A Phase 1/2a Study to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Single and Multiple Doses of IONIS-ENaCRx in Healthy Volunteers and Patients With Cystic Fibrosis

Study Overview
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Brief Summary
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This Phase 1/2a study is a double-blinded (subject and Investigator), randomized, placebo-controlled, dose-escalation study to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of single and multiple nebulized doses of IONIS-ENaCRx.

Detailed Description
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This study will be conducted in 3 parts: a single ascending dose (SAD) leading to a multiple ascending dose (MAD) in healthy volunteers, followed by a MAD in patients with cystic fibrosis. The study will enroll up to 88 participants. The study will consist of 4 single-dose randomized cohorts. Participants enrolled will receive a single inhaled dose of the Study Drug (IONIS-ENaCRx or placebo) on Day 1.

Official Title
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A Double-Blind, Placebo-Controlled, Dose-Escalation, Phase 1/2a Study to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Single and Multiple Doses of ION-827359, an Antisense Oligonucleotide Inhibitor of ENaC, Administered to Healthy Volunteers and Patients With Cystic Fibrosis

Conditions
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Healthy Subjects, Cystic Fibrosis

Intervention / Treatment
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* Drug: IONIS-ENaCRx
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria (Healthy Volunteers) Females must be non-pregnant and non-lactating, and either surgically sterile or post-menopausal. Males must be surgically sterile or, abstinent or, if engaged in sexual relations with a woman of child-bearing potential, the subject or the subject's non-pregnant female partner must be using a highly effective contraceptive method Willing to refrain from strenuous exercise/activity for at least 72 hours prior to study visits Body mass index (BMI) < 35 kg/m2 with a minimum weight of 45 kg Normal diffusing capacity in the lung (≥ 80% predicted) at Screening Exclusion Criteria (Healthy Volunteers) Clinically-significant (CS) abnormalities in medical history, screening laboratory results, physical or physical examination that would render a subject unsuitable for inclusion, including but not limited to: Urine protein/creatinine (P/C) ratio ≥ 0.2 mg/mg Positive test (including trace) for blood on urinalysis Alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin, alkaline phosphatase (ALP), serum creatinine, blood urea nitrogen (BUN), fasting blood glucose, potassium > upper limit of normal (ULN) Platelet count < LLN Active infection requiring systemic antiviral or antimicrobial therapy that will not be completed prior to Study Day 1 Respiratory infection within 4 weeks of Study Day 1 Presence or past history of CS chronic respiratory disease, including any current history (or within 2 years) of asthma. History of allergic rhinitis is acceptable Forced expiratory volume in 1 second (FEV1) < 80% of predicted at Screening or an FEV1/FVC ratio of < 0.7 Smoking of a tobacco or nicotine-containing product within the previous 6 months (use of a nicotine patch is permitted) or a smoking history of ≥ 10 pack years Any CS finding on chest radiograph Uncontrolled hypertension (blood pressure [BP] > 160/100 mm Hg) at Screening Treatment with another investigational drug, biological agent, or device within one month of screening, or 5 half-lives of investigational agent, whichever is longer Any history of previous treatment with an oligonucleotide Regular use of alcohol within 6 months prior to screening or hard drugs within 1 year prior to screening, or positive urine drug screen at Screening Blood donation of 50 to 499 mL within 30 days of screening or of > 499 mL within 60 days of screening Inclusion Criteria (Cystic Fibrosis Participants) Females must be non-pregnant and non-lactating, and either surgically sterile or post-menopausal. Males must be surgically sterile or, abstinent or, if engaged in sexual relations with a woman of child-bearing potential, the subject or the subject's non-pregnant female partner must be using a highly effective contraceptive method Confirmed diagnosis of CF by seat chloride and/or genetics by referring clinician FEV1 >/= 50% of predicted Stable CF disease as judged by the Investigator Weight > 40 kg Exclusion Criteria (Cystic Fibrosis Participants) Clinically-significant (CS) abnormalities in medical history, screening laboratory results, physical or physical examination that would render a subject unsuitable for inclusion, including but not limited to: Abnormal liver function defined as > 2 times upper limit of normal (ULN) for bilirubin, or 3 time ULN for ALT, AST, or alkaline phosphatase Platelet count < LLN Active infection requiring systemic antiviral or antimicrobial therapy that will not be completed prior to Study Day 1 Respiratory infection within 4 weeks of Study Day 1 Colonization with Burkholderia cepacia or M. abscessus

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

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: IONIS-ENaCRx<br>Ascending single and multiple doses of IONIS-ENaCRx inhaled or nebulized. | Drug: IONIS-ENaCRx<br>* Ascending single and multiple doses of IONIS-ENaCRx inhaled or nebulized.<br>|
| Placebo Comparator: Placebo<br>Placebo comparator calculated volume to match active comparator inhaled or nebulized. | Drug: Placebo<br>* Placebo comparator calculated volume to match active comparator inhaled or nebulized.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and Tolerability as Measured by the Number of Participants with at least one Treatment-Emergent Adverse Event |  | Up to 113 Days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cmax: maximum observed drug concentration in plasma of IONIS-ENaCRx |  | Up to 113 Days | 
| Tmax: time taken to reach maximal concentration in plasma of IONIS-ENaCRx |  | Up to 113 Days | 
| AUCt: area under the plasma concentration-time curve from time zero to time t for IONIS-ENaCRx |  | Up to 113 Days | 
| CL/F: apparent total clearance of IONIS-ENaCRx |  | Up to 113 Days | 
| t1/2λz: termination half-life of IONIS-ENaCRx |  | Up to 113 Days | 
| The amount of administered dose of IONIS-ENaCRx excreted in urine over a 24-hour period |  | Up to 113 Days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ENaC, ION-827359