Study of WVE-004 in Patients With C9orf72-associated Amyotrophic Lateral Sclerosis (ALS) or Frontotemporal Dementia (FTD) (FOCUS-C9)

A Multicenter, Randomized, Double-blind, Placebo-controlled, Phase 1b/2a Study of WVE-004 Administered Intrathecally to Patients With C9orf72-associated Amyotrophic Lateral Sclerosis (ALS) or Frontotemporal Dementia (FTD)

This is a Phase 1b/2a multicenter, randomized, double-blind, placebo-controlled study to evaluate the safety, tolerability, PK, and PD of intrathecal (IT) WVE-004 in adult patients with C9orf72-associated ALS or FTD. To participate in the study, patients must have a documented mutation (GGGGCC [G4C2] repeat expansion) in the first intronic region of the C9orf72 gene and be diagnosed with ALS or FTD.

Study Overview

• Status: Terminated
• Conditions: ALS; FTD
• Intervention / Treatment: Drug: WVE-004; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 35
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • North Ryde, New South Wales, Australia, 2109
      • Macquarie University
  • Queensland
    • Brisbane, Queensland, Australia, QLD 4066
      • The Wesley Hospital
  • Western Australia
    • Nedlands, Western Australia, Australia, 6009
      • Perron Institute
• Belgium
  • Leuven, Belgium, 3000
    • UZ Leuven
• Canada
  • Ontario
    • Toronto, Ontario, Canada, M4N 3M5
      • Sunnybrook Health Sciences Centre
  • Quebec
    • Montréal, Quebec, Canada
      • McGill University Health Center - Research Institute
• Ireland
  • Dublin, Ireland, D08 NHY1
    • St James Hospital - Ireland
• Netherlands
  • Rotterdam, Netherlands, 3015
    • Erasmus University MC
  • Utrecht, Netherlands
    • Universitair Medisch Centrum Utrecht
• New Zealand
  • Auckland, New Zealand, 1023
    • Auckland City Hospital
  • Christchurch, New Zealand, 8011
    • New Zealand Brain Research Institute
• Sweden
  • Solna, Sweden
    • Karolinska University Hospital
• United Kingdom
  • Cambridge, United Kingdom
    • University of Cambridge
  • London, United Kingdom, WC1N 3BG
    • University College London Hospital
  • London, United Kingdom, WC2R 2LS
    • King's College Hospital
  • Oxford, United Kingdom, OX3 7LF
    • University of Oxford - Nuffield Department of Clinical Neurosciences
  • Sheffield, United Kingdom, S10 2TN
    • University of Sheffield

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. ALS-specific: Diagnosis of ALS based on clinical manifestations.
2. ALS-specific: Clinically diagnosed possible, laboratory supported probable, probable, or definite criteria for diagnosing ALS according to the World Federation of Neurology revised El Escorial criteria.
3. ALS-specific: Patients receiving riluzole have been on a stable dose for a minimum of 30 days.
4. ALS-specific: Patients on edaravone have received a minimum of 1 cycle (28 days).
5. ALS-specific: Patients discontinuing riluzole or edaravone had the last dose administered ≥1 month prior to Screening.
6. FTD-specific: Must have Global Clinical Dementia Rating - Frontotemporal Lobar Degeneration (CDR® plus NACC FTLD) score of 0.5 or 1.
7. FTD-specific: Able to undergo periodic magnetic resonance imaging (MRI) of the brain. Participants with mixed phenotype (ALS and FTD) need not undergo MRI if their ALS symptoms prevent it.
8. Mixed-phenotype: Patients who are mixed phenotype (ALS and FTD) must meet both the ALS-specific and FTD-specific criteria.

Exclusion Criteria:

1. Clinically significant medical finding on the physical examination other than C9orf72-associated ALS or FTD that, in the judgment of the Investigator, will make the patient unsuitable for participation in, and/or completion of the trial procedures
2. Received any other investigational drug, biological agent, or device within 1 month or 5 half-lives of study agent, whichever is longer. Received an investigational oligonucleotide, within the past 6 months or 5 half-lives of the drug, whichever is longer.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: WVE-004 (Dose A) or placebo	Drug: WVE-004; WVE-004 is a stereopure antisense oligonucleotide (ASO); Drug: Placebo; Artificial cerebrospinal fluid (aCSF)
Experimental: WVE-004 (Dose B) or placebo	Drug: WVE-004; WVE-004 is a stereopure antisense oligonucleotide (ASO); Drug: Placebo; Artificial cerebrospinal fluid (aCSF)
Experimental: WVE-004 (Dose C) or placebo	Drug: WVE-004; WVE-004 is a stereopure antisense oligonucleotide (ASO); Drug: Placebo; Artificial cerebrospinal fluid (aCSF)
Experimental: WVE-004 (Dose D) or placebo	Drug: WVE-004; WVE-004 is a stereopure antisense oligonucleotide (ASO); Drug: Placebo; Artificial cerebrospinal fluid (aCSF)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Safety: Proportion of patients with adverse events (AEs)	Period 1 Day 1 to Period 2 Week 24 (end of study)

Secondary Outcome Measures

Outcome Measure	Time Frame
Pharmacokinetic: Concentration of WVE-004 in cerebrospinal fluid (CSF)	Period 1 Day 1 to Period 2 Week 24 (end of study)
Pharmacodynamic: Change from baseline in concentration of poly-GP levels in the CSF	Period 1 Day 1 to Period 2 Week 24 (end of study)

Collaborators and Investigators

• Sponsor: Wave Life Sciences Ltd.
• Investigators: Study Director: Medical Director, MD, Wave Life Sciences

Study record dates

Study Major Dates

• Study Start (Actual): June 28, 2021
• Primary Completion (Actual): June 27, 2023
• Study Completion (Actual): June 27, 2023

Study Registration Dates

• First Submitted: June 11, 2021
• First Submitted That Met QC Criteria: June 11, 2021
• First Posted (Actual): June 18, 2021

Study Record Updates

• Last Update Posted (Actual): October 23, 2023
• Last Update Submitted That Met QC Criteria: October 18, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Metabolic Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurologic Manifestations; Neurobehavioral Manifestations; Neurocognitive Disorders; Neuromuscular Diseases; Neurodegenerative Diseases; Spinal Cord Diseases; TDP-43 Proteinopathies; Proteostasis Deficiencies; Dementia; Language Disorders; Communication Disorders; Speech Disorders; Frontotemporal Lobar Degeneration; Aphasia; Motor Neuron Disease; Amyotrophic Lateral Sclerosis; Frontotemporal Dementia; Aphasia, Primary Progressive; Pick Disease of the Brain
• Other Study ID Numbers: WVE-004-001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes