Huntington's Disease Clinical Trials Research Articles

Huntington's Disease Clinical Trials Corner: March 2024.

In this edition of the Huntington's Disease Clinical Trials Update, we expand on the ongoing program from VICO Therapeutics and on the recently terminated VIBRANT-HD clinical trials. We also discuss updates from uniQure's AMT-130 program and PTC therapeutics' trial of PTC518 and list all currently registered and ongoing clinical trials in Huntington's disease.

Huntington's Disease Clinical Trials Corner: July 2023.

In this edition of the Huntington's Disease Clinical Trials Corner, we expand on the GENERATION HD2 (tominersen) and on the Asklepios Biopharmaceutical/BrainVectis trial with AB-1001. We also comment on the recent findings from the PROOF-HD trial, and list all currently registered and ongoing clinical trials in Huntington's disease.

The Emerging Landscape of Small-Molecule Therapeutics for the Treatment of Huntington's Disease.

Huntington's disease (HD) is a progressive neurodegenerative disorder caused by a CAG repeat expansion in the huntingtin gene (HTT). The new insights into HD's cellular and molecular pathways have led to the identification of numerous potent small-molecule therapeutics for HD therapy. The field of HD-targeting small-molecule therapeutics is accelerating, and the approval of these therapeutics to combat HD may be expected in the near future. For instance, preclinical candidates such as naphthyridine-azaquinolone, AN1, AN2, CHDI-00484077, PRE084, EVP4593, and LOC14 have shown promise for further optimization to enter into HD clinical trials. This perspective aims to summarize the advent of small-molecule therapeutics at various stages of clinical development for HD therapy, emphasizing their structure and design, therapeutic effects, and specific mechanisms of action. Further, we have highlighted the key drivers involved in HD pathogenesis to provide insights into the basic principle for designing promising anti-HD therapeutic leads.

Suicidality Risk Factors Across the CARE-HD, 2CARE, and CREST-E Clinical Trials in Huntington Disease.

Suicidality is a common concern in the routine care of persons with Huntington disease (HD) and for the many participants in HD clinical trials. In a previous analysis, we identified baseline and time-dependent factors associated with suicidal ideation and attempts from 2CARE, a large, randomized, double-blind clinical trial. The present analysis extends our prior methodology to 2 other large interventional HD clinical trials, CARE-HD and CREST-E. We observed relationships across studies between suicidality events and prior suicidal ideation at baseline, antidepressant/anxiolytic use, chorea, increasing age, and several domains in the Unified Huntington Disease Rating Scale (UHDRS) Behavioral Assessment (depressed mood, low self-esteem, aggression, and active suicidality). These data may form the basis for a subscale of demographic and UHDRS items with the potential for prospectively identifying suicidality risk in HD clinics and clinical trials. 2CARE and CREST are registered at clinicaltrials.gov. 2CARE NCT00608881, registered February 6, 2008; first enrollment March 2008. CREST-E NCT00712426, registered July 10, 2008; first enrollment September 2009. CARE-HD, not registered; first enrollment July 1997.

Recommendations to Optimize the Use of Volumetric MRI in Huntington's Disease Clinical Trials.

Volumetric magnetic resonance imaging (vMRI) has been widely studied in Huntington's disease (HD) and is commonly used to assess treatment effects on brain atrophy in interventional trials. Global and regional trajectories of brain atrophy in HD, with early involvement of striatal regions, are becoming increasingly understood. However, there remains heterogeneity in the methods used and a lack of widely-accessible multisite, longitudinal, normative datasets in HD. Consensus for standardized practices for data acquisition, analysis, sharing, and reporting will strengthen the interpretation of vMRI results and facilitate their adoption as part of a pathobiological disease staging system. The Huntington's Disease Regulatory Science Consortium (HD-RSC) currently comprises 37 member organizations and is dedicated to building a regulatory science strategy to expedite the approval of HD therapeutics. Here, we propose four recommendations to address vMRI standardization in HD research: (1) a checklist of standardized practices for the use of vMRI in clinical research and for reporting results; (2) targeted research projects to evaluate advanced vMRI methodologies in HD; (3) the definition of standard MRI-based anatomical boundaries for key brain structures in HD, plus the creation of a standard reference dataset to benchmark vMRI data analysis methods; and (4) broad access to raw images and derived data from both observational studies and interventional trials, coded to protect participant identity. In concert, these recommendations will enable a better understanding of disease progression and increase confidence in the use of vMRI for drug development.

The Impact of Anosognosia on Clinical and Patient-Reported Assessments of Psychiatric Symptoms in Huntington's Disease.

Psychiatric symptoms are widely prevalent in Huntington's disease (HD) and exert greater impact on quality of life than motor manifestations. Despite this, psychiatric symptoms are frequently underrecognized and undertreated. Lack of awareness, or anosognosia, has been observed at all stages of HD and may contribute to diminished patient self-reporting of psychiatric symptoms. We sought to evaluate the impact of anosognosia on performance of commonly used clinical rating scales for psychiatric manifestations of HD. We recruited 50 HD patients to undergo a formal psychiatrist evaluation, the Problem Behavior Assessment-Short Form (PBA-s), and validated self-report rating scales for depression, anxiety, and anger. Motor impairment, cognitive function, and total functional capacity were assessed as part of clinical exam. Patient awareness of motor, cognitive, emotional, and functional capacities was quantified using the Anosognosia Rating Scale. Convergent validity, discriminant validity, classification accuracy, and anosognosia effect was determined for each psychiatric symptom rating scale. Anosognosia was identified in one-third of patients, and these patients underrated the severity of depression and anxiety when completing self-report instruments. Anosognosia did not clearly influence self-reported anger, but this result may have been confounded by the sub-optimal discriminant validity of anger rating scales. Anosognosia undermines reliability of self-reported depression and anxiety in HD. Self-report rating scales for depression and anxiety may have a role in screening, but results must be corroborated by provider and caregiver input when anosognosia is present. HD clinical trials utilizing patient-reported outcomes as study endpoints should routinely evaluate participants for anosognosia.

Genetic and Functional Analyses Point to FAN1 as the Source of Multiple Huntington Disease Modifier Effects

A recent genome-wide association study of Huntington disease (HD) implicated genes involved in DNA maintenance processes as modifiers of onset, including multiple genome-wide significant signals in a chr15 region containing the DNA repair gene Fanconi-Associated Nuclease 1 (FAN1). Here, we have carried out detailed genetic, molecular, and cellular investigation of the modifiers at this locus. We find that missense changes within or near the DNA-binding domain (p.Arg507His and p.Arg377Trp) reduce FAN1's DNA-binding activity and its capacity to rescue mitomycin C-induced cytotoxicity, accounting for two infrequent onset-hastening modifier signals. We also idenified a third onset-hastening modifier signal whose mechanism of action remains uncertain but does not involve an amino acid change in FAN1. We present additional evidence that a frequent onset-delaying modifier signal does not alter FAN1 coding sequence but is associated with increased FAN1 mRNA expression in the cerebral cortex. Consistent with these findings and other cellular overexpression and/or suppression studies, knockout of FAN1 increased CAG repeat expansion in HD-induced pluripotent stem cells. Together, these studies support the process of somatic CAG repeat expansion as a therapeutic target in HD, and they clearly indicate that multiple genetic variations act by different means through FAN1 to influence HD onset in a manner that is largely additive, except in the rare circumstance that two onset-hastening alleles are present. Thus, an individual's particular combination of FAN1 haplotypes may influence their suitability for HD clinical trials, particularly if the therapeutic agent aims to reduce CAG repeat instability.

Huntington's Disease Clinical Trials Corner: April 2020.

In this edition of the Huntington's Disease Clinical Trials Corner we expand on the UniQure AMT-130 and on the Neurocrine Biosciences KINECT-HD trials, and list all currently registered and ongoing clinical trials in Huntington's disease.

Author response: Risk factors for suicidality in Huntington disease: An analysis of the 2CARE clinical trial.

On behalf of all authors, I am appreciative of Drs. Rato and Ferreira for their observations on our article.1 We agree that the pragmatic step of excluding severe psychiatric disease in a long study introduces limitations for what conclusions can be drawn. Drs. Rato and Ferreira highlight the risk factors for suicidality at large that were also relevant in our study population, which we believe supports that surveillance for these things may be effective in lessening suicidality risk during Huntington disease (HD) clinical trials. It would perhaps be surprising or worrisome if the standard risks did not apply in the HD population here, so confirmation of this notion is valuable. The associations between chorea and the total functional capacity score of 0 in any domain have some association with risk (both p = 0.06), as well as predictive testing's association with risk for suicide attempt ( p = 0.05). These items, and perhaps others, may help make risk mitigation more sensitive if used in a composite model. This idea will require further study, development, and testing. We agree that how the structured environment of a clinical trial influences risk, including the possibility of placebo effects or unspecified participation effects, and deserves further study. Please see our discussion paragraph, “The effects of participation in HD clinical trials on suicidal risk is not clear…”1

A Systematic Review of Neuropsychiatric Symptoms and Functional Capacity in Huntington's Disease.

Neuropsychiatric symptoms are known to increase caregiver burden and decrease patient quality of life among patients with Huntington's disease. Functional capacity is an outcome commonly used in Huntington's disease clinical trials to quantify disease progression or intervention response. Some studies have examined the relationship between neuropsychiatric symptoms and functional capacity; however, this evidence has not been synthesized. The authors reviewed existing evidence on the association between neuropsychiatric symptoms and functional capacity in Huntington's disease. A systematic review was conducted using PubMed and CINAHL. Articles were included if they described primary research in humans with Huntington's disease, measured one or more neuropsychiatric symptoms and functional capacity, and reported statistical methods to identify associations between the two concepts. Additional eligible articles were identified through reference mining and review of other relevant literature. Fourteen articles were eligible for review. Neuropsychiatric symptoms were measured individually, in clusters (i.e., depression, anxiety, and suicide items contributing to a depression cluster score), or with an overall score. Significant associations with decreased functional capacity were found most commonly with depression (N=7, median r=0.48) and apathy (N=5, median r=0.47). Other neuropsychiatric symptoms, clusters, and overall scores were all associated with functional capacity in three or fewer studies. There is some evidence that depression and apathy are associated with decreased functional capacity in Huntington's disease. Other neuropsychiatric symptoms have been infrequently examined. Further knowledge of the relationships between neuropsychiatric symptoms and functional capacity will identify areas for intervention and improvement of outcomes in patients with Huntington's disease.

Huntington's Disease Clinical Trials Corner: January 2019.

In this edition of the Huntington's Disease Clinical Trials Corner we expand on the GENERATION-HD1 and PACE-HD trials, and we list all currently registered and ongoing clinical trials in Huntington's disease.

Huntington's Disease Clinical Trials Corner: August 2018.

In the third edition of the Huntington’s Disease Clinical Trials Corner we list all currently registered and ongoing clinical trials, expand on the SIGNAL trial (NCT02481674), and cover the recently finished CREST-E trial (NCT00712426).

Analysis of Participant Withdrawal in Huntington Disease Clinical Trials.

Analysis of Participant Withdrawal in Huntington Disease Clinical Trials.

Analysis of Participant Withdrawal in Huntington Disease Clinical Trials.

Excellent retention in Huntington disease (HD) clinical trials is essential for testing new therapies. The stage of disease, cognitive status, and availability of a care partner may influence retention in HD clinical trials. We sought to analyze reasons for early withdrawal in three HD clinical trials, and evaluated if either baseline characteristics or follow-up assessments were associated with time to withdrawal. Analyses of participant withdrawal were performed for three randomized, double-blind, placebo-controlled trials including the CARE-HD (coenzyme Q10 and remacemide in HD, n = 347), DOMINO (pilot study of minocycline in HD, n = 114), and 2CARE (coenzyme Q10 in HD, n = 609) trials. Reasons for withdrawal were obtained by review of textual data in the study databases. Participant demographic and clinical characteristics were analyzed as potential predictors of time to withdrawal using Cox-proportional hazards models. Estimated probabilities of withdrawal at 12 months were 2.9% for CARE-HD, 10.5% for DOMINO, and 5.9% for 2CARE. The top reasons for withdrawal (202 in total), expressed as mean percentage across the three trials, were loss to follow-up (23.2%), death (15.9%), and loss of interest/desire to participate (15.2%). Baseline and time-dependent variables associated with time to withdrawal were mainly motor, behavioral, and functional scores. Age, gender, ethnicity, and educational level were not associated with time to withdrawal in any of the three studies. The estimated withdrawal probability at 12 months ranged from 2.9% to 10.5% in the three HD trials considered here. A possible strategy to improve retention of participants in future HD clinical trials is to enroll individuals with higher baseline functional and behavioral status.

Fifteen Years of Clinical Trials inHuntington's Disease: A Very Low ClinicalDrug Development Success Rate.

Drug development in Huntington's disease (HD) is particularly challenging, and only two compounds are approved by the FDA. It is therefore essential to appraise drug development programs in order to understand the reasons for their failure during the early stages of development. To describe the landscape of HD therapeutic development and critically explore the causes of compound attrition in the different stages of drug development, from phase 1 to phase 4. All HD clinical trials registered in the WHO International Clinical Trials Search Portal, from inception to May 2017, were analyzed. Two independent authors selected and extracted data. Success rate in a trial phase was calculated as the number of compounds that progressed to the next trial phase divided by the number of compounds in that phase. The overall success rate was calculated as the ratio between the number of compounds that receive regulatory approval and the total number of compounds. Ninety-nine trials assessing 41 compounds and eleven non-pharmacological interventions (devices and cell therapies) were identified. Twenty-four (24.2%) were phase 1 trials, 46 (46.5%) phase 2, 20 (20.2%) phase3, and two (2.0%) phase4. Sixty trials (60.6%) received industry sponsorship. The most frequently studied compounds were creatine, latrepirdine and pridopidine. The mean number of participants enrolled was 92.0 and the length of treatment was 262.9 days, and both increased from phase 1 to phase 3 trials. The success rate was 25.0% from phase 1 to phase 2, 19.4% from phase 2 to phase3, and 14.3% from phase 3 to approval. The overall success rate was 3.5%. Although HD is a rare condition, 99 HD trials were identified in a comprehensive clinical trial registry. We found a low success rate at earlier phases of drug-development and a very low trial success rate at later phases. There is a significant gap between drug discovery and development success rates that warrants careful appraisal and improvement.

Chapter 19 - Cognitive assessment in Huntington disease clinical drug trials

Several Huntington disease (HD) clinical trials are in progress and on the horizon. Potential treatments are increasingly being targeted at ameliorating the cognitive decline in HD. This necessitates a careful consideration of trial designs, including endpoint strategies suitable for testing cognitive function. The aim of this chapter is to evaluate and consider the use of cognitive measures in HD clinical trials. We first consider the role of cognition in clinical trial endpoint models, including a review of previous HD clinical trials that have included cognitive measures. We evaluate strategies for selecting cognitive tools for HD clinical trials, and consider cognitive assessments that have been used in other neuropsychiatric disorders, namely Alzheimer disease and schizophrenia. Next, we describe a general framework for selecting patient-based outcomes in clinical trials, and apply this framework to the selection of cognitive outcomes. Using the HD-Cognitive Assessment Battery (HD-CAB), a new cognitive battery designed for clinical trials, we illustrate the evaluation of cognitive outcomes in terms of their responsivity, reliability, validity, appropriateness, precision, interpretability, feasibility, and acceptability. Finally, we articulate a pathway for continued development of cognitive tools that would pave the way for finding treatments that ameliorate cognitive decline in HD.

Chapter 18 - Motor outcome measures in Huntington disease clinical trials

Deficits in motor function are a hallmark of Huntington disease (HD). The Unified Huntington's Disease Rating Scale Total Motor Score (UHDRS-TMS) is a categoric clinical rating scale assessing multiple domains of motor disability in HD. The UHDRS-TMS or subsets of its items have served as primary or secondary endpoints in numerous clinical trials. In spite of a well-established video-based annual online certification system, intra- and interrater variability, subjective error, and rater-induced placebo effects remain a concern. In addition, the UHDRS-TMS was designed to primarily assess motor symptoms in manifest HD. Recently, advancement of technology resulted in the introduction of the objective Q-Motor (i.e., Quantitative-Motor) assessments in biomarker studies and clinical trials in HD. Q-Motor measures detected motor signs in blinded cross-sectional and longitudinal analyses of manifest, prodromal, and premanifest HD cohorts up to two decades before clinical diagnosis. In a multicenter clinical trial in HD, Q-Motor measures were more sensitive than the UHDRS-TMS and exhibited no placebo effects. Thus, Q-Motor measures are currently explored in several multicenter trials targeting both symptomatic and disease-modifying mechanisms. They may supplement the UHDRS-TMS, increase the sensitivity and reliability in proof-of-concept studies, and open the door for phenotype assessments in clinical trials in prodromal and premanifest HD.

Oxidative stress is increased in C. elegans models of Huntington’s disease but does not contribute to polyglutamine toxicity phenotypes

Huntington's disease (HD) is an adult onset neurodegenerative disorder for which there is currently no cure. While HD patients and animal models of the disease exhibit increased oxidative damage, it is currently uncertain to what extent oxidative stress contributes to disease pathogenesis. In this work, we use a genetic approach to define the role of oxidative stress in HD. We find that a C. elegans model of HD expressing a disease-length polyglutamine tract in the body wall muscle is hypersensitive to oxidative stress and shows an upregulation of antioxidant defense genes, indicating that the HD worm model has increased levels of oxidative stress. To determine whether this increase in oxidative stress contributes to the development of polyglutamine-toxicity phenotypes in this HD model, we examined the effect of deleting individual superoxide dismutase (sod) genes in the HD worm model. As predicted, we found that deletion of sod genes in the HD worm model resulted in a clear increase in sensitivity to oxidative stress. However, we found that increasing oxidative stress in the HD worm model did not exacerbate deficits caused by polyglutamine toxicity. We confirmed these observations in two worm models expressing disease-length polyglutamine tracts in neurons. Furthermore, we found that treatment with antioxidants failed to rescue movement deficits or decrease aggregation in HD worm models. Combined, this suggests that the increase in oxidative stress in worm models of HD does not contribute to the phenotypic deficits observed in these worms, and provides a possible explanation for the failure of antioxidants in HD clinical trials.

The development of a new computer adaptive test to evaluate chorea in Huntington disease: HDQLIFE Chorea.

Huntington's disease (HD) is an autosomal dominant neurodegenerative disease associated with motor, behavioral, and cognitive deficits. The hallmark symptom of HD, chorea, is often the focus of HD clinical trials. Unfortunately, there are no self-reported measures of chorea. To address this shortcoming, we developed a new measure of chorea for use in HD, HDQLIFE Chorea. Qualitative data and literature reviews were conducted to develop an initial item pool of 141 chorea items. An iterative process, including cognitive interviews, expert review, translatability review, and literacy review, was used to refine this item pool to 64 items. These 64 items were field tested in 507 individuals with prodromal and/or manifest HD. Exploratory and confirmatory factor analyses (EFA and CFA, respectively) were conducted to identify a unidimensional set of items. Then, an item response theory graded response model (GRM) and differential item functioning analyses were conducted to select the final items for inclusion in this measure. EFA and CFA supported the retention of 34 chorea items. GRM and DIF supported the retention of all of these items in the final measure. GRM calibration data were used to inform the selection of a 6-item, static short form and to program the HDQLIFE Chorea computer adaptive test (CAT). CAT simulation analyses indicated a 0.99 correlation between the CAT scores and the full item bank. The new HDQLIFE Chorea CAT and corresponding 6-item short form were developed using established rigorous measurement development standards; this is the first self-reported measure developed to evaluate the impact of chorea on HRQOL in HD. This development work indicates that these measures have strong psychometric properties; future work is needed to establish test-retest reliability and responsiveness to change.

Practice Effects and Stability of Neuropsychological and UHDRS Tests Over Short Retest Intervals in Huntington Disease.

In Huntington disease (HD), cognitive changes due to disease-progression or treatment are potentially confounded by "practice effects" (PE)--performance improvement from prior exposure to test materials. A practice run-in ("dual baseline") was used in an HD cognitive trial to determine if PE could be minimized and evaluate performance trajectories over multiple visits. Non-depressed adults (N = 36) with mild to moderate HD-related cognitive deficits participated in a clinical trial to examine the efficacy of citalopram to enhance cognition. Cognitive tests were administered at three visits (2 weeks separating each visit), before active treatment randomization. Some tests were also administered at screening. Therefore 3-4 pre-treatment repetitions were available. We examined test improvement using repeated-measures ANOVAs with planned pairwise comparisons. Despite the practice run-in and use of alternate test forms, results indicated ongoing improvements over at least three test sessions on all three UHDRS cognitive tests. Trails A and B showed improvements between the third and fourth session, which suggests that one pre-baseline visit may not be effective in reducing practice on this important and commonly used test. Overall, 7 out of 13 variables showed some degree of short-term PE, even after multiple sessions and alternate forms. Tests assessing processing speed and memory may be particularly confounded by ongoing PE across at least 2-3 sessions. Practice run-in periods and alternate forms may help minimize the impact of such effects in HD clinical trials but awareness of which tests are most susceptible to PE is important in clinical trial design.