Huntington’s Disease Clinical Trials Corner: April 2022

VIBRANT-HD (NCT05111249)

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) [1]

Intervention: Once weekly oral branaplam, a small molecule splicing modulator

Description: The VIBRANT-HD study, sponsored by Novartis Pharmaceuticals, aims to evaluate the dose of branaplam required to lower mutant huntingtin (mHTT) levels in the cerebrospinal fluid (CSF) of HD patients, to a degree expected to achieve disease modification.

VIBRANT-HD is a phase 2 multicentre study with a recruitment target of 75 early HD participants. It has a double-blind, placebo-controlled, multiple-dose design with three dose cohorts and 4:1 active to control randomization rate at each cohort. Participants will be followed up during a dose range finding period of 17 weeks followed by a blinded dose extension of 53 weeks. After the dose is determined, participants will roll over into an Open Label Extension (OLE) study during approximately 1 year that may be prolonged through an amendment or in a separate extension study.

The trial has already started recruiting in Canada, France, Germany, Hungary and Spain and more sites will open recruitment soon.

The primary outcomes will be the reduction of mHTT in CSF from baseline to week 17 and the safety and tolerability from baseline up to approximately two years.

Sponsor/Funders: Novartis Pharmaceuticals

Comments: Branaplam was initially investigated for the treatment of spinal muscular atrophy (SMA) (NCT02268552) where it has shown to stabilise SMN2 pre-mRNA [7]. In the open-label SMA study most adverse events were disease-related with the drug showing a favourable safety profile. Subsequent analysis showed that branaplam also downregulated HTT expression through the enhanced inclusion of a ‘poison exon’ containing a premature stop codon. In consequence, there was a decrease in human HTT mRNA in SMA patients while studies with the BACHD mouse model have shown dose-dependent decreases in mHTT protein levels [8, 9]. PTC Therapeutics has also announced another first-in-patient trial of an oral HTT-lowering splice modulator, PTC518, which will be covered in a future edition of Clinical Trials Corner [10].

SELECT-HD (NCT05032196)

Study title: A Multicenter, Randomized, Double-blind, Placebo Controlled, Phase 1b/2a Study of WVE-003 Administered Intrathecally in Patients With Huntington’s Disease [2]

Intervention: WVE-003, an allele-selective antisense oligonucleotide (ASO)

Description: WVE-003 is an ASO that targets the single-nucleotide polymorphism (SNP) SNP3, an allelic variant linked to the expanded CAG repeat tract in HTT pre-mRNA. The SELECT-HD trial aims to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of WVE-003 administered intrathecally. The active drug will be compared with intrathecal placebo in participants with stage 1 HD who carry SNP3 variant and are aged between 25 and 60 years.

This trial is a phase 1b/2a, multicentre, international, placebo-controlled, double-blind study. SELECT-HD has a single and multiple-ascending dose design. In each cohort, participants will be assigned to receive the active ASO or placebo. The trial has a recruitment target of 36 participants that will be followed up during a minimum of 36 weeks. Recruitment is already open in Canada, France, Poland, Germany, Spain and the United Kingdom.

The primary outcome will be safety and tolerability. Secondary outcomes include pharmacokinetic and pharmacodynamic measurements in plasma and CSF as well as fluid biomarkers and the composite UHDRS (cUHDRS)[2, 11, 12].

Sponsor/Funders: Wave Life Sciences Ltd

Comments: The CAG expansion in the HTT gene is allelically linked to different SNPs enriched in the mutant allele. SNP3 is estimated to be present in the expanded allele of approximately 40% of adults with HD [13]. WVE-003 incorporates a modified phosphoryl guanidine-containing (PN) backbone that has shown to increase the tissue exposure, half-life in the central nervous system and potency of the ASO compared to first generation molecules used in previous HD trials by Wave Life Sciences Ltd [4, 5]. WVE-003 has shown to selectively decrease mHTT mRNA in vitro, as well as in the cortex and striatum in the BACHD transgenic mice. In addition, the presence of SNP3 on the CAG-expanded HTT allele can be identified with 1-2 weeks turnaround time through a novel investigational assay [12].

Results from the PRECISION HD1/2 trials (NCT03225833 and NCT03225846) [4, 5] did not support further development of WVE-120102 and WVE-120101 (see below). Wave Life Sciences has modified the design of SELECT-HD to incorporate learnings from previous trials including a new ASO chemistry, different doses, new methods for rapid patient identification and an adaptative study design.

GENERATION HD1 (NCT03761849)

Study title: A Randomized, Multicenter, Double-Blind, Placebo-Controlled, Phase 3 Clinical Study to Evaluate the Efficacy and Safety of Intrathecally Administered RO7234292 (RG6042) in Patients With Manifest Huntington’s Disease [3].

Intervention: Tominersen (120 mg) – formerly known as IONIS-HTT_Rx / ISIS443139 / RG6042 – is an antisense oligonucleotide that targets the HTT transcript non-allele-selectively with the aim of lowering the production of mutant huntingtin protein.

Description: The GENERATION-HD1 trial, sponsored by Hoffmann-La Roche, aimed to evaluate the efficacy and safety of intrathecal tominersen in adults (25 to 65 years of age) with manifest HD (i.e. a Unified Huntington’s Disease Rating Scale (UHDRS) Diagnostic Confidence Level (DCL) of 4, a UHDRS Independence Score above or equal to 70, and a CAG-age Product (CAP) score equal or greater than 400) and functional independence at baseline to maintain self-care and core activities of daily living, comparing with intrathecal placebo, for disease modification. Initially it was planned to be administered every four (Q4) or every eight (Q8) weeks. However, following the results from the OLE study (NCT03342053) showing increased frequency of adverse events in the four-weekly group [14] the phase 3 protocol was amended to two less frequent dosing frequencies: 120mg tominersen every eight or every 16 weeks.

This trial was a phase 3, international, multi-centre, randomized, placebo controlled, double-blind, parallel study. It had three study arms. The intervention was planned to be administered for 101 weeks, and participants were planned to be followed up for 29 months.

This trial recruited 791 participants over 97 study sites. It started enrolment in 2019. This pivotal trial had two primary clinical outcomes for regulatory purposes, the UHDRS Total Functional Capacity (TFC) for the FDA, and the cUHDRS for the EMA [15]. Secondary outcomes included 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, CSF mHTT, CSF neurofilament light chain (NfL), and MRI brain volumes.

Sponsor/Funders: Hoffman-La Roche

Comments: In 2021, following unblinded review of the data by an Independent Data Monitoring Committee the trial was prematurely terminated [16]. Although there were significant decreases in CSF mHTT, preliminary analysis showed that the Q8 cohort had performed worse in clinical scales compared to placebo, whereas the Q16 group did not show significant differences. These changes affected cognitive, motor, functional scales and the cUHDRS [17].

Participants in the eight-weekly group had transient increases in CSF NfL of approximately 30% above baseline at week 21; these were present but lesser (approximately 10%) in the Q16 cohort. There was an increased frequency of serious adverse events in the Q8 cohort together with dose-dependent increases in ventricular volume and three cases of hydrocephalus [16]. Multiple reasons may be accountable for the results in GENERATION HD1. It is possible that a toxic effect was mediated by excessive dosing. Increased CSF proteins and CSF white cell counts found in the study suggest the possibility of dose-dependent inflammatory reactions against the ASO [18] leading to neuronal death and CSF NfL increases. Subsequently, inflammation could also mediate ventricular increases through increased CSF viscosity as reported in a previous case with tominersen [19] and in patients with SMA receiving the ASO nusinersen [20]. An adverse effect of lowering wild-type huntingtin cannot be excluded, but is impossible to deconvolve from drug exposure which is inevitably in close relationship to huntingtin lowering.

Post-hoc exploratory analysis of GENERATION-HD1 suggested that younger participants with lower CAP scores performed better compared to the remaining subgroups. Consequently, Roche is developing a new phase 2 clinical trial in this subgroup of patients [17] with lower doses, in the hope of identifying a therapeutic window for the compound.

PRECISION-HD1 (NCT03225833) and PRECISION-HD2 (NCT03225846)

Study title: A Multicenter, Randomized, Double-blind, Placebo-controlled, Phase 1b/2a Study of WVE-120101 Administered Intrathecally in Patients With Huntington’s Disease [4] and A Multicenter, Randomized, Double-blind, Placebo-controlled, Phase 1b/2a Study of WVE-120102 Administered Intrathecally in Patients With Huntington’s Disease [5].

Intervention: Respectively WVE-120101 and WVE-120102, two distinct allele-selective ASOs.

Description: The PRECISION-HD trials aimed to compare the safety, tolerability, pharmacokinetics and pharmacodynamics of single and multiple ascending doses of WVE-120101 and WVE-120102, respectively, administered intrathecally, comparing with intrathecal placebo, for disease modification in people with HD (i.e. clinical diagnostic motor features of HD, a UHDRS DCL of 4, and a UHDRS TFC between 13 and 7, inclusively) who carried SNPs rs362307 or rs362331, respectively, and were aged between 25 and 65 years old. These trials were phase 1b/2a, multi-centre, international, randomized, placebo controlled, double-blind, parallel studies. They had a combined single ascending dose/multiple ascending dose design, comprising five cohorts with progressively higher ASO doses (2 mg, 4 mg, 8 mg, 16 mg and 32 mg).

In each cohort, participants were allocated to receive a single dose or three doses of the ASO or a placebo. These trials finally recruited 61 participants (PRECISION-HD1) and 88 participants (PRECISION-HD2)

The WVE-120101 and WVE-120102 compounds are ASOs targeting the pre-mRNA HTT transcript of two allelic variants linked to the expanded CAG repeat tract in the HTT gene, with the aim of selectively reducing the production of mHTT protein while leaving the concentration of wild-type huntingtin protein relatively unaltered. Each participant’s involvement lasted for 210 days. The primary outcome was safety and tolerability at 210 days. The secondary outcomes involve pharmacokinetic measurements in plasma; pharmacodynamic measures in CSF, including mHTT; and the UHDRS TFC.

Sponsor/Funders: Wave Life Sciences Ltd.

Comments: Preliminary results of the PRECISION-HD1 and PRECISION-HD2 did not show significant decreases in mHTT or total HTT at the doses tested. There was no dose-responsiveness, suggesting that higher doses would be unlikely to show decreases in the concentration of CSF mHTT. There was no increase in CSF NfL. Overall, the ASOs were well tolerated at lower doses. However, 40% of the participants receiving the 32 mg dose in PRECISION-HD1 and 46% in PRECISION-HD had serious adverse events at higher doses [4, 5].

Following these findings both trials were terminated in March 2021, however, Wave Life Sciences has developed SELECT-HD with WVE-003 (as described above), a new ASO with improved chemical structure targeting a third SNP [2].