Study of ARO-RAGE in Healthy Subjects and Patients With Inflammatory Lung Disease

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety, tolerability, and pharmacokinetics of ARO-RAGE in normal healthy volunteers (NHVs) and in participants with inflammatory lung disease (asthma, cystic fibrosis [CF]). In Part 1 of the study, NHVs will receive a single dose of ARO-RAGE or placebo. In Part 2 of the study, adult participants with inflammatory lung disease will receive 2 doses of ARO-RAGE or placebo. Additional NHVs may be randomized to receive 1 or 2 doses of ARO-RAGE or placebo at Sponsor discretion. Dose levels in Part 2 will be determined based on cumulative safety and pharmacodynamic data from Part 1.

Official Title
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A Phase 1/2a Study Evaluating the Effects of ARO-RAGE Inhalation Solution in Healthy Subjects and Patients With Inflammatory Lung Disease

Conditions
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Asthma, Cystic Fibrosis

Intervention / Treatment
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* Drug: ARO-RAGE
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Normal pulmonary function tests at Screening (NHVs only) Confirmed diagnosis of asthma based on source verifiable medical record (asthma patients only) Confirmed diagnosis of Cystic Fibrosis based on source verifiable medical record (CF patients only) No abnormal finding of clinical relevance at Screening (other than asthma for asthma patients and CF for CF patients) Stable dose of asthma controller medications prior to Screening (asthma patients only) If on allergen-specific immunotherapy, participants must be on a stable maintenance dose Stable regimen of CF therapy for at least 6 weeks prior to Screening (CF patients only) Non-smoking Women of childbearing potential must have a negative pregnancy test, cannot be breastfeeding, and must be willing to use contraception. Males must not donate sperm during the study and for at least 12 weeks following the last dose of study drug Willing to provide written informed consent and to comply with study requirements Exclusion Criteria: Acute lower respiratory infection or asthma/CF exacerbation within 30 days prior to first dose Positive COVID-19 test during Screening window Use of immunosuppressive medication within 90 days prior to first dose Receipt of any intranasal vaccine within 30 days prior to first dose Use of systemic corticosteroid therapy within 90 days prior to first dose Clinically significant health concerns (other than asthma in asthma patients or CF in CF patients) Human Immunodeficiency virus (HIV) infection, seropositive for Hepatitis B Virus (HBV), seropositive for Hepatitis C Virus (HCV) Uncontrolled hypertension Unwilling to limit alcohol consumption to within moderate limits for the duration of the study Use of illicit drugs Use of an investigational agent or device within 30 days prior to first dose Note: additional inclusion/exclusion criteria may apply per protocol

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: Sequential Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ARO-RAGE<br>ARO-RAGE Inhalation | Drug: ARO-RAGE<br>* single or multiple doses of ARO-RAGE by inhalation of nebulized solution<br>|
| Placebo Comparator: Placebo<br>(0.9% NaCl) | Drug: Placebo<br>* calculated volume to match active treatment by inhalation of nebulized solution<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) |  | From first dose of study drug through the end of study (EOS; up to 113 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from Baseline Over Time in Forced Expiratory Volume (FEV1) |  | Baseline through EOS (up to 113 days) or until serum soluble receptor for advance glycation end products (sRAGE) is ≥ 70% of baseline value | 
| Change from Baseline Over Time in Forced Vital Capacity (FVC) |  | Baseline through EOS (up to 113 days) or until serum sRAGE is ≥ 70% of baseline value | 
| Change from Baseline Over Time in Diffusing Capacity for Carbon Monoxide (DLCO) |  | Baseline through EOS (up to 113 days) or until serum sRAGE is ≥ 70% of baseline value | 
| PK of ARO-RAGE: Maximum Observed Plasma Concentration (Cmax) |  | single dose phase: up to 48 hours post-dose; multiple dose phase: up to 6 hours post-dose on Days 1 and 29 for NHVs and CF participants, and up to 24 hours post-dose for participants with asthma | 
| PK of ARO-RAGE: Time to Maximum Observed Plasma Concentration (Tmax) |  | single dose phase: up to 48 hours post-dose; multiple dose phase: up to 6 hours post-dose on Days 1 and 29 for NHVs and CF participants, and up to 24 hours post-dose for participants with asthma | 
| PK of ARO-RAGE: Area Under the Plasma Concentration versus Time Curve From Zero to 24 Hours (AUC0-24) |  | single dose phase: up to 48 hours post-dose; multiple dose phase: up to 6 hours post-dose on Days 1 and 29 for NHVs and CF participants, and up to 24 hours post-dose for participants with asthma | 
| PK of ARO-RAGE: Area Under the Plasma Concentration versus Time Curve From Zero to the Last Quantifiable Plasma Concentration (AUClast) |  | single dose phase: up to 48 hours post-dose; multiple dose phase: up to 6 hours post-dose on Days 1 and 29 for NHVs and CF participants, and up to 24 hours post-dose for participants with asthma | 
| PK of ARO-RAGE: Area Under the Plasma Concentration versus Time Curve From Zero to Infinity (AUCinf) |  | single dose phase: up to 48 hours post-dose; multiple dose phase: up to 6 hours post-dose on Days 1 and 29 for NHVs and CF participants, and up to 24 hours post-dose for participants with asthma | 
| PK of ARO-RAGE: Terminal Elimination Half-Life (t1/2) |  | single dose phase: up to 48 hours post-dose; multiple dose phase: up to 6 hours post-dose on Days 1 and 29 for NHVs and CF participants, and up to 24 hours post-dose for participants with asthma | 
| PK of ARO-RAGE: Apparent Systemic Clearance (CL/F) |  | single dose phase: up to 48 hours post-dose; multiple dose phase: up to 6 hours post-dose on Days 1 and 29 for NHVs and CF participants, and up to 24 hours post-dose for participants with asthma | 
| PK of ARO-RAGE: Apparent Terminal-Phase Volume of Distribution (VZ/F) |  | single dose phase: up to 48 hours post-dose; multiple dose phase: up to 6 hours post-dose on Days 1 and 29 for NHVs and CF participants, and up to 24 hours post-dose for participants with asthma | 
| PK of ARO-RAGE: Recovery of Unchanged Drug in Urine Over 0 to 24 Hours (Amount Excreted; Ae) |  | Through 24 hours post-dose | 
| PK of ARO-RAGE: Percentage of Administrated Drug Recovered in Urine Over 0 to 24 hours |  | Through 24 hours post-dose | 
| PK of ARO-RAGE: Renal Clearance (CLr) |  | single dose phase: up to 48 hours post-dose; multiple dose phase: up to 6 hours post-dose on Days 1 and 29 for NHVs and CF participants, and up to 24 hours post-dose for participants with asthma |