Huntington’s Disease Clinical Trials Corner: April 2020

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.

In this edition, we highlight the UniQure AMT-130 (NCT04120493) [1], and the Neurocrine Biosciences KINECT-HD trial (NCT04102579) [2]. We tabulate all currently registered and ongoing clinical trials in Tables 2 to 4. For further details on the methodology used, please refer to the first edition of Huntington’s Disease Clinical Trials Corner [3].

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

ONGOING CLINICAL TRIALS

A list of all ongoing clinical trials is given in Tables 2, 3 and 4.

In addition to the trials covered below, it is worth mentioning that Wave Life Sciences made a preliminary announcement of results from their ongoing PRECISION-HD2 trial (NCT03225846) [4]. This is a phase 1b/2a trial investigating WVE-120102, an intrathecal allele-selective antisense oligonucleotide (ASO). When compared with placebo, this drug was shown to reduce CSF mutant huntingtin by 12.4% (95% CI 0.40 to 24.58), while CSF total huntingtin and neurofilament light (NfL) remained unchanged. Whist statistically significant, this reduction was derived from a comparison of all ASO doses pooled together (mean change from baseline –6.0% [95% CI –9.57 to 4.85]) against a placebo arm showing a somewhat larger change than might be expected due to disease progression from natural history studies (mean change from baseline 9.5% [95% CI 1.77 to 20.38]). The ASO was also considered to be “generally safe and well tolerated among patients receiving doses up to 16 mg”. No results were disclosed about the PRECISION-HD1 trial (NCT03225833) [5], testing WVE-120101, another intrathecal allele-selective ASO targeting a different single-nucleotide polymorphism. As a result, a new 32 mg dosage cohort will added to both trials and further updates are awaited from the broader program [6].

AMT-130 (NCT04120493)

Study title: A Phase I/II, Randomized, Double-blind, Sham Control Study to Explore Safety, Tolerability, and Efficacy Signals of Multiple Ascending Doses of Striatally-Administered rAAV5-miHTT Total Huntingtin Gene (HTT) Lowering Therapy (AMT-130) in Early Manifest Huntington Disease [1].

Intervention: Single-time intrastriatal injection of AAV5-miHTT [7].

Description: The AMT-130 trial, sponsored by UniQure, aims to evaluate the safety, tolerability and proof-of-concept of a single-time bilateral intrastriatal injection of AAV5-miHTT in adults (25 to 65 years of age) with manifest HD (i.e. clinically symptomatic and genetically confirmed [CAG≥44]) and early disease stage, comparing with sham injection, for disease progression.

Individuals who have received any experimental agent or participation in the following are not eligible for this study: any investigational trial within 60 days or five half-lives prior to screening; with a deep brain stimulator in situ; with history of gene therapy, RNA or DNA targeted HD specific investigational agent, cell transplantation or other experimental cerebral surgery; contraindications for lumbar punctures or 3 Tesla MRI; putaminal and caudate volumes per side inferior to 2.5 and 2.0 cm³, respectively; brain or spinal cord pathology that may interfere with CSF homeostasis and circulation, increased intracranial pressure, malformations or tumours; hospitalization for major medical reason or major surgical procedure involving general anaesthesia within 12 weeks of screening; current use of medications to treat or that can aggravate chorea, or unstable concomitant medication within 3 months of screening.

This trial is an US-based, multi-centre, randomized, sham-controlled, double-blind, parallel study. It will have 3 study arms: the low dose group, where participants will receive a single total dose of 6×10¹² genome copies of AAV5-miHTT via a MRI-guided convection-enhanced delivery; the high dose group, where participants will receive a single total dose of 6×10¹³ genome copies of AAV5-miHTT via a MRI-guided convection-enhanced delivery; and the imitation surgery arm, where participants will receive bilateral partial thickness burr holes with no intrastriatal injections. The study will last 5 years, where participants will be blind to treatment allocation for 18 months, followed by an unblinded period of 3.5 years.

The trial has already started recruitment [8], and has a recruitment target of 26 participants, across 4 sites. It will follow a multiple ascending dose design, with a first cohort of 10 participants (stage 2 HD; 6 randomized to low dose and 4 to sham surgery) and a second cohort of 16 participants (stage 1-2 HD; 10 randomized to high dose and 6 to sham surgery).

The primary outcome will be safety, measured at 18 months, and the secondary outcome will be CSF biomarkers, namely levels of the vector DNA and miRNA expression at 60 months. Other outcomes include: biofluid and imaging biomarkers; clinical scales such as the UHDRS motor, cognitive, behaviour and functional subscales, the Huntington’s Disease Cognitive Assessment Battery (HD-CAB), the Neuro-QoL, HDQLIFE and Hospital Anxiety and Depression Scale (HADS); and quantitate motor assessments (i.e. Q-Motor).

Sponsors/funders: UniQure Biopharma B.V..

Comments: The AAV5-miHTT is an engineered microRNA (miRNA) targeting both human wild-type and mutant huntingtin for degradation. It is delivered via an adeno-associated viral vector serotype 5 (AAV5). This is the first human trial of an AAV-mediated gene therapy in Huntington’s disease.

If it functions as intended, upon injection into the brain parenchyma using MRI-guided convection-enhanced delivery, the AAV5-miHTT will bind to cell receptors and will be internalised by neurons and transported to the nucleus. There, the miRNA will be uncoated from the viral vector and remains episomal. After expression and processing of the miHTT transgene by the endogenous RNA interference machinery into a hairpin structure, the miRNA is transported into the cytoplasm. There the mature miRNA will load in the RNA-induced silencing complex and bind huntingtin mRNA, targeting it for cleavage and degradation. In theory, this mechanism of action makes this method irreversible, and animal models have demonstrated long-lasting miRNA expression over time after a single injection.

The efficacy and safety of this miRNA and vector has been assessed in cultured human neurons, and in vivo in multiple animal models such as mice, non-human primates and transgenic minipigs. Transgene expression accompanied by huntingtin lowering has been seen in the injected and distant structures such as the cortex.

The selected vector – AAV5 – has been tested in 4 clinical studies across haematological and metabolic disorders. When given intravenously it appears safe and tolerable, showing low activity to pre-existing neutralizing antibodies. However this is the first time it has been used for intraparenchymal delivery into the brain.

The AAV5-miHTT will be injected to the caudate and putamen bilaterally via MRI-guided convection-enhanced delivery. This approach involves surgical exposure of the brain tissue, and insertion of small diameter catheters into the injected structures. Injection usually takes long time periods (several hours) and a pressure gradient in order to saturate the targeted tissues. Even with these techniques, there is limited tissue distribution after injection. In non-human models both the vector and huntingtin lowering have been demonstrated to be present in distant structures, such as the cortex. It is unclear whether this occurs via axonal transport or by some other mechanism such as secretion and absorption of miRNA-containing exosomes.

This is a challenging trial using a novel therapeutic approach. The community will be looking forward to learning more about the feasibility of the approach, its safety, and efficacy.

KINECT-HD (NCT04102579)

Study title: A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study to Assess the Efficacy, Safety, and Tolerability of Valbenazine for the Treatment of Chorea Associated With Huntington Disease [2].

Intervention: Once daily valbenazine, [9] a VMAT2 inhibitor.

Description: The KINECT-HD trial, sponsored by Neurocrine Biosciences and the Huntington Study Group, aims to evaluate the efficacy, safety and tolerability of valbenazine in adults (18 to 75 years of age) with a clinical diagnosis of HD with chorea, compared with placebo. The purpose is to assess whether valbenazine is more effective than placebo in reducing chorea associated with HD.

Individuals with the following are not eligible: a history of prior VMAT2 inhibitor therapy; swallowing difficulties; who are pregnant or breastfeeding; or with a history of long QT syndrome, cardiac tachyarrhythmia, left bundle-branch block, atrioventricular block, bradycardia or hear failure; unstable or serious medical or psychiatric illness; significant suicidal risk; substance dependence or abuse; unstable antidepressant regimen; previous history of gene therapy; receiving an investigational drug within 30 days of baseline visit; and blood donation or significant blood loss (≥550 mL) within 30 days of baseline visit.

KINECT-HD is an international, multi-centre, randomized, double-blind, controlled, parallel phase 3 trial. It has 2 study arms: the active group, where participants will receive valbenazine once daily up to 80 mg based on tolerability for 12 weeks; and the comparator group, where participants will receive a placebo capsule once daily for 12 weeks.

The study will last around 15 weeks, with an 8-week dose adjustment (i.e. 40 mg > 60 mg > 80 mg) based on tolerability followed by 4 weeks of dose maintenance, and will enrol 120 participants equally distributed across groups. Recruitment is currently ongoing, and approximately 55 centres across the US and Canada will be involved.

The primary outcome measure is change in chorea at 12 weeks measured as a sum of the chorea items of the UHDRS Total Motor Score. Secondary outcomes include subjective impression of change; quality of life and digital biomarkers.

Sponsors/funders: Neurocrine Biosciences and the Huntington Study Group.

Comments: Valbenazine is a vesicular monoamine transporter 2 (VMAT2) inhibitor previously approved by FDA for tardive dyskinesia. It is a prodrug of dihydrotetrabenazine that reduces dopamine release into the synaptic cleft by selectively inhibiting pre-synaptic VMAT2.

There are two other VMAT2 inhibitors on the market: tetrabenazine (3-times daily) and deutatrabenazine (twice-daily), both of them approved by FDA for chorea associated with HD. Apart from dosage regimen, it is unclear if there are differences between these two modestly effective drugs, which have comparable safety profiles with risks of suicidality, parkinsonism and QT prolongation [10–12].

Currently, valbenazine is FDA-approved for tardive dyskinesia (40 mg daily for one week followed by 80 mg daily thereafter) and has had an unsuccessful trial in paediatric Tourette’s syndrome.

Conflicts of interest

FBR and EJW were sub-investigators on LEGATO-HD (NCT02215616), IONIS HTT_Rx (NCT02519036) and IONIS HTT_Rx OLE (NCT03342053), are sub-investigators on the Roche GENERATION-HD (NCT03761849), Roche Natural History Study (NCT03664804) and Roche GEN-EXTEND (NCT03842969) trials, and EJW was a sub-investigator on the Amaryllis (NCT02197130). EJW is the chief investigator of the Roche GEN-PEAK trial (NCT04000594) and FBR is a sub-investigator. The authors did not make use of confidential or privileged information: all materials included in this manuscript were collected from publicly available sources. FBR has provided consultancy services to GLG. EJW has participated in scientific advisory boards with Hoffmann-La Roche Ltd, Ionis, Shire, GSK, Wave Life Sciences, PTC Therapeutics, Takeda and Mitoconix. All honoraria were paid through UCL Consultants Ltd, a wholly owned subsidiary of UCL. Their Host Institution, University College London Hospitals NHS Foundation Trust, has received funds as compensation for conducting clinical trials for Ionis Pharmaceuticals, Pfizer and Teva Pharmaceuticals. Hoffman La Roche Ltd has supported UCL with research funding for EJW.