Huntington’s Disease Clinical Trials Corner: August 2023

INTRODUCTION

The Clinical Trials Corner is a regular feature devoted to highlighting ongoing and recently completed clinical trials in Huntington’s disease (HD). Clinical trials previously reviewed by the Huntington’s Disease Clinical Trials Corner are listed in Table 1.

In this edition, we highlight the ongoing clinical trials GENERATION HD2 (NCT05686551) [1] and the Asklepios Biopharmaceutical/BrainVectis trial with AB-1001 (NCT05541627) [2]. Finally, we discuss also results from the PROOF-HD (NCT04556656) [3] trial in the “Breaking news” section. We tabulate all currently registered and ongoing clinical trials in Tables 2 to 4. For further details on the methodology used, please refer to the first edition of Huntington’s Disease Clinical Trials Corner [4].

If you would like to draw attention to specific trials, please feel free to email us at: c.fraga@ucl.ac.uk and e.wild@ucl.ac.uk.

ONGOING CLINICAL TRIALS

A list of all registered clinical trials is given in Tables 2, 3 and 4.

GENERATION HD2 (NCT05686551) [1]

Study title: A Study to Evaluate the Safety, Biomarkers, and Efficacy of Tominersen Compared With Placebo in Participants With Prodromal and Early Manifest Huntington’s Disease

Intervention: Intrathecally administered tominersen (120 mg) – formerly known as IONIS-HTTRx/ ISIS443139 / RG6042– is an antisense oligonucleotide that targets the Huntingtin (HTT) transcript non-allele-selectively lowering the production of mutant huntingtin protein.

Description: The GENERATION HD2 clinical trial aims to evaluate the safety, efficacy and biomarker effects of two doses of tominersen (60 mg and 100 mg) administered to patients between 25 and 50 years of age with prodromal and early manifest HD (equivalent stages 2 and 3 of the Huntington’s disease Integrated Staging System [5] (HD-ISS)) and a CAG-age product (CAP score) between 400 and 500.

GENERATION HD2 is a phase 2, international, multicentre, randomized, placebo-controlled, double-blind parallel study with the aim of selecting a safe dose of tominersen that lowers CSF mutant Huntingtin (mHTT) protein and shows a tendency towards efficacy. Participants will be randomized 1 : 1:1 to receive intrathecal infusions every 16 weeks with 60 mg or 100 mg of tominersen or placebo.

Participants will receive the study drug during 16 months followed a safety follow up period of 5 months and an optional OLE. After the 16-month double-blind treatment period concludes, participants will remain on blinded treatment until all study participants have completed 16 months of treatment

GENERATION HD2 plans to recruit 360 participants in 15 countries. The primary outcome will be safety. Other primary outcomes include change in cerebrospinal fluid (CSF) white cells, change in CSF total protein, change in CSF mHTT, change in structural brain MRI and clinical change measured through the Total Functional Capacity (TFC) and the composite Unified Huntington’s Disease Rating Scale (cUHDRS) [6, 7].

Sponsor/Funders: Hoffman-La Roche

Comments: Tominersen has been tested in the phase 1b/2a IONIS-HTT_RX (NCT02519036) [8], its OLE (NCT03342053) [9], and the phase 3 GENERATION HD1 [10] (NCT03761849) clinical trials, showing dose dependent decreases in CSF mHTT. In GENERATION HD1 (NCT03761849), following two loading doses of 120 mg with an interval of 4 weeks, early and moderate HD participants received placebo or tominersen at a dose of 120 mg every eight (Q8) or every 16 (Q16) weeks. In 2021 the trial was prematurely stopped following an unblinded review, showing that participants in the Q8 cohort had worse scores in clinical scales compared to participants on placebo, while there were no significant differences between the Q16 group and placebo [11]. There were also dose-dependent increases in ventricular volume over the study period, above 25% over 69 weeks in patients on the Q8 dose regime and above 15% increases among participants in the Q16 cohort [11]. These ventricular increases receded after tominersen administration was paused [11].

More recently, a post-hoc subgroup analysis of GENERATION HD1 by the study sponsor showed a non-statistically significant beneficial tendency among Q16 participants that were below the median for the age and disease burden, measured through the CAP score (a product of age and CAG repeat length). In this subgroup, point estimates for the cUHDRS as well as its functional, cognitive, and motor subscales, were in the favourable direction at 69 weeks. These effects were more marked in participants with lower exposure to the drug [7].

Based on these results the sponsor has developed the GENERATION HD2 trial, where younger participants with lower disease burden will receive lower doses of the drug with a 16-weeks interval without loading doses. GENERATION HD2 will evaluate whether there is potential benefit for Q16 administration of the lower 60 mg and 100mg doses in this study population.

AB-1001 (NCT05541627) [2]

Study title: A Study to Evaluate AB-1001 Striatal Administration in Adults With Early Manifest Huntington’s Disease

Intervention: AB-1001 (also known as BV-101 and AAVrh10.CAG.hCYP46A1) is an adeno-associated viral vector serotype Rh10 containing the human cholesterol 24-hydroxylase gene administered through one-off intrastriatal bilateral injections

Description: The goal of the AB-1001 trial is to evaluate the safety of the intrastriatal administration of AAVrh10.CAG.hCYP46A1 in adults (18–65 years) with early manifest HD. It will evaluate two doses of the gene therapy construct administered through bilateral injections into the caudate and putamen.

The study plans to recruit between 12 and 18 participants in France and consists of a dose-finding and a dose expansion periods with participants being followed up total of 5 years following screening [12].

Eligible participants need to have stable HD and striatal volumes in the screening MRI, being larger than 2.3 cm per side for the putamen and larger than 1.7 cm per side for the caudate. Exclusion criteria include unstable or serious medical conditions other than HD, previous gene therapy or administration experimental agents through brain surgery or inability to undergo the study procedures.

Secondary outcomes include change from baseline in volumetric MRI, cUHDRS, CSF mHTT, neurofilament light chain (NfL) and 24-OH-cholesterol as well as changes in magnetic resonance spectroscopy and in the positron emission tomography (PET) fluoro-deoxyglucose (FDG) striatal profile.

Sponsor/Funders: Asklepios Biopharmaceutical (AskBio) / BrainVectis

Comments: Changes in cellular cholesterol metabolism are associated with neurodegeneration in HD [13]. The cholesterol 24-hydroxylase (CYP46A1) enzyme converts cholesterol to 24S-hydroxycholesterol which can cross the blood-brain barrier and be degraded in the periphery [14]. However, the concentrations of CYP46A1 are decreased in the striatum of HD patients and animal models of HD [15]. Consistently, there is increased accumulation of cholesterol in striatal neurons [15]. Administration of CYP46A1 gene therapy to the zQ175 knock-in HD mice restored cholesterol homeostasis and prevents neuronal dysfunction decreasing mHTT aggregates, improving axonal transport of BDNF and endosomal trafficking [16].

AB-1001 has shown to improve motor behaviour, decrease mHTT aggregates and NfL concentrations in the R6/2 mouse model of HD [17]. MRI-guided striatal infusions of AB-1001 are also well tolerated in non-human primates [17]. However, the complex cholesterol pathways have not been well studied in human HD patients. Any intraparenchymal gene therapy approach to HD is permanent and high-risk by definition, and it remains to be seen whether any potential benefits will justify the risk.

During this trial, participants will be recruited first into a dose-finding cohort receiving either a low dose (4x10⁸ vg/μL) or a high dose (1.1x10⁹ vg/ μL) of the study construct. The data will be reviewed for dose-limiting toxicities after each cohort is fully recruited and the dose expansion cohort will receive the dose selected after the initial phase. This study is already recruiting participants in France and presents a different approach for disease modification compared to HTT-lowering therapies.

BREAKING NEWS

Sigma-1-regulated pathways are altered in different neurodegenerative disorders, including HD [18]. Activation of the sigma-1-receptor positively influences these pathways in model systems [19]. The PROOF-HD (NCT04556656) [3] clinical trial investigated pridopidine, a sigma-1-receptor agonist at a dose of 45 mg twice a day versus placebo. Pridopidine was previously tested as a dopaminergic stabiliser in the HART (NCT00724048 [20], NCT01306929 [21]), MermaiHD (NCT00665223 [22, 23]), and PRIDE-HD (NCT02006472 [24], NCT02494778 [25]) but failed to meet primary endpoints.

In the PROOF-HD trial, the primary (TFC) and the key secondary (cUHDRS) endpoints were not met at 65 weeks [26]. The drug was again well tolerated without significant side effects. A planned subgroup analysis showed possible benefit in treated participants compared with placebo, when participants on antidopaminergics were excluded [26]. The significance of these findings is unclear, and antidopaminergic medications are widely used in HD to treat motor and behavioural symptoms. Based on these findings the company is now considering its options for the future of the compound.