Huntington’s disease Clinical Trials Corner: February 2018

Journal of Huntington’s Disease 7 (2018) 89–98 DOI 10.3233/JHD-189001 IOS Press 89 Huntington’s Disease Clinical Trials Corner: February 2018 Filipe B. Rodriguesa,b,cand Edward J. Wilda,∗ aHuntington’s Disease Centre, University College London, UK bLaboratory of Clinical Pharmacology and Therapeutics, Faculty of Medicine, University of Lisbon, Portugal cClinical Pharmacology Unit, Instituto de Medicina Molecular, Lisbon, Portugal Abstract. In the second edition of the Huntington’s Disease Clinical Trials Corner we list all currently registered and ongoing clinical trials, summarise the top-line results of the recently-announced IONIS-HTTRX trial (NCT02519036), expand on Wave Life Sciences’ PRECISION-HD1 (NCT03225833) and PRECISION-HD2 (NCT03225846), and cover one recently finished trial: the FIRST-HD deutetrabenazine trial (NCT01795859). Keywords: Huntington disease, clinical trials INTRODUCTION The Huntington’s Disease Clinical Trials Corner is a regular section devoted to highlighting ongoing and recently completed clinical trials in Huntington’s disease (HD). Clinical trials previously reviewed by the Huntington’s Disease Clinical Trials Corner are listed in Table 1. Table 1 Clinical trials previously reviewed by the Huntington’s Disease Clinical Trials Corner Registration ID Trial name Intervention Edition NCT02519036 IONIS-HTTRx IONIS-HTTRx September NCT02215616 LEGATO-HD Laquinimod 2017(6) NCT02197130 Amaryllis PF-02545920 NCT02006472 Pride-HD Pridopidine In this edition, we summarise the recentlyannounced top-line results from the phase 1b/2a IONIS-HTTRX huntingtin-lowering antisense oligonucleotide (ASO) trial (NCT02519036) [1]; highlight the new Wave Life Sciences allele-selective ∗Correspondence to: Edward J. Wild, UCL Huntington’s Disease Centre, Russell Square 10-12, London, WC1B 5EH, UK. E-mail: [email protected]. ASO trials, PRECISION-HD1 (NCT03225833) [2] and PRECISION-HD2 (NCT03225846) [3], and summarise the results of the FIRST-HD (NCT01795859) [4, 5] trial of deutetrabenazine. Finally 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 September 2017 edition of Huntington’s Disease Clinical Trials Corner [6]. If you would like to draw attention to specific trials, please feel free to email us at: E-mails: [email protected] and [email protected]. BREAKING NEWS December 11th 2017 saw the initial announcement of top-line results from the first-in-human phase 1b/2a trial of IONIS-HTTRX, the first ASO designed to lower huntingtin protein (HTT) to be tested in people with HD (NCT02519036) [1]. The announcement came in the form of a press release from the sponsor, Ionis Pharmaceuticals [7], and was followed by substantial media coverage [8, 9]. As we detailed in the previous Clinical Trials Corner [6], the trial had safety as its primary endpoint. Encouragingly, the release reported that “the safety and tolerability profile . . . ISSN 1879-6397/18/$35.00 © 2018 – IOS Press and the authors. All rights reserved This article is published online with Open Access and distributed under the terms of the Creative Commons Attribution Non-Commercial License (CC BY-NC 4.0). 90 F.B. Rodrigues and E.J. Wild / Huntington’s Disease Clinical Trials Corner: February 2018 Table 2 Ongoing pharmacological clinical trials registered at the World Health Organization (WHO) International Clinical Trials Research Platform (ICTRP) for people with Huntington’s disease (HD). N/S, not specified; PD, Parkinson’s disease; VMAT2, Vesicular Monoamine Transporter 2. New trials since the last Clinical Trials Corner are indicatedby ∗ Registration ID Trial name Intervention Mechanism of Population Comparison Main outcome Study design Estimated Sponsor Location Action Enrolment NCT03342053∗IONIS-HTTRX OLE ISIS 443139 Allelenonselective antisense oligonucleotide HD None Safety and tolerability at 74 weeks Open label extension 46 Ionis Pharmaceuticals Inc. Canada, Germany and UK (multi-centre) NCT03225833∗PRECISION-HD1 WVE-120102 Allele-selective antisense oligonucleotide HD Placebo Safety and tolerability at 1 and 120 days Randomized, double-blind, placebocontrolled, combined single ascending dose/multiple ascending dose trial 48 Wave Life Sciences Ltd. Canada and Poland (multi-centre) NCT03225846∗PRECISION-HD2 WVE-120102 Allele-selective antisense oligonucleotide HD Placebo Safety and tolerability at 1 and 120 days Randomized, double-blind, placebocontrolled, combined single ascending dose/multiple ascending dose trial 48 Wave Life Sciences Ltd. Canada and Poland (multi-centre) EUCTR2016003730-25-NL CHALLENGEHD SBT-020 Mitochondriatargeted cytoprotective peptide Early HD Placebo Safety and tolerability at 7 and 28 days Randomized, double-blind, placebocontrolled, parallel trial 24 Stealth Biotherapeutics Netherlands (single centre) NCT03019289 – Pridopidine Dopaminergic stabilizer Healthy individuals and HD None Pharmacodynamic at 1 day Single dose, open-label, single group trial 38 Teva Branded Pharmaceutical Products, R&D Inc. Germany (single centre) NCT02453061 TRIHEP 3 Triheptanoin Anaplerotic therapy HD Placebo Pharmacodynamic efficacy at 6 months Randomized, double-blind, placebocontrolled, parallel trial 100 Institut National de la Sant´ eEt de la Recherche M´ edicale, Ultragenyx Pharmaceutical Inc France, Netherlands (multi centre) (Continued) F.B. Rodrigues and E.J. Wild / Huntington’s Disease Clinical Trials Corner: February 2018 91 Table 2 (Continued) Registration ID Trial name Intervention Mechanism of Population Comparison Main outcome Study design Estimated Sponsor Location Action Enrolment 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) NCT02507284 STAIR SRX246 Vasopressin 1a Receptor Antagonist Early and moderate HD with irritability Placebo Feasibility at 12 weeks Randomized, double-blind, placebocontrolled, parallel trials 108 Azevan Pharmaceuticals, National Institute of Neurological Disorders and Stroke (NINDS), and NeuroNEXT Network USA (multi centre) NCT02494778 Open PRIDE-HD Pridopidine Dopaminergic stabilizer PRIDE-HD completers None Safety at 104 weeks Single group, open label extension of PRIDE-HD 300 Teva Branded Pharmaceutical Products, R&D Inc. Australia, Austria, Canada, Denmark, France, Germany, Italy, Netherlands, Poland, Russia, UK, USA (multi 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, placebocontrolled, parallel trial 116 Vaccinex Inc., Huntington Study Group USA (multi centre) NCT02336633 REVHD Resveratrol Dietary supplement HD Placebo Neuroimaging biomarkers at 1 year Randomized, double-blind, placebocontrolled, parallel trial 102 Assistance Publique – Hˆ opitaux de Paris France (multi centre) 92 F.B. Rodrigues and E.J. Wild / Huntington’s Disease Clinical Trials Corner: February 2018 NCT02215616 LEGATO-HD Laquinimod Immunomodulatory molecule HD Placebo Efficacy at 1, 3, 6, and 12 months Randomized, double-blind, placebocontrolled, parallel trial 400 Teva Branded Pharmaceutical Products, R&D Inc. Canada, Czech Republic, France, Germany, India, Israel, Italy, Netherlands, Portugal, Russia, Spain, UK, USA (multi centre) EUCTR2013002545-10-SE OSU6162 Open1309 (–)-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) NCT00652457 MEM-HD Memantine NMDA receptor antagonist HD and memory or concentration difficulties Placebo Efficacy at 3 and 6 months Randomized, double-blind, placebocontrolled, cross-over trial 60 University of California, San Diego, Forest Laboratories USA (multi centre) NCT00632645 NEUROHD Olanzapine Dopamine agonist HD with motor or behavioural symptoms Tetrabenazine or tiapride Efficacy at 12 months Randomized, open-label, controlled, parallel trial 180 Assistance Publique – Hˆ opitaux de Paris, France (single centre) NCT01306929 OPEN-HART Pridopidine Dopaminergic stabilizer HART or PRIDE-HD completers None Safety at 2 years Single group, open label extension of HART 235 Teva Branded Pharmaceutical Products, R&D Inc. Canada, USA (multi centre) NCT00514774 UDCA-HD Ursodiol Bile acid HD Placebo Safety, tolerability and pharmacokinetics at 35 days Randomized, double-blind, placebocontrolled, parallel trial 21 Oregon Health and Science University, Huntington Study Group, Huntington Society of Canada N/S ACTRN12616001 611415 VCAS-HD Varenicline Nicotinic acid receptor partial agonist HD Placebo Efficacy at 10 weeks Randomized, double-blind, placebocontrolled, parallel trial 40 University of Auckland New Zealand (single centre) F.B. Rodrigues and E.J. Wild / Huntington’s Disease Clinical Trials Corner: February 2018 93 Table 3 Ongoing invasive non-pharmacological clinical trials registered at the World Health Organization (WHO) International Clinical Trials Research Platform (ICTRP) for people with Huntington’s disease (HD). AD, Alzheimer’s disease, CBD; Corticobasal Degeneration; DBS, deep brain stimulation; ET, Essential Tremor; GP, Globus pallidus; HT, Holmes Tremor; MNC, mononuclear cells; MS, Multiple Sclerosis; PD, Parkinson’s disease; TD, Tardive dyskinesia; WD, Wilson’s disease. New trials since the last Clinical Trials Corner are indicated by∗ Registration ID Trial name Intervention Mechanism of Population Comparison Main outcome Study design Estimated Sponsor Location Action Enrolment NCT03252535∗ADORE-HD Cellavita Stem cell therapy HD Placebo Efficacy at 120 days Randomized, double-blind, placebocontrolled, 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, shamcontrolled, parallel trial 50 Heinrich-Heine University, KKS Netzwerk, Medtronic, The George Institute, EHDN, CHDI Foundation, Inc. Austria, 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) NCT02263430 – GP DBS Deep brain stimulation HD with chorea Sham stimulation Efficacy at 12 months Randomized, double-blind, placebocontrolled, parallel trial 8 Beijing Pins Medical Co., Ltd, Beijing Tiantan Hospital China (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) 94 F.B. Rodrigues and E.J. Wild / Huntington’s Disease Clinical Trials Corner: February 2018 Table 4 Ongoing non-invasive non-pharmacological clinical trials registered at the World Health Organization (WHO) International Clinical Trials Research Platform (ICTRP) for people with Huntington’s disease (HD). AD, Alzheimer’s disease; ALS, Amyotrophic Lateral Sclerosis; ET, Essential Tremor; HT, Holmes Tremor; MS, Multiple Sclerosis; PD, Parkinson’s disease; TD, Tardive dyskinesia. New trials since the last Clinical Trials Corner are indicated by∗ Registration ID Trial name Intervention Mechanism of Population Comparison Main outcome Study design Esimated Sponsor Location Action Enrolment NCT03344601∗PACE-HD Supported structured aerobic exercise training program Physiotherapy HD Activity as usual Data completeness, recruitment, retention, asfety, adherence, fidelity and acceptability at 12 months Nested open-label, randomized controlled parallell trial 120 Cardiff University and CHDI Foundation, Inc Germany, Spain and USA (multi centre) NCT03306888∗– Physical Activity Coaching Intervention Physiotherapy Premanifest and early HD None Change in physical activity at 4 months Single group, open-label trial 14 Columbia University USA (single centre) ACTRN12617 001269325∗ – 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) NCT02990676 CogTrainHD Computerised Cognitive Training Cognitive training HD No intervention Feasibility at 4 years Open-label, controlled, parallel trial 50 Cardiff University UK (single centre) NCT01879267 – Endurance exercise training Physiotherapy HD and healthy controls None Motor effects 6 months Single group, open-label trial with parallel healthy controls arm 40 University of Zurich Switzerland (single centre) NCT02464293 – Mindfulnessbased Cognitive Therapy Cognitive therapy Premanifest and early HD with behavioural symptoms None Behavioural effect at 2 weeks, 3 months and 1 year Single group, open-label trial 16 Lancaster University, Central Manchester University Hospitals NHS Foundation Trust UK (single centre) (Continued) F.B. Rodrigues and E.J. Wild / Huntington’s Disease Clinical Trials Corner: February 2018 95 Table 4 (Continued) Registration ID Trial name Intervention Mechanism of Population Comparison Main outcome Study design Esimated Sponsor Location Action Enrolment NCT02216474 – tDCS Transcranial magnetic stimulation HD or Tourette Syndrome Sham stimulation Efficacy at 2 weeks Randomized, double-blind, placebocontrolled, cross-over trial 100 Birmingham and Solihull Mental Health NHS Foundation Trust, University of Birmingham UK (single centre) NCT02750982 – Laughter Therapy Cognitive therapy HD, AD, ALS, brain injury, MS, PD, post/stroke or spinal cord injury None Behavioural effects at 8 weeks Single group, open-label trial 24 Brown, Theodore R., M.D., MPH USA (single centre) NCT01602276 – tDCS Transcranial magnetic stimulation Subcortical brain damage, including HD Sham stimulation Efficacy at 1 month Randomized, single-blind, placebocontrolled, cross-over trial, with parallel healthy control arm 150 Johns Hopkins University USA (single centre) 96 F.B. Rodrigues and E.J. Wild / Huntington’s Disease Clinical Trials Corner: February 2018 supports continued development”. More excitingly, dose-dependent reductions in cerebrospinal fluid mutant huntingtin concentration were seen in patients who received IONIS-HTTRx. C. Frank Bennett, Ionis’ Senior Vice President of Research, noted that the mutant huntingtin reduction “substantially exceeded our expectations”. As a result, Roche has exercised its option to license the drug and will now be responsible for future development of the program. In a separate statement for the HD community, Ionis confirmed that an efficacy trial was planned and that “future studies for the program will be conducted globally, including in the US” [10]. Meanwhile, an open-label extension is underway for the 46 participants who took part in the original study (Table 2, NCT03342053) [11]. This is a significant positive announcement in a therapeutic program with substantial promise for disease-modification in HD. Naturally, it will need to be supported by release of more detailed data from the trial,andpeer-reviewedpublicationoftheresults.The sponsor has committed to supplying these updates in the first half of 2018 [10]. ONGOING CLINICAL TRIALS A list of all ongoing clinical trials is given in Tables 2, 3 and 4. PRECISION-HD1 (NCT03225833) and PRECISION-HD2 (NCT03225846) Study titles: A Multicenter, Randomized, Doubleblind, Placebo-controlled, Phase 1b/2a Study of WVE-120101 Administered Intrathecally in Patients With Huntington’s Disease [2] and A Multicenter, Randomized, Double-blind, Placebo-controlled, Phase 1b/2a Study of WVE-120102 Administered Intrathecally in Patients With Huntington’s Disease [3]. Intervention: Respectively WVE-120101 and WVE-120102, two distinct allele-selective ASOs [12]. Description: The PRECISION-HD trials aim to compare the safety, tolerability, pharmacokinetics and pharmacodynamics of single and multiple ascending doses of WVE-120101 and WVE-120102, respectively, administered intrathecally, comparing with intrathecal placebo, for disease modification in people with HD (i.e. clinical diagnostic motor features of HD, a Unified Huntington’s Disease Rating Scale (UHDRS) Diagnostic Confidence Level of 4, and a UHDRS Total Functional Capacity (TFC) between 13 and 7, inclusively) who carry a targeted single nucleotide polymorphism (SNP) rs362307 or rs362331, respectively, and are aged between 25 and 65 years old. These trials are phase 1b/2a, multi-centre, international, randomized, placebo controlled, double-blind, parallel studies. They have a combined single ascending dose/multiple ascending dose design, comprising four cohorts of progressively higher ASO doses. In each cohort, participants will be allocated to receive a single dosage or three dosages of the ASO or a placebo. Each trial has the recruitment target of 48 participants; currently recruitment is open in Canada and Poland. The WVE-120101 and WVE-120102 compounds are ASOs targeting the pre-mRNA transcript of two allelic variants linked to the expanded CAG repeat tract in the HTT gene, with the aim of selectively reducing the production of mutant huntingtin protein while leaving the level of wild-type huntingtin protein relatively unaltered. Each participant’s involvement will last for 210 days. The primary outcome is safety and tolerability at 210 days. The secondary outcomes involve pharmacokinetic measurements in plasma; pharmacodynamic measures in cerebrospinal fluid, including mutant huntingtin; and the UHDRS TFC. Sponsors/funders: Wave Life Sciences Ltd. Comments: The CAG expansion in the HTT gene is frequently allelically linked to three different SNPs that collectively are thought to be present in at least 80% of the gene expansion carriers of European ancestry [13]. These two trials are running in parallel and will target two of these SNPs. Participants’ DNA samples will first be screened for the presence of one of both SNPs, and then further tested to establish whether either SNP is allelic to the HTT CAG expansion. While the molecule tested in the IONIS-HTTRx trial and its open-label extension (NCT02519036) [1] is expected to reduce the translation of both wild-type and mutant pre-mRNA, the PRECISION-HD ASOs were designed to target selectively the mutant premRNA and mark it for degradation by RNase H. This selectivity is attained by means of targeting the most frequent SNPs associated with mutant HTT. The theoretical advantage is that this may reduce the potential long-term risk stemming from lowering of wild-type huntingtin and associated loss-of-function [14]. However, it is also worth noting that no safety concerns have so far been identified in the ongoing, allele-nonselective IONIS-HTTRx programme [6]. F.B. Rodrigues and E.J. Wild / Huntington’s Disease Clinical Trials Corner: February 2018 97 Wave’s platform is also distinguished by the ability to specify the chirality of each phosphorothioate bond in the ASO backbone, which has the potential to improve characteristics such as stability and target mRNA degradation [15]. Each approach – both in terms of chiral purity and allele-selectivity – has potential advantages and disadvantages [12]. Each SNP-selective compound will have to go through independent testing and approval; the testing process to establish suitability is novel and time-consuming; and some mutation-carriers will be ineligible by virtue of possessing no suitable SNPs. Together, the Wave and IONIS platforms will be informative and provide safety and efficacy information relating to different HTT lowering approaches. COMPLETED CLINICAL TRIALS FIRST-HD (NCT01795859) Study title: A Randomized Double-Blind, PlaceboControlled Study of SD-809 Extended Release for the Treatment of Chorea Associated With Huntington Disease [4, 16]. Intervention: Deutetrabenazine or SD-809, a vesicular monoamine transporter type 2 (VMAT2) selective inhibitor. Description: The goal of FIRST-HD trial was to compare the efficacy and safety of oral deutetrabenazine against an oral placebo, both taken twice daily and titrated to optimal dosage, for symptomatic relief of chorea in adults with stage 1 to 3 manifest HD (i.e. motor signs characteristic of HD plus HTT CAG repeat length ≥36 plus a UHDRS TFC ≥5) and with significant chorea (i.e. a UHDRS total maximum chorea score (TMC) of 8 or higher). This trial was a phase 3, multi-centre, international, randomized, placebo controlled, double blind, parallel study. It recruited 90 participants from Canada and the United States. Participant involvement lasted for 13 weeks. The primary outcome was change from baseline in the UHDRS TMC at weeks 9 and 12. The UHDRS TMC is a subscore of UHDRS total motor score (TMS) that only includes the chorea-related items, and ranges from 0 to 28. The secondary outcomes were the Patient Global Impression of Change (PGIC), the Clinician Global Impression Change (CGIC), the Short Form 36 Health Survey (SF-36), the Berg Balance Test (BBT), and adverse events. Sponsors/funders: Teva Pharmaceutical Industries Results: The trial was completed on December 2014 and the results published in July 2016 [16]. It showed deutetrabenazine to be superior to placebo in decreasing chorea associated with HD, objectively and subjectively, and to improve quality of life, but not balance. Interestingly, in a post-hoc analysis, dystonia subscores on TMS also lessened with deutetrabenazine. In regards to safety, deutetrabenazine was comparable with placebo, with the exception of weight gain that was more prevalent in the active treatment arm. It is noteworthy that this study was not powered to investigate adverse events and further information is required to draw definitive conclusions about safety. In April 2017, the FDA approved this drug for the treatment of chorea associated with HD. Like tetrabenazine, its label includes a contraindication for patients who are suicidal, or who have untreated or inadequately treated depression. Deutetrabenazine is a modified version of tetrabenazine containing deuterium (i.e. a stable isotope of hydrogen with mass number of 2) in strategic positions. This modification is intended to provide better pharmacokinetic properties (i.e. slower enzymatic degradation) to this otherwise chemically-identical compound, due to stronger bonds between carbon and deuterium. Still, little is known about how deutetrabenazine compares with tetrabenazine, an older VMAT2 inhibitor also approved by FDA. In ARC-HD–a multicentre, international, single arm, open label study – the Huntington Study Group explored the safety of switching overnight from a stable and efficacious dosage of tetrabenazine to deutetrabenazine (NCT01897896) [17]. In a preliminary report, about 50% of the sample had at least one adverse event, but the drug was well tolerated with low rates of neuropsychiatric adverse events [18]. Unfortunately no head-to-head blinded comparison has been made between these compounds or is planned. Indirect treatment comparisons showed no apparent efficacy difference [19]. The safety results are contradictory [19, 20], possibly due to a statistical artefact [21]. Overall these results call for close postlicensing surveillance to guide informed prescribing decisions. ACKNOWLEDGMENTS The authors are supported by CHDI Foundation, Inc. (salary support to FBR for conduct of the