An international consortium of Huntington disease (HD) experts has developed the first-ever staging system for a genetic neurologic condition ― an important step toward developing new therapeutics to treat the disease before symptoms present.
Researchers liken the Huntington's Disease Integrated Staging System (HD-ISS) to the system currently used to stage cancer. It groups patients according to their underlying biological, clinical, and functional characteristics.
It also includes criteria to biologically define HD stages across the entire disease spectrum, from birth to death, which is something that has not been done before. For now, the HD-ISS is intended only for research, but it could one day be modified for use in the clinic, investigators write.
"This systematization is of critical importance to select the most appropriate target population for clinical trials and studies," co-investigator Cristina Sampaio, MD, chief medical officer at the CHDI Foundation, Princeton, New Jersey, told Medscape Medical News.
"By providing a methodology to precisely define cases early in the neurodegenerative process, the HD-ISS will be instrumental in conducting trials in the very early disease stages," Sampaio added.
The position paper was published in the July issue of The Lancet Neurology.
New Approach Needed
There is no approved therapy to slow HD progression. Clinical trials currently enroll patients with demonstrable symptoms, which limits the ability to test therapeutics that could delay or prevent neurodegeneration.
HD is rare, occurring in about 2.7 per 100,000 individuals worldwide. It is caused by a mutation in the HTT gene involving a DNA segment known as a CAG trinucleotide repeat.
Currently, HD is diagnosed on the basis of clinical signs that emerge late in the disease course, an approach developed before the discovery of the HTT gene and the development of the genetic test for the CAG mutation.
The disease phase prior to diagnosis has been described as presymptomatic, premanifest, or prodromal. However, the three terms have varying definitions that make it difficult to compare study results across trials.
Because drug development had focused on the overt motor sign phase of the disease, there was no real need for an evidence-based staging system that classified disease phases from birth, the investigators note.
"Now, the research community and regulators recognize that it is critical to conduct trials early in the disease when no signs or overt symptoms are measurable," Sampaio said.
Defining Disease Stages
Work on the staging system was done through the Huntington's Disease Regulatory Science Consortium, an international project begun in 2018 among biotech and pharma companies, academic institutions, and nonprofit research and advocacy organizations.
Overall, more than 50 clinicians and researchers were involved in developing the HD-ISS.
Using modeling data from four large observational studies that included patients with HD and control groups, researchers identified four different stages of HD:
Stage 0: Begins at birth with identification of HTT gene mutations but no detectable pathologic changes.
Stage 1: Begins when biomarker changes are detected via MRI by a volume decrease in six brain areas.
Stage 2: Begins when clinical signs of HD are present, as determined through motor and cognitive assessments.
Stage 3: Begins when functional decline is evident, with worsening on the Independence Scale and the Total Functional Capacity of the Unified Huntington's Disease Rating Scale.
Applying the HD-ISS to clinical trials requires the collection of information routinely recorded in HD research, as well as some additional data; but researchers say its application is straightforward.
The HD-ISS uses a numerical staging system similar to that used in the US Food and Drug Administration's guidance for Alzheimer's disease (AD) and integrates the prodromal, presymptomatic, or premanifest phase of the disease. This distinguishes it from earlier classification systems.
The HD-ISS can be adapted if new HD biomarkers are identified.
"As research results are generated, this will further validate the HD-ISS and potentially lead to the development of a derivative, and possibly simplified, system for clinical practice," Sampaio said.
The new system goes further than a more recent proposal from the Movement Disorder Society task force, which addresses earlier stages in HD but doesn't consider objective biomarker data.
Question of Timing
Commenting on the findings for Medscape Medical News, Erin Furr-Stimming, MD, neurologist and director of the Huntington's Disease Society of America Center of Excellence with McGovern Medical School, UTHealth, Houston, Texas, said targeting early-stage disease will be key.
"Similar to more common neurodegenerative diseases such as AD and PD [Parkinson's disease], there is a period of at least a decade when changes are occurring in the nervous system, prior to the manifestation of clinical symptoms and signs significant enough to warrant a clinical diagnosis," Furr-Stimming said.
She noted that multiple trials of disease-modifying agents for AD, PD, and HD have failed for a multitude of reasons, "but one consistent question that is relevant to all these diseases is that of timing: should we intervene and test these therapies earlier?
"The premanifest or prodromal period may be the ideal time to intervene with a disease-modifying therapy, prior to onset of any neurodegeneration," Furr-Stimming said.
The CHDI Foundation provided financial support to the Critical Path Institute for the Huntington's Disease Regulatory Science Consortium, including all working group efforts. Sampio is an employee of and receives salary from CHDI Management. She has also received consultancy honorariums (unrelated to HD) from Pfizer, Kyowa Kirin, vTv Therapeutics, GW Pharmaceuticals, Neuraly, Neuroderm, Green Valley Pharmaceuticals, and Pinteon Pharmaceuticals. A full list of disclosures for the other researchers is in the original article. Furr-Stimming reported no relevant financial relationships.
Lancet Neurol. 2022;21:632-644. Abstract
Kelli Whitlock Burton is a journalist for Medscape Medical News who writes about neurology and psychiatry.
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Cite this: First-Ever Huntington Staging System May Jump-Start Drug Development for Early-Stage Disease - Medscape - Jun 28, 2022.