Huntington’s Disease Clinical Trials Corner: January 2019

Study title

A Randomized, Multicenter, Double-Blind, Placebo-Controlled, Phase III Clinical Study to Evaluate the Efficacy and Safety of Intrathecally Administered RO7234292 (RG6042) in Patients With Manifest Huntington’s Disease [1].

Intervention

RG6042 (120 mg) – formerly known as IONIS-HTT_Rx / ISIS443139 – an antisense oligonucleotide that targets the HTT transcript allele-nonspecifically with the aim of lowering the production of mutant huntingtin protein [8].

Description

The GENERATION-HD1 trial, sponsored by Hoffmann-La Roche, aims to evaluate the efficacy, safety, and biomarker effects of monthly and bimonthly (i.e. every other month) 120 mg of intrathecal RG6042 in adults (25 to 65 years of age) with manifest HD (i.e. a UHDRS Diagnostic Confidence Level of 4, a UHDRS Independence Score [IS] above or equal to 70, and a CAG-age Product equal or greater than 400) and intact functional independence at baseline to maintain self-care and core activities of daily living, comparing with intrathecal placebo, for disease modification.

This trial is a phase 3, international, multi-centre, randomized, placebo controlled, double-blind, parallel study. It will have 3 study arms: monthly intrathecal injections of 120 mg RG6042; monthly intrathecal injections alternating between 120 mg RG6042 and placebo; and monthly intrathecal placebo. The intervention will be administered for 25 months, and participants will be followed for 29 months. All participants are expected to be invited to an optional open-label extension (OLE) involving monthly or bimonthly (i.e. every other month) drug administration after the end of the blinded phase of the study, assuming the program is continuing.

The trial had not started recruitment at the time of writing, but has a recruitment target of 660 participants, over around 15 countries and 80 to 90 study sites, and it is planned to start enrolment by early 2019. It is currently public that recruitment will happen in the United States of America and Canada, where expected clinical sites were announced in December [9]. Details about further countries and sites will be released in the future.

This pivotal trial will have two primary clinical outcomes for regulatory purposes, the UHDRS Total Functional Capacity (TFC) for the FDA, and the composite UHDRS (cUHDRS) [10] for the EMA [11]. Secondary outcomes will involve other components of the UHDRS, clinical global impression, adverse events, the Montreal Cognitive Assessment (MoCA), the Columbia-Suicide Severity Rating Scale (C-SSRS), pharmacokinetic markers, cerebrospinal fluid mutant huntingtin and neurofilament light chain, and MRI brain volumes.

Comments

This trial is the first to test huntingtin-lowering in a pivotal phase 3 trial, and is part of a development plan that includes the completed first-in-man phase 1b/2a IONIS-HTT_RX (NCT02519036) trial [12], its ongoing OLE (NCT03342053) [13], the now-recruiting HD Natural History Study (NCT03664804) [14], and the imminent GENERATION-HD1 (NCT03761849) trial [1]. The phase 1b/2a involved 46 people with early stage HD and showed RG6042 to be safe and well-tolerated, and to reduce cerebrospinal fluid mutant huntingtin concentrations in a dose-dependent manner [15]. Results are currently being prepared for peer-reviewed publication [11]. After completion, all participants were invited to an OLE study aimed at studying long-term safety, tolerability, pharmacokinetics and pharmacodynamics of RG6042 over 15 months; this is currently ongoing. Participants entering the OLE were randomly allocated to monthly or bimonthly intrathecal doses of 120 mg RG6042.

The HD Natural History Study is a prospective longitudinal observational study that aims to recruit 100 people with early stage HD, matched individually to the participants of the open label extension study [16]. It aims to measure clinical and biomarkers (i.e. cerebrospinal fluid neurofilament light chain, mutant huntingtin and tau, brain MRI volumes, and digital biomarkers) over a 15-month period in a sample comparable to the phase 1b/2a and open label extension studies. Participants are being recruited in United States of America, Canada, Germany and United Kingdom. Participants will be offered continued open-label access to RG6042 after study termination.

Notably, for the pivotal phase 3 trial, GENERATION-HD1, Roche has opted for an enrichment strategy based on the inclusion criterion “CAG-age Product superior to 400”. The CAG-age product (CAP score) is an estimate of lifetime exposure to mHTT toxicity [17], given by:

[HTT CAG repeat length – 33.66] × age

Together with the remaining inclusion criteria, namely the UHDRS Diagnostic Confidence Level of 4, a UHDRS IS above or equal to 70, and functional independence at baseline, the use of a CAP score cutoff aims to produce a relatively homogeneous sample of early stage participants, whose expected progression during trial follow-up is greater and less variable [17]. This should improve the statistical power of the sample. It produces rigid minimum age cutoffs for each HTT CAG repeat length, as shown in Table 5. This criterion will doubtless be a point of focus in discussions with potential volunteers.

Study title

A Longitudinal Cohort Study With Nested Randomised Pragmatic Controlled Trial to Evaluate Physical Activity and Exercise Related Outcomes in People With Huntington’s Disease (PACE-HD) [2].

Intervention

Supported structured aerobic exercise training program (18 face-to-face coaching sessions of ∼1 hour).

Description

The PACE-HD trial, sponsored by Cardiff University and CHDI Foundation, Inc., aims to evaluate the feasibility, tolerability, and safety of supported structured aerobic exercise training program in adults (≥18 years of age) with genetically confirmed early manifest HD, compared with activity as usual.

PACE-HD is an international, multi-centre, observation study with a nested randomized, controlled, open label, parallel study. It will involve 120 participants, 60 of whom will take part on a longitudinal observational evaluation of physical fitness and physical activity over a period of 12 months, while the remaining 60 will be randomized to a supported structured aerobic exercise training program, or exercise as usual over a period of 12 months. Recruitment is currently open at various sites in the United States of America, Germany, and Spain.

The primary outcomes are data completeness, recruitment, retention, safety, adherence, fidelity, and acceptability. Secondary outcomes include exercise tests, walk endurance measures, the HD Pro-Triad, the Brunel Lifestyle Physical Activity Questionnaire, and digital biomarkers.

Comments

With multiple trials of agents intended to engage with the core pathobiology of HD underway, and more planned, the relevance of clinical interventions such as rehabilitation therapies, as both stand-alone and adjunctive therapies, has never been more significant. Similar to current management guidelines for Parkinson’s disease [18] and multiple sclerosis [19], rehabilitation therapies - including physiotherapy, occupation therapy, exercise and physical activity - could be used alongside disease-modifying interventions with the potential to maximize patient outcomes.

Animal models of HD have provided pre-clinical evidence that exercise has the potential to modify disease progression. In R6/1 mice, sustained wheel running was shown to improve gait and motor coordination, as well as reduce striatal neuron loss [20]. More recent work with the longer life-span CAG140 mouse model demonstrated that 6 months of treadmill training resulted in increased striatal dopamine D2 receptor expression and dopamine neurotransmitter levels, reduction in HTT aggregate formation, as well as improved behavioural and cognitive symptoms [21]. These pre-clinical findings have set the stage for several clinical feasibility studies in people with early and moderate HD [22–25], as well as in several multi-disciplinary rehabilitation trials [26–30].

Combined pre-clinical and clinical data provide support for the evaluation of exercise as a therapeutic intervention strategy in HD. A recent systematic review reported on findings from 20 studies and found preliminary support for the benefits of exercise and physical activity in terms of motor function, gait speed, and balance [31, 32]. The review also reported a range of physical and social benefits identified through patient-reported outcomes. Interventions incorporating aerobic and strengthening exercises were most prevalent across studies, and several studies noted improvement or maintenance of motor function over 9 months or longer.

In order for rehabilitation interventions to be considered an important adjunctive therapy alongside pharmacological interventions, high-quality studies using innovative statistical methods and trials designs are needed. PACE-HD is a pragmatic study that includes both a longitudinal observational study and a nested (i.e. within-cohort) randomized controlled trial of a 12-month physical therapy and exercise intervention. The intervention incorporates the use of wearable physical activity monitors to measure both outcomes and activity levels throughout the trial. The study is conducted alongside Enroll-HD, which minimizes subject burden and will provide a basis for comparative analysis on disease progression measures. Results of this study are due in the summer of 2020.

A formal Clinical Guideline for Exercise in HD is currently in development. This will provide evidence-based recommendations for healthcare providers and persons with HD, and is planned to be available later in 2019.