Safety and Tolerability of WVE-120101 in Patients With Huntington's Disease (PRECISION-HD1)

A Multicenter, Randomized, Double-blind, Placebo-controlled, Phase 1b/2a Study of WVE-120101 Administered Intrathecally in Patients With Huntington's Disease

PRECISION-HD1 is a Phase 1b/2a multicenter, randomized, double-blind, placebo-controlled study to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of single and multiple doses of WVE-120101 in adult patients with early manifest Huntington's disease (HD) who carry a targeted single nucleotide polymorphism (SNP) rs362307 (SNP1).

Study Overview

• Status: Terminated
• Conditions: Huntington's Disease
• Intervention / Treatment: Drug: WVE-120101; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 61
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Sidney, New South Wales, Australia, 2145
      • Westmead Hospital
  • Queensland
    • Herston, Queensland, Australia, QLD 4006
      • Royal Brisbane & Women's Hospital
  • Victoria
    • Carlton, Victoria, Australia, 3053
      • Royal Melbourne Hospital
    • Clayton, Victoria, Australia, 3168
      • Monash Health
    • Melbourne, Victoria, Australia, 3004
      • Alfred Health
    • Parkdale, Victoria, Australia, 3195
      • Calvary Health Care Bethlehem
  • Western Australia
    • Perth, Western Australia, Australia, 6910
      • North Metropolitan Health Service
• Canada
  • Alberta
    • Edmonton, Alberta, Canada, T6G 2B7
      • University of Alberta
  • Ontario
    • Toronto, Ontario, Canada, M3B 2S7
      • Centre for Movement Disorders
  • Quebec
    • Montreal, Quebec, Canada, H2X0A9
      • Center Hospitalier de l'Universite de Montreal
• Denmark
  • Aarhus, Denmark, 8200
    • Aarhus Universitets Hospital
  • Copenhagen, Denmark, 2100
    • Rigshospitalet
  • Odense, Denmark, 5000
    • Odense University Hospital and University of Southern Denmark
• France
  • Créteil, France, 94010
    • Hospital Henri Mondor
  • Paris, France, 75646
    • Institut du Cerveau et de la Moelle Epinière
• Germany
  • Muenster, Germany, 48149
    • George-Huntington-Institut GmbH
• Poland
  • Gdańsk, Poland, 80-462
    • Szpital Sw. Wojciecha
  • Warsaw, Poland, 02-957
    • Instytut Psychiatrii i Neurologii
• United Kingdom
  • Liverpool, United Kingdom, L7 8XP
    • Royal Liverpool University Hospital
  • Devon
    • Exeter, Devon, United Kingdom, EX2 5DW
      • Royal Devon and Exeter Hospital NHS Trust
  • Glasgow City
    • Glasgow, Glasgow City, United Kingdom, G12 0XH
      • Queen Elizabeth University Hospital - PPDS

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 25 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Key Inclusion Criteria:

• Prescreened with targeted SNP on the same allele as the pathogenic CAG expansion
• Ambulatory, male or female patients aged ≥25 - ≤65 years
• Clinical diagnostic motor features of HD, defined as Unified Huntington's Disease Rating Scale (UHDRS) Diagnostic Confidence Score = 4
• Early manifest HD, Stage I or Stage II based on UHDRS Total Functional Capacity Scores ≥7 and ≤13

Key Exclusion Criteria:

• Malignancy or received treatment for malignancy, other than treated basal cell or squamous cell carcinoma of the skin, within the previous 5 years.
• Received investigational drug or implantable device in prior 3 months or investigational oligonucleotide in prior 6 months or 5 half-lives of the oligonucleotide, whichever is longer
• Clinically significant medical condition, unstable psychiatric symptoms, substance abuse, or pregnancy
• Inability to undergo brain MRI
• Bone, spine, bleeding, or other disorder that exposes the patient to risk of injury or unsuccessful lumbar puncture

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: Double

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: WVE-120101 (Dose A) or placebo	Drug: WVE-120101; WVE-120101 is a stereopure antisense oligonucleotide (ASO); Drug: Placebo; 0.9% Sodium Chloride
Experimental: WVE-120101 (Dose B) or placebo	Drug: WVE-120101; WVE-120101 is a stereopure antisense oligonucleotide (ASO); Drug: Placebo; 0.9% Sodium Chloride
Experimental: WVE-120101 (Dose C) or placebo	Drug: WVE-120101; WVE-120101 is a stereopure antisense oligonucleotide (ASO); Drug: Placebo; 0.9% Sodium Chloride
Experimental: WVE-120101 (Dose D) or placebo	Drug: WVE-120101; WVE-120101 is a stereopure antisense oligonucleotide (ASO); Drug: Placebo; 0.9% Sodium Chloride
Experimental: WVE-120101 (Dose E) or placebo	Drug: WVE-120101; WVE-120101 is a stereopure antisense oligonucleotide (ASO); Drug: Placebo; 0.9% Sodium Chloride

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety: Number of Patients With Treatment-emergent Adverse Events (TEAEs)	All TEAEs reported or observed during the study, including TEAEs resulting from concurrent illnesses, reactions to concurrent medications, or progression of disease states	Day 1 to end of study (up to Day 182 [32 mg cohort]/ Day 210 [all other cohorts])
Safety: Severity of Adverse Events	Number of patients who experienced a severe treatment-emergent adverse event. Severity was evaluated using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0	Day 1 to end of study (up to Day 182 [32 mg cohort]/ Day 210 [all other cohorts])
Safety: Number of Patients With Serious TEAEs	A serious TEAE is defined as any event that results in death, is immediately life threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, or is a congenital anomaly/birth defect not present at Prescreening.	Day 1 to end of study (up to Day 182 [32 mg cohort]/ Day 210 [all other cohorts])
Safety and Tolerability: Number of Patients Who Withdraw Due to TEAEs		Day 1 to end of study (up to Day 182 [32 mg cohort]/ Day 210 [all other cohorts])

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacokinetics (PK): Maximum Observed Concentration (Cmax)	Cmax of WVE-120101 in plasma	Patients participating in Period 1 (SAD) had PK samples collected on Day 1 predose through 24-48 hours postdose. Patients participating in Period 2 (MAD) had PK samples collected predose on Day 112 and through 4 hours postdose.
PK: Time of Occurrence of Cmax (Tmax)	tmax of WVE-120101 in plasma	Patients participating in Period 1 (SAD) had PK samples collected on Day 1 predose through 24-48 hours postdose. Patients participating in Period 2 (MAD) had PK samples collected predose on Day 112 and through 4 hours postdose.
PK: Area Under the Plasma Concentration-time Curve (AUClast)	AUClast from time 0 to the last quantifiable concentration of WVE-120101 in plasma	Patients participating in Period 1 (SAD) had PK samples collected on Day 1 predose through 24-48 hours postdose. Patients participating in Period 2 (MAD) had PK samples collected predose on Day 112 and through 4 hours postdose.
PK: Terminal Elimination Half Life	Terminal elimination half life of WVE-120101 in plasma (t1/2)	Patients participating in Period 1 (SAD) had PK samples collected on Day 1 predose through 24-48 hours postdose. Patients participating in Period 2 (MAD) had PK samples collected predose on Day 112 and through 4 hours postdose.
Pharmacodynamics	Percentage change from baseline in concentration of mutant huntingtin (mHTT) protein in CSF	Day 1 to last observation - up to Day 140 (32 mg cohort) or Day 196 (all other cohorts)
Clinical Effects: Total Functional Capacity (TFC)	Percentage change from baseline to the last measured time point in the Total Functional Capacity score, administered as part of the Unified Huntington's Disease Rating Scale (UHDRS). Total Functional Capacity is scored 13 (normal) to 0 (severe disability).	Day 1 to last observation - up to Day 140 (32 mg cohort) or Day 196 (all other cohorts)

Collaborators and Investigators

• Sponsor: Wave Life Sciences Ltd.

Publications and helpful links

General Publications

• Rodrigues FB, Wild EJ. Huntington's Disease Clinical Trials Corner: April 2020. J Huntingtons Dis. 2020;9(2):185-197. doi: 10.3233/JHD-200002.
• Rodrigues FB, Wild EJ. Huntington's Disease Clinical Trials Corner: February 2018. J Huntingtons Dis. 2018;7(1):89-98. doi: 10.3233/JHD-189001.

Study record dates

Study Major Dates

• Study Start (Actual): July 17, 2017
• Primary Completion (Actual): May 11, 2021
• Study Completion (Actual): May 11, 2021

Study Registration Dates

• First Submitted: July 17, 2017
• First Submitted That Met QC Criteria: July 20, 2017
• First Posted (Actual): July 21, 2017

Study Record Updates

• Last Update Posted (Actual): February 10, 2022
• Last Update Submitted That Met QC Criteria: February 9, 2022
• Last Verified: February 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurocognitive Disorders; Genetic Diseases, Inborn; Basal Ganglia Diseases; Movement Disorders; Neurodegenerative Diseases; Dyskinesias; Heredodegenerative Disorders, Nervous System; Dementia; Cognition Disorders; Chorea; Huntington Disease
• Other Study ID Numbers: WVE-HDSNP1-001

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No