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

Study Overview
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Brief Summary
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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.

Official Title
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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)

Conditions
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ALS, FTD

Intervention / Treatment
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* Drug: WVE-004
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: ALS-specific: Diagnosis of ALS based on clinical manifestations. 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. ALS-specific: Patients receiving riluzole have been on a stable dose for a minimum of 30 days. ALS-specific: Patients on edaravone have received a minimum of 1 cycle (28 days). ALS-specific: Patients discontinuing riluzole or edaravone had the last dose administered ≥1 month prior to Screening. FTD-specific: Must have Global Clinical Dementia Rating - Frontotemporal Lobar Degeneration (CDR® plus NACC FTLD) score of 0.5 or 1. 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. Mixed-phenotype: Patients who are mixed phenotype (ALS and FTD) must meet both the ALS-specific and FTD-specific criteria. Exclusion Criteria: 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 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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

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

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | 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 | Measure Description | 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) |