The UHDRS Symposium held on Nov. 2, 2016, in conjunction with HSG 2016, presented research findings and discussed the merits of using the Modified UHDRS Score as an efficacy endpoint for HD clinical trials. To view the agenda, click here.
With the advent of novel therapeutics targeting the causal pathway of Huntington Disease (HD), the planning of ground-breaking clinical trials that aim to slow or prevent clinical progression of this devastating disease are underway. A key challenge in this context is how to best optimize resources while successfully addressing core study objectives. Trial length and size must be feasible, while maintaining the ability to capture clinically meaningful progression with variables that can demonstrate longitudinal clinical change over the minimal time necessary to prove a drug effect on slowing clinical progression.
In this Symposium, the key parameters influencing optimization of resources and maintaining core study objectives in neurodegenerative clinical trials will be discussed with a focus on HD using the Unified Huntingtons Disease Research Scale (UHDRS). Perspectives and examples will be presented from the Alzheimer’s field, and recent results of a novel multi-dataset analyses using the UHDRS in two major prospective cohort studies (i.e. TRACK-HD, COHORT) and clinical trials (e.g. CARE-HD) will be presented. The core aim of the Symposium is to engage the HD community, including members of the HSG, EHDN, patient advocacy groups, members of the academy, and industry colleagues in a timely discussion of these results, and to determine whether majority consensus exists that this approach meets the stated goals of capturing clinically meaningful progression in HD while maximizing trial efficiency.
The results across the datasets (n~1,500 cases, average three years clinical follow-up in early HD) suggest that composites of UHDRS variables which capture core motor, cognitive, and functional decline enhance signal-to-noise vs. individual variables, and that modest enrichment of target populations (e.g. inclusion thresholds based upon CAP scores) enhances clinical progression rates. The best performing composite was an equally weighted Z-scores sum of several UHDRS variables, which we currently refer to as the “Modified UHDRS Score” (final name pending). In summary, the Modified UHDRS Score appears to be a good candidate endpoint for HD clinical trials as it showed the largest signal-to-noise for detecting change over time among the studies, and it represents several core domains (i.e. functional, cognitive, and motor) that might be targeted by novel therapeutic candidates. Similarly, a modest enrichment strategy based upon CAP scores appears to enhance trial efficiency.
Maximizing efficiency of trial design while maintaining core study objectives using a modified UHDRS score promises to test the most promising therapeutic candidates to limit clinical progression in HD in an efficient and sustainable framework for individuals who suffer from this rare, severe, fatal, neurodegenerative disease, along with members of the academy, industry, and patient advocacy groups charged with quickly delivering on the promise of these dramatic scientific advances.