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: The study will include two distinct periods. Period 1 will evaluate single ascending doses (SAD), and Period 2 will evaluate multiple ascending doses (MAD) of WVE‐004. Period 2 cohorts will be based upon available clinical biomarker and safety data alongside nonclinical data. The maximum dose in Period 2 will not exceed a monthly dose of 11.2 mg, which is the human equivalent dose (HED) of the no observed adverse effect level (NOAEL) as established in the ongoing 13‐week Good Laboratory Practice (GLP) study in cynomolgus monkeys. Dose escalation beyond the NOAEL established in the 13‐week repeat dose toxicity study (11.2 mg monthly) will not occur until the supportive nonclinical data from subsequent chronic toxicity studies are submitted in a substantial amendment to the IMPD and approved by the competent authorities. Patients may participate in Period 1 (SAD) and Period 2 (MAD) or Period 2 only. All patients enrolled in Period 1 cohorts will have the opportunity to receive multiple doses in Period 2. All cohorts will include both ALS and FTD patients, and sentinel patients may be diagnosed with either ALS or FTD. The Sponsor will continue to evaluate available nonclinical and clinical data to optimize the dose level and frequency for multiple dosing but intends to evaluate up to 4 dose levels in Period 1 and Period 2, and 2 dose frequencies in Period 2. Cohorts in both Period 1 and Period 2 will be enrolled and dosed in a sequential manner. Cohorts that follow the initial dose cohort in Period 1 and Period 2 will not initiate until the requirements for dose escalation are met (as defined in the protocol on page 4‐8). This study will utilize both a Dose Escalatio CONDITION: ; ALS ; dementia 10012272 10029317 PRIMARY OUTCOME: 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 OUTCOME: Secondary Endpoint(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 ; Exploratory Endpoint(s) ; Biomarker Assessments: ; • Change from baseline in concentration of neurodegeneration markers ; (including, but not limited to, neurofilament light chain in CSF and/or plasma, ; or the extracellular domain of the P75 neurotrophin receptor [P75NTRECD] in ; urine) ; Laboratory Assessments of Clinical Effects: ; • Change from baseline on electrocardiogram ; • Change from baseline on pulmonary function tests ; • Change from baseline in magnetic resonance imaging (MRI) ; Clinical Assessments: ; • Change from baseline in the following assessments of clinical signs and ; symptoms: ; Functional Assessments ; * CDR® plus NACC FTLD ; * ALS Functional Rating Scale‐Revised (ALSFRS‐R) ; * Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ‐40) ; * Hand‐held dynamometry (HHD) ; * Neuropsychiatric Inventory Questionnaire (NPI‐Q)© ; Cognitive Assessments ; * Trails Making A and B ; * Stroop Test ; * Verbal Fluency ; * Symbol Digit Modalities Test (SDMT) ; 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) I