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.
|NCT02519036||IONIS-HTTRx||IONIS-HTTRxa||September 2017 |
|NCT03225833||PRECISION-HD1||WVE-120101||February 2018 |
|NCT02481674||SIGNAL||VX15/2503||August 2018 |
|NCT03761849||GENERATION-HD1||RG6042a||January 2019 |
|NCT02535884||HD-DBS||Deep brain stimulation||June 2019 |
|NCT04120493||AMT-130||AAV5-miHTT||April 2020 |
|NCT05111249||VIBRANT-HD||Branaplam||April 2022 |
|NCT04514367||SHIELD HD||Observational study|
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)  and the recently completed SIGNAL (NCT05358717)  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 .
|Registration ID||Trial name||Intervention||Mechanism of Action||Population||Comparison||Main outcome||Study design||Estimated Enrolment||Sponsor||Location|
|NCT05509153*||–||N-Acetyl Cysteine||Antioxidant||Premanifest HD||Placebo||Efficacy at 36 months||Randomized, double-blind,||160||Western Sydney Local Health District||Australia|
|ISRCTN56240656*||FELL-HD||Felodipine||Calcium channel blocker||Early HD||None||Safety at 62 weeks||Non-randomised, multiple dose||18||Cambridge University||United Kingdom|
|NCT05358821*||–||SAGE-718||Positive allosteric modulator of NMDA||Early and moderate HD||Placebo||Change in cognition at 28 days||Double-blind, placebo-controlled, single dose design||80||Sage Therapeutics||United States|
|NCT05358717*||PIVOT HD||PTC518||Small molecule splicing modulator||PreHD, prodromal and early HD||Placebo||Safety at 113 days||Randomized, double-blind, placebo controlled, parallel assignment, multiple dose.||162||PTC therapeutics||France, Germany, Netherlands, United Kingdom, United States|
|NCT05475483*||–||SOM-3355 (bevantolol hydrochloride)||Beta-blocker||Early and moderate HD||Placebo||Efficacy at 8 weeks||Randomized, double-blind, placebo-controlled, parallel assignment multiple-dose,||129||SOM Biotech||France, Germany, Italy, Poland, Spain, Switzerland, United Kingdom|
|ACTRN12621001755820*||–||SLS-005 (Trehalose)||Disaccharide||Early HD, ALS, SCA3||None||Efficacy at 24 weeks||Non-randomized, open-label||15-18 (4 ALS, 10 HD, 4 SCA3)||Seelos Therapeutics||Australia|
|NCT05541627*||–||BV-101||AAV encoding for CYP46A1, enzyme converting cholesterol to 24-OH-cholesterol||Early HD||None||Safety at week 52||Non-randomized, open-label, sequential, single ascending dose||18||BrainVectis/AskBio||N/S|
|NCT05107128*||DIMENSION||SAGE-718||Positive allosteric modulator of NMDA||Early and moderate HD||Placebo||Change in cognition at 85 days||Double-blind, placebo-controlled, single dose design||178||Sage Therapeutics||Australia, Canada, United States|
|NCT05111249*||VIBRANT HD||Branaplam||Small molecule splicing modulator||Early HD||Placebo||Reduction of mHTT protein at week 17Safety at 104 weeks||Double-blind, placebo-controlled, multiple dose design||75||Novartis Pharmaceuticals||Belgium, Canada, France, Germany, Hungary, Italy, Spain, United Kingdom, United States|
|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|
|NCT 05243017||–||AMT-130||rAAV5-miHTT||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||Nonselective 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)|
|EUCTR 2019-002178-30-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)|
|NCT 02509793||–||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)|
|NCT 03297177||–||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|
|RBR-463yhb3*||–||Multimodal physiotherapy||Balance intervention with rhythmic cues||HD||Educational program||Balance||Randomized, double-blinded, parallel assignment trial||36||São Paulo University||Brazil|
|ACTRN12622000908730*||–||Online platform||Computerised cognitive training||Premanifest and early HD||Lifestyle education||Change in cognition at 12 weeks||Randomized, blinded (investigator, statistician) parallel assignment trial||50||Monash University, Australia||Australia|
|ISRCTN11906973*||HD-DRUM||Training app||Drumming||Premanifest, early and moderate HD||Standard medical care||Feasibility||Randomized, parallel assignment trial||50||Cardiff University, UK||UK|
|NCT05326451*||–||Transcranial Direct Current Stimulation||Transcranial electrical stimulation||Early and moderate HD||None||Treatment completion, acceptability and safety||Non-randomized, open label, single group trial||10||The University of Texas Health Science Center, Houston, USA||USA (single centre)|
|ACTRN12622000345785*||–||Multidisciplinary therapy coaching program||Education||Premanifest and early HD||Lifestyle guidance||Barriers and motivators to engagement in telehealth interventions and digital health literacy||Randomized, single blind, parallel assignment trial||84||Perpetual limited||Australia|
|NCT 04917133||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 - Hopitaux 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)|
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) , VIBRANT-HD (NCT05111249) , 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) .
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 . 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 . There is a plan for a longer open-label extension trial after the termination of the phase 2a study.
COMPLETED CLINICAL TRIALS
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) , 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 . SEMA4D is a protein of the semaphorin family involved in immune regulation . In the brain, it regulates the transition to reactive states in glial cells . Blockade of SEMA4D with immunotherapy improved pathology and clinical phenotypes in the YAC128 mice .
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)  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 .
In contrast, the VIBRANT-HD (NCT05111249)  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 . 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 .
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 . 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 .
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.
CONFLICTS OF INTEREST
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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Feigin A , Evans EE , Fisher TL , et al., Pepinemab antibody blockade of SEMA4D in early Huntington’s disease: A randomized, placebo-controlled, phase 2 trial. Nat Med. (2022) ;28: :2183–2193.
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Wave Life Sciences Ltd. Study of WVE-003 in Patients With Huntington’s Disease. https://clinicaltrials.gov/ct2/show/NCT05032196; 2021.
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). https://clinicaltrials.gov/ct2/show/NCT05111249; 2021.
UniQure Biopharma B.V. . Safety and Proof-of-Concept (POC) Study With AMT-130 in Adults With Early Manifest Huntington Disease. https://clinicaltrials.gov/ct2/show/NCT04120493; 2019.
UniQure Biopharma B.V. . Safety and Efficacy of AMT-130 in European Adults With Early Manifest Huntington’s Disease. https://clinicaltrials.gov/ct2/show/NCT05243017; 2022.
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