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)

INTERVENTION: Product Code: WVE‐004 Pharmaceutical Form: Powder for solution for injection INN or Proposed INN: not yet assigned CAS Number: N/A Current Sponsor code: WVE‐004 Other descriptive name: Synthetic stereopure antisense oligonucleotide targeting human C9orf72 hexanucleotide repeat‐containing mRNA transcripts Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 10‐ Pharmaceutical form of the placebo: Solution for injection Route of administration of the placebo: Intrathecal use CONDITION: Amyotrophic Lateral Sclerosis and Frontotemporal Dementia ; MedDRA version: 21.1 Level: PT Classification code 10002026 Term: Amyotrophic lateral sclerosis System Organ Class: 10029205 ‐ Nervous system disorders ; MedDRA version: 21.1 Level: PT Classification code 10068968 Term: Frontotemporal dementia System Organ Class: 10029205 ‐ Nervous system disorders Therapeutic area: Diseases [C] ‐ Nervous System Diseases [C10] PRIMARY OUTCOME: Main Objective: Evaluate the safety and tolerability of WVE‐004 in patients with ALS or FTD with a documented mutation in the C9orf72 gene. Primary end point(s): Incidence of patients with AEs, the incidence of patients with severe AEs, incidence of patients with SAEs, and the incidence of patients who withdraw due to AEs.; ; Secondary Objective: •Characterize the pharmacokinetics (PK) of WVE‐004 in plasma.; •Characterize cerebrospinal fluid (CSF) concentration of WVE‐004.; •Evaluate the pharmacodynamic (PD) effect of WVE‐004 via measurement of poly‐glycine‐proline (poly‐GP) in CSF.; Timepoint(s) of evaluation of this end point: Period 1: week 1 ‐ 24; Period 2: week 1 ‐ 24 SECONDARY OUTCOME: Secondary end point(s): • Pharmacokinetic parameters of WVE‐004 in plasma; • CSF concentration of WVE‐004; • Change from baseline in concentration of poly‐GP levels in the CSF Timepoint(s) of evaluation of this end point: Period 1: week 1 ‐ 24; Period 2: week 1 ‐ 24 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 1 cycle (28 days). 5. Patients discontinuing riluzole or edaravone had the last dose administered =1 month prior to Screening. FTD‐Specific INCLUSION CRITERIA: 6. FTD: Must have Global Clinical Dementia Rating – Frontotemporal Lobar Degeneration (CDR® plus NACC FTLD) score of 0.5 or 1. 7. 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: 8. Patient