The Safety and PK Study of Inhaled ICF004 in Healthy Chinese Volunteers

This is a randomized, double-blind, placebo-controlled Phase 1 study of ICF004 dry powder for inhalation in healthy Chinese adult participants. The study will evaluate the safety, tolerability, and plasma pharmacokinetics (PK) of ICF004 after single and multiple inhaled doses.

ICF004 is being developed as a potential treatment for progressive fibrosing interstitial lung disease (PF-ILD). PF-ILD includes interstitial lung diseases in which lung fibrosis continues to worsen. This progression may lead to worsening respiratory symptoms, declining lung function, and increasing fibrosis on high-resolution computed tomography. Current treatment options remain limited.

Preclinical studies suggest that ICF004 may affect signaling pathways involved in fibrosis, including pathways related to transforming growth factor beta 1 (TGF-beta 1). These effects may lower the abnormal deposition of collagen and other extracellular matrix components in the lungs. Administration by inhalation is intended to deliver ICF004 directly to the lungs. This route may achieve higher local lung exposure with a lower administered dose while limiting systemic exposure.

The study consists of a single ascending dose (SAD) part and a multiple ascending dose (MAD) part. Approximately 73 healthy male and female participants will be enrolled. Eligible participants will be 18 to 50 years of age and able to use the dry powder inhalation device correctly.

In each part, participants will be randomly assigned to receive ICF004 or matching placebo. The matching placebo will be administered using the same type of dry powder inhalation device. Participants, investigators, and other applicable study personnel will remain blinded to treatment assignment.

Part 1: Single Ascending Dose

The SAD part will evaluate the safety, tolerability, and plasma PK of ICF004 after a single inhaled dose. Approximately 41 participants will be enrolled across 5 sequential dose cohorts:

Cohort 1: 1 mg, with 3 participants randomized to ICF004 or placebo in a 2:1 ratio.

Cohort 2: 4 mg, with 10 participants randomized to ICF004 or placebo in a 4:1 ratio.

Cohort 3: 8 mg, with 10 participants randomized to ICF004 or placebo in a 4:1 ratio.

Cohort 4: 12 mg, with 10 participants randomized to ICF004 or placebo in a 4:1 ratio.

Cohort 5: 16 mg, with 8 participants randomized to ICF004 or placebo in a 3:1 ratio.

Participants will enter the clinical study unit on Day -1 and receive a single dose of ICF004 or placebo on Day 1. Participants may leave the study unit on Day 2 after completing the required assessments. They will return for safety assessments on Day 4. Researchers will conduct a telephone follow-up on Day 7 to collect information about adverse events and concomitant medications or treatments.

Safety assessments in the SAD part will include adverse event monitoring, local irritation assessments, vital signs, physical examinations, clinical laboratory tests, 12-lead electrocardiograms, and pulmonary function tests. Local irritation monitoring will include symptoms such as cough, wheezing, chest tightness, sore throat, choking, itchy throat, and a feeling of a foreign object in the throat.

Blood samples for plasma PK assessment will be collected within 1 hour before dosing and at 5, 10, 20, 30, and 45 minutes after dosing. Additional samples will be collected at 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 24 hours after dosing.

The SAD PK assessments will include maximum observed plasma concentration (Cmax), time to maximum observed plasma concentration (Tmax), area under the plasma concentration-time curve (AUC), terminal elimination half-life, terminal elimination rate constant, apparent clearance, apparent volume of distribution, mean residence time, and the percentage of AUC extrapolated to infinity.

Part 2: Multiple Ascending Dose

The MAD part will evaluate the safety, tolerability, and plasma PK of ICF004 after repeated inhaled doses. The dose levels and dry powder inhalation regimen used in this part may be adjusted based on available results from the SAD part.

Approximately 32 participants will be enrolled across 4 planned MAD cohorts. Two cohorts are planned to receive study treatment once daily (QD), and two cohorts are planned to receive study treatment twice daily (BID). Each cohort will include 8 participants randomized in a 6:2 ratio to receive ICF004 or matching placebo.

Participants will receive multiple inhaled doses from Day 1 through Day 7. Participants in the QD cohorts will receive study treatment once daily. Participants in the BID cohorts will generally receive study treatment twice daily. On Day 7, participants in the BID cohorts will receive only the morning dose, which will be their last dose.

Participants may leave the clinical study unit on Day 8 after completing the required assessments. They will return for additional safety assessments on Day 11. Researchers will conduct a telephone follow-up on Day 14 to collect information about adverse events and concomitant medications or treatments.

Safety assessments in the MAD part will include adverse event monitoring, local irritation assessments after dosing, vital signs, physical examinations, clinical laboratory tests, 12-lead electrocardiograms, pulmonary function tests, and other protocol-specified assessments. Local irritation will be monitored for 4 hours after each dose.

For the QD cohorts, intensive plasma PK samples will be collected before and through 24 hours after the first dose on Day 1. Additional predose samples will be collected on Days 3 through 7. After the last dose on Day 7, intensive PK samples will be collected through 24 hours post-dose.

For the BID cohorts, intensive plasma PK samples will be collected before and through 12 hours after the first dose on Day 1. The 12-hour sample will be collected before the second dose. Additional samples will be collected before the morning doses on Days 3 through 7. The Day 7 morning dose will be the last dose. Intensive PK samples will then be collected through 24 hours after that dose.

Each scheduled PK blood sample will have a volume of approximately 4 mL. When applicable, an additional PK sample may be collected if a participant withdraws early or discontinues study treatment. Plasma samples will be processed and managed according to the study laboratory manual.

The MAD PK assessments will include PK parameters after the first dose and after the last dose. First-dose parameters will include Cmax, Tmax, and AUC. Multiple-dose and steady-state parameters will include maximum, average, and trough plasma concentrations; time to maximum plasma concentration; AUC to the last measurable concentration; AUC over a dosing interval; AUC extrapolated to infinity; terminal elimination half-life; terminal elimination rate constant; apparent clearance; apparent volume of distribution; degree of fluctuation; peak-to-trough swing; and accumulation ratios based on Cmax and AUC.

Safety Evaluation

The primary safety outcome is the occurrence of treatment-emergent adverse events (TEAEs). A TEAE is an adverse event that begins or worsens after the first dose of ICF004 or placebo. Researchers will monitor TEAEs from Day 1 through Day 7 in the SAD part and from Day 1 through Day 14 in the MAD part.

Safety findings may include local irritation symptoms and clinically significant abnormalities identified through clinical laboratory tests, 12-lead electrocardiograms, pulmonary function tests, vital signs, or physical examinations. The investigator will determine the clinical significance of abnormal findings and whether they should be recorded as adverse events.

The study is designed to characterize the safety, tolerability, and plasma PK of ICF004 in healthy participants. It is not designed to evaluate whether ICF004 treats PF-ILD or any other disease.

Inclusion criteria

• Fully understand the study procedures and methods, volunteer to participate in this study, and sign the written informed consent form.
• Healthy adult participants, male or female, aged 18 to 50 years (inclusive).
• Body Mass Index (BMI) ≥ 18 and < 28 kg/m²; body weight ≥ 50.0 kg and < 90.0 kg for males, and ≥ 45.0 kg and < 90.0 kg for females.
• Medically healthy as determined by the investigator, based on the absence of clinically significant abnormalities in physical examinations, laboratory tests, vital signs, chest X-ray, and electrocardiogram (ECG).
• Able to use the inhalation device correctly and effectively.
• Agree to use effective contraceptive measures throughout the study period. Female participants of childbearing potential must agree to use effective contraception from the screening period until 6 months after the last dose. During this period, female participants must agree to have no plans for pregnancy or egg donation/harvesting; male participants must agree to have no plans to father a child or donate sperm. Their male or female partners of childbearing potential must also agree to use effective contraceptive measures during this period.

Exclusion criteria

• History of any clinically significant disease (including past and current history), including but not limited to respiratory, cardiovascular, gastrointestinal, hematological, endocrine, immunological, dermatological, malignant tumor, neuropsychiatric, ear/nose/throat (ENT), or metabolic diseases; or any other condition that, in the opinion of the investigator (or sub-investigator), makes the participant unsuitable for the study.
• Major surgery within 6 months prior to dosing, planned surgery during the study, or previous surgery that may significantly affect the pharmacokinetics or safety evaluation of the study drug.
• Current oral diseases that may affect the study, as judged by the investigator (e.g., oropharyngeal candidiasis, oral ulcers, oral mucosal lesions).
• Fever (body temperature > 37.5°C) or symptomatic respiratory infection within 1 month prior to dosing; any infection requiring systemic antibiotics or antivirals within 3 months prior to screening; or a history of recurrent infections.
• Positive test results for Human Immunodeficiency Virus (HIV), Hepatitis B surface antigen (HBsAg), Treponema pallidum (syphilis) antibody, or Hepatitis C Virus (HCV) antibody.
• Alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), or total bilirubin exceeding the upper limit of normal (ULN) at the screening or baseline visit.
• Forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) < 80% of the predicted value, or FEV1/FVC < 0.7, or arterial oxygen saturation < 95% at the screening or baseline visit.
• Smoking (including e-cigarettes) within 6 months prior to dosing, or a positive smoking (nicotine/cotinine) test.
• History of drug abuse within 3 months prior to screening, or a positive urine drug screen.
• Participation in any drug or medical device clinical trial within 3 months prior to screening.
• Blood donation or blood loss ≥ 400 mL within 3 months prior to dosing.
• Difficulty in venous blood sampling, intolerance to venipuncture, or a history of needle or blood phobia (vasovagal syncope).
• Known allergy to the study drug or any of its ingredients.
• Female participants who are pregnant or lactating, or who plan to become pregnant from the time of the study through 6 months after the last dose.
• Any condition that, in the opinion of the investigator, makes the participant unsuitable for participation in the study.