Huntington’s Disease Clinical Trials Corner: November 2022

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 PIVOT HD (NCT05358717) [1] and the recently completed SIGNAL (NCT05358717) [2] clinical 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 Huntington’s Disease Clinical Trials Corner [3].

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.

In this edition we also introduce a ‘breaking news’ section where we will provide recent updates about the ongoing SELECT-HD (NCT05032196) [4], VIBRANT-HD (NCT05111249) [5], and uniQure AMT-130 (NCT05243017 and NCT04120493) [6, 7] trials.

ONGOING CLINICAL TRIALS

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

PIVOT HD (NCT05358717)

Study title: A Study to Evaluate the Safety and Efficacy of PTC518 in Participants With Huntington’s Disease (HD) [1].

Intervention: Once daily oral PTC518, a small molecule HTT splicing modulator.

Description: The PIVOT HD study aims to evaluate the safety and efficacy of PTC518, a Huntingtin (HTT) lowering small molecule in patients with HD. Participants need to be fully independent with scores in the HD normalized prognostic index (PINHD) between 0.18 and 4.93, encompassing from prodromal to early manifest participants.

PIVOT HD is a phase 2a randomized, multicentre, international, placebo-controlled, parallel assignment trial with a recruitment target of 162 participants. Participants will be randomized to receive 5 mg, 10 mg or 20 mg of PTC518 or placebo during 12 weeks. Recruitment is already open in the United States, Germany and the United Kingdom while sites in Australia, France and Netherlands are expected to start recruitment soon. The primary outcome will be safety and tolerability at 113 days while secondary outcomes include reduction in mutant HTT (mHTT) protein in cerebrospinal fluid (CSF) and total mHTT protein in blood, alongside effects in imaging biomarkers.

Sponsor/Funders: PTC Therapeutics.

Comments: PTC518 has been specifically developed for HD through a drug discovery platform to identify splicing modulators among > 300,000 compounds. PTC518 is an orally bioavailable small molecule that modulates the splicing of HTT pre-mRNA leading to the inclusion of a pseudoexon [8]. This inclusion results in a premature termination codon, leading to the degradation of HTT mRNA. Consequently, non-allele selective decreases in the HTT protein are expected. PTC518 is expected to decrease mHTT uniformly across the brain, including cortical and striatal areas and drug effects are potentially titratable and reversible. The sponsor claims that, in contrast to branaplam mdash  mdash the other splicing modulator to have reached a clinical trial in HD –PTC518 is not effluxed from brain, permitting lower doses with less potential liability from systemic HTT lowering. The study drug has been already tested in healthy volunteers during a phase 1 clinical trial (PTC518-CNS-001-HD) showing a favourable safety profile, and leading to dose-dependent decreases in HTT mRNA in blood [9]. There is a plan for a longer open-label extension trial after the termination of the phase 2a study.

COMPLETED CLINICAL TRIALS

SIGNAL (NCT02481674)

Study title: A Study in Subjects with Late Prodromal and Early Manifest HD to Assess the Safety, Tolerability, Pharmacokinetics, and Efficacy of Pepinemab (SIGNAL)

Intervention: Pepinemab (VX15/2503), an anti-semaphorin 4D antibody (SEMA4D) [2], administered as once monthly infusions

Description: The SIGNAL trial aimed to investigate the effects of pepinemab in participants with early manifest or late prodromal HD. It was divided into two cohorts. Cohort A included 36 participants receiving placebo or pepinemab during 6 months, followed by 6 months where the drug was administered to all study participants.

In cohort B early manifest (n = 179) and late prodromal (n = 86) HD participants received four-weekly intravenous administrations of pepinemab at a dose of 20 mg/kg. Participants were treated during 18 months followed by 3 months safety follow up. The primary outcome for this study was safety and tolerability. Coprimary efficacy outcomes included the clinical global impression of change (CGIC) and two subitems from the HD cognitive assessment battery (HD CAB): the one-touch stockings of Cambridge (OTS) and paced tapping (PTAP).

Sponsor/Funders: Vaccinex Inc.

Comments: Neuroinflammation is one of the core pathogenic mechanisms in HD [10]. SEMA4D is a protein of the semaphorin family involved in immune regulation [11]. In the brain, it regulates the transition to reactive states in glial cells [2]. Blockade of SEMA4D with immunotherapy improved pathology and clinical phenotypes in the YAC128 mice [12].

The safety profile showed similar tolerability and adverse events between participants in the active drug and participants in the placebo group. Efficacy outcomes for early manifest participants did not show significant differences in the CGIC scale, although there were statistically significant changes favouring the active arm in the OTS, while findings in the PTAP were not significant. In contrast, clinical scales including the UHDRS-Total Motor Score, UHDRS-Total Functional Capacity; or the quantitative Q-motor assessment tool did not differ between groups.

Structural imaging findings showed statistically significantly reduced rates of caudate atrophy treatment and increased FDG-PET signal in patients on active treatment. The sponsor has interpreted these as supportive of a therapeutic effect, but it is also possible that other explanations such as inflammation or oedema could produce these outcomes.

There were no significant differences in efficacy outcomes among late prodromal participants. A post hoc analysis of early manifest participants showed that participants with more advanced disease tended to show better clinical outcomes. In consequence, a future phase 3 clinical trial with pepinemab could include participants with moderate stage HD. It has not yet been announced whether a larger trial will be run or what form it may take.

BREAKING NEWS

In this new section we will provide brief updates about ongoing or recently terminated clinical trials.

The SELECT-HD (NCT05032196) [4] clinical trial investigates WVE-003, an allele selective antisense oligonucleotide targeting HTT pre-mRNA at different doses versus placebo. A recent press release from Wave Life Sciences Ltd. reported that participants receiving a single administration of WVE-003 (combined data for 30 mg and 60 mg groups) had decreased CSF mHTT concentrations compared to baseline, while the concentrations of the wild-type Huntingtin (wtHTT) protein remained unchanged. There was no dose-dependent effect found and nor did these results reach statistical significance. Additional subjects are now being recruited to these dosing cohorts. Adverse events were well balanced between groups, but there were increases in the concentrations of CSF neurofilament light protein (NfL) -a marker of axonal damage- from baseline in some patients. The trial is currently ongoing and a higher dose cohort is expected to be recruited soon [13].

In contrast, the VIBRANT-HD (NCT05111249) [5] clinical trial evaluates branaplam, an orally available small molecule repurposed from spinal muscular atrophy (SMA) trials. Branaplam decreases the concentrations of mHTT and wtHTT through pseudoexon inclusion [14]. Dosing in VIBRANT-HD has been suspended in August based on findings suggesting incipient peripheral neuropathy in some patients, including clinical manifestations, neurophysiological abnormalities and increases in blood NfL [15].

Finally, the uniQure AMT-130 clinical trials (NCT05243017 and NCT04120493) [6, 7] investigates the effects of AMT-130. AMT-130 consists of a viral vector containing a microRNA targeting the HTT gene (AAV5-miHTT). This gene therapy is administered intracranially and its effects are expected to last for years. AMT-130 has been administered to 10 patients with early HD at a low dose, showing decreases of CSF mHTT of 53.8%compared to baseline in the treated group [16]. However, in July three suspected unexpected adverse reactions (SUSARs) were reported among participants in the higher-dose cohort. These participants showed inflammatory responses and severe headaches in the weeks after drug administration and have recovered since then. Enrolment in the lower dose cohort continued but recruitment was paused in the higher dose cohort waiting for further safety review, being restarted only recently [17].