A Phase 1/2a Study Evaluating the Effects of ARO-MUC5AC Inhalation Solution in Healthy Subjects and Patients with Muco-Obstructive Lung Disease

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Arrowhead Pharmaceuticals Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Respiratory Tract Diseases [C08]

Trial duration

21 Jun 2023 → 12 Nov 2024

Decision date (initial)

2024-08-04

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Arrowhead Pharmaceuticals, Inc.

External identifiers

EU CT number

2024-514809-67-00

EudraCT number

2022-003467-21

ClinicalTrials.gov

NCT05292950

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Others

To assess the safety and tolerability of ARO-MUC5AC in normal healthy volunteers (NHVs) and patients

Secondary objectives 1

1. To assess the pulmonary safety of ARO-MUC5AC in NHVs and patients using spirometry and to assess the pharmacokinetics (PK) of ARO-MUC5AC in NHVs and patients. Exploratory: To assess the pharmacodynamics (PD) of ARO-MUC5AC in NHVs and patients and to assess the efficacy of ARO-MUC5AC in patients.

Conditions and MedDRA coding

Asthma and Chronic obstructive pulmonary disease

Study design 2 periods

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 28

1. 1. Asthma Cohorts: Male or nonpregnant, nonlactating female volunteers
2. 2. Asthma Cohorts: Age 18 to 65 years at Screening. Age 19 to 65 years at Screening, where applicable according to local regulation
3. 3. Asthma Cohorts: Diagnosis of asthma which must have been confirmed and documented (based on source verifiable medical record) for at least 12 months prior to Screening
4. 4. Asthma Cohorts: Documented treatment with a total daily dose of inhaled corticosteroids ≥500 mcg fluticasone propionate dry powder formulation (or equipotent inhaled corticosteroid) for at least 3 months prior to Screening
5. 5. Asthma Cohorts: Documented treatment with at least 1 additional maintenance asthma controller medication (eg, a long-acting β2-agonist [LABA], a leukotriene receptor antagonist [LTRA], or a long-acting muscarinic antagonist [LAMA]) for at least 3 months prior to Screening
6. 6. Asthma Cohorts: Prebronchodilator ppFEV1 between 40% and 80% inclusive at Screening, prior to sputum induction
7. 7. Asthma Cohorts: Stable dose of asthma controller medications for at least 28 days prior to Screening
8. 8. Asthma Cohorts: If on allergen-specific immunotherapy, patients must be on a stable maintenance dose for at least 90 days prior to first dose
9. 9. Asthma Cohorts: If on biologic therapy for asthma (eg, anti-IgE, anti-IL5/IL5R, anti-IL4R, or anti-thymic stromal lymphopoietin [TSLP]), patients must be on a stable maintenance dose for at least 16 weeks prior to first dose
10. 10. Asthma Cohorts: Chest x-ray taken at Screening that, according to the Investigator, excludes significant alternative respiratory disease
11. 11. Asthma Cohorts: Able and willing to provide written informed consent prior to the performance of any study-specific procedures
12. 12. Asthma Cohorts: BMI between 18.0 and 35.0 kg/m2 at Screening
13. 13. Asthma Cohorts: A 12-lead ECG at Screening with no abnormalities that may compromise participant’s safety in this study
14. 14. Asthma Cohorts: Nonsmoker (defined as someone who has not smoked a cigarette for at least 6 months) with current nonsmoking status confirmed by urine cotinine at Screening AND previous smoking history prior to 6 months must be <10 pack-years. Subjects may be on nicotine replacement (patch or gum). Nicotine e-cigarettes (vapor) are not permitted. A positive urine cotinine result due to nicotine replacement is acceptable for enrollment at the discretion of the PI.
15. 15. COPD Cohorts: Male or nonpregnant, nonlactating female volunteers
16. 16. COPD Cohorts: Age 40 to 70 years at Screening
17. 17. COPD Cohorts: Diagnosis of COPD for at least 12 months prior to Screening, based on source verifiable medical record, confirmed with a post-bronchodilator ratio of FEV1 to FVC < 0.7 at Screening
18. 18. COPD Cohorts: History of chronic bronchitis (defined as both cough and phlegm “most days a week” or “several days a week”) elicited on the SGRQ-C at Screening
19. 19. COPD Cohorts: Current smoker or ex-smoker (meaning >1 year of smoking cessation) with a smoking history of ≥ 10 pack-years
20. 20. COPD Cohorts: Post-bronchodilator ppFEV1 between 40% and 80% inclusive at Screening, prior to sputum induction
21. 21. COPD Cohorts: Subjects treated with either single, double, or triple therapy for COPD, as described below: a) Single therapy consisting of: long-acting beta agonist (LABA) or long-acting muscarinic antagonist (LAMA); b) Double therapy consisting of: LABA + LAMA, or LABA + inhaled corticosteroid (ICS), or LAMA + ICS; c) Triple therapy consisting of: LABA + LAMA + ICS; and d) Please note that additional use of other agents, such as azithromycin or roflumilast, will not exclude the subject
22. 22. COPD Cohorts: All treatments for COPD have been stable for at least 1 month prior to Screening (meaning no new medications or changes in dose quantity or dose frequency) and subject is willing to continue this treatment regimen without change for study duration.
23. 23. COPD Cohorts: Able and willing to provide written informed consent prior to the performance of any study-specific procedures
24. 24. COPD Cohorts: BMI between 18.0 and 35.0 kg/m2 at Screening
25. 25. COPD Cohorts: A 12-lead ECG at Screening with no abnormalities that may compromise participant’s safety in this study
26. 26. COPD Cohorts: Participants of childbearing potential must agree to use a highly effective form of contraception in addition to a condom, during the study and for at least 90 days following the end of the study or last dose of study drug, whichever is later. Subjects must not donate sperm or eggs during the study and for at least 90 days following the end of the study or last dose of study drug, whichever is later
27. 27. COPD Cohorts: Able and willing to comply with all study assessments and adhere to the protocol schedule
28. 28. COPD Cohorts: Able to produce an induced sputum sample at Screening that meets criteria of acceptable quality

Exclusion criteria 52

1. 1. Asthma Cohorts: Acute lower respiratory infection or asthma exacerbation within 30 days prior to first dose
2. 2. Asthma Cohorts: Acute upper respiratory infection within 7 days prior to first dose: a) In the case of an upper respiratory infection within 7 days of the first dose, the PI may elect to extend the Screening period to >28 days such that the first dose is given >7 days following clinical resolution of the infection. In no case will the Screening period be extended to >45 days
3. 3. Asthma Cohorts: Positive COVID-19 test during Screening window. Any record of positive test during the Screening window, whether a protocol-mandated antigen test or any NAAT or antigen test obtained outside of this study, serves as a potential exclusion criterion: a) In the event of a positive COVID-19 test during Screening, and if the PI deems the subject clinically appropriate to proceed to study drug dosing and no other exclusion criteria are met (eg, #1), the PI may elect to proceed to randomize the subject. In such a case, the first dose may not be given until >7 days after both clinical resolution of infection and conversion of antigen test from positive to negative, whichever is later. If necessary, the Screening period may be extended to >28 days, but in no case will the Screening period be extended to >45 days.
4. 4. Asthma Cohorts: Prior history of bronchial thermoplasty treatment
5. 5. Asthma Cohorts: Diagnosis of vocal cord dysfunction, reactive airways dysfunction syndrome, panic attacks with hyperventilation, or other mimics of asthma
6. 6. Asthma Cohorts: Any concomitant pulmonary disease that, in the opinion of the Investigator, will interfere with the evaluation of the study drug or interpretation of patient safety or study results (including, but not limited to: interstitial lung disease, cystic fibrosis, lung cancer, tuberculosis, and bronchiectasis). Note that patients with only radiographic findings of bronchiectasis may be included
7. 7. Asthma Cohorts: Known unresolved parasitic infection or prior parasitic infection that has required antiparasitic therapy within 30 days prior to first dose
8. 8. Asthma Cohorts: Any history of organ transplant
9. 9. Asthma Cohorts: HIV infection, as shown by presence of anti-HIV antibodies (seropositive)
10. 10. Asthma Cohorts: Seropositive for HBV or HCV (positive result for anti-HCV antibody must be confirmed with positive HCV RNA test for exclusion)
11. 11. Asthma Cohorts: Uncontrolled hypertension (SBP >150 mmHg or DBP >100 mmHg) at Screening
12. 12. Asthma Cohorts: A history of Torsades de Pointes, ventricular rhythm disturbances (eg, ventricular tachycardia or fibrillation), pathologic sinus bradycardia (<50 bpm with symptoms), heart block (excluding first-degree block, being PR prolongation only), congenital long QT syndrome, new ST segment elevation or depression, or new Q wave on ECG. Participants with a history of atrial arrhythmias may be enrolled if the PI judges the safety risk to be low. Participants with a history of cardiac rhythm abnormality that has been treated with a device (eg, pacemaker) may be enrolled if the PI judges the safety risk to be low
13. 13. Asthma Cohorts: A family history of congenital long QT syndrome or unexplained sudden cardiac death
14. 14. Asthma Cohorts: Use of medications known to prolong the QTc interval within 30 days prior to first dose (eg, azithromycin)
15. 15. Asthma Cohorts: Use of theophylline within 30 days prior to first dose
16. 16. Asthma Cohorts: Symptomatic heart failure (per NYHA guidelines), unstable angina, myocardial infarction, severe cardiovascular disease (ejection fraction <20%), TIA, or CVA within 24 weeks prior to first dose
17. 17. Asthma Cohorts: History of malignancy within the past 5 years except for adequately treated basal cell carcinoma, squamous cell skin cancer, superficial bladder tumors, or in situ cervical cancer. Participants with other curatively treated malignancies who have no evidence of metastatic disease and >5-year disease-free interval may be enrolled if the PI judges the risk of recurrence to be low
18. 18. Asthma Cohorts: History of major surgery within 12 weeks prior to first dose
19. 19. Asthma Cohorts: Unwilling to limit alcohol consumption to within moderate limits for the duration of the study, as follows: not more than 14 units per week for women and 21 units per week for men (1 unit=150 mL of wine, 360 mL of beer, or 45 mL of 40% alcohol)
20. 20. Asthma Cohorts: Use of illicit drugs (such as cocaine, PCP) within 1 year prior to Screening or positive urine drug screen at Screening (a urine drug screen deemed positive due to prescription medications or for benzodiazepines, opioids, or marijuana is acceptable and inclusion is at the discretion of the PI). Subjects who smoke or vape prescription THC/marijuana may be enrolled if the PI judges the safety risk to be low
21. 21. Asthma Cohorts: Use of an investigational agent or device within 30 days or 5 half-lives (whichever is longer) prior to first dose or current participation in an investigational study
22. 22. Asthma Cohorts: Donation or loss of whole blood (excluding the volume of blood that will be drawn during the Screening procedures of this study) prior to first dose as follows: 50 mL to 499 mL of whole blood within 30 days, or more than 499 mL of whole blood within 56 days prior to first dose
23. 23. Asthma Cohorts: Any finding at Screening or any concomitant medical or psychiatric condition or social situation that would make it difficult to comply with protocol requirements or to complete the study, or would put the participant at additional safety risk
24. 24. Asthma Cohorts: Participants who are unable to return for all scheduled study visits
25. 25. Asthma Cohorts: Any of the following laboratory values at Screening: a) ALT or AST >2× ULN; b) eGFR <60 mL/min/1.73m2
26. 26. Asthma Cohorts: Known allergy or possible allergy to either ARO-MUC5AC or to its excipients
27. 27. COPD Cohorts: Acute lower respiratory infection or COPD exacerbation within 30 days prior to first dose
28. 28. COPD Cohorts: Acute upper respiratory infection within 7 days prior to first dose: a) In the case of an upper respiratory infection within 7 days of the first dose, the PI may elect to extend the Screening period to >28 days such that the first dose is given >7 days following clinical resolution of the infection. In no case will the Screening period be extended to >45 days
29. 29. COPD Cohorts: Positive COVID-19 test during Screening window. Any record of positive test during the Screening window, whether a protocol-mandated antigen test or any NAAT or antigen test obtained outside of this study, serves as a potential exclusion criterion: a) In the event of a positive COVID-19 test during Screening, and if the PI deems the subject clinically appropriate to proceed to study drug dosing and no other exclusion criteria are met (eg, #1), the PI may elect to proceed to randomize the subject. In such a case, the first dose may not be given until >7 days after both clinical resolution of infection and conversion of antigen test from positive to negative, whichever is later. If necessary, the Screening period may be extended to >28 days, but in no case will the Screening period be extended to >45 days
30. 30. COPD Cohorts: Any significant, concomitant pulmonary disease that, in the opinion of the Investigator, will interfere with the evaluation of the study drug or interpretation of patient safety or study results (including, but not limited to: interstitial lung disease, cystic fibrosis, lung cancer, and tuberculosis)
31. 31. COPD Cohorts: History of lung volume reduction surgery (either surgical or bronchoscopic) or pneumonectomy
32. 32. COPD Cohorts: Need for chronic (>15 hours/day) oxygen support at Screening
33. 33. COPD Cohorts: Prior history of bronchial thermoplasty treatment
34. 34. COPD Cohorts: Participation in the acute phase of pulmonary rehabilitation (ie started < 4 weeks prior to Screening)
35. 35. COPD Cohorts: Known unresolved parasitic infection or prior parasitic infection that has required antiparasitic therapy within 30 days prior to first dose
36. 36. COPD Cohorts: Any history of organ transplant or active listing for a solid organ transplant at Screening
37. 37. COPD Cohorts: HIV infection, as shown by presence of anti-HIV antibodies (seropositive)
38. 38. COPD Cohorts: Seropositive for HBV or HCV (positive result for anti-HCV antibody must be confirmed with positive HCV RNA test for exclusion)
39. 39. COPD Cohorts: Uncontrolled hypertension (SBP >150 mmHg or DBP >100 mmHg) at Screening
40. 40. COPD Cohorts: A history of Torsades de Pointes, ventricular rhythm disturbances (eg, ventricular tachycardia or fibrillation), pathologic sinus bradycardia (<50 bpm with symptoms), heart block (excluding first-degree block, being PR prolongation only), congenital long QT syndrome, new ST segment elevation or depression, or new Q wave on ECG. Participants with a history of atrial arrhythmias may be enrolled if the PI judges the safety risk to be low. Participants with a history of cardiac rhythm abnormality that has been treated with a device (eg, pacemaker) may be enrolled if the PI judges the safety risk to be low
41. 41. COPD Cohorts: A family history of congenital long QT syndrome or unexplained sudden cardiac death
42. 42. COPD Cohorts: Symptomatic heart failure (per NYHA guidelines), unstable angina, myocardial infarction, severe cardiovascular disease (ejection fraction <20%), TIA, or CVA within 24 weeks prior to first dose
43. 43. COPD Cohorts: History of malignancy within the past 5 years except for adequately treated basal cell carcinoma, squamous cell skin cancer, superficial bladder tumors, or in situ cervical cancer. Participants with other curatively treated malignancies who have no evidence of metastatic disease and >5-year disease-free interval may be enrolled if the PI judges the risk of recurrence to be low
44. 44. COPD Cohorts: History of major surgery within 12 weeks prior to first dose
45. 45. COPD Cohorts: Unwilling to limit alcohol consumption to within moderate limits for the duration of the study, as follows: not more than 14 units per week for women and 21 units per week for men (1 unit=150 mL of wine, 360 mL of beer, or 45 mL of 40% alcohol)
46. 46. COPD Cohorts: Use of illicit drugs (such as cocaine, PCP) within 1 year prior to Screening or positive urine drug screen at Screening (a urine drug screen deemed positive due to prescription medications or for benzodiazepines, opioids, or marijuana is acceptable and inclusion is at the discretion of the PI). Subjects who smoke or vape prescription THC/marijuana may be enrolled if the PI judges the safety risk to be low
47. 47. COPD Cohorts: Use of an investigational agent or device within 30 days or 5 half-lives (whichever is longer) prior to first dose or current participation in an investigational study
48. 48. COPD Cohorts: Donation or loss of whole blood (excluding the volume of blood that will be drawn during the Screening procedures of this study) prior to first dose as follows: 50 mL to 499 mL of whole blood within 30 days, or more than 499 mL of whole blood within 56 days prior to first dose
49. 49. COPD Cohorts: Any finding at Screening or any concomitant medical or psychiatric condition or social situation that would make it difficult to comply with protocol requirements or to complete the study, or would put the participant at additional safety risk
50. 50. COPD Cohorts: Participants who are unable to return for all scheduled study visits
51. 51. COPD Cohorts: Any of the following laboratory values at Screening: a) ALT or AST >2× ULN; b) eGFR <50 mL/min/1.73m2
52. 52. COPD Cohorts: Known allergy or possible allergy to either ARO-MUC5AC or to its excipients

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The incidence and frequency of treatment-emergent adverse events (TEAEs) over time through end of study (EOS)

Secondary endpoints 3

1. 1. Change from baseline over time through EOS in forced expiratory volume (FEV1) as a safety assessment
2. 2. Change from baseline over time through EOS in forced vital capacity (FVC) as a safety assessment
3. 3. Plasma PK parameters of ARO-MUC5AC

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Arrowhead Pharmaceuticals Inc.

Sponsor organisation

Arrowhead Pharmaceuticals Inc.

Address

177 East Colorado Boulevard Suite 700

City

Pasadena

Postcode

91105-1976

Country

United States

Scientific contact point

Organisation

Arrowhead Pharmaceuticals Inc.

Contact name

Clinical Trial Team

Public contact point

Organisation

Arrowhead Pharmaceuticals Inc.

Contact name

Clinical Trial Team

Third parties 6

Locations

2 EU/EEA countries · 4 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 33 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

3 submissions — initial application plus substantial / non-substantial modifications