In this edition of the Huntington’s Disease Clinical Trials Corner, we expand on the GENERATION HD2 (tominersen) and on the Asklepios Biopharmaceutical/BrainVectis trial with AB-1001. We also comment on the recent findings from the PROOF-HD trial, and list all currently registered and ongoing clinical trials in Huntington’s disease.
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|
|NCT02481674||SIGNAL||Pepinemabb||November 2022 |
|NCT05686551||GENERATION HD2||Tominersena||July 2023|
aIONIS-HTTRx, RG6042, and tominersen refer to the same molecule. bVX15/2503 and pepinemab refer to the same molecule. cAAVrh10.CAG.hCYP46A1, BV-101, AB-1001 refer to the same molecule.
In this edition, we highlight the ongoing clinical trials GENERATION HD2 (NCT05686551)  and the Asklepios Biopharmaceutical/BrainVectis trial with AB-1001 (NCT05541627) . Finally, we discuss also results from the PROOF-HD (NCT04556656)  trial in the “Breaking news” section. 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|
|NCT04556656*||PROOF-HD||Pridopidine||Sigma-1 receptor activation||Early HD||Placebo||Change in function at 65 weeks||Randomized, double-blind, parallel assignment, single dose trial||499||Prilenia therapeutics||Austria, Canada, Czechia, France, Germany, Italy, Netherlands, Poland, Spain, United Kingdom, United States|
|NCT05686551*||GENERATION HD2||Tominersen||Non allele selective antisense oligonucleotide||Prodromal and early manifest HD||Placebo||Safety at 24 months||Randomized, double-blind, dose-finding trial||360||Hoffmann-La Roche||United States, Spain, more sites to be condirmed|
|NCT05655520*||–||SAGE-718||Positive allosteric modulator of NMDA||PreHD, early and moderate HD||None||Safety at 13 months||Single-dose open label trial||300||Sage Therapeutics||United States|
|NCT03019289*||–||Pridopidine||Sigma-1 receptor activation||Healthy controls, early and moderate HD||None||Sigma-1 receptor occupancy||Multiple dose, open label trial||23||Prilenia therapeutics / Teva||Germany|
|NCT02494778*||Open PRIDE HD||Pridopidine||Sigma-1 receptor activation||Early and moderate HD||Placebo||Efficacy at 106 weeks||Open-label extension||400||Prilenia therapeutics / Teva||Australia, Austria, Canada, France, Germany, Italy, Netherlands, Poland, Russia, United Kingdom, United States|
|NCT02006472*||PRIDE HD||Pridopidine||Sigma-1 receptor activation||Early and moderate HD||Placebo||Efficacy at 26 weeks||Randomized, double-blind, parallel assignment, dose-finding trial||408||Prilenia therapeutics / Teva||Australia, Austria, Canada, Denmark, France, Germany, Italy, Poland, Russia, Netherlands, United Kingdom, United States|
|NCT01306929*||OPEN-HART||Pridopidine||Sigma-1 receptor activation||HD||None||Safety up to 72 months||Randomized, placebo-controlled, dose-ranging, parallel-group study.||134||Prilenia therapeutics / Teva||Canada, Inited States|
|NCT05509153||–||N-Acetyl Cysteine||Antioxidant||Premanifest HD||Placebo||Efficacy at 36 months||Randomized, double-blind trial||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 trial||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 trial||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 trial||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 trial||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||–||AB-1001 (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||AskBio/ BrainVectis||France|
|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|
|NCT05243017||–||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||–||Deutetra-benazine||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||Antihyper-glycemic/ 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||–||Deutetra-benazine||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||Pharmaco-dynamics 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||Pharmaco-dynamics 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||Pharmaco-dynamic efficacy at 6 months||Randomized, double-blind, controlled, parallel trial||100||Institut National de la Sant Et de la Recherche M dicale, 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|
|ChiCTR2300069844*||–||Repetitive transcranial magnetic stimulation||Transcranial magnetic stimulation||HD||None||EEG||Non-randomized, open label, single group trial||20||Shenzhen People’s Hospital||China|
|ISRCTN47330596*||–||Psychological intervention||Guided self help||Premanifest and manifest HD||Usual treatment||Feasibility at 3 and 6 months||Interventional randomized controlled trial||30||Leicestershire Partnership NHS Trust, UK||UK|
|RBR-463yhb3||–||Multimodal physiotherapy||Balance intervention with rhythmic cues||HD||Educational program||Balance||Randomized, double-blinded, parallel assignment trial||36||São Paulo University, Brazil||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|
|ISRCTN119069*73||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|
|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||–||Multidisci-plinary 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||–||Neuropsy-chiatric treatment protocol||Multidisci-plinary 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||Physio-therapy||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)|
GENERATION HD2 (NCT05686551) 
Study title: A Study to Evaluate the Safety, Biomarkers, and Efficacy of Tominersen Compared With Placebo in Participants With Prodromal and Early Manifest Huntington’s Disease
Intervention: Intrathecally administered tominersen (120 mg) – formerly known as IONIS-HTTRx/ ISIS443139 / RG6042– is an antisense oligonucleotide that targets the Huntingtin (HTT) transcript non-allele-selectively lowering the production of mutant huntingtin protein.
Description: The GENERATION HD2 clinical trial aims to evaluate the safety, efficacy and biomarker effects of two doses of tominersen (60 mg and 100 mg) administered to patients between 25 and 50 years of age with prodromal and early manifest HD (equivalent stages 2 and 3 of the Huntington’s disease Integrated Staging System  (HD-ISS)) and a CAG-age product (CAP score) between 400 and 500.
GENERATION HD2 is a phase 2, international, multicentre, randomized, placebo-controlled, double-blind parallel study with the aim of selecting a safe dose of tominersen that lowers CSF mutant Huntingtin (mHTT) protein and shows a tendency towards efficacy. Participants will be randomized 1 : 1:1 to receive intrathecal infusions every 16 weeks with 60 mg or 100 mg of tominersen or placebo.
Participants will receive the study drug during 16 months followed a safety follow up period of 5 months and an optional OLE. After the 16-month double-blind treatment period concludes, participants will remain on blinded treatment until all study participants have completed 16 months of treatment
GENERATION HD2 plans to recruit 360 participants in 15 countries. The primary outcome will be safety. Other primary outcomes include change in cerebrospinal fluid (CSF) white cells, change in CSF total protein, change in CSF mHTT, change in structural brain MRI and clinical change measured through the Total Functional Capacity (TFC) and the composite Unified Huntington’s Disease Rating Scale (cUHDRS) [6, 7].
Sponsor/Funders: Hoffman-La Roche
Comments: Tominersen has been tested in the phase 1b/2a IONIS-HTTRX (NCT02519036) , its OLE (NCT03342053) , and the phase 3 GENERATION HD1  (NCT03761849) clinical trials, showing dose dependent decreases in CSF mHTT. In GENERATION HD1 (NCT03761849), following two loading doses of 120 mg with an interval of 4 weeks, early and moderate HD participants received placebo or tominersen at a dose of 120 mg every eight (Q8) or every 16 (Q16) weeks. In 2021 the trial was prematurely stopped following an unblinded review, showing that participants in the Q8 cohort had worse scores in clinical scales compared to participants on placebo, while there were no significant differences between the Q16 group and placebo . There were also dose-dependent increases in ventricular volume over the study period, above 25% over 69 weeks in patients on the Q8 dose regime and above 15% increases among participants in the Q16 cohort . These ventricular increases receded after tominersen administration was paused .
More recently, a post-hoc subgroup analysis of GENERATION HD1 by the study sponsor showed a non-statistically significant beneficial tendency among Q16 participants that were below the median for the age and disease burden, measured through the CAP score (a product of age and CAG repeat length). In this subgroup, point estimates for the cUHDRS as well as its functional, cognitive, and motor subscales, were in the favourable direction at 69 weeks. These effects were more marked in participants with lower exposure to the drug .
Based on these results the sponsor has developed the GENERATION HD2 trial, where younger participants with lower disease burden will receive lower doses of the drug with a 16-weeks interval without loading doses. GENERATION HD2 will evaluate whether there is potential benefit for Q16 administration of the lower 60 mg and 100mg doses in this study population.
AB-1001 (NCT05541627) 
Study title: A Study to Evaluate AB-1001 Striatal Administration in Adults With Early Manifest Huntington’s Disease
Intervention: AB-1001 (also known as BV-101 and AAVrh10.CAG.hCYP46A1) is an adeno-associated viral vector serotype Rh10 containing the human cholesterol 24-hydroxylase gene administered through one-off intrastriatal bilateral injections
Description: The goal of the AB-1001 trial is to evaluate the safety of the intrastriatal administration of AAVrh10.CAG.hCYP46A1 in adults (18–65 years) with early manifest HD. It will evaluate two doses of the gene therapy construct administered through bilateral injections into the caudate and putamen.
The study plans to recruit between 12 and 18 participants in France and consists of a dose-finding and a dose expansion periods with participants being followed up total of 5 years following screening .
Eligible participants need to have stable HD and striatal volumes in the screening MRI, being larger than 2.3 cm per side for the putamen and larger than 1.7 cm per side for the caudate. Exclusion criteria include unstable or serious medical conditions other than HD, previous gene therapy or administration experimental agents through brain surgery or inability to undergo the study procedures.
Secondary outcomes include change from baseline in volumetric MRI, cUHDRS, CSF mHTT, neurofilament light chain (NfL) and 24-OH-cholesterol as well as changes in magnetic resonance spectroscopy and in the positron emission tomography (PET) fluoro-deoxyglucose (FDG) striatal profile.
Sponsor/Funders: Asklepios Biopharmaceutical (AskBio) / BrainVectis
Comments: Changes in cellular cholesterol metabolism are associated with neurodegeneration in HD . The cholesterol 24-hydroxylase (CYP46A1) enzyme converts cholesterol to 24S-hydroxycholesterol which can cross the blood-brain barrier and be degraded in the periphery . However, the concentrations of CYP46A1 are decreased in the striatum of HD patients and animal models of HD . Consistently, there is increased accumulation of cholesterol in striatal neurons . Administration of CYP46A1 gene therapy to the zQ175 knock-in HD mice restored cholesterol homeostasis and prevents neuronal dysfunction decreasing mHTT aggregates, improving axonal transport of BDNF and endosomal trafficking .
AB-1001 has shown to improve motor behaviour, decrease mHTT aggregates and NfL concentrations in the R6/2 mouse model of HD . MRI-guided striatal infusions of AB-1001 are also well tolerated in non-human primates . However, the complex cholesterol pathways have not been well studied in human HD patients. Any intraparenchymal gene therapy approach to HD is permanent and high-risk by definition, and it remains to be seen whether any potential benefits will justify the risk.
During this trial, participants will be recruited first into a dose-finding cohort receiving either a low dose (4x108 vg/μL) or a high dose (1.1x109 vg/ μL) of the study construct. The data will be reviewed for dose-limiting toxicities after each cohort is fully recruited and the dose expansion cohort will receive the dose selected after the initial phase. This study is already recruiting participants in France and presents a different approach for disease modification compared to HTT-lowering therapies.
Sigma-1-regulated pathways are altered in different neurodegenerative disorders, including HD . Activation of the sigma-1-receptor positively influences these pathways in model systems . The PROOF-HD (NCT04556656)  clinical trial investigated pridopidine, a sigma-1-receptor agonist at a dose of 45 mg twice a day versus placebo. Pridopidine was previously tested as a dopaminergic stabiliser in the HART (NCT00724048 , NCT01306929 ), MermaiHD (NCT00665223 [22, 23]), and PRIDE-HD (NCT02006472 , NCT02494778 ) but failed to meet primary endpoints.
In the PROOF-HD trial, the primary (TFC) and the key secondary (cUHDRS) endpoints were not met at 65 weeks . The drug was again well tolerated without significant side effects. A planned subgroup analysis showed possible benefit in treated participants compared with placebo, when participants on antidopaminergics were excluded . The significance of these findings is unclear, and antidopaminergic medications are widely used in HD to treat motor and behavioural symptoms. Based on these findings the company is now considering its options for the future of the compound.
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 (NCT03342053), 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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