Safety and Tolerability of WVE-120101 in Patients With Huntington's Disease

Study Overview
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Brief Summary
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PRECISION-HD1 is a Phase 1b/2a multicenter, randomized, double-blind, placebo-controlled study to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of single and multiple doses of WVE-120101 in adult patients with early manifest Huntington's disease (HD) who carry a targeted single nucleotide polymorphism (SNP) rs362307 (SNP1).

Official Title
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A Multicenter, Randomized, Double-blind, Placebo-controlled, Phase 1b/2a Study of WVE-120101 Administered Intrathecally in Patients With Huntington's Disease

Conditions
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Huntington's Disease

Intervention / Treatment
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* Drug: WVE-120101
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Prescreened with targeted SNP on the same allele as the pathogenic CAG expansion Ambulatory, male or female patients aged ≥25 - ≤65 years Clinical diagnostic motor features of HD, defined as Unified Huntington's Disease Rating Scale (UHDRS) Diagnostic Confidence Score = 4 Early manifest HD, Stage I or Stage II based on UHDRS Total Functional Capacity Scores ≥7 and ≤13 Key Exclusion Criteria: Malignancy or received treatment for malignancy, other than treated basal cell or squamous cell carcinoma of the skin, within the previous 5 years. Received investigational drug or implantable device in prior 3 months or investigational oligonucleotide in prior 6 months or 5 half-lives of the oligonucleotide, whichever is longer Clinically significant medical condition, unstable psychiatric symptoms, substance abuse, or pregnancy Inability to undergo brain MRI Bone, spine, bleeding, or other disorder that exposes the patient to risk of injury or unsuccessful lumbar puncture

Ages Eligible for Study
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Minimum Age: 25 Years
Maximum Age: 65 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: Sequential Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: WVE-120101 (Dose A) or placebo<br> | Drug: WVE-120101<br>* WVE-120101 is a stereopure antisense oligonucleotide (ASO)<br>Drug: Placebo<br>* 0.9% Sodium Chloride<br>|
| Experimental: WVE-120101 (Dose B) or placebo<br> | Drug: WVE-120101<br>* WVE-120101 is a stereopure antisense oligonucleotide (ASO)<br>Drug: Placebo<br>* 0.9% Sodium Chloride<br>|
| Experimental: WVE-120101 (Dose C) or placebo<br> | Drug: WVE-120101<br>* WVE-120101 is a stereopure antisense oligonucleotide (ASO)<br>Drug: Placebo<br>* 0.9% Sodium Chloride<br>|
| Experimental: WVE-120101 (Dose D) or placebo<br> | Drug: WVE-120101<br>* WVE-120101 is a stereopure antisense oligonucleotide (ASO)<br>Drug: Placebo<br>* 0.9% Sodium Chloride<br>|
| Experimental: WVE-120101 (Dose E) or placebo<br> | Drug: WVE-120101<br>* WVE-120101 is a stereopure antisense oligonucleotide (ASO)<br>Drug: Placebo<br>* 0.9% Sodium Chloride<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety: Number of Patients With Treatment-emergent Adverse Events (TEAEs) | All TEAEs reported or observed during the study, including TEAEs resulting from concurrent illnesses, reactions to concurrent medications, or progression of disease states | Day 1 to end of study (up to Day 182 [32 mg cohort]/ Day 210 [all other cohorts]) | 
| Safety: Severity of Adverse Events | Number of patients who experienced a severe treatment-emergent adverse event. Severity was evaluated using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 | Day 1 to end of study (up to Day 182 [32 mg cohort]/ Day 210 [all other cohorts]) | 
| Safety: Number of Patients With Serious TEAEs | A serious TEAE is defined as any event that results in death, is immediately life threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, or is a congenital anomaly/birth defect not present at Prescreening. | Day 1 to end of study (up to Day 182 [32 mg cohort]/ Day 210 [all other cohorts]) | 
| Safety and Tolerability: Number of Patients Who Withdraw Due to TEAEs |  | Day 1 to end of study (up to Day 182 [32 mg cohort]/ Day 210 [all other cohorts]) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics (PK): Maximum Observed Concentration (Cmax) | Cmax of WVE-120101 in plasma | Patients participating in Period 1 (SAD) had PK samples collected on Day 1 predose through 24-48 hours postdose. Patients participating in Period 2 (MAD) had PK samples collected predose on Day 112 and through 4 hours postdose. | 
| PK: Time of Occurrence of Cmax (Tmax) | tmax of WVE-120101 in plasma | Patients participating in Period 1 (SAD) had PK samples collected on Day 1 predose through 24-48 hours postdose. Patients participating in Period 2 (MAD) had PK samples collected predose on Day 112 and through 4 hours postdose. | 
| PK: Area Under the Plasma Concentration-time Curve (AUClast) | AUClast from time 0 to the last quantifiable concentration of WVE-120101 in plasma | Patients participating in Period 1 (SAD) had PK samples collected on Day 1 predose through 24-48 hours postdose. Patients participating in Period 2 (MAD) had PK samples collected predose on Day 112 and through 4 hours postdose. | 
| PK: Terminal Elimination Half Life | Terminal elimination half life of WVE-120101 in plasma (t1/2) | Patients participating in Period 1 (SAD) had PK samples collected on Day 1 predose through 24-48 hours postdose. Patients participating in Period 2 (MAD) had PK samples collected predose on Day 112 and through 4 hours postdose. | 
| Pharmacodynamics | Percentage change from baseline in concentration of mutant huntingtin (mHTT) protein in CSF | Day 1 to last observation - up to Day 140 (32 mg cohort) or Day 196 (all other cohorts) | 
| Clinical Effects: Total Functional Capacity (TFC) | Percentage change from baseline to the last measured time point in the Total Functional Capacity score, administered as part of the Unified Huntington's Disease Rating Scale (UHDRS). Total Functional Capacity is scored 13 (normal) to 0 (severe disability). | Day 1 to last observation - up to Day 140 (32 mg cohort) or Day 196 (all other cohorts) |