RARE Daily

Triplet Therapeutics Initiates Natural History Study of Huntington’s Disease

May 28, 2020

Triplet Therapeutics has initiated a natural history study of Huntington’s disease to assess clinical outcomes and biomarkers that will inform upcoming interventional clinical trials.

The study, called SHIELD HD, enrolled its first patients last week in Toronto, Canada.

Huntington’s disease (HD) is a genetic disorder linked to a mutation in the HTT gene characterized by an increase in the number of CAG repeats within the gene. The presence of these repeats, beyond a certain threshold, wreaks havoc on brain function, affecting mood, cognition, and motor skills, ultimately leading to death. It is known that the number of repeat sequences expand over time in patients, increasing the toxic impact on cells, particularly neurons. The DNA damage response (DDR) pathway plays a central role in driving this process.

“HD is a devastating neurodegenerative disease with limited treatment options. SHIELD HD is an important step toward a better understanding of the disease,” said Irina Antonijevic, Triplet’s chief medical officer. “The more we understand, the closer we can get to developing therapies that prevent or delay symptom onset and halt or slow progression.

SHIELD HD is a prospective, longitudinal natural history study that will enroll approximately 60 HD gene expansion carriers and follow them for up to two years at clinical sites in North America and Europe. The study will assess a range of clinical outcomes and biomarkers including cognitive, motor, and functional measures such as the composite Unified HD Rating Scale (cUHDRS), brain MRI data, DDR gene expression, and the blood and spinal fluid biomarker known as neurofilament light chain. SHIELD HD results will augment data from upcoming clinical trials and inform their interpretation.

The study includes both early manifest and pre-manifest individuals, enriched for pre-manifest individuals who have begun to show signs or symptoms. The duration of SHIELD HD is designed to observe a rate of decline in key clinical outcomes that is clinically meaningful.

The first patients to participate in SHIELD HD were screened in the last two weeks in the clinic of Mark Guttman at the Centre for Movement Disorders at the University of Toronto. Guttman has published extensively on HD, including studies of biomarkers and symptoms characteristic of early manifest and pre-manifest disease.

“We are at the beginning of a new era in treating neurodegenerative repeat expansion disorders, with research on HD leading the way,” said Guttman. “SHIELD HD will help us better understand how to measure and monitor early signs of the disease and will inform future interventional trials aiming to treat the underlying cause before significant damage has occurred.”

Triplet is developing treatments for HD and other repeat expansion disorders, a group of more than 50 known genetic diseases associated with expanded DNA nucleotide repeats.

To precisely reduce activity of select DDR targets, Triplet is developing antisense oligonucleotide and small interfering RNA development candidates designed to prevent or delay disease onset and stop or slow disease progression, selecting the appropriate modality based on the specific disease. The approach targets the fundamental driver of disease, operating upstream of other approaches currently in development.

“Large-scale human genetic studies by the academic community have revolutionized the way we identify the underlying genetic drivers of repeat expansion disorders including HD,” said Nessan Bermingham, Triplet’s president, CEO, and co-founder. “Our targeted approach is based on results from these studies with our internal research providing insight into the central role the DDR mechanism plays in these diseases. Our approach has the potential to address a broad range of repeat disorders addressing unmet medical needs for hundreds of thousands of patients.”

Photo: Nessan Bermingham, Triplet Therapeutics president, CEO, and co-founder

Author: Rare Daily Staff

Stay Connected

Sign up for updates straight to your inbox.