Asthma, Chronic Obstructive Pulmonary Disease
Conditions
Brief summary
The purpose of this study is to evaluate the safety, tolerability, and pharmacokinetics (PK) of ARO-MUC5AC in normal healthy volunteers (NHVs), patients with moderate-to-severe asthma and patients with moderate-to-severe chronic obstructive pulmonary disease (COPD). In part 1 NHVs will receive a single dose of ARO-MUC5AC or placebo. In part 2 of the study, NHVs, adult patients with asthma, and adult patients with COPD will receive 3 doses of ARO-MUC5AC or placebo.
Interventions
DRUGARO-MUC5AC
single or multiple doses of ARO- MUC5AC by inhalation of nebulized solution
DRUGPlacebo
calculated volume to match active treatment by inhalation of nebulized solution
Sponsors
Arrowhead Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
Yes
Inclusion criteria
* Normal pulmonary function tests at Screening (NHVs only) * Confirmed diagnosis of asthma or COPD based on source verifiable medical record (asthma and COPD patients only) * No abnormal finding of clinical relevance at Screening (NHVs only) * Stable dose of asthma controller medications for at least 28 days prior to Screening (asthma patients only) * Documented treatment with an inhaled corticosteroid and at least 1 additional maintenance asthma controller medication for at least 3 months prior to Screening (asthma patients only) * Non-smoking (NHVs and asthma patients) * Current smoker or ex-smoker with smoking history of ≥ 10 pack-years (COPD patients only) * All COPD treatments have been stable for at least one month prior to Screening (COPD patients only) * Able to produce an induced sputum sample at Screening * 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 90 days 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 within 30 days prior to first dose and/or acute upper respiratory infection within 7 days prior to first dose * Positive COVID-19 test during Screening window * Any history of chronic pulmonary disease (NHVs only) * Any concomitant pulmonary disease in asthma or COPD patients that could interfere with the evaluation of the study drug or interpretation of patient safety or study results * Use of theophylline within 30 days prior to first dose * History of lung volume reduction surgery or pneumonectomy (COPD patients) * Need for chronic oxygen support at Screening * Clinically significant health concerns (other than asthma in asthma 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/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | From first dose of study drug up to Day 29 (single dose phase), and up to Day 85 (multiple dose phase) | An adverse event (AE) is any untoward medical occurrence, which does not necessarily have to have a causal relationship with treatment. TEAEs will be defined as AEs with onset after administration of the study drug, or when a preexisting medical condition increases in severity or frequency after study drug administration. A serious AE (SAE) is an AE occurring during any study phase, and at any dose of study drug that: results in death; is immediately life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability or incapacity; results in a congenital abnormality or birth defect; is an important medical event that may jeopardize the subject or may require medical intervention to prevent one of the outcomes listed above. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change Over Time From Baseline in Forced Expiratory Volume (FEV1), SAD Cohorts | Baseline, Day 1: 15, 60, 120 minutes (mins) post-dose, Days 2,3, 8, 15, 22, 29 (end of study [EOS]) | — |
| Change Over Time From Baseline in FEV1, MAD Cohorts | Baseline, Day 1 (15, 60, 120 mins post-dose), Days 2, 3, 8, 15 (15, 60, 120 mins post-dose), 22, 29 (15, 60, 120 mins post-dose), 30, 35, 36, 43, 50, 57, 71, 85 (EOS) | — |
| Change Over Time From Baseline in Forced Vital Capacity (FVC), SAD Cohorts | Baseline, Day 1: 15, 60, 120 minutes (mins) post-dose, Days 2, 3, 8, 15, 22, 29 (end of study [EOS]) | Day 1: Predose, at 0.5, 1, 2, 4, 6, 8, and 12 hours postdose (based on start of inhalation); Day 2: 24 hours postdose; Day 3: 48 hours postdose |
| Change Over Time From Baseline in FVC, MAD Cohorts | Baseline, Day 1 (15, 60, 120 mins post-dose), Days 2, 8, 15 (15, 60, 120 mins post-dose), 22, 29 (15, 60, 120 mins post-dose), 30, 35, 36, 43, 50, 57, 71, 85 (EOS) | — |
| Pharmacokinetics (PK) of ARO-MUC5AC: Maximum Observed Plasma Concentration (Cmax), SAD Cohorts | Day 1: Predose, at 0.5, 1, 2, 4, 6, 8, and 12 hours postdose (based on start of inhalation); Day 2: 24 hours postdose; Day 3: 48 hours postdose | — |
| PK of ARO-MUC5AC: Time to Cmax (Tmax), SAD Cohorts | Day 1: Predose, at 0.5, 1, 2, 4, 6, 8, and 12 hours postdose (based on start of inhalation); Day 2: 24 hours postdose; Day 3: 48 hours postdose | — |
| PK of ARO-MUC5AC: Area Under the Plasma Concentration Versus Time Curve From Time 0 to the Time of the Last Measurable Concentration (AUC0-t), SAD Cohorts | Day 1: Predose, at 0.5, 1, 2, 4, 6, 8, and 12 hours postdose (based on start of inhalation); Day 2: 24 hours postdose; Day 3: 48 hours postdose | — |
| PK of ARO-MUC5AC: Area Under the Plasma Concentration Versus Time Curve From Zero to 24 Hours (AUC0-24), SAD Cohorts | Day 1: Predose, at 0.5, 1, 2, 4, 6, 8, 12, and 24 hours postdose (based on start of inhalation) | — |
| PK of ARO-MUC5AC: Area Under the Plasma Concentration Versus Time Curve From Zero to Infinity (AUCinf), SAD Cohorts | Day 1: Predose, at 0.5, 1, 2, 4, 6, 8, and 12 hours postdose (based on start of inhalation); Day 2: 24 hours postdose; Day 3: 48 hours postdose | — |
| PK of ARO-MUC5AC: Terminal Elimination Half-Life (t1/2), SAD Cohorts | Day 1: Predose, at 0.5, 1, 2, 4, 6, 8, and 12 hours postdose (based on start of inhalation); Day 2: 24 hours postdose; Day 3: 48 hours postdose | — |
| PK of ARO-MUC5AC: Apparent Systemic Clearance (CL/F), SAD Cohorts | Day 1: Predose, at 0.5, 1, 2, 4, 6, 8, and 12 hours postdose (based on start of inhalation); Day 2: 24 hours postdose; Day 3: 48 hours postdose | — |
| PK of ARO-MUC5AC: Apparent Terminal-Phase Volume of Distribution (Vz/F), SAD Cohorts | Day 1: Predose, at 0.5, 1, 2, 4, 6, 8, and 12 hours postdose (based on start of inhalation); Day 2: 24 hours postdose; Day 3: 48 hours postdose | — |
| PK of ARO-MUC5AC: Recovery of Unchanged Drug in Urine Over 24 Hours (Amount Excreted; Ae), SAD Cohorts Only | Day 1: Predose and cumulatively from 0 to 6 hours and 6 to 24 hours postdose. | — |
| PK of ARO-MUC5AC: Fraction of Respirable Delivered Dose (RDD) Excreted Unchanged in Urine Over 24 Hours Postdose, as a Percentage (Fe), SAD Cohorts Only | Day 1: Predose and cumulatively from 0 to 6 hours and 6 to 24 hours postdose. | — |
| PK of ARO-MUC5AC: Renal Clearance (CLr), SAD Cohorts Only | Day 1: Predose and cumulatively from 0 to 6 hours and 6 to 24 hours postdose. | — |
| PK of ARO-MUC5AC: Maximum Observed Plasma Concentration (Cmax), MAD Cohorts | NHV Cohorts: Day 1: Predose, 0.5, 1, 2, 4, and 6 hours postdose (based on start of inhalation); Day 15: Predose; Day 29: Predose, 0.5, 1, 2, 4, and 6 hours postdose. | — |
| PK of ARO-MUC5AC: Tmax, MAD Cohorts | NHV Cohorts: Day 1: Predose, 0.5, 1, 2, 4, and 6 hours postdose (based on start of inhalation); Day 15: Predose; Day 29: Predose, 0.5, 1, 2, 4, and 6 hours postdose. | — |
| PK of ARO-MUC5AC: AUC0-t, MAD Cohorts | NHV Cohorts: Day 1: Predose, 0.5, 1, 2, 4, and 6 hours postdose (based on start of inhalation); Day 15: Predose; Day 29: Predose, 0.5, 1, 2, 4, and 6 hours postdose. | — |
Countries
Australia, New Zealand, Poland, South Korea, Spain, Thailand, United Kingdom
Participant flow
Recruitment details
The study was divided into initial normal healthy volunteer (NHV) cohorts evaluating single ascending doses (SADs), followed by NHV and asthma and chronic obstructive pulmonary disorder (COPD) patient cohorts evaluating multiple ascending doses (MADs).
Pre-assignment details
The SAD portion included 4 sequentially enrolled NHV cohorts treated with placebo-matched escalating single dose levels. The MAD portion consisted of 3 NHV, 2 asthma, and 1 COPD cohorts, where each sequential cohort was treated with an escalating placebo-matched dose level. Placebo cohorts were pooled for analysis within each population.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 33.75 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 4 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants |
| Race/Ethnicity, Customized Asian | 24 Participants |
| Race/Ethnicity, Customized Black or African American | 1 Participants |
| Race/Ethnicity, Customized More Than 1 Race | 2 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Pacific Islander | 1 Participants |
| Race/Ethnicity, Customized Not Reported | 0 Participants |
| Race/Ethnicity, Customized Other, Nor Specified | 0 Participants |
| Race/Ethnicity, Customized White | 5 Participants |
| Sex: Female, Male Female | 44 Participants |
| Sex: Female, Male Male | 33 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk | EG011 affected / at risk | EG012 affected / at risk | EG013 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 8 | 0 / 4 | 0 / 4 | 0 / 4 | 0 / 4 | 0 / 8 | 0 / 6 | 0 / 6 | 0 / 8 | 0 / 4 | 0 / 7 | 0 / 6 | 0 / 2 | 0 / 6 |
| other Total, other adverse events | 6 / 8 | 3 / 4 | 0 / 4 | 4 / 4 | 4 / 4 | 6 / 8 | 4 / 6 | 6 / 6 | 4 / 8 | 1 / 4 | 3 / 7 | 2 / 6 | 2 / 2 | 4 / 6 |
| serious Total, serious adverse events | 0 / 8 | 0 / 4 | 0 / 4 | 0 / 4 | 0 / 4 | 0 / 8 | 0 / 6 | 0 / 6 | 0 / 8 | 0 / 4 | 0 / 7 | 0 / 6 | 0 / 2 | 0 / 6 |
Outcome results
None listed