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Huntington’s Disease Clinical Trials Corner: November 2022


 In this edition of the Huntington’s Disease Clinical Trials Corner, we expand on the PIVOT HD (PTC518), and SIGNAL (pepinemab) trials, and list all currently registered and ongoing clinical trials in Huntington’s disease.

We also introduce a ‘breaking news’ section highlighting recent updates about the SELECT HD, uniQure AMT-130, and VIBRANT HD clinical trials.


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.

Table 1

Clinical trials previously reviewed by the Huntington’s Disease Clinical Trials Corner

Trial nameInterventionEdition
NCT02519036IONIS-HTTRxIONIS-HTTRxaSeptember 2017 [3]
NCT03225833PRECISION-HD1WVE-120101February 2018 [18]
NCT02481674SIGNALVX15/2503August 2018 [19]
NCT03761849GENERATION-HD1RG6042aJanuary 2019 [20]
NCT03344601PACE-HDPhysical activity
NCT02535884HD-DBSDeep brain stimulationJune 2019 [21]
NCT04120493AMT-130AAV5-miHTTApril 2020 [22]
NCT05111249VIBRANT-HDBranaplamApril 2022 [23]
NCT04514367SHIELD HDObservational study
NCT02481674SIGNALPepinemabbNovember 2022

aIONIS-HTTRx, RG6042, and tominersen refer to the same molecule. bVX15/2503 and pepinemab refer to the same molecule.

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 to 4. For further details on the methodology used, please refer to the first edition of Huntington’s Disease Clinical Trials Corner [3].

Table 2

Ongoing pharmacological clinical trials registered at the World Health Organization (WHO) International Clinical Trials Research Platform (ICTRP) for people with Huntington’s disease (HD). N/S, not specified; PD, Parkinson’s disease; VMAT2, Vesicular Monoamine Transporter 2. Note: IONIS-HTTRx, ISIS 443139, RG6042 and tominersen refer to the same molecule. New trials since the last Clinical Trials Corner are indicated by *

Registration IDTrial nameInterventionMechanism of ActionPopulationComparisonMain outcomeStudy designEstimated EnrolmentSponsorLocation
NCT05509153*N-Acetyl CysteineAntioxidantPremanifest HDPlaceboEfficacy at 36 monthsRandomized, double-blind,160Western Sydney Local Health DistrictAustralia
ISRCTN56240656*FELL-HDFelodipineCalcium channel blockerEarly HDNoneSafety at 62 weeksNon-randomised, multiple dose18Cambridge UniversityUnited Kingdom
NCT05358821*SAGE-718Positive allosteric modulator of NMDAEarly and moderate HDPlaceboChange in cognition at 28 daysDouble-blind, placebo-controlled, single dose design80Sage TherapeuticsUnited States
NCT05358717*PIVOT HDPTC518Small molecule splicing modulatorPreHD, prodromal and early HDPlaceboSafety at 113 daysRandomized, double-blind, placebo controlled, parallel assignment, multiple dose.162PTC therapeuticsFrance, Germany, Netherlands, United Kingdom, United States
NCT05475483*SOM-3355 (bevantolol hydrochloride)Beta-blockerEarly and moderate HDPlaceboEfficacy at 8 weeksRandomized, double-blind, placebo-controlled, parallel assignment multiple-dose,129SOM BiotechFrance, Germany, Italy, Poland, Spain, Switzerland, United Kingdom
ACTRN12621001755820*SLS-005 (Trehalose)DisaccharideEarly HD, ALS, SCA3NoneEfficacy at 24 weeksNon-randomized, open-label15-18 (4 ALS, 10 HD, 4 SCA3)Seelos TherapeuticsAustralia
NCT05541627*BV-101AAV encoding for CYP46A1, enzyme converting cholesterol to 24-OH-cholesterolEarly HDNoneSafety at week 52Non-randomized, open-label, sequential, single ascending dose18BrainVectis/AskBioN/S
NCT05107128*DIMENSIONSAGE-718Positive allosteric modulator of NMDAEarly and moderate HDPlaceboChange in cognition at 85 daysDouble-blind, placebo-controlled, single dose design178Sage TherapeuticsAustralia, Canada, United States
NCT05111249*VIBRANT HDBranaplamSmall molecule splicing modulatorEarly HDPlaceboReduction of mHTT protein at week 17Safety at 104 weeksDouble-blind, placebo-controlled, multiple dose design75Novartis PharmaceuticalsBelgium, Canada, France, Germany, Hungary, Italy, Spain, United Kingdom, United States
NCT05032196SELECT-HDWVE-003Allele-selective antisense oligonucleotideEarly HDPlaceboSafety at 36 weeksRandomized, double-blind, placebo-controlled, combined single ascending dose/multiple ascending dose trial36Wave Life Sciences Ltd.Australia, Canada, Denmark, France, Germany, Poland, Spain and United Kingdom
NCT 05243017AMT-130rAAV5-miHTTEarly HDNoneSafety at 6 monthsNon-randomized, sequential ascending, multiple-dose trial15UniQure Biopharma B.V.Germany, Poland, United Kingdom
NCT04713982DeutetrabenazineVMAT2 inhibitorHD with choreaNoneChange in speech outcome at 10 weeksSingle-arm open label trial30Vanderbilt University Medical CenterUSA (single centre)
NCT04826692MetforminAntihyperglycemic/ AMPK activatorEarly and moderate HDPlaceboChange in cognition at 52 weeksRandomized, parallel assignment, double-blinded trial60Instituto de Investigacion Sanitaria La FeSpain (single centre)
NCT04514367ANX005C1q inhibitorEarly HDNoneSafety at 36 weeksSingle-dose open label trial28Annexon, IncUSA (multi-centre)
NCT04421339MelatoninMelatonin receptor agonistHD with sleep disturbancePlaceboSleep quality at 9 weeksRandomised, cross-over, single-blinded (participant/caregiver)20The University of Texas Health Science Center, HoustonUSA (single centre)
NCT04400331ValbenazineVMAT2 inhibitorEarly and moderate HDNoneSafety at 104 weeksOpen label, single arm trial150Neurocrine BiosciencesUSA and Canada
NCT04301726DeutetrabenazineVMAT2 inhibitorHD with dysphagiaPlaceboDysphagia at 18 monthsRandomized, parallel assignment, triple blinded trial48Fundacion Huntington Puerto RicoN/S
NCT04478734HUNTIAMThiamine and biotinB vitaminsHDModerate vs High doses of thiamine and biotinSafety at 52 weeksRandomized, parallel assignment, open-label trial24Fundación Pública Andaluza para la gestión de la Investigación en SevillaSpain (single centre)
NCT04201834RisperidoneDopamine antagonistEarly and moderate HD with choreaNoneChange in motor scales at 12 weeksNon-randomized, open label (assessor-blind), uncontrolled trial12University of RochesterUSA (single centre)
NCT04071639Haloperidol, risperidone, sertraline and coenzyme Q10Multiple (dopamine antagonists, selective serotonin reuptake inhibitor, dietary supplement)Early and moderate HDCoenzyme Q10Efficacy at 5 yearsRandomized, open label, controlled, parallel trial100Second Affiliated Hospital, School of Medicine, Zhejiang UniversityChina (single centre)
NCT04120493AMT-130rAAV5-miHTTNonselective miRNAEarly HDSham interventionSafety at 18 monthsRandomized, double-blind, sham-controlled, parallel trial26UniQure Biopharma B.V.USA (multi-centre)
NCT04102579KINECT-HDValbenazineVMAT2 inhibitorHD with choreaPlaceboEfficacy at 12 weeksRandomized, double-blind, placebo-controlled, parallel trial120Neurocrine Biosciences, Huntington Study GroupUSA (multi-centre)
EUCTR 2019-002178-30-DKWVE-120102Allele-selective antisense oligonucleotideHDNoneSafety and tolerability at 97 weeksOpen-label extension70Wave Life Sciences Ltd.Australia, Canada, Denmark, France, Poland and United Kingdom (multi-centre)
NCT04000594GEN-PEAKRG6042Allele-nonselective antisense oligonucleotideHDNonePharmacodynamics and pharmacokinetics at multiple timepoints until 6 monthsNon-randomized. open-label, multiple-dose, parallel trial20Hoffmann-La RocheThe Netherlands and UK (multi-centre)
NCT03980938Neflamapimodp38α MAPK inhibitorEarly HDPlaceboChange in cognitive scales at 10 weeksRandomized, double-blind, placebo-controlled, cross-over trial16EIP Pharma Inc, Voisin Consulting, Inc.UK (single centre)
NCT03842969GEN-EXTENDRG6042Allele-nonselective antisense oligonucleotideHDNoneSafety and tolerability at up to 5 yearsOpen-label extension1050Hoffmann-La RocheUSA, Canada, Europe (multi-centre)
NCT03761849GENERATION-HD1RG6042Allele-nonselective antisense oligonucleotideHDPlaceboClinical efficacy at 101 weeksRandomized, double-blind, placebo-controlled, parallel trial909Hoffmann-La RocheUSA, Canada, Europe (multi-centre)
NCT03515213FenofibratePPARα agonistHDPlaceboPharmacodynamics at 6 monthsRandomized, double-blind, placebo-controlled, parallel trial20University of California, IrvineUSA (single centre)
NCT03764215Tasigna HDNilotinibSelective Bcr-Abl tyrosine kinase inihbitorHDNoneSafety, tolerability and pharmacodynamics at 3 monthsOpen label, multiple ascending dose20Georgetown UniversityUSA (single centre)
NCT03225833PRECISION-HD1WVE-120101Allele-selective antisense oligonucleotideHDPlaceboSafety and tolerability at 1 and 120 daysRandomized, double-blind, placebo-controlled, combined single ascending dose/multiple ascending dose trial48Wave Life Sciences Ltd.Australia, Canada, Denmark, France, Poland and United Kingdom (multi-centre)
NCT03225846PRECISION-HD2WVE-120102Allele-selective antisense oligonucleotideHDPlaceboSafety and tolerability at 1 and 120 daysRandomized, double-blind, placebo-controlled, combined single ascending dose/multiple ascending dose trial60Wave Life Sciences Ltd.Australia, Canada, Denmark, France, Poland and United Kingdom (multi-centre)
NCT02453061TRIHEP 3TriheptanoinAnaplerotic therapyHDSafflower oilPharmacodynamic efficacy at 6 monthsRandomized, double-blind, controlled, parallel trial100Institut National de la Santé Et de la Recherche Médicale, Ultragenyx Pharmaceutical IncFrance, Netherlands (multi-centre)
NCT 02509793TetrabenazineVMAT2 inhibitorHD with impulsivityNoneCognitive and behavioural effects at 8 weeksSingle group, open-label trial20University of Texas Health Science Center, and H. Lundbeck A/SUSA (single centre)
NCT02481674SIGNALVX15/2503Anti-semaphorin 4D monoclonal antibodyLate premanifest or early HDPlaceboSafety and tolerability at 15 and 21 monthsRandomized, double-blind, placebo-controlled, parallel trial240Vaccinex Inc., Huntington Study GroupUSA (multi-centre)
EUCTR2013-002545-10-SEOSU6162Open1309(-)-OSU616Monoaminergic stabilizerHD, PD, brain trauma, stroke, myalgic encephalomyelitis and narcolepsyNoneSafety at 3, 6 and 12 monthsSingle group, open-label trial240A. Carlsson Research ABSweden (multi-centre)
NCT00514774UDCA-HDUrsodiolBile acidHDPlaceboSafety, tolerability and pharmacokinetics at 35 daysRandomized, double-blind, placebo-controlled, parallel trial21Oregon Health and Science University, Huntington Study Group, Huntington Society of CanadaN/S
Table 3

Ongoing invasive non-pharmacological clinical trials registered at the World Health Organization (WHO) International Clinical Trials Research Platform (ICTRP) for people with Huntington’s disease (HD). AD, Alzheimer’s disease, CBD; Corticobasal Degeneration; DBS, deep brain stimulation; ET, Essential Tremor; GP, Globus pallidus; HT, Holmes Tremor; MNC, mononuclear cells; MS, Multiple Sclerosis; PD, Parkinson’s disease; TD, Tardive dyskinesia; WD, Wilson’s disease. New trials since the last Clinical Trials Corner are indicated by *

Registration IDTrial nameInterventionMechanism of ActionPopulationComparisonMain outcomeStudy designEsimated EnrolmentSponsorLocation
NCT04244513GPi DBSDeep brain stimulationHD with choreaSham interventionEfficacy at 3 and 6 monthsRandomized, double-blind, sham-controlled, cross-over trial40Beijing Municipal Administration of Hospitals, MedtronicChina (multi-centre)
NCT04219241ADORE-EXTCellavitaStem cell therapyHDNoneEfficacy and safety at 2 yearsOpen label extension35Azidus Brasil, Cellavita Pesquisa Científica LtdaBrazil (single centre)
ISRCTN52651778TRIDENTFoetal stem cell transplantStem cell therapyEarly stage HDUsual careSafety at 4 weeksRandomized, open label, controlled, parallel trial30Cardiff UniversityUK (single centre)
NCT02728115SAVE-DHCellavitaStem cell therapyHDNoneSafety at 5 yearsNon-randomized, open label, uncontrolled, parallel trial6Azidus BrasilBrazil (single centre)
NCT03252535ADORE-HDCellavitaStem cell therapyHDPlaceboEfficacy at 120 daysRandomized, double-blind, placebo-controlled, parallel trial35Azidus BrasilBrazil (single centre)
NCT 03297177Autologous stem/stromal cellsAutologous stem/stromal cell injectionHD, AD, PD, CBD, MSNoneSafety at 5 yearsSingle group, open-label trial300Healeon Medical Inc, Global Alliance for Regenerative Medicine, Regeneris MedicalUSA and Honduras (multi-centre)
NCT02535884HD-DBSGP DBSDeep brain stimulationModerate HD with choreaSham interventionEfficacy at 12 monthsRandomized, double-blind, sham-controlled, parallel trial50Heinrich-Heine University, KKS Netzwerk, Medtronic, The George Institute, EHDN, CHDI Foundation, Inc.Austria, France Germany, Switzerland (multi-centre)
NCT01834053BMACHCBone Marrow Derived MNC transplantBone marrow transplantHD with choreaNoneCognitive and behavioural effects at 6 monthsSingle group, open-label trial50Chaitanya Hospital, PuneIndia (single centre)
NCT02252380Magnetic Resonance Guided Focused UltrasoundExtracranial stereotactic radioablationHD, ET, HT, PD, WD, dystonia, TD, or orofacial dyskinesiasNoneAdverse events after the procedureSingle group, open-label trial10InSightecCanada (single centre)
Table 4

Ongoing non-invasive non-pharmacological clinical trials registered at the World Health Organization (WHO) International Clinical Trials Research Platform (ICTRP) for people with Huntington’s disease (HD). AD, Alzheimer’s disease; ALS, Amyotrophic Lateral Sclerosis; ET, Essential Tremor; HT, Holmes Tremor; MS, Multiple Sclerosis; N/S, not specified, PD, Parkinson’s disease; TD, Tardive dyskinesia. New trials since the last Clinical Trials Corner are indicated by *

Registration IDTrial nameInterventionMechanism of ActionPopulationComparisonMain outcomeStudy designEstimated EnrolmentSponsorLocation
RBR-463yhb3*Multimodal physiotherapyBalance intervention with rhythmic cuesHDEducational programBalanceRandomized, double-blinded, parallel assignment trial36São Paulo UniversityBrazil
ACTRN12622000908730*Online platformComputerised cognitive trainingPremanifest and early HDLifestyle educationChange in cognition at 12 weeksRandomized, blinded (investigator, statistician) parallel assignment trial50Monash University, AustraliaAustralia
ISRCTN11906973*HD-DRUMTraining appDrummingPremanifest, early and moderate HDStandard medical careFeasibilityRandomized, parallel assignment trial50Cardiff University, UKUK
NCT05326451*Transcranial Direct Current StimulationTranscranial electrical stimulationEarly and moderate HDNoneTreatment completion, acceptability and safetyNon-randomized, open label, single group trial10The University of Texas Health Science Center, Houston, USAUSA (single centre)
ACTRN12622000345785*Multidisciplinary therapy coaching programEducationPremanifest and early HDLifestyle guidanceBarriers and motivators to engagement in telehealth interventions and digital health literacyRandomized, single blind, parallel assignment trial84Perpetual limitedAustralia
NCT 04917133HUNT’ACTIVAdapted physical workshops plus classic 4-week rehabilitation programPhysical activity, cycling, horse riding, situation tests, cultural outingsMid-stage HDClassic 4-week rehabilitation programMotor function at 1 monthRandomized, parallel assignment trial32Assistance Publique - Hopitaux de ParisFrance (single centre)
NCT04429230Transcranial pulsed current stimulationTranscranial electrical stimulationHDSham interventionFeasibility at one yearRandomised, crossover double-blinded trial15Western University, CanadaN/S
ACTRN12620000281998Ketogenic dietHDNoneChange in cognition and motor scores at 12 weeksNon-randomized, open label, single group trial10Waikato HospitalNew Zealand (-)
ACTRN12619000870156Transcranial alternating current stimulationTranscranial magnetic stimulationPremanifest and early HDSham interventionBiomarkersRandomized, open-label, cross-over trials60Monash University, Epworth Centre for Innovation in Mental HealthAustralia (single centre)
ACTRN12618001717246Multidisciplinary therapy programExercise, cognitive training, lifestyle guidance and social activitiesPremanifest HDStandard of careFeasibility and safetyClustered, non-randomized, open label, parallel trial40Edith Cowan University, Deakin University and LotterywestAustralia (two centres)
NCT03417583Neuropsychiatric treatment protocolMultidisciplinary interventionHD with neuropsychiatric symptomsStandard of careChange in quality of life at 18 monthsNon-randomized, assessor-blinded, parallel trial100Vanderbilt University Medical Center and Teva Pharmaceuticals USAUSA (single centre)
CTRI/2018/01/011359Repetitive transcranial magnetic stimulationTranscranial magnetic stimulationEarly to moderate HD and PDSham stimulationEfficacy at 5 daysRandomized, single-blind, placebo-controlled, parallel trial40Vinay GoyalIndia (single centre)
NCT03344601PACE-HDSupported structured aerobic exercise training programPhysiotherapyHDActivity as usualData completeness, recruitment, retention, safety, adherence, fidelity and acceptability at 12 monthsNested open-label, randomized controlled parallel trial120Cardiff University and CHDI Foundation, IncGermany, Spain and USA (multi-centre)
ACTRN12617001269325Swallowing skill trainingSpeech and language therapyHD and ALSNoneSwallowing function and quality of life at 2 weeksSingle group, open-label trial54University of CanterburyNew Zealand (single centre)

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

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.


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.


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.


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].


CE-F 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.


CEF was an investigator in the LEGATO-HD (NCT02215616), IONIS HTTRx OLE (NCT-03342053), 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 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), uniQure AMT-130 (NCT05243017), 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.



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