Open-label Extension (OLE) Study of WVE-004 in Patients With C9orf72-associated Amyotrophic Lateral Sclerosis (ALS) and/or Frontotemporal Dementia (FTD)

A Multicenter, Open-label Extension (OLE) Study to Evaluate the Safety, Pharmacodynamics, and Clinical Effects of WVE-004 in Patients With C9orf72-associated Amyotrophic Lateral Sclerosis (ALS) and/or Frontotemporal Dementia (FTD)

This is an OLE study conducted to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and clinical effects of WVE-004 in adult participants with ALS, FTD, or mixed ALS/FTD phenotype with a documented mutation in the C9orf72 gene. To participate in the study, participants must have successfully completed Phase 1b/2a WVE-004-001 study.

Study Overview

• Status: Terminated
• Conditions: Amyotrophic Lateral Sclerosis; Frontotemporal Dementia
• Intervention / Treatment: Drug: WVE-004 10 mg Q12W

• Study Type: Interventional
• Enrollment (Actual): 8
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Netherlands
  • Rotterdam, Netherlands, 3015
    • Erasmus MC
  • Utrecht, Netherlands
    • Universitair Medisch Centrum Utrecht
• United Kingdom
  • Oxford, United Kingdom, OX3 7LF
    • University of Oxford - Nuffield Department of Clinical Neurosciences

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Participants successfully completed the Phase 1b/2a study with WVE-004, WVE-004-001.
• Participant has the ability and is willing to provide informed consent prior to any study procedures. In instances where signed written informed consent is unable to be obtained it is acceptable for the participant to provide consent with legally authorized representative signing on the participant's behalf.
• In the opinion of the Investigator, the participant is able to tolerate all study procedures, is willing to comply with all other protocol requirements, and tolerated study drug in the parent study.
• Participant is willing to practice highly effective contraception for the duration of the study and for 5 months after the last dose of study drug if the participant or their partner are of childbearing potential. In addition, willingness to forego sperm or ova (egg) donation for the duration of the study and 5 months after completion of the study.
• Participant has identified a study partner(s) for the duration of the study.

Exclusion Criteria:

• Participant has a clinically significant medical finding on the physical examination other than C9orf72-associated ALS or FTD that, in the judgment of the Investigator or Sponsor, will make the participant unsuitable for participation in and/or completion of the trial procedures.
• Participant received any other investigational drug, biological agent, or device within 1 month or 5 half-lives of study agent, whichever is longer. Participant received an investigational oligonucleotide within the past 6 months or 5 half-lives of the drug, whichever is longer.
• Participant has a positive hepatitis B surface antigen or hepatitis C antibody test.
• Participant who are pregnant (as determined by a serum pregnancy test) or breast feeding at the Screening visit, or plans to become pregnant during the trial.
• Participants deemed to be at significant risk for suicidal behavior, based on Investigator assessment and/or active suicidal ideation.
• Participant has a bone, spine, bleeding (e.g., hemophilia, Von Willebrand disease, or liver disease), or other disorder that exposes the participant to a risk of injury or unsuccessful lumbar puncture (LP).
• Participant received prior treatment with viral or cellular-based gene therapy.
• Participant anticipates using antiplatelet or anticoagulant therapy during the course of the study. Participants who received antiplatelet or anticoagulant therapy must complete a washout period before the Screening visit.
• Participant was noncompliant, in the opinion of the Investigator or Sponsor, when participating in study WVE-004-001.
• Participant is directly or indirectly involved in the conduct and administration of this trial as an Investigator, sub-investigator, trial coordinator, or other trial staff member, or the participant is a first-degree family member, significant other, or relative residing with one of the above persons involved directly or indirectly in the trial.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: WVE-004 (Dose A)	Drug: WVE-004 10 mg Q12W; Eligible participants successfully completed the Phase 1b/2a WVE-004-001 study, met all inclusion criteria, and none of the exclusion criteria. Participants were administered 10 mg of WVE-004 by intrathecal (IT) injection once every 12 weeks (Q12W) for 96 weeks.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Occurrences of Participants With Adverse Events (AEs) Severe AEs, Serious Adverse Events (SAEs), and Withdrawals Due to AEs	A treatment-emergent adverse event (TEAE) is defined as any event not present before exposure to study treatment or any event already present that worsens in either intensity or frequency after exposure to study treatment.	Day 1 to Week 24 (early termination cutoff)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Clinical Dementia Rating Plus National Alzheimer's Coordinating Center Frontotemporal Lobar Degeneration (CDR Plus NACC FTLD)	Disease progression was measured using the CDR plus NACC FTLD scale. The evaluation included assessments of both cognitive and functional measures, including memory, orientation, judgment and problem-solving, involvement in community affairs, home and hobbies, personal care, language and behavior, and comportment and personality. The rating for each domain was scored using a scale of 0 (none) to 3 (severe) based on the participant's function in relation to cognitive ability (not impairment due to other factors) and past performance (or baseline level of functioning). The overall rating for each domain was summed to provide a global clinical measure of the disease. The CDR plus NACC FTLD score ranges from 0 to 24, with a higher score indicating more severe impairment.	Day 1 to Week 120 (end of study)
Change From Baseline in ALS Functional Rating Scale-Revised (ALSFRS-R)	ALSFRS-R is an instrument to monitor the function of participants with ALS and their disease progression. The components of the scale are grouped into 4 factors or domains that encompass gross motor tasks, fine motor tasks, bulbar functions, and respiratory functions. These components measure speech, salivation, swallowing, writing, feeding, dressing, turning, walking, climbing, breathing, dyspnea, orthopnea, and respiratory insufficiency. Each component is scaled from 0 to 4, with 4 being normal, and a total score is calculated	Day 1 to Week 120 (end of study)
Change From Baseline in Handheld Dynamometry (HHD)	Handheld dynamometry was used to provide an objective quantitative measurement of strength, a key hallmark of decline in ALS disease progression. For the HHD assessment, participants would be sitting in a hard-backed chair with armrests or a wheelchair. Muscle strength was tested using the HHD device. Measurements were recorded in pounds. A value of 0 was assigned to a given muscle if a participant could not assume the testing position due to weakness.	Day 1 to Week 120 (end of study)
Change From Baseline in Pulmonary Function Testing (Forced Vital Capacity (FVC))	Pulmonary function tests (PFTs) are tests that show how well your lungs are working. The tests measure lung volume, capacity, rates of flow, and gas exchange.	Day 1 to Week 120 (end of study)
Change From Baseline in Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ)-5	The ALSAQ-5 is specifically used to provide a brief assessment of the impacts of ALS on participants. Participants were asked to think about the difficulties they have experienced during the reporting period and scale each event as never/rarely/sometimes/often/always or cannot do at all.	Day 1 to Week 120 (end of study)
Change From Baseline in the Concentration of Poly-glycine-proline (Poly-GP) Levels in the Cerebrospinal Fluid (CSF)	CSF samples were collected to determine the concentration of poly-GP levels in CSF.	From Baseline to Week 12

Collaborators and Investigators

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

Study record dates

Study Major Dates

• Study Start (Actual): December 14, 2022
• Primary Completion (Actual): June 27, 2023
• Study Completion (Actual): June 27, 2023

Study Registration Dates

• First Submitted: January 4, 2023
• First Submitted That Met QC Criteria: January 4, 2023
• First Posted (Actual): January 13, 2023

Study Record Updates

• Last Update Posted (Actual): September 9, 2026
• Last Update Submitted That Met QC Criteria: September 8, 2026
• Last Verified: July 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Mental Disorders; Neuromuscular Diseases; Metabolic Diseases; Neurocognitive Disorders; Dementia; Neurodegenerative Diseases; Spinal Cord Diseases; TDP-43 Proteinopathies; Proteostasis Deficiencies; Motor Neuron Disease; Frontotemporal Lobar Degeneration; Nutritional and Metabolic Diseases; Amyotrophic Lateral Sclerosis; Frontotemporal Dementia
• Other Study ID Numbers: WVE-004-002

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