Safety, Tolerability and Pharmacokinetics of L608 in Healthy Adults

Study Overview
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Brief Summary
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This is a Phase I, randomized, double-blinded, placebo-controlled single ascending dose, sequential-group study to evaluate the safety, tolerability, and PK of single ascending doses of L608 inhalation in healthy volunteers.

Detailed Description
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L608 inhalation Solution (L608) is developed by Pharmosa Biopharm Inc. (PBI) as a new liposomal Iloprost formulation for inhalation use in the treatment of patients with PAH (WHO Group 1). As a liposomal formulation of iloprost, L608 is intended to reduce the dosing frequency, as well as provide sustained and selective release along with achieving therapeutically relevant iloprost level. Meanwhile, L608 is expected to mitigate burst release related local irritation and systemic side effects (e.g., hypotension due to plasma peak) in clinical practice. This Phase I, randomized, double-blinded, placebo-controlled study will be conducted in healthy volunteers in Australia to evaluate the safety, tolerability, and pharmacokinetic of L608. The dose escalation design is applied in this study. The sentinel dosing design will be applied for all cohorts.

Official Title
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A Phase I, Randomized, Double-blinded, Placebo-controlled Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of Single Ascending Doses of L608 for Inhalation in Healthy Subjects

Conditions
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Pulmonary Arterial Hypertension

Intervention / Treatment
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* Drug: L608 Inhalation Solution
* Drug: Placebo solution


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Men and women aged between 18 and 65 (inclusive) at the time of Screening visit. Females must not be pregnant or lactating. Body Mass Index (BMI) of ≥18.5 and ≤30.0 kg/m2 Non-smokers or former smokers who have smoked ≤ 100 cigarettes in their lifetime and have not consumed any tobacco or tobacco-containing products for at least 3 months prior to Screening. Females must not be pregnant or lactating and must use acceptable, highly effective double contraception from Screening until 3 months after the last dose of the Investigational product. Key Exclusion Criteria: Subjects with contraindications or sensitivity to any components of the study treatment. Subjects with medical histories (within 3 months prior to Screening) or ongoing conditions of any clinically significant and/or any other medical conditions which may jeopardize the safety of the subjects and/or effect the results of the study at the Investigator's discretion. Subjects with histories or active conditions of unexplained bleeding events, hemoptysis, abnormal bleeding tendencies, and/or coagulation disorders. Subjects who voluntarily participate in this study and sign the informed consent form prior to any study procedures. Subjects with histories or active conditions of asthma, sleep apnea, chronic obstructive pulmonary disease (COPD), pulmonary fibrosis, bronchiectasis, bronchospasm, and/or reactive airway. Subjects who have had childhood asthma which have resolved as deemed by the PI can be considered. Subjects with histories or active conditions of myocardial infarction (MI), cerebrovascular accident (CVA), coronary artery disease (CAD), unstable angina, heart failure, significant cardiac arrhythmias, congenital or acquired valvular heart disease with clinically insignificant symptom, suspected lung congestion, and/or pulmonary arterial hypertension (PAH) causing by venous thromboembolism. Subjects with systolic blood pressure < 90 mmHg or > 160 mmHg and/or diastolic blood pressure < 50 mmHg or > 95 mmHg at Screening or check-in visit. Subjects with FEV1 less than 80% predicted, FVC ˂80% predicted, or resting oxygen saturation less than 95% at Screening or check-in visit. Subjects with histories of drug or alcohol abuse within 1 year prior to subject check-in (Day -1). Regular alcohol consumption defined as > 10 standard drinks per week. Consumption of products containing caffeine/methylxanthines, poppy seeds and/or alcohol within 48 hours before dosing and products containing grapefruit and/or pomelo (shown to inhibit cytochrome P450 [CYP] 3A4 activity) within 10 days prior to drug administration. Positive results of human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), and pregnancy test. Blood donation or significant blood loss (>480 ml) within 3 months prior to Screening. Subjects are pregnant or breast feeding.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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: Single Group Assignment
Interventional Model Description: Randomized, Placebo-controlled, double-blinded, single ascending dose escalation
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: L608 Liposomal inhalation solution<br>Eight subjects will be enrolled in each cohort and be randomized to receive assigned dose of L608 or placebo (6:2). | Drug: L608 Inhalation Solution<br>* subjects will be randomized at a ratio of 1:1 (for Sentinel dosing) followed by 5:1 for rest of the cohort to receive the assigned dose of L608 or placebo<br>|
| Experimental: Placebo<br>Eight subjects will be enrolled in each cohort and be randomized to receive assigned dose of L608 or placebo (6:2). | Drug: Placebo solution<br>* subjects will be randomized at a ratio of 1:1 (for Sentinel dosing) followed by 5:1 for rest of the cohort to receive the assigned dose of L608 or placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The incidence of dose limiting toxicity (DLT) | The percentage of subjects with dose limiting toxicity (DLT) within 14 days after dosing | Baseline to Day 14 | 
| The incidence of treatment emergent adverse events (TEAEs) and serious adverse events (SAEs) | The percentage of subjects with treatment emergent adverse events (TEAEs) and serious adverse events (SAEs) within 21 days after dosing. | Baseline to Day 21 | 
| Frequency and severity of treatment emergent adverse events (TEAEs) and serious adverse events (SAEs) | The frequency and severity of treatment emergent adverse events (TEAEs) and serious adverse events (SAEs) within 21 days after dosing. | Baseline to Day 21 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AUC0-t | Area under the plasma concentration-time curve from time 0 to the last quantifiable concentration | Baseline to 24 hours | 
| AUC0-∞ | Area under the plasma concentration-time curve from time 0 to infinity | Baseline to 24 hours | 
| %AUCextrap | AUC extrapolated from the last measurable concentration to infinity as a percentage of total AUC | Baseline to 24 hours | 
| Cmax | Maximum observed plasma concentration | Baseline to 24 hours | 
| Tmax | Time to reach the maximum observed plasma concentration | Baseline to 24 hours | 
| T1/2 | Apparent plasma terminal elimination half-life | Baseline to 24 hours | 
| CL/F | Apparent total plasma clearance | Baseline to 24 hours | 
| Vz/F | Apparent volume of distribution during the terminal phase | Baseline to 24 hours | 
| kel | Terminal elimination rate constant | Baseline to 24 hours |