Safety, Tolerability and Pharmacokinetics of L608 in Healthy Adults

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

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.

Study Overview

• Status: Completed
• Conditions: Pulmonary Arterial Hypertension
• Intervention / Treatment: Drug: L608 Inhalation Solution; Drug: Placebo solution

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 64
• Phase: Phase 1

Contacts and Locations

Study Locations

• Australia
  • South Australia
    • Adelaide, South Australia, Australia, SA 5000
      • CMAX Clinical Research Pty Ltd

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Description

Key Inclusion Criteria:

1. Men and women aged between 18 and 65 (inclusive) at the time of Screening visit. Females must not be pregnant or lactating.
2. Body Mass Index (BMI) of ≥18.5 and ≤30.0 kg/m2
3. 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.
4. 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:

1. Subjects with contraindications or sensitivity to any components of the study treatment.
2. 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.
3. Subjects with histories or active conditions of unexplained bleeding events, hemoptysis, abnormal bleeding tendencies, and/or coagulation disorders.
4. Subjects who voluntarily participate in this study and sign the informed consent form prior to any study procedures.
5. 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.
6. 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.
7. 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.
8. Subjects with FEV1 less than 80% predicted, FVC ˂80% predicted, or resting oxygen saturation less than 95% at Screening or check-in visit.
9. 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.
10. 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.
11. Positive results of human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), and pregnancy test.
12. Blood donation or significant blood loss (>480 ml) within 3 months prior to Screening.
13. Subjects are pregnant or breast feeding.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Single Group Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: L608 Liposomal inhalation solution; 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; 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; Other Names: Placebo solution
Experimental: Placebo; Eight subjects will be enrolled in each cohort and be randomized to receive assigned dose of L608 or placebo (6:2).	Drug: Placebo solution; 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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Pharmosa Biopharm Inc.
• Collaborators: Novotech (Australia) Pty Limited

Study record dates

Study Major Dates

• Study Start (Actual): August 30, 2023
• Primary Completion (Actual): September 2, 2024
• Study Completion (Actual): September 2, 2024

Study Registration Dates

• First Submitted: June 9, 2023
• First Submitted That Met QC Criteria: July 6, 2023
• First Posted (Actual): July 11, 2023

Study Record Updates

• Last Update Posted (Actual): October 16, 2024
• Last Update Submitted That Met QC Criteria: October 11, 2024
• Last Verified: October 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Lung Diseases; Hypertension, Pulmonary; Pulmonary Arterial Hypertension; Pharmaceutical Solutions
• Other Study ID Numbers: PBI L608p1

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No