Focus-C9 (Wave)

Study of WVE-004 in patients with C9orf72-associated ALS or FTD

UK Chief Investigator

Jonathan Rohrer, University College London

Research summary

A multicentre, randomised, 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).

Inclusion / exclusion criteria

Inclusion criteria

ALS-specific inclusion criteria

  1. Diagnosis of ALS based on clinical manifestations.

  2. ALS: 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. Patients receiving riluzole have been on a stable dose for a minimum of 30 days.

  4. Patients on edaravone have received a minimum of one cycle (28 days).

  5. Patients discontinuing riluzole or edaravone had the last dose administered ≥ 1 month prior to screening.

FTD-specific inclusion criteria

  1. FTD: must have Global Clinical Dementia Rating – frontotemporal lobar degeneration (CDR® plus NACC FTLD) score of 0.5 or 1.

  2. FTD: able to undergo periodic magnetic resonance imaging (MRI) of the brain. Patients with mixed phenotype (ALS and FTD) need not undergo MRI if their ALS symptoms prevent it.

Mixed phenotype (ALS and FTD) inclusion criteria

Patients who are mixed phenotype (ALS and FTD) must meet both the ALS-specific and FTD-specific criteria.

Inclusion criteria common to both diseases

  1. Patient must have the ability and be willing to provide written informed consent prior to any trial-related procedures.

  2. Documented mutation (GGGGCC [G4C2] repeat expansion) in the first intronic region of the C9orf72 gene.

  3. Body mass index (BMI) ≤ 32 kg/m2.

  4. Forced vital capacity (FVC) of >50% predicted.

  5. Age of ≥18 and ≤80 years at screening visit.

  6. Willing and able to comply with scheduled visits, drug administration plan, laboratory tests, trial restrictions, and all trial procedures.

  7. Willingness to practice highly effective contraception for the duration of the trial and 5-half-lives (ie 106 days) after last dose of study drug if patients or their partners are of childbearing potential. Non-childbearing potential and highly effective methods of contraception are defined in the protocol.

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, including, but not limited to:

    • Prior or ongoing medical conditions, including acute illness, within 28 days of screening visit.

    • Clinically significant abnormality on laboratory testing at screening.

  2. Positive hepatitis B surface antigen or hepatitis C antibody test.

  3. Known to be positive for human immunodeficiency virus (HIV).

  4. History of substance use disorder (except nicotine) within six months prior to the screening visit.

  5. Significant cognitive impairment or unstable psychiatric illness, including active psychosis, active suicidal ideation, recent suicide attempt, or untreated major depression, within the last 90 days, as determined by the investigator. Mental status, psychiatric medical history, and eligibility for the study must be documented in the screening questionnaire.

  6. Pregnant (as determined by a serum pregnancy test) or breast feeding at the screening visit, or plans to become pregnant during the trial.

  7. Clinically significant abnormality on screening electrocardiogram (ECG), including, but not limited to, a confirmed QT interval using Fridericia's correction method (QTcF) of ≥450 msec for males or ≥470 msec for females.

  8. Bone, spine, bleeding, or other disorder that exposes the patient to risk of injury or unsuccessful lumbar puncture.

  9. Dementia due to a condition other than C9orf72-associated ALS or FTD, including, but not limited to, Alzheimer disease, Parkinson disease, dementia with Lewy bodies, Huntington's disease, or vascular dementia.

Prior or concomitant medications

  1. Positive for opioids (unprescribed), cocaine, amphetamines, methadone, barbiturates, methamphetamine, and phencyclidine at the screening visit.

  2. Changes in nutritional or herbal supplements or concomitant medications within one month prior to screening visit or plans to modify dose or regimen during the trial.

  3. Received prior treatment with viral or cellular-based gene therapy.

  4. Received any other investigational drug, biological agent, or device within one month of 5-half-lives of study agent, whichever is longer. Received an investigational oligonucleotide, within the past six months or 5-half-lives of the drug, whichever is longer.

Trial compliance

  1. Implantable central nervous system (CNS) device that may interfere with ability to administer trial drug via lumbar puncture or undergo MRI scan.

  2. Deemed to be at significant risk for suicidal behaviour based on investigator assessment and/or active suicidal ideation.

  3. Known hypersensitivity to any oligonucleotide, as demonstrated by a systemic allergic reaction, such as changes in pulse, blood pressure, breathing function, etc.

  4. Patient 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 patient is a first-degree family member, significant other, or relative residing with one of the above persons involved directly or indirectly in the trial.

Current status

Active – recruiting


  • John Radcliffe Hospital, Oxford

  • King's College Hospital, London

  • Royal Hallamshire Hospital, Sheffield

  • University College London Hospitals

Information about study sites

Recruitment group(s)

Participant with the relevant condition

Recruitment target(s)

22 participants (UK)

Key dates

Actual opening date: 23 September 2021

Recruitment planned end date: 9 April 2023


Wave Life Sciences Ltd


Wave Life Sciences Ltd

Study design


Intervention (if applicable)

Not applicable

Phase (if applicable)

Not applicable

Outcome measures

Incidence of patients

  • with AEs

  • with severe AEs

  • with SAEs

  • who withdraw due to AEs

Publications / Results reports

Links will be provided when papers are published.