1 study — that it was worth exploring 8 weekly dosing — was gold," Wild said. The 8 weekly regimen was introduced to the open label extension phase, and this phase "led us to the conclusion at the 9-month time point that we don't actually need the 4 weekly dosing arm anymore. We get the knockdown [of mutant protein] in the ideal range with less frequent dosing."
The 9-month data "have really affirmed that strategy," Wild said. "It's a real relief for everyone that we can expect effective lowering with 8 weekly dosing, or perhaps even less frequently."
A "Fascinating" Finding
Wild, who describes himself as a "neurofilament light kind of guy" also tracked serum levels of this biomarker. Serum neurofilament light (sNFL) is typically regarded as an indicator of neuronal damage, and researchers in many neurodegenerative disorder studies measure sNFL to stratify severity of disease and to track response to treatment.
Wild anticipated the sNFL levels would decrease over time as the mutant protein levels dropped in CSF, he said at the meeting. However, an unexpected picture emerged. Although the levels remained low initially, sNFL levels actually increased, peaking at approximately 5 months. Thereafter, the sNFL levels dropped back to baseline levels — on their own and while the RG6042 levels continued to decrease.
Why did this occur? "The real answer is we don't know," he said. "We've never effectively treated Huntington's disease before."
"We could have got a very easy-to-understand signal from neurofilament," Wild said. "What we got was an absolutely fascinating signal."
With the goal of finding the dosing regimen that promotes both efficacy and safety, a phase 3 study is now underway comparing 8 weekly dosing, 16 weekly dosing (essentially three times a year), and placebo over 2 years. The target enrollment worldwide is 660 participants, including both healthy volunteers and people with early HD.
Commenting on the primary publication in NEJM, Kenneth H. Fischbeck, MD, and Nancy S. Wexler, PhD, write in accompanying editorial: "There was a dose-dependent increase in the concentration of HTTRx and a decrease in levels of mutant huntingtin protein in the spinal fluid. Remarkably, the reduction in the levels of mutant huntingtin was in a range that is expected to have therapeutic benefit on the basis of studies in animals."
"This is a pathbreaking trial that strongly supports further development of HTTRx as a treatment for Huntington's disease," they note. "Now, 26 years after the discovery of the etiologic gene, a path to modifying Huntington's disease seems clear, with implications for other neurodegenerative diseases that have a known genetic cause."
The next step is to determine whether the agent demonstrates a clinical effect in a larger cohort followed over a longer time, they note. Fischbeck is from the National Institute of Neurological Disorders and Stroke at the National Institutes of Health in Bethesda, Maryland, and Wexler is affiliated with the Departments of Neurology and Psychiatry, College of Physicians and Surgeons, Columbia University and Hereditary Disease Foundation in New York City.
"The phase 3 trial that has just begun is appropriately designed to determine whether this intervention has a clinically meaningful effect," they add.
Ionis Pharmaceuticals supported the study. F. Hoffman-La Roche and Genentech licensed RG6042 from Ionis in 2017. Genentech would commercialize RG6042 in the United States if the agent receives FDA approval. Wild has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with F. Hoffmann-La Roche. Wild also received a research grant to University College London by F. Hoffmann-La Roche. Fischbeck and Wexler have disclosed no relevant financial relationships.
American Academy of Neurology (AAN) 2019 Annual Meeting: Abstract #S16.005. Presented May 6, 2019.
Medscape Medical News © 2019
Cite this: Damian McNamara. Novel Treatment for Huntington's Shows Early Promise - Medscape - May 08, 2019.