Huntington’s Disease Clinical Trials Corner: April 2022
In this edition of the Huntington’s Disease Clinical Trials Corner we expand on GENERATION HD1, PRECISION-HD1 and PRECISION-HD2, SELECT-HD, and VIBRANT-HD trials, and list all currently registered and ongoing clinical trials in Huntington’s disease.
The Huntington’s Disease Clinical Trials Corner is a regular section devoted to highlighting ongoing and recently completed clinical trials in Huntington’s disease (HD). We are pleased to return, after a longer pandemic-imposed hiatus than we had intended, with a refreshed and expanded regular authorship. Clinical trials previously reviewed by the Huntington’s Disease Clinical Trials Corner are listed in table 1.
|NCT02519036||IONIS-HTTRx||IONIS-HTTRx*||September 2017 |
|NCT03225833||PRECISION-HD1||WVE-120101||February 2018 |
|NCT02481674||SIGNAL||VX15/2503||August 2018 |
|NCT03761849||GENERATION-HD1||RG6042*||January 2019 |
|NCT02535884||HD-DBS||Deep brain stimulation||June 2019 |
|NCT04120493||AMT-130||AAV5-miHTT||April 2020 |
In this edition, we highlight the ongoing trials VIBRANT-HD (NCT05111249)  and SELECT-HD (NCT05032196) . We will also cover recently terminated clinical trials GENERATION HD1 (NCT03761849) , PRECISION-HD1 (NCT03225833)  and PRECISION-HD2 (NCT03225846) .
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 .
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 ongoing clinical trials is given in Tables 2, 3 and 4.
|Registration ID||Trial name||Intervention||Mechanism of Action||Population||Comparison||Main outcome||Study design||Estimated Enrolment||Sponsor||Location|
|NCT05032196*||SELECT-HD||WVE-003||Allele-selective antisense oligonucleotide||Early HD||Placebo||Safety at 36 weeks||Randomized, double-blind, placebo-controlled, combined single ascending dose/multiple ascending dose trial||36||Wave Life Sciences Ltd.||Australia, Canada, Denmark,France, Germany, Poland, Spain and United Kingdom|
|NCT05243017*||AMT-130||rAAV-miHTT||Non allele selective miRNA||Early HD||None||Safety at 6 months||Non-randomized, sequential ascending, multiple-dose trial||15||UniQure Biopharma B.V.||Germany, Poland, United Kingdom|
|NCT04713982*||-||Deutetrabenazine||VMAT2 inhibitor||HD with chorea||None||Change in speech outcome at 10 weeks||Single-arm open label trial||30||Vanderbilt University Medical Center||USA (single centre)|
|NCT04826692*||-||Metformin||Antihyperglycemic/ AMPK activator||Early and moderate HD||Placebo||Change in cognition at 52 weeks||Randomized, parallel assignment, double-blinded trial||60||Instituto de Investigacion Sanitaria La Fe||Spain (single centre)|
|NCT04514367*||-||ANX005||C1q inhibitor||Early HD||None||Safety at 36 weeks||Single-dose open label trial||28||Annexon, Inc||USA (multi-centre)|
|NCT04421339*||-||Melatonin||Melatonin receptor agonist||HD with sleep disturbance||Placebo||Sleep quality at 9 weeks||Randomised, cross-over, single-blinded (participant/caregiver)||20||The University of Texas Health Science Center, Houston||USA (single centre)|
|NCT04400331*||-||Valbenazine||VMAT2 inhibitor||Early and moderate HD||None||Safety at 104 weeks||Open label, single arm trial||150||Neurocrine Biosciences||USA and Canada|
|NCT04301726*||-||Deutetrabenazine||VMAT2 inhibitor||HD with dysphagia||Placebo||Dysphagia at 18 months||Randomized, parallel assignment, triple blinded trial||48||Fundacion Huntington Puerto Rico||N/S|
|NCT04478734*||HUNTIAM||Thiamine and biotin||B vitamins||HD||Moderate vs High doses of thiamine and biotin||Safety at 52 weeks||Randomized, parallel assignment, open-label trial||24||Fundación Pública Andaluza para la gestión de la Investigación en Sevilla||Spain (single centre)|
|NCT04201834||-||Risperidone||Dopamine antagonist||Early and moderate HD with chorea||None||Change in motor scales at 12 weeks||Non-randomized, open label (assessor-blind), uncontrolled trial||12||University of Rochester||USA (single centre)|
|NCT04071639||-||Haloperidol, risperidone, sertraline and coenzyme Q10||Multiple (dopamine antagonists, selective serotonin reuptake inhibitor, dietary supplement)||Early and moderate HD||Coenzyme Q10||Efficacy at 5 years||Randomized, open label, controlled, parallel trial||100||Second Affiliated Hospital, School of Medicine, Zhejiang University||China (single centre)|
|NCT04120493||AMT-130||rAAV5-miHTT||Non allele selective miRNA||Early HD||Sham intervention||Safety at 18 months||Randomized, double-blind, sham-controlled, parallel trial||26||UniQure Biopharma B.V.||USA (multi-centre)|
|NCT04102579||KINECT-HD||Valbenazine||VMAT2 inhibitor||HD with chorea||Placebo||Efficacy at 12 weeks||Randomized, double-blind, placebo-controlled, parallel trial||120||Neurocrine Biosciences, Huntington Study Group||USA (multi-centre)|
|EUCTR2019-002178-30-DK||-||WVE-120102||Allele-selective antisense oligonucleotide||HD||None||Safety and tolerability at 97 weeks||Open-label extension||70||Wave Life Sciences Ltd.||Australia, Canada, Denmark, France, Poland and United Kingdom (multi-centre)|
|NCT04000594||GEN-PEAK||RG6042||Allele- nonselective antisense oligonucleotide||HD||None||Pharmacodynamics and pharmacokinetics at multiple timepoints until 6 months||Non-randomized. open-label, multiple-dose, parallel trial||20||Hoffmann-La Roche||The Netherlands and UK (multi-centre)|
|NCT03980938||-||Neflamapimod||p38α MAPK inhibitor||Early HD||Placebo||Change in cognitive scales at 10 weeks||Randomized, double-blind, placebo-controlled, cross-over trial||16||EIP Pharma Inc, Voisin Consulting, Inc.||UK (single centre)|
|NCT03842969||GEN-EXTEND||RG6042||Allele-nonselective antisense oligonucleotide||HD||None||Safety and tolerability at up to 5 years||Open-label extension||1050||Hoffmann-La Roche||USA, Canada, Europe (multi-centre)|
|NCT03761849||GENERATION-HD1||RG6042||Allele-nonselective antisense oligonucleotide||HD||Placebo||Clinical efficacy at 101 weeks||Randomized, double-blind, placebo-controlled, parallel trial||909||Hoffmann-La Roche||USA, Canada, Europe (multi-centre)|
|NCT03515213||-||Fenofibrate||PPARα agonist||HD||Placebo||Pharmacodynamics at 6 months||Randomized, double-blind, placebo-controlled, parallel trial||20||University of California, Irvine||USA (single centre)|
|NCT03764215||Tasigna HD||Nilotinib||Selective Bcr-Abl tyrosine kinase inihbitor||HD||None||Safety, tolerability and pharmacodynamics at 3 months||Open label, multiple ascending dose||20||Georgetown University||USA (single centre)|
|NCT03225833||PRECISION-HD1||WVE-120101||Allele-selective antisense oligonucleotide||HD||Placebo||Safety and tolerability at 1 and 120 days||Randomized, double-blind, placebo-controlled, combined single ascending dose/multiple ascending dose trial||48||Wave Life Sciences Ltd.||Australia, Canada, Denmark, France, Poland and United Kingdom (multi-centre)|
|NCT03225846||PRECISION-HD2||WVE-120102||Allele-selective antisense oligonucleotide||HD||Placebo||Safety and tolerability at 1 and 120 days||Randomized, double-blind, placebo-controlled, combined single ascending dose/multiple ascending dose trial||60||Wave Life Sciences Ltd.||Australia, Canada, Denmark, France, Poland and United Kingdom (multi-centre)|
|NCT02453061||TRIHEP 3||Triheptanoin||Anaplerotic therapy||HD||Safflower oil||Pharmacodynamic efficacy at 6 months||Randomized, double-blind, controlled, parallel trial||100||Institut National de la Santé Et de la Recherche Médicale, Ultragenyx Pharmaceutical Inc||France, Netherlands (multi-centre)|
|NCT02509793||-||Tetrabenazine||VMAT2 inhibitor||HD with impulsivity||None||Cognitive and behavioural effects at 8 weeks||Single group, open-label trial||20||University of Texas Health Science Center, and H. Lundbeck A/S||USA (single centre)|
|NCT02481674||SIGNAL||VX15/2503||Anti-semaphorin 4D monoclonal antibody||Late premanifest or early HD||Placebo||Safety and tolerability at 15 and 21 months||Randomized, double-blind, placebo-controlled, parallel trial||240||Vaccinex Inc., Huntington Study Group||USA (multi-centre)|
|EUCTR2013-002545-10-SE||OSU6162Open1309||(-)-OSU616||Monoaminergic stabilizer||HD, PD, brain trauma, stroke, myalgic encephalomyelitis and narcolepsy||None||Safety at 3, 6 and 12 months||Single group, open-label trial||240||A. Carlsson Research AB||Sweden (multi-centre)|
|NCT00514774||UDCA-HD||Ursodiol||Bile acid||HD||Placebo||Safety, tolerability and pharmacokinetics at 35 days||Randomized, double-blind, placebo-controlled, parallel trial||21||Oregon Health and Science University, Huntington Study Group, Huntington Society of Canada||N/S|
|Registration ID||Trial name||Intervention||Mechanism of Action||Population||Comparison||Main outcome||Study design||Esimated Enrolment||Sponsor||Location|
|NCT04244513||-||GPi DBS||Deep brain stimulation||HD with chorea||Sham intervention||Efficacy at 3 and 6 months||Randomized, double-blind, sham-controlled, cross-over trial||40||Beijing Municipal Administration of Hospitals, Medtronic||China (multi-centre)|
|NCT04219241||ADORE-EXT||Cellavita||Stem cell therapy||HD||None||Efficacy and safety at 2 years||Open label extension||35||Azidus Brasil, Cellavita Pesquisa Científica Ltda||Brazil (single centre)|
|ISRCTN52651778||TRIDENT||Foetal stem cell transplant||Stem cell therapy||Early stage HD||Usual care||Safety at 4 weeks||Randomized, open label, controlled, parallel trial||30||Cardiff University||UK (single centre)|
|NCT02728115||SAVE-DH||Cellavita||Stem cell therapy||HD||None||Safety at 5 years||Non-randomized, open label, uncontrolled, parallel trial||6||Azidus Brasil||Brazil (single centre)|
|NCT03252535||ADORE-HD||Cellavita||Stem cell therapy||HD||Placebo||Efficacy at 120 days||Randomized, double-blind, placebo-controlled, parallel trial||35||Azidus Brasil||Brazil (single centre)|
|NCT03297177||-||Autologous stem/stromal cells||Autologous stem/stromal cell injection||HD, AD, PD, CBD, MS||None||Safety at 5 years||Single group, open-label trial||300||Healeon Medical Inc, Global Alliance for Regenerative Medicine, Regeneris Medical||USA and Honduras (multi-centre)|
|NCT02535884||HD-DBS||GP DBS||Deep brain stimulation||Moderate HD with chorea||Sham intervention||Efficacy at 12 months||Randomized, double-blind, sham-controlled, parallel trial||50||Heinrich-Heine University, KKS Netzwerk, Medtronic, The George Institute, EHDN, CHDI Foundation, Inc.||Austria, France Germany, Switzerland (multi-centre)|
|NCT01834053||BMACHC||Bone Marrow Derived MNC transplant||Bone marrow transplant||HD with chorea||None||Cognitive and behavioural effects at 6 months||Single group, open-label trial||50||Chaitanya Hospital, Pune||India (single centre)|
|NCT02252380||-||Magnetic Resonance Guided Focused Ultrasound||Extracranial stereotactic radioablation||HD, ET, HT, PD, WD, dystonia, TD, or orofacial dyskinesias||None||Adverse events after the procedure||Single group, open-label trial||10||InSightec||Canada (single centre)|
|Registration ID||Trial name||Intervention||Mechanism of Action||Population||Comparison||Main outcome||Study design||Estimated Enrolment||Sponsor||Location|
|NCT04917133*||HUNT'ACTIV||Adapted physical workshops plus classic 4-week rehabilitation program||Physical activity, cycling, horse riding, situation tests, cultural outings||Mid-stage HD||Classic 4-week rehabilitation program||Motor function at 1 month||Randomized, parallel assignment trial||32||Assistance Publique - Hôpitaux de Paris||France (single centre)|
|NCT04429230*||-||Transcranial pulsed current stimulation||Transcranial electrical stimulation||HD||Sham intervention||Feasibility at one year||Randomised, crossover double-blinded trial||15||Western University, Canada||N/S|
|ACTRN12620000281998||-||Ketogenic diet||-||HD||None||Change in cognition and motor scores at 12 weeks||Non-randomized, open label, single group trial||10||Waikato Hospital||New Zealand (-)|
|ACTRN12619000870156||-||Transcranial alternating current stimulation||Transcranial magnetic stimulation||Premanifest and early HD||Sham intervention||Biomarkers||Randomized, open-label, cross-over trials||60||Monash University, Epworth Centre for Innovation in Mental Health||Australia (single centre)|
|ACTRN12618001717246||-||Multidisciplinary therapy program||Exercise, cognitive training, lifestyle guidance and social activities||Premanifest HD||Standard of care||Feasibility and safety||Clustered, non-randomized, open label, parallel trial||40||Edith Cowan University, Deakin University and Lotterywest||Australia (two centres)|
|NCT03417583||-||Neuropsychiatric treatment protocol||Multidisciplinary intervention||HD with neuropsychiatric symptoms||Standard of care||Change in quality of life at 18 months||Non-randomized, assessor-blinded, parallel trial||100||Vanderbilt University Medical Center and Teva Pharmaceuticals USA||USA (single centre)|
|CTRI/2018/01/011359||-||Repetitive transcranial magnetic stimulation||Transcranial magnetic stimulation||Early to moderate HD and PD||Sham stimulation||Efficacy at 5 days||Randomized, single-blind, placebo-controlled, parallel trial||40||Vinay Goyal||India (single centre)|
|NCT03344601||PACE-HD||Supported structured aerobic exercise training program||Physiotherapy||HD||Activity as usual||Data completeness, recruitment, retention, safety, adherence, fidelity and acceptability at 12 months||Nested open-label, randomized controlled parallel trial||120||Cardiff University and CHDI Foundation, Inc||Germany, Spain and USA (multi-centre)|
|ACTRN12617001269325||-||Swallowing skill training||Speech and language therapy||HD and ALS||None||Swallowing function and quality of life at 2 weeks||Single group, open-label trial||54||University of Canterbury||New Zealand (single centre)|
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: 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 . 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 .
Study title: A Multicenter, Randomized, Double-blind, Placebo Controlled, Phase 1b/2a Study of WVE-003 Administered Intrathecally in Patients With Huntington’s Disease 
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 . 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 .
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.
Completed clinical trials
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 .
Intervention: Tominersen (120 mg) – formerly known as IONIS-HTTRx / 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  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 . 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 . 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 .
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 . 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  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  and in patients with SMA receiving the ASO nusinersen . 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  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  and A Multicenter, Randomized, Double-blind, Placebo-controlled, Phase 1b/2a Study of WVE-120102 Administered Intrathecally in Patients With Huntington’s Disease .
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 .
CE-F receives support from a Wellcome Trust Collaborative Award (200181/Z/15/Z). SJT receives research grant funding from the CHDI Foundation, Vertex Pharmaceuticals, the UK Medical Research Council, the Wellcome Trust (200181/Z/15/Z), 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.
CONFLICTS OF INTEREST
CEF was an investigator in the LEGATO-HD (NCT02215616), IONIS HTTRx OLE (NCT03342053), GENERATION-HD1 (NCT03761849), Roche Natural History Study (NCT03664804), Roche GEN-EXTEND (NCT03842969), Roche GEN-PEAK (NCT04000594), uniQure AMT-130 (NCT05243017) and Triplet Therapeutics SHIELD-HD (NCT04406636) trials.
FBR is a full-time Medpace UK Ltd employee. FBR was an investigator on LEGATO-HD (NCT02215616), IONIS HTTRx (NCT02519036), IONIS HTTRx OLE (NCT03342053), GENERATION-HD1 (NCT03761849), Roche Natural History Study (NCT03664804), Roche GEN-EXTEND (NCT03842969), Roche GEN-PEAK (NCT04000594), Triplet Therapeutics SHIELD-HD (NCT04406636) and Novartis VIBRANT-HD (NCT05111249) studies. FBR has provided consultancy services to GLG, Hoffman La Roche Ltd, Evigrade, and Enroll-HD Clinical Trials Committee.
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 analogs licensed to Adrestia Therapeutics. SJT was an investigator on IONIS HTTRx (NCT02519036), IONIS HTTRx OLE (NCT03342053), GENERATION-HD1 (NCT03761849), Roche Natural History Study (NCT03664804) and Roche GEN-EXTEND (NCT03842969) trials.
EJW has undertaken consultancy/advisory board work with Hoffman La Roche Ltd, Triplet Therapeutics, PTC Therapeutics, Takeda, Vico Therapeutics, Voyager, Huntington Study Group, Teitur Trophics, EcoR1 Capital, PTC Therapeutics, 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) trials and Roche GEN-PEAK trial (NCT04000594).
The authors did not make use of confidential or privileged information: all materials included in this manuscript were collected from publicly available sources.
Novartis Pharmaceuticals. 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). 2021. https://clinicaltrials.gov/ct2/show/NCT05111249.
Wave Life Sciences Ltd. Study of WVE-003 in Patients With Huntington’s Disease. 2021. https://clinicaltrials.gov/ct2/show/NCT05032196.
Hoffman-La Roche. A Study to Evaluate the Efficacy and Safety of Intrathecally Administered RO7234292 (RG6042) in Patients With Manifest Huntington’s Disease. 2019. https://clinicaltrials.gov/ct2/show/NCT03761849.
Wave Life Sciences Ltd. Safety and Tolerability of WVE-120101 in Patients With Huntington’s Disease. 2017. https://clinicaltrials.gov/ct2/show/NCT03225833.
Wave Life Sciences Ltd. Safety and Tolerability of WVE-120102 in Patients With Huntington’s Disease. 2017. https://clinicaltrials.gov/ct2/show/NCT03225846.
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Gubser Keller C, Shin Y, Monteys AM, et al. An orally available, brain penetrant, small molecule lowers huntingtin levels by enhancing pseudoexon inclusion. Nat Commun 2022; 13: 1150.
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