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

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.

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