Huntington’s Disease Clinical Trials Corner: March 2024

INTRODUCTION

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

We have changed the title of this series from “Huntington’s Disease Clinical Trials Corner” to “Huntington’s Disease Clinical Trials Update”. This reflects our commitment to delivering a comprehensive and scholarly exploration of the latest developments in HD research in a series that has been regularly published since 2017.

In this edition, we highlight the VO659-CT01 (NCT05822908) [1] and the VIBRANT-HD (NCT05111249) [2] clinical trials. Finally, in the “Breaking news” section, we discuss preliminary announcements from UniQure’s AMT-130 program (NCT04120493 [3] and NCT05243017 [4]) and the PIVOT HD (NCT05358717) [5] trials.

We tabulate all currently registered and ongoing clinical trials in Tables 2 –4. For further details on the methodology used, please refer to the first edition of this series [6].

If you would like to draw attention to specific trials, please feel free to email us at: and .

ONGOING CLINICAL TRIALS

A list of all registered clinical trials is given in Tables 2 –4.

VO659-CT01 (NCT05822908) [1].

Study title: A Safety and Pharmacokinetics Trial of VO659 in SCA1, SCA3 and HD.

Intervention: Intrathecally administered VO659, an antisense oligonucleotide (ASO) targeting CAG repeats.

Description: The VO659 clinical trial, sponsored by VICO Therapeutics, aims to evaluate the safety and tolerability of four intrathecal doses of VO659 in adults (≥25 and ≤60 years of age) with mild to moderate spinocerebellar ataxia 1 (SCA1) or spinocerebellar ataxia 3 (SCA3) and in patients with early HD.

This study is a phase 1/2a clinical trial aiming to recruit 65 patients assigned to dose-ascending treatment cohorts. The first two cohorts will include only SCA1 and SCA3 participants while from cohort three onwards also HD patients will be included. Participants will be treated with four doses of VO659 every four weeks and will be followed up for additional 23 weeks after the last dose.

The primary outcome will be safety, determined through the proportion of adverse events, laboratory parameters in blood and cerebrospinal fluid (CSF), brain MRI and suicidal ideation. The main secondary outcomes are related to characterizing the pharmacokinetic data of VO659. Additional exploratory include assessing the pharmacodynamic profile and clinical effects of VO659.

Sponsor/Funders: VICO Therapeutics B. V.

Comments: There are nine neurodegenerative disorders caused by expanded CAG repeats, leading to elongated polyglutamine (polyQ) stretches in the encoded proteins. These enlarged polyQ proteins are believed to trigger neuronal death partially or substantially through gain-of-function mechanisms [7]. In these conditions, decreasing the concentrations of the mutant proteins could modify disease course.

VO659 is an antisense oligonucleotide (ASO) that targets the RNA produced from CAG repeats in DNA, having the potential to treat all polyQ disorders with a single compound. Its HTT mechanism acts through steric blocking of protein translation, leading to decreased concentrations of polyQ proteins without degrading the mRNA transcript. In SCA3 it induces exon skipping of the exon containing the CAG repeat, leading to a premature stop codon. VO659 has a preference to bind larger CAG repeats, being expected to lower the mutant proteins to a larger extent than the wild-type isoforms. Its RNA target implies it should act on exon-1-containing RNA HTT species, potentially including misspliced exon 1 variants.

VO659 produced dose-dependent reductions in mutant polyQ proteins in different mouse models of polyQ diseases. In the R6/2 HD mice, intracerebroventricular dosing led to decreased mutant Huntingtin (mHTT) concentrations alongside increased brain volumes and improved motor performance [8].

A study with intrathecal dosing of VO659 in non-human primates showed good drug distribution, with larger concentrations in the spinal cord, cerebellum and cortical regions compared with deep subcortical structures. There were no increases in neurofilament light (NfL) protein in the cerebrospinal fluid (CSF) of treated animals. VO659 has a long half-life after intrathecal administration, supporting infrequent dosing regimes [9].

The main drawback of this approach is its lack selectivity against other wild-type CAG-repeat containing genes, requiring close monitoring particularly prior to dose increases. This trial is already recruiting and the first participant with SCA3 was dosed in April 2023 [10].

COMPLETED CLINICAL TRIALS

VIBRANT-HD (NCT05111249) [2].

Study title: A Dose Range Finding Study With Open-Label Extension to Evaluate the Safety of Oral LMI070/Branaplam in Early Manifest Huntington’s Disease (VIBRANT-HD).

Intervention: Oral branaplam, a small molecule splicing modulator lowering the production of the Huntingtin (HTT) protein.

Description: The VIBRANT-HD clinical trial, sponsored by Novartis, aimed to select a safe and tolerable dose of branaplam that lowered mHTT in CSF to a degree sufficient to achieve disease modification.

It was a phase 2 clinical trial including adults (≥25 and ≤75 years of age) with early manifest HD. This double-blind, placebo-controlled study evaluated the effects of multiple doses of branaplam in three dose cohorts. The study drug was planned to be administered during a period of 17 weeks followed by a blinded extension of 53 additional weeks.

The primary outcome of VIBRANT-HD was to determine the dose-response relationship of branaplam on mHTT protein change from baseline to week 17 as well as the safety during the study period.

The recruitment target was 75 participants. However, the trial was stopped after 26 participants were enrolled in the first study cohort, due to the identification of findings suggestive of peripheral neuropathy in treated participants.

Sponsor/Funders: Novartis Pharmaceuticals

Comments: Branaplam was initially developed for the treatment of spinal muscular atrophy as it restores the full-length SMN2 transcript [11]. However, it also lowers HTT expression through the inclusion of a pseudoexon leading to premature stop codons in the mature HTT transcript. Branaplam rescued motor phenotypes in the BACHD mice and has wide distribution after oral administration, including good penetration into the basal ganglia [11].

Preclinical studies also found peripheral axonal damage in dogs treated with branaplam. In consequence, the study protocol of VIBRANT-HD included detailed assessments to detect peripheral neuropathy [12]. Soon after the recruitment of the first cohort there were signals suggestive of peripheral neuropathy in two participants, with 78% of study participants eventually developing at least one sign or symptom of peripheral neuropathy during the study period. These findings led initially to the temporary suspension of the drug and eventually the termination of the study.

Preliminary analysis presented in 2023 showed that there were decreases of CSF mHTT up to 26.6% in treated patients at 17 weeks. However, there were also NfL increases in serum after 9 weeks of treatment although these tended to decrease thereafter, even in patients that continued dosing longer than 9 weeks. There were also increases in ventricular volume up to 9.5% at 17 weeks in patients on branaplam compared to 1.6% volume increases in participants on placebo. Following termination of the study, adverse findings in volumetric MRI and peripheral neuropathy showed evidence of reversal. Similar adverse events were reported in GENERATION HD1 (NCT03761849), testing tominersen, a non-allele selective ASO targeting HTT [13].

While disappointing, these findings affirm the value of NfL as a reactive potential marker of safety and undesirable neuroaxonal damage for clinical trials in HD. As discussed below, another small-molecule splicing modulator has since been reported as not showing any such early increases in NfL, suggesting these untoward reactions are neither a class effect of HTT-lowering splice modulators, nor of HTT lowering in general.

BREAKING NEWS

AMT130 is a modified viral vector engineered to express a microRNA targeting exon 1 HTT mRNA (rAAV5-miHTT). Intracranial administration of AMT130 at two different doses is being tested in two clinical trials including early HD participants (NCT04120493 [3] and NCT05243017 [4]). Following a pause in recruitment [14] the trial was restarted in 2023. Two updates from the sponsor in 2023 showed that following an expected initial increase in CSF NfL shortly after the surgical procedure, the concentrations of the biofluid biomarker returned to baseline concentrations. There were no persistent serious adverse events. The sponsor also reported favorable trends in clinical scales compared with matched natural history cohorts, although only six participants had follow up periods longer than 18 months [15, 16].

PTC518 is an orally bioavailable small-molecule splicing modulator that targets HTT mRNA. It is being tested in early HD patients participating in the PIVOT-HD (NCT05358717) [5] clinical trial. An interim data analysis in June 2023 showed that at 12 weeks there was dose-dependent lowering of HTT in blood cells. There were high concentrations of PTC518 in CSF. Importantly, there were no increases in CSF NfL and no treatment-related adverse events despite intense monitoring for peripheral neuropathy [17].

FUNDING

CEF has received speaking honoraria from Roche España. SJT receives research grant funding from the CHDI Foundation, Vertex Pharmaceuticals, the UK Medical Research Council, the Wellcome Trust and the UK Dementia Research Institute that receives its funding from DRI Ltd., funded by the UK MRC, Alzheimer’s Society, and Alzheimer’s Research UK. EJW is supported by CHDI Foundation, Inc. EJW reports grants from CHDI Foundation, and F. Hoffmann-La Roche Ltd.

CONFLICT OF INTEREST

CEF was an investigator in the LEGATO-HD (NCT02215616), IONIS HTTRx OLE (NCT0-3342053), GENERATION-HD1 (NCT03761849), Roche Natural History Study (NCT03664804), Roche GEN-EXTEND (NCT03842969), Roche GEN-PEAK (NCT04000594), uniQure AMT-130 (NCT05243017), Triplet Therapeutics SHIELD-HD (NCT04406636), VIBRANT-HD (NCT05111249), PIVOT HD (NCT05358717) trials.

SJT has undertaken consultancy services for Annexon, Alphasights, Alnylam Pharmaceuticals Inc., Atalanta Pharmaceuticals (SAB), F. Hoffmann-La Roche Ltd/Genentech, Guidepoint, Horama, Locanobio, LoQus23 Therapeutics Ltd (SAB), Novartis Pharma, PTC Therapeutics, Sanofi, Spark Therapeutics, Takeda Pharmaceuticals Ltd, Triplet Therapeutics (SAB), University College Irvine and Vertex Pharmaceuticals Incorporated. All honoraria for these consultancies were paid through the offices of UCL Consultants Ltd., a wholly owned subsidiary of University College London. SJT has a patent Application number 2105484.6 on the FAN1-MLH1 interaction and structural analogues licensed to Adrestia Therapeutics. SJT was an investigator on IONIS HTTRx (NCT02519036), IONIS HTTRx OLE (NCT03342053), GENERATION-HD1 (NCT03761849), Roche Natural History Study (NCT03664804), uniQure AMT-130 (NCT05-243017), SHIELD-HD (NCT04406636), PIVOT HD (NCT05358717) and Roche GEN-EXTEND (NCT03842969) trials.

EJW has undertaken consultancy/advisory board work with Hoffman La Roche Ltd, Triplet Therapeutics, Takeda, Vico Therapeutics, Voyager, Huntington Study Group, Teitur Trophics, EcoR1 Capital, PTC Therapeutics, Alnylam, Annexon Biosciences and Remix Therapeutics. He has participated in advisory boards for Hoffmann La Roche, Triplet therapeutics and PTC therapeutics. All honoraria for these consultancies were paid through the offices of UCL Consultants Ltd., a wholly owned subsidiary of University College London. He holds a stock option for Triplet Therapeutics in part compensation for advisory board membership. EJW was an investigator in the Amaryllis (NCT02197130), LEGATO-HD (NCT02215616), IONIS HTTRx (NCT02519036), IONIS HTTRx OLE (NCT03342053), GENERATION-HD1 (NCT03761849), Roche Natural History Study (NCT03664804), Roche GEN-EXTEND (NCT03842969), VIBRANT-HD (NCT05111249), PIVOT HD (NCT05358717), Roche GEN-PEAK trial (NCT04000594) and uniQure AMT-130 (NCT05243017).

The authors did not make use of confidential or privileged information: all materials included in this manuscript were collected from publicly available sources.