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. 2025 Nov 26;15(1):156–166. doi: 10.1177/18796397251399751

Huntington's disease clinical trials update: October 2025

Mena Farag 1, Sarah J Tabrizi 1, Edward J Wild 1,✉
PMCID: PMC12847458  PMID: 41295902

Abstract

In this edition of the Huntington's Disease Clinical Trials Update, we expand on the launch of the phase II/III clinical trial of SKY-0515 from Skyhawk Therapeutics and the phase I/II clinical trial of SPK-10001 from Spark Therapeutics. We also report positive topline data from uniQure's phase I/II clinical trial of AMT-130 after 36 months of follow-up. Further updates include recent developments in Roche's tominersen programme within GENERATION HD2, progress with votoplam (PTC518) in PIVOT-HD by PTC Therapeutics and developments in the collaborative PTC Therapeutics/Novartis programme. We additionally discuss regulatory developments regarding pridopidine following the negative PROOF-HD study. Finally, we provide an updated listing of all registered and ongoing clinical trials in Huntington's disease.

Keywords: Huntington's disease, clinical trials

Plain language summary

In this edition of the Huntington's Disease Clinical Trials Update, we expand on the launch of the phase II/III clinical trial of SKY-0515 from Skyhawk Therapeutics and the phase I/II clinical trial of SPK-10001 from Spark Therapeutics. We also report positive topline data from uniQure's phase I/II clinical trial of AMT-130 after 36 months of follow-up. Further updates include recent developments in Roche's tominersen programme within GENERATION HD2, progress with votoplam (PTC518) in PIVOT-HD by PTC Therapeutics and developments in the collaborative PTC Therapeutics/Novartis programme. We additionally discuss regulatory developments regarding pridopidine following the negative PROOF-HD study. Finally, we provide an updated listing of all registered and ongoing clinical trials in Huntington's disease.

Introduction

The Clinical Trials Update is a regular feature devoted to highlighting ongoing and recently completed clinical trials in Huntington's disease (HD). Clinical trials previously reviewed in this section are listed in Table 1. For current and completed studies discussed here, endorsement status by the European Huntington's Disease Network (EHDN) is now also indicated.

Table 1.

Clinical trials previously reviewed by the Huntington's disease clinical trials update.

Trial Name Intervention Endorsed by EHDN Edition
NCT02519036 IONIS-HTTRx IONIS-HTTRx a Yes September 2017 1
NCT02215616 LEGATO-HD Laquinimod Yes
NCT02197130 Amaryllis PF-02545920 Yes
NCT02006472 PRIDE-HD Pridopidine Yes
NCT03225833 PRECISION-HD1 WVE-120101 Yes February 2018 2
NCT03225846 PRECISION-HD2 WVE-120102 Yes
NCT01795859 FIRST-HD Deutetrabenazine No
NCT02481674 SIGNAL VX15/2503 No August 2018 3
NCT00712426 CREST-E Creatine No
NCT03761849 GENERATION HD1 RG6042 a Yes January 2019 4
NCT03344601 PACE-HD Physical activity Yes
NCT02535884 HD-DBS Deep brain stimulation Yes June 2019 5
NCT02453061 TRIHEP3 Triheptanoin No
NCT04120493 AMT-130 AAV5-miHTT Yes April 2020 6
NCT04102579 KINECT-HD Valbenazine No
NCT05111249 VIBRANT-HD Branaplam Yes April 2022 7
NCT04514367 ANX005 ANX-005 No
NCT04406636 SHIELD HD Observational study Yes
NCT03761849 GENERATION HD1 Tominersen a Yes
NCT05032196 SELECT-HD WVE-003 Yes
NCT03225833 PRECISION-HD1 WVE-120101 Yes
NCT03225846 PRECISION-HD2 WVE-120102 Yes
NCT02481674 SIGNAL Pepinemab b No November 2022 8
NCT05358717 PIVOT-HD PTC518 Yes
NCT05686551 GENERATION HD2 Tominersen a Yes August 2023 9
NCT05541627 AB-1001 AAVrh10.CAG.hCYP46A1 c No
NCT05822908 VO659-CT01 VO659 No March 2024 10
NCT05111249 VIBRANT-HD Branaplam Yes
NCT06254482 PIVOT-HD PTC518 (extension study) Yes September 2024 11
NCT06585449 ALN-HTT02 ALN-HTT02 Yes March 2025 12
NCT05107128 DIMENSION SAGE-718 Yes
NCT05655520 PURVIEW SAGE-718 Yes
*NCT06873334 FALCON-HD SKY-0515 No October 2025
*NCT06826612 N/A SPK-10001 No
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a

IONIS-HTTRx, RG6042 and tominersen refer to the same molecule.

b

VX15/2503 and pepinemab refer to the same molecule.

c

AAVrh10.CAG.hCYP46A1, BV-101 and AB-1001 refer to the same molecule.

In this edition, we expand on the launch of the phase II/III clinical trial of SKY-0515 (NCT06873334) 13 (FALCON-HD) from Skyhawk Therapeutics and the phase I/II clinical trial of SPK-10001 (NCT06826612) 14 from Spark Therapeutics. We also report positive topline data from uniQure's phase I/II clinical trial of AMT-130 (NCT04120493; NCT05243017)15,16 after 36 months of follow-up. Further updates include recent developments in Roche's tominersen programme within GENERATION HD2 (NCT05686551), 17 progress with votoplam (PTC518) in PIVOT-HD (NCT05358717; NCT06254482)18,19 by PTC Therapeutics and developments in the collaborative PTC Therapeutics/Novartis programme. We additionally discuss regulatory developments regarding pridopidine following the negative PROOF-HD (NCT04556656) 20 study. Finally, we provide an updated listing of all registered and ongoing clinical trials in Huntington's disease.

We tabulate all currently registered and ongoing clinical trials in Tables 2–4. For further details on the methodology used, please refer to the first edition of this series. 1

Table 2.

Pharmacological clinical trials registered at the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) for people with Huntington's disease (HD) since the first edition of the “Huntington's Disease Clinical Trials Corner”.

Registration ID Trial Name Intervention Mechanism of Action Population Comparison Main Outcome Study Design Estimated Enrolment Sponsor Location(s)
NCT06873334* FALCON-HD SKY-0515 mRNA splicing modulator to lower mHTT and PMS1 Early HD; UHDRS TFC ≥10 Placebo Changes in blood mHTT, brain volume (MRI) and UHDRS at 12 months Randomized, double-blind, placebo-controlled, dose-ranging, parallel assignment 120 Skyhawk Therapeutics, Inc. Australia, New Zealand
(multi-centre)
NCT06853743* NAD-HD Nicotinamide riboside Vitamin B3 derivative; NAD+ precursor Early and moderate HD Placebo Change in composite UHDRS at 24 months Randomized, double-blind, placebo-controlled, parallel assignment 120 Oslo University Hospital Norway
(single centre)
NCT06826612* - Intraparenchymal infusion of SPK-10001 into caudate and putamen bilaterally AAV-mediated gene therapy delivering therapeutic construct to striatum HD-ISS stage 1 or 2 HD; UHDRS TFC ≥11 Placebo/sham surgery Change in UHDRS TFC; safety/TEAEs Randomized, sequential dose-escalation, quadruple-masked, parallel assignment 53 Spark Therapeutics, Inc. USA
(multi-centre)
NCT06585449 - ALN-HTT02 RNA interference selectively targeting exon 1 of HTT mRNA HD-ISS stage 2 or early stage 3 HD Placebo Frequency of TEAEs in both the double-blind and open-label phases, monitored over 12 months Randomized, double-blind, parallel assignment, single dose 54 Alnylam Pharmaceuticals Canada, Germany, UK
(multi-centre)
CTIS2024-514328-18-00 VO659-CT01 Intrathecal administration of VO659 ASO targeting mutant HTT and ataxin RNA to reduce toxic protein levels SCA1, SCA3, HD None Safety, tolerability, and pharmacokinetics of multiple doses Open-label, non-randomized 23 Vico Therapeutics B.V. Denmark, France, Germany, Israel, Netherlands, UK
(multi-centre)
CTIS2024-518875-73-00 TEMET-HD Metformin Modulation of cellular energy metabolism via AMP-activated protein kinase activation HD Placebo Change in UHDRS cognitive score after 6 and 12 months Randomized, double-blind, placebo-controlled 60 IIS La Fe Spain
(pending)
NCT06474650 — LPM3770164 VMAT2 inhibitor Healthy controls None Pharmacokinetics pre-dose and up to 240 h post-dose Randomized, open-label, two-period, double-crossover (phase I) study 16 Luye Pharma Group Ltd China
(single centre)
NCT06469853 — MBF-015 Histone deacetylase 1/2 inhibitor Early and moderate HD None Safety and tolerability at 43 days Open-label, single centre (phase IIa) study 10 Medibiofarma S.L. Spain
(single centre)
NCT06312189 — Valbenazine VMAT2 inhibitor HD with chorea; participated in study NBI-98854-HD3006 (NCT04400331) None Number of participants with TEAEs up to week 106 Non-randomized, open-label 7 Neurocrine Biosciences Canada
(multi-centre)
NCT06254482 — PTC518 Small molecule splicing modulator Participants who completed the treatment period in PTC518-CNS-002-HD None Number of participants with TEAEs up to month 30; blood total HTT levels up to month 28 Randomized, double-blind, parallel assignment, extension (phase IIb) study 250 PTC Therapeutics Australia, Austria, Canada, France, Germany, Italy, Netherlands, New Zealand, Spain, UK
(multi-centre)
NCT06097780 — Nestacell Dental pulp stem cell Early and moderate HD Placebo Efficacy at 1 year Randomized, double-blind, parallel assignment, multiple dose 120 Azidus Brasil N/S
NCT06024265 — ER2001 Small interfering RNA Early HD None Safety at 6.5 months Multiple dose, open-label trial 15 ExoRNA Bioscience China
(single centre)
2022-001565-12 — PTC518 Small molecule splicing modulator Premanifest, prodromal and early HD None Safety at 24 months, blood total HTT levels at 24 months Randomized, double-blind, parallel assignment, multiple dose 250 PTC Therapeutics France, Germany, Netherlands, UK, USA
(multi-centre)
NCT05822908 — VO659 CAG-targeting ASO Early HD, mild-moderate SCA1, mild-moderate SCA3 None Safety at 253 days Open-label, non-randomized, sequential assignment, multiple ascending dose 65 (19 HD, 19 SCA1 and 27 SCA3) VICO Therapeutics B.V. France, Germany, Italy, Poland, the Netherlands, UK
(multi-centre)
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, UK, USA
(multi-centre)
NCT05686551 GENERATION HD2 Tominersen Non-allele-selective ASO Prodromal and early HD Placebo Safety at 24 months Randomized, double-blind, dose-finding trial 360 Hoffmann-La Roche USA, Spain, more sites to be confirmed
(multi-centre)
NCT05655520† PURVIEW SAGE-718 Positive allosteric modulator of NMDA Premanifest, early and moderate HD None Safety at 13 months Single-dose open-label trial 153 Sage Therapeutics Canada, USA
(multi-centre)
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
(single centre)
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, UK, USA
(multi-centre)
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, UK, USA
(multi-centre)
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, USA
(multi-centre)
NCT05509153 NAC-preHD NAC Antioxidant Premanifest HD Placebo Efficacy at 36 months Randomized, double-blind trial 160 Western Sydney Local Health District Australia
(multi-centre)
ISRCTN56240656† FELL-HD Felodipine Calcium channel blocker Early HD None Safety at 62 weeks Non-randomised, multiple dose trial 18 Cambridge University UK
(single centre)
NCT05358821† SURVEYOR 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 69 Sage Therapeutics USA
(multi-centre)
NCT05358717 PIVOT HD PTC518 Small molecule splicing modulator Premanifest, 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, UK, USA
(multi-centre)
NCT05475483 - Bevantolol hydrochloride (SOM-3355) 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, UK
(multi-centre)
ACTRN12621001755820 - Trehalose (SLS-005) 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
(two centres)
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
(single centre)
NCT05107128† DIMENSION SAGE-718 Positive allosteric modulator of NMDA Early and moderate HD Placebo Change in cognition at 84 days Double-blind, placebo-controlled, single dose design 189 Sage Therapeutics Australia, Canada, USA
(multi-centre)
NCT05111249† VIBRANT HD Branaplam Small molecule splicing modulator Early HD Placebo Reduction of mHTT protein at week 17
Safety at 104 weeks		 Double-blind, placebo-controlled multiple dose design 75 Novartis Pharmaceuticals Belgium, Canada, France, Germany, Hungary, Italy, Spain, UK, USA
(multi-centre)
NCT05032196† SELECT-HD WVE-003 Allele-selective ASO 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, UK
(multi-centre)
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, UK
(multi-centre)
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 Investigación 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, Canada
(multi-centre)
NCT04301726 — Deutetrabenazine VMAT2 inhibitor HD with dysphagia Placebo Dysphagia at 18 months Randomized, parallel assignment, triple blinded trial 48 Fundación Huntington Puerto Rico N/S
NCT04478734; CTIS2023-508637-14-00 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 ASO HD None Safety and tolerability at 97 weeks Open-label extension 70 Wave Life Sciences Ltd Australia, Canada, Denmark, France, Poland, UK
(multi-centre)
NCT04000594† GEN-PEAK RG6042 Allele-nonselective ASO HD None Pharmacodynamics and pharmacokinetics at multiple timepoints until 6 months Non-randomized. open-label, multiple-dose, parallel trial 20 Hoffmann-La Roche Netherlands, 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 ASO 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 ASO 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 inhibitor 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 ASO 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, UK
(multi-centre)
NCT03225846† PRECISION-HD2 WVE-120102 Allele-selective ASO 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, UK
(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
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AAV: adeno-associated virus; AMP: adenosine monophosphate; AMPK: AMP-activated protein kinase; ASO: antisense oligonucleotide; HD: Huntington's disease; HD-ISS: Huntington's Disease Integrated Staging System; HTT: huntingtin; MAPK: mitogen-activated protein kinase; mHTT: mutant huntingtin; miRNA: microRNA; MRI: magnetic resonance imaging; mRNA: messenger ribonucleic acid; NAC: N-acetylcysteine; NAD+: nicotinamide adenine dinucleotide (oxidised form); NMDA: N-methyl-D-aspartate; N/S: not specified; PD: Parkinson's disease; PMS1: post-meiotic segregation 1; PPARα: peroxisome proliferator-activated receptor alpha; RNA: ribonucleic acid; SCA1: spinocerebellar ataxia 1; SCA3: spinocerebellar ataxia 3; TD: tardive dyskinesia; TEAEs: treatment-emergent adverse events; TFC: Total Functional Capacity; UHDRS: Unified Huntington's Disease Rating Scale; VMAT2: vesicular monoamine transporter 2. Note: IONIS-HTTRx, ISIS 443139, RG6042 and tominersen refer to the same molecule. New trials added since the last Clinical Trials Update are indicated by *. Pharmacological trials terminated are indicated by †.

Table 3.

Invasive non-pharmacological clinical trials registered at the WHO ICTRP for people with HD since the first edition of the “Huntington's Disease Clinical Trials Corner”.

Registration ID Trial Name Intervention Mechanism of Action Population Comparison Main Outcome Study Design Estimated Enrolment Sponsor Location(s)
NCT06444217 FibroTG-HD Skin biopsy Skin biopsy Individuals with a CAG ≥36 allele (with reduced or full penetrance) None In vitro validation of a RNA trans-splicing gene therapy for the correction of supernumerary CAG repeats into fibroblasts derived from skin biopsies Open-label, single group assignment 20 University Hospital, Angers France
(single centre)
NCT06097780 — Nestacell Dental pulp stem cell Early and moderate HD Placebo Efficacy at 1 year Randomized, double-blind, parallel assignment, multiple dose 120 Azidus Brasil N/S
NCT04244513 — GPi DBS DBS 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 HD Usual care Safety at 4 weeks Randomized, open-label, controlled, parallel trial 30 Cardiff University, UK 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 Honduras, USA
(multi-centre)
NCT02535884 HD-DBS GP DBS DBS 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 — MR-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)
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AD: Alzheimer's disease; CBD: corticobasal degeneration; DBS: deep brain stimulation; ET: essential tremor; GP: globus pallidus; GPi: globus pallidus internus; HD: Huntington's disease; HT: Holmes tremor; ICTRP: International Clinical Trials Registry Platform; MNC: mononuclear cells; MR: magnetic resonance; MS: multiple sclerosis; N/S: not specified; RNA: ribonucleic acid; PD: Parkinson's disease; TD: tardive dyskinesia; WD: Wilson's disease; WHO: World Health Organization.

Table 4.

Non-invasive non-pharmacological clinical trials registered at the WHO ICTRP for people with HD since the first edition of the “Huntington's Disease Clinical Trials Corner”.

Registration ID Trial Name Intervention Mechanism of Action Population Comparison Main Outcome Study Design Estimated Enrolment Sponsor Location(s)
NCT07136844* Acti-Adult Syde® wearable device; standardised functional tests; disease-specific clinical scales Digital mobility and activity monitoring with magneto-inertial sensors to capture real-world gait and upper limb function Ambulatory adults with neurological or metabolic movement disorders (including HD) and obesity Parallel disease cohorts 95th centile of stride velocity (SV95C) every 6 months for up to 2 years Non-randomized, parallel assignment, open-label; diagnostic purpose 300 Centre Hospitalier Universitaire de Liège Belgium
(single centre)
NCT07010705* MEND-HD ActiGraph LEAP (wearable device); Axivity AX6 (wearable device) Digital health technologies to quantify gait, mobility and chorea (wearable sensor-based endpoints) HD-ISS stage 2 or early stage 3 Healthy controls Known-group validity and inter-method reliability of digital measures of stride time variability and total time in chorea Observational (case-control, prospective) 100 University of Rochester USA
(single centre)
NCT06843252* — Active tDCS Non-invasive brain stimulation modulating cortical excitability and frontostriatal networks to improve cognition and behaviour Early and moderate HD Sham tDCS (crossover) Study completion, acceptability, side effects; secondary: cognition (FAB), behaviour (PBA-s) Randomized, double-blind, sham-controlled, crossover pilot trial 16 The University of Texas Health Science Center at San Antonio USA
(single centre)
NCT06807892* CARE-MH Synergistic management (simultaneous cognitive-motor exergames); sequential management (separate cognitive then motor training) Cognitive-motor training via exergames aiming to improve neuroplasticity, balance, motor and cognitive function Early HD Synergistic vs sequential management Berg Balance Scale (BBS) Randomized, parallel-group, open-label supportive care trial 40 University Hospital, Angers France
(single centre)
NCT06774443 HT-HD Neuropsychological assessment (Hinting Task) Assessment of social cognition deficits, specifically Theory of Mind HD Healthy controls Sensitivity of the Hinting Task in detecting social cognition impairments in HD Observational (case-control, cross-sectional) 52 University Medical Center Groningen Netherlands
(single centre)
NCT06693466 HD-P1 Experimental pain assessment (pain facilitation, facial expression, and conditioned pain modulation) Assessment of pain processing mechanisms and sensory modulation in HD HD None Feasibility of experimental pain assessment protocols in HD Observational (cohort, cross-sectional) 20 Leiden University Medical Center Netherlands
(single centre)
NCT06634628 iMagemHTT-009 PET imaging with novel radioligand [11C]CHDI-00491009 Radioligand binding to aggregated mHTT for quantification HD None VT of [11C]CHDI-00491009 measured via PET imaging Non-randomized, sequential assignment 27 CHDI Foundation, Inc. Belgium
(single centre)
NCT06626308 BIO-MH Brain fMRI and gait assessment using 3D virtual reality fMRI to assess early subcortical biomarkers and virtual reality-based gait analysis for detecting preclinical motor abnormalities Premanifest HD Healthy controls BOLD signal changes in subcortical regions and alterations in gait parameters Observational (case-control) 20 University Hospital, Grenoble France
(single centre)
NCT06626412 — PET of SV2A using the radioligand 18F-SynVesT-1 Radioligand binding to SV2A for quantification of synaptic density Late premanifest HD Volumetric MRI Baseline differences and longitudinal changes in synaptic density and brain volume Non-randomized, single-group assignment 35 Universitaire Ziekenhuizen KU Leuven Belgium
(single centre)
NCT06585332 — Hand grip strength as a screening tool for respiratory dysfunction Assessment of neuromuscular function related to respiratory effort HD None Maximal hand grip strength, voluntary peak cough flow, maximal expiratory pressure, maximal inspiratory pressure Observational (case only) 70 General University Hospital Prague
(single centre)
NCT06546488 CAT-HD Behavioral assessments Standardised assessment batteries using the DSCT and SAGE HD SDMT, SWR SDMT compared to DSCT; SAGE score compared to SDMT and SWR scores Observational (case only) 76 Ohio State University USA
(single centre)
NCT06490367 TREHD TRE diet TRE diet, specifically maintaining a 6-8-h eating window every day for 12 weeks Premanifest, prodromal and early HD None Change from baseline in the daily eating period at week 13 Prospective interventional, open-label, single-arm trial 25 Oregon Health and Science University USA
(single centre)
NCT06414967 MUSIC-HD Music therapy Music therapy using a digital music therapy tool combined with conventional management Early HD None Change in irritability after 3 months Single group, open-label 15 Poitiers University Hospital France
(single centre)
RBR-75ys4s9 — Dance therapy Dance sessions offered by physiotherapists using auditory and visual stimuli HD, PD, dystonia Standard medical treatment Quality of life improvement Two-arm randomized controlled trial with a blinded examiner 100 Universidade Federal de Juiz de Fora Brazil
(single centre)
ChiCTR2300069844 — Repetitive transcranial magnetic
stimulation		 Transcranial magnetic stimulation HD None EEG Non-randomized, open-label, single group trial 20 Shenzhen People's Hospital China
(single centre)
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
(single centre)
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
(single centre)
ACTRN12622000908730 — Online platform Computerized 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
(two centres)
ISRCTN11906973 HD-DRUM Training app Drumming Premanifest, early and moderate HD Standard medical care Feasibility Randomized, parallel assignment trial 50 Cardiff University, UK UK
(single centre)
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
(two centres)
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 Randomized, crossover double-blinded trial 15 Western University, Canada N/S
ACTRN12620000281998 — Ketogenic diet 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, 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)
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3D: three-dimensional; AD: Alzheimer's disease; ALS: amyotrophic lateral sclerosis; BOLD: blood oxygen level-dependent; DSCT: Digit Symbol Coding Test; EEG: electroencephalography; ET: essential tremor; FAB: Frontal Assessment Battery; fMRI: functional magnetic resonance imaging; HD: Huntington's disease; HT: Holmes tremor; ICTRP: International Clinical Trials Registry Platform; mHTT: mutant huntingtin; MRI: magnetic resonance imaging; MS: multiple sclerosis; N/S: not specified; PBA-s: Problem Behaviors Assessment - short; PD: Parkinson's disease; PET: positron emission tomography; SAGE: Self-Administered Gerocognitive Examination; SDMT: Symbol Digit Modalities Test; SV2A: synaptic vesicle glycoprotein 2A; SWR: Stroop Word Reading; TD: tardive dyskinesia; tDCS: transcranial direct current stimulation; TRE: time-restricted eating; VT: volume of distribution; WHO: World Health Organization. New trials since the last Clinical Trials Update are indicated by *.

If you would like to draw attention to specific trials, please feel free to email us at: mena.farag@ucl.ac.uk and e.wild@ucl.ac.uk.

Ongoing clinical trials

A list of all registered clinical trials is given in Tables 2–4.

SKY-0515 (NCT06873334) 13

Study Title: Study of SKY-0515 for Safety, Efficacy and Pharmacodynamics in Participants with Huntington's Disease (FALCON-HD).

Intervention: Oral SKY-0515 (low, mid, or high dose) or matched placebo, administered once daily for 12 months. SKY-0515 is an mRNA-splicing modulator designed to reduce both wild-type HTT and mutant huntingtin (mHTT) protein by lowering HTT mRNA levels, and to suppress post-meiotic segregation 1 (PMS1) protein, a mediator of somatic CAG repeat expansion and known driver of HD progression.13,21,22

Description: The FALCON-HD study, sponsored by Skyhawk Therapeutics, Inc., is a phase II/III randomised, double blind, placebo-controlled, dose ranging clinical trial to evaluate the pharmacodynamics, safety and efficacy of SKY-0515 in people with HD. This multi-centre clinical trial will enrol 120 adults (≥25 years) with genetically confirmed HD (CAG repeat length ≥40) who meet defined functional and motor thresholds (specifically Unified Huntington's Disease Rating Scale (UHDRS) Total Functional Capacity (TFC) ≥ 10; Total Motor Score (TMS) ≥ 6). The clinical trial design comprises a screening period lasting up to four weeks, a 12-month double-blind treatment period and a four-week follow-up period thereafter. Participants will be randomised (1:1:1:1) to one of three once-daily dose levels of SKY-0515 or placebo. Safety and efficacy will be assessed through regular clinical trial visits, laboratory tests, brain MRI and standardised clinical assessments, including the UHDRS.

Primary outcome measures are change from baseline to 12 months in blood mHTT protein levels, MRI-derived brain volumes and UHDRS scores. Other outcome measures include changes in other HD-related biomarkers and long-term safety of SKY-0515.

Sponsor/Funders: Skyhawk Therapeutics, Inc.

EHDN Endorsed Trial: No

Comments: On 9th July 2024, Skyhawk Therapeutics announced positive results from its phase I trial of SKY-0515 (ACTRN12623001161617) 21 in healthy volunteers, initiated in late 2023. 22 SKY-0515 produced dose-dependent reductions in HTT mRNA, with maximum decreases of 67% after a single 16 mg dose and 72% after 14 days of 9 mg daily dosing. 22 Reductions were observed across all dose levels, and the drug was generally well-tolerated. On 17th September 2025, Skyhawk Therapeutics reported further positive findings from the first interim analysis of this phase 1 trial. 23 At day 84, treatment with SKY-0515 resulted in dose-dependent reductions of mHTT protein level in blood, including a 29% reduction at the 3 mg dose and a 62% reduction at the 9 mg dose. SKY-0515 was generally well tolerated at both dose levels. 23

On 20th June 2025, Skyhawk Therapeutics announced that the first patient was dosed in the phase II/III FALCON-HD study (NCT06873334) 13 in Adelaide, Australia, 24 marking the initiation of the registrational trial programme across multiple sites in Australia and New Zealand.

SKY-0515 is designed to reduce both HTT and PMS1 proteins, the latter implicated in somatic CAG repeat expansion, a mechanistic process increasingly recognised as a key driver of neuronal loss in HD.25,26 Genome-wide association and mismatch repair studies indicate that targeting PMS1 and other DNA repair genes could help prevent progressive neuronal pathogenesis in striatal and cortical regions.27,28 This important phase II/III clinical trial of SKY-0515 will assess whether HTT and PMS1 lowering can offer greater therapeutic benefit than HTT reduction alone in early-stage HD.

SPK-10001 (NCT06826612) 14

Study Title: A Randomized Study of SPK-10001 Gene Therapy in Participants with Huntington's Disease.

Intervention: One-time bilateral intraparenchymal infusion of SPK-10001 (also known as RG6662) into the caudate and putamen, compared with placebo surgery. 14 SPK-10001 is an engineered adeno-associated virus (AAV) vector delivering an artificial microRNA designed to selectively target human HTT mRNA. 29

Description: The SPK-10001 clinical trial, sponsored by Spark Therapeutics, Inc., is a phase I/II multicentre, randomized, sequential, dose-escalation study evaluating the safety, tolerability, and preliminary efficacy of SPK-10001, an investigational gene therapy, in people with HD. Eligible participants receive a one-time bilateral intraparenchymal infusion of SPK-10001 into the caudate and putamen, or undergo a placebo surgical procedure. The clinical trial is structured in four sequential parts: an initial open-label cohort (Part A) in which all participants receive SPK-10001; a randomized, double-blind, placebo-surgery-controlled cohort (Part B); an open-label crossover (Part C) in which participants initially assigned to placebo surgery receive SPK-10001; and a long-term follow-up phase (Part D) for all participants following completion of active treatment. Up to 53 adults (aged 25–65 years) with genetically confirmed HD (CAG repeat length ≥40), evidence of striatal atrophy and preserved functional capacity (defined as UHDRS TFC ≥11) will be enrolled into the clinical trial.

Primary outcome measures are safety and tolerability, measured by the incidence and severity of treatment-emergent adverse events (TEAEs) over a five-year follow-up period, and change from baseline in UHDRS TFC score at 24 months. Secondary outcome measures include changes from baseline in motor progression assessed by digital motor testing at 12, 18 and 24 months; changes in composite UHDRS (cUHDRS) scores at 12, 18 and 24 months; and changes in UHDRS TFC scores at 12 and 18 months.

Sponsor/Funders: Spark Therapeutics, Inc.

EHDN Endorsed Trial: No

Comments: Data on SPK-10001 were presented at the 31st Annual Meeting of the Huntington Study Group (HSG), held in Cincinnati, Ohio from 7th to 9th November 2024, and at the Cure Huntington's Disease Initiative (CHDI) 20th Annual HD Therapeutics Conference, held in Palm Springs, California from 24th to 27th February 2025.29,30 Preclinical studies of SPK-10001, an engineered AAV vector delivering an artificial microRNA targeting human HTT mRNA, demonstrated a consistent, dose-dependent reduction of HTT mRNA and protein in HD mouse models following direct intrastriatal injection, compared with untreated controls. Reductions of up to 40% in HTT mRNA and up to 70% in HTT protein were well-tolerated and remained stable over a 12-month period. In contrast to uniQure's AMT-130 gene therapy, SPK-10001 targets an RNA sequence downstream of exon 1, promising valuable insights into the relative importance of the exon 1a splice variant as opposed to full length mHTT. In nonhuman primate studies, robust and consistent suppression of HTT protein throughout the caudate and putamen was achieved only through direct intraparenchymal administration, whereas intra cerebrospinal fluid (CSF) routes (intraventricular, intrathecal or intracisternal) failed to achieve satisfactory target engagement in these regions. Safety data in cynomolgus macaques indicated that the surgical procedure was generally well-tolerated with minimal perioperative immunosuppression. Transient elevations in CSF neurofilament light chain (NfL) protein were observed in all animals but returned to baseline within 12 months. Levels of HTT suppression were stable over the same period and highly consistent within dose groups. 29 On 12th June 2025, Spark Therapeutics and Roche issued a joint community update via a letter announcing that the first participant had been dosed with RG6662, also known as SPK-10001, and that the programme will be fully transitioned to Roche. 31

These findings and the update from Spark Therapeutics and Roche represent an important step in the development and progress of gene therapy for HD, particularly in light of the news below from the first gene therapy to be tested in HD patients. Early preclinical data support target engagement and tolerability of SPK-10001; however, safety, efficacy and clinical benefit in humans remain to be established. Long-term monitoring will be essential to determine the durability of any therapeutic effects, ongoing safety and potential functional impact as results from the ongoing phase I/II clinical trial become available.

Breaking news

In this section we provide brief updates about ongoing or recently terminated clinical trials.

The AMT-130 (NCT04120493; NCT05243017)15,16 study, sponsored by uniQure Biopharma B.V., is investigating the effects of AMT-130, a one-time intracranially administered gene therapy that uses an AAV vector (AAV5-miHTT) to deliver a microRNA targeting the HTT gene. The treatment is intended to provide long-lasting supression of HTT expression. On 24th September 2025, uniQure released positive topline results from the phase I/II clinical trial of AMT-130. 32 The prespecified analysis included 29 treated participants (17 high-dose, 12 low-dose), with 12 patients per cohort reaching 36 months of follow-up. Outcomes were compared with propensity score-matched external controls from the Enroll-HD natural history dataset (n = 940 for high dose; n = 626 for low dose). At 36 months, high-dose AMT-130 met the primary endpoint, demonstrating a statistically significant 75% slowing of disease progression versus controls, as measured by the cUHDRS (P = 0.003; mean change from baseline −0.38 vs −1.52). A key secondary endpoint, UHDRS TFC, showed a 60% slowing of decline (P = 0.033; −0.36 vs −0.88). Additional secondary measures indicated favourable trends, including Symbol Digit Modalities Test (SDMT) (88% slowing; P = 0.057; −0.44 vs. −3.73), Stroop Word Reading (SWR) (113% slowing; P = 0.002; 0.88 vs. −6.98) and UHDRS TMS (59% slowing; P = 0.174; 2.01 vs. 4.88). Fluid biomarker analysis also showed a mean reduction of 8.2% in CSF NfL from baseline at 36 months, which provides supportive biomarker evidence of target engagement and disease modification. AMT-130 was overall well-tolerated, with an acceptable safety profile observed in both the high-dose and low-dose cohorts. 32 The sponsor reported that the consistently sustained improvements across functional, motor and cognitive outcomes at 36 months in the high-dose cohort, compared with the more variable findings at the lower dose, suggest a dose-dependent effect of AMT-130. Overall, the press release indicates that AMT-130 may have disease-modifying potential in HD and has the potential to meaningfully slow disease progression. The sponsor has also provisionally announced plans to submit a Biologics Licence Application to the US Food and Drug Administration in early 2026, with a potential US launch later that year pending regulatory approval. 32 Peer-reviewed publication is expected and will permit close scrutiny of all the data, but the topline results appear to be the most encouraging seen so far in a clinical trial of a therapy intended to deflect the course of HD.

The GENERATION HD2 (NCT05686551) 17 study, sponsored by Roche, released an update on 17th April 2025 regarding the tominersen programme. 33 Tominersen is an intrathecally administered antisense oligonucleotide (ASO) therapy designed to lower HTT expression. GENERATION HD2 is a phase II, randomised, double-blind, placebo-controlled, dose-finding clinical trial comparing 60 mg tominersen, 100 mg tominersen and placebo. In the most recent update provided by Roche, the Independent Data Monitoring Committee (IDMC) reported that tominersen continues to demonstrate an acceptable safety profile and recommended continuation of the trial, while advising discontinuation of the 60 mg arm while continuing with the 100 mg dose, which was judged more likely to provide clinical benefit. 33 This update is encouraging following the IDMC decision in March 2021 to halt the phase III GENERATION HD1 (NCT03761849) 34 study, due to an unfavourable benefit-risk profile. 35 In GENERATION HD2 (NCT05686551), 17 participants who had been receiving the 60 mg dose will transition to the 100 mg dose in a blinded manner, while those in the placebo group will remain in their original assignment. Although this update does not establish efficacy, it represents a data-driven refinement of the study design to prioritise the dose most likely to demonstrate therapeutic benefit. The clinical trial remains ongoing, and definitive conclusions regarding clinical benefit will only be possible once the data are unblinded and fully analysed. This is anticipated to be late 2026.

The PIVOT-HD (NCT05358717; NCT06254482)18,19 study, sponsored by PTC Therapeutics, released an update on 5th May 2025 regarding PTC518 (also known as votoplam), an orally administered huntingtin mRNA splice modulator. 36 The study met its primary endpoint, showing dose-dependent reductions in blood HTT protein levels at week 12, along with a favourable safety and tolerability profile across all dose levels and disease stages. Results from the full 12-month cohort show that HD-ISS stage 2 participants showed dose-dependent reductions in blood HTT protein (up to 39% with the 10 mg dose) and emerging trends suggesting potential clinical benefit, including favourable changes on the composite UHDRS and TMS subscale. For HD-ISS stage 3 participants, more modest trends were observed, with apparent benefit in the 5 mg group but less consistent effects in the 10 mg group, raising the possibility that treatment response may differ by disease stage. At 24 months, data from an early cohort (n = 21) demonstrated dose-dependent reductions in plasma NfL levels (−8.9% at 5 mg and −14% at 10 mg) and favourable trends on cUHDRS, TFC and SDMT subscales, compared with a propensity-matched natural history cohort from the Enroll-HD registry. Importantly, for all dose levels and disease stages, PTC518 showed a favourable safety and tolerability profile with no treatment-related serious adverse events or NfL spikes observed. These findings support ongoing investigation of PTC518, which is currently being assessed in the open-label extension (NCT06254482). 19 While these results are promising and suggestive of early signs of clinical benefit, definitive evidence of efficacy, functional impact and long-term safety will require confirmation in the ongoing open-label extension and potential subsequent phase III study. On that note, Novartis released a community update on 15th July 2025 announcing a global licence and collaboration agreement with PTC Therapeutics for the development of votoplam (PTC518). 37 Under this agreement, Novartis will assume sponsorship of the long-term extension study and lead any future phase III development. Novartis has indicated that analysis of the phase II data is ongoing and that discussions with regulatory authorities, clinical experts and patient advocacy groups are underway to inform the design of the next phase of development.

On 25th July 2025, Prilenia and Ferrer announced that the European Medicines Agency's Committee for Medicinal Products for Human Use had recommended refusal of marketing authorisation for pridopidine in HD. 38 This decision follows the outcome of the phase III PROOF-HD (NCT04556656) 20 study, which enrolled 499 participants and evaluated a single daily dose of 45 mg pridopidine versus placebo. The primary endpoint, change in UHDRS TFC score from baseline to week 65, was not met, indicating no significant slowing of disease progression over the 15-month treatment period. 38

Acknowledgements

The authors have no acknowledgments to report.

Footnotes

Funding: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: 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.

The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: MF was a sub-investigator in the ALN-HTT02 (NCT06585449), GENERATION HD2 (NCT05686551), PTC518 (NCT05358717; NCT06254482) and uniQure AMT-130 (NCT05243017) clinical 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 analogues licensed to Adrestia Therapeutics. SJT was an investigator in the ALN-HTT02 (NCT06585449), IONIS HTTRx (NCT02519036), IONIS HTTRx OLE (NCT03342053), GENERATION HD1 (NCT03761849), GENERATION HD2 (NCT05686551), Roche Natural History Study (NCT03664804), Roche GEN-EXTEND (NCT03842969), PTC518 (NCT05358717; NCT06254482), SHIELD-HD (NCT04406636) and uniQure AMT-130 (NCT05243017) clinical 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, Remix Therapeutics and Skyhawk Therapeutics. All honoraria for these consultancies were paid through the offices of UCL Consultants Ltd, a wholly owned subsidiary of University College London. EJW was an investigator in the ALN-HTT02 (NCT06585449), Amaryllis (NCT02197130), LEGATO-HD (NCT02215616), IONIS HTTRx (NCT02519036), IONIS HTTRx OLE (NCT03342053), GENERATION HD1 (NCT03761849), GENERATION HD2 (NCT05686551), Roche Natural History Study (NCT03664804), Roche GEN-EXTEND (NCT03842969), Roche GEN-PEAK (NCT04000594), PTC518 (NCT05358717; NCT06254482), uniQure AMT-130 (NCT05243017) and VIBRANT-HD (NCT05111249) clinical trials.

SJT and EJW are Editorial Board Members of this journal but were not involved in the peer review process of this article nor had access to any information regarding its peer review.

Data availability: Data sharing not applicable as no datasets generated and/or analysed for this study.

References

Articles from Journal of Huntington's Disease are provided here courtesy of SAGE Publications

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