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

Conditions: Healthy Subjects; Cystic Fibrosis

Summary: 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.

Eligibility criteria:
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

Keywords: ion-827359 enac