By Deborah Borfitz 

June 28, 2022 | An international consortium of scientists has come up with a staging system for Huntington’s disease that tracks with its underlying biological, clinical, and functional characteristics in patients, as seen in those participating in four large prospective cohort studies. It was a complex, consensus-building feat that opens the door to clinical trials of drugs in the earliest phases of the rare, inherited neurodegenerative condition, according to Cristina Sampaio, M.D., Ph.D., chief clinical officer at the CHDI Foundation (Princeton, New Jersey). 

The newly developed framework, termed the Huntington’s Disease Integrated Staging System (HD-ISS), precisely classifies individuals as being in one of four stages of the disease, which now has roughly 20 drugs under development (half in clinical trials) to slow its progress. “Most of the ongoing trials are still targeting a fairly advanced population, which in the terminology of the HD-ISS would be stage 3 [decline in function] or late stage 2 [detectable clinical phenotype],” Sampaio says. 

A full description of the HD-ISS and its development was recently published as a position paper in The Lancet Neurology (DOI: 10.1016/S1474-4422(22)00120-X) and Sampaio was a senior author. The CHDI Foundation, a nonprofit that describes itself as “collaborative enablers” dedicated to facilitating the development of therapeutics for Huntington’s disease, financed the initiative.  

No company has a therapy for stage 0 (individuals with the Huntington’s disease genetic mutation without any detectable pathological change) or stage 1 (measurable indicators of underlying pathophysiology) that has progressed into human studies, she says. But that is expected to change, based on the relatively recent discovery of targets against the target genes that can modify disease progression, such as MSH3. 

The only way to identify people in stage 0 or 1 is if they agree to predictive genetic testing and, among the participants within the large observational study and research platform Enroll-HD, their willingness to do so sits at about 80%, says Sampaio. Among the overall at-risk population, however, the figure is only about 15%. 

Getting tested can be psychologically distressing, she points out. Children with a parent who has Huntington’s disease have a 50-50 chance of getting it themselves, and in cluster regions in Latin America where both parents are affected the odds are even worse. It is one of the most prevalent of rare diseases, with hundreds of researchers globally dedicated to its study. 

The Holdups 

The HD-ISS is the first staging system ever developed for a genetic neurological condition. The holdup for Huntington’s has been due to both the lack of a pressing need, since therapeutics evaluated in trials so far have been aimed at symptomatic disease, and insufficient suitable clinical data. A requirement for an appropriate structure for consensus-building within the scientific community and the long duration of Huntington’s disease have also played a part, Sampaio says.  

Creation of the Huntington’s Disease Regulatory Science Consortium by the nonprofit Critical Path (C-Path) Institute, a public-private partnership with the U.S. Food and Drug Administration, effectively addressed the need for a collaborative space where experts from 37 member organizations could evaluate the available evidence and debate its interpretation, she continues. Conclusions were reached by consensus—Sampaio and two CHDI Foundation directors (Emily Gantman and Alexandra Mansbach) were among the members—and subsequently endorsed by a wide range of stakeholders.  

Voting required at least 80% majority for adoption but, after much lively discussion, every vote within the group was 100% unanimous, she reports. The consortium’s full membership at the time included 24 biotech and pharma companies, eight nonprofit research or advocacy organizations, five academic institutions, and 19 individual scientific advisors. 

The course of Huntington’s disease is about 60 years, since people are born with the mutated gene, although the period between the start of neurodegeneration and death is roughly four decades, Sampaio says. In contrast, the diagnosis-to-death odyssey for individuals with amyotrophic lateral sclerosis is at best 10 years.   

Because Huntington’s is so protracted, most of the clinical trials up to now have involved symptomatic people in the late phase of the disease, she says. The hope is that more studies will focus on the pre-symptomatic population where disease-modifying therapies have the best shot of making a dent.  

Stepwise Process 

Development of HD-ISS used four publicly available datasets: Enroll-HD, IMAGE-HD, PREDICT-HD, and TRACK-HD. Enroll-HD, the largest of these with over 21,000 current participants and more than 25,000 since its initiation in 2010, is an ongoing clinical research platform and longitudinal observational study for Huntington’s disease families that is maintained by the CHDI Foundation, Sampaio says. 

IMAGE-HD is an Australian-based, multi-modal longitudinal MRI study and TRACK-HD is a four-nation prospective observational biomarker study, both involving participants with premanifest and early symptomatic Huntington’s disease. PREDICT-HD is a 32-site observational study of persons who have the gene expansion for Huntington’s disease but are not yet experiencing symptoms.  

Consensus on the staging system was reached in a stepwise manner, starting with an agreement on the means for making decisions within the group, says Sampaio. The adopted method relies on rigorous evidence gathering and empirical data to develop statistical models and validate conclusions and is a familiar process to most people in the medical and scientific community. 

The next step was to develop the list of questions to be systematically investigated, having to do primarily with how the disease progresses and the most important measurements reflecting that progression, she says. These were ultimately answered through the published literature, with the cutoff points between one stage of the disease and the next addressed via statistical modeling.  

Four Stages 

Huntington’s disease is a trinucleotide repeat disorder, explains Sampaio, and stage 0 describes someone born with a CAG mutation that is pathological in size (40 or more repeats). This was demonstrated in the position paper but “reasonably well known already.” These individuals have a 90% probability of becoming symptomatic at some point of their life. 

For stage 1, six volumetric neuroimaging assessments were candidates for biological markers of pathogenesis but only two—caudate volumetric MRI and putamen volumetric MRI, adjusted for head size—were selected to capture the transition into the process of neurodegeneration, she says. These were consistently the imaging biomarkers showing atrophy the earliest. 

One motor assessment (full Total Motor Score) and one cognitive assessment (Symbol Digit Modalities Test) were selected as stage 2 landmarks. For stage 3, the Independence Scale and Total Functional Capacity (TFC) assessments were chosen over the TFC occupation sub-score. Given the lengthy duration of stage 3, it was also divided into three broad conceptual groupings of mild, moderate, and severe functional deficits requiring no additional quantitative measurements.  

Individuals in stage 0 or 1 account for only about 10% of those in the study cohorts the researchers examined, which of course skews more toward stage 3 of the disease, Sampaio says. About 1.4 million people worldwide have been clinically diagnosed. Current estimates put the prevalence rate at 12 to 14 people per 100,000. 

Progress Expected 

The HD-ISS will help enable clinical trials by providing specific, unambiguous criteria for selecting participants, says Sampaio. Up to now, ad hoc methods have been employed, impeding progress by precluding comparisons across studies. For populations very early in the course of their disease (i.e., stage 0 or 1), any sort of enrollment criteria has been difficult to even define. 

The staging system has the potential to transform how Huntington’s disease clinical research is conducted, enabling study of the earliest disease phases and planning of preventive clinical trials, as well as facilitating data aggregation and sharing, she adds. It is also expected to speak to policymakers and regulators who can’t be expected to know any one disease at such a granular level.  

Researchers working on therapeutics for Huntington’s disease are encouraged to access the data in Enroll-HD after signing a data use agreement, says Sampaio. The CHDI Foundation is committed to open science and doing whatever it can to accelerate research and development efforts—ideally, those aimed at delaying or preventing neurodegeneration in patients while function is still intact.