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.

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)

1. Females must be non-pregnant and non-lactating, and either surgically sterile or post-menopausal.
2. 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
3. Willing to refrain from strenuous exercise/activity for at least 72 hours prior to study visits
4. Body mass index (BMI) < 35 kg/m2 with a minimum weight of 45 kg
5. Normal diffusing capacity in the lung (≥ 80% predicted) at Screening

Exclusion Criteria (Healthy Volunteers)

1. 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:

   1. Urine protein/creatinine (P/C) ratio ≥ 0.2 mg/mg
   2. Positive test (including trace) for blood on urinalysis
   3. 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)
   4. Platelet count < LLN

2. Active infection requiring systemic antiviral or antimicrobial therapy that will not be completed prior to Study Day 1

3. Respiratory infection within 4 weeks of Study Day 1

4. 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

5. Forced expiratory volume in 1 second (FEV1) < 80% of predicted at Screening or an FEV1/FVC ratio of < 0.7

6. 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

7. Any CS finding on chest radiograph

8. Uncontrolled hypertension (blood pressure [BP] > 160/100 mm Hg) at Screening

9. Treatment with another investigational drug, biological agent, or device within one month of screening, or 5 half-lives of investigational agent, whichever is longer

10. Any history of previous treatment with an oligonucleotide

11. 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

12. 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)

1. Females must be non-pregnant and non-lactating, and either surgically sterile or post-menopausal.
2. 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
3. Confirmed diagnosis of CF by seat chloride and/or genetics by referring clinician
4. FEV1 >/= 50% of predicted
5. Stable CF disease as judged by the Investigator
6. Weight > 40 kg

Exclusion Criteria (Cystic Fibrosis Participants)

1. 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:

   1. Abnormal liver function defined as > 2 times upper limit of normal (ULN) for bilirubin, or 3 time ULN for ALT, AST, or alkaline phosphatase
   2. Platelet count < LLN

2. Active infection requiring systemic antiviral or antimicrobial therapy that will not be completed prior to Study Day 1

3. Respiratory infection within 4 weeks of Study Day 1

4. Colonization with Burkholderia cepacia or M. abscessus