Study Evaluating the Effects of ARO-RAGE in Healthy Subjects and Patients with Inflammatory 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 → 17 Apr 2025

Decision date (initial)

2024-07-09

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Arrowhead Pharmaceuticals, Inc.

External identifiers

EU CT number

2023-509654-60-00

EudraCT number

2022-003466-20

WHO UTN

U1111-1274-1543

ClinicalTrials.gov

NCT05276570

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Others, Safety

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

Secondary objectives 2

1. To assess the pulmonary safety of ARO-RAGE in NHVs and patients using spirometry and diffusion capacity measurements and to assess pharmacokinetics (PK) of ARO-RAGE in NHVs and patients.
2. Exploratory: To assess pharmacodynamic (PD) effects of ARO-RAGE in NHVs and patients and to assess the efficacy of ARO-RAGE in patients.

Conditions and MedDRA coding

Inflammatory Lung Disease

Study design 2 periods

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 31

1. 1. Asthma Cohorts C1-C3: Male or nonpregnant, nonlactating female volunteers.
2. 2. Asthma Cohorts C1-C3: Age 18 to 60 years at Screening. Age 19 to 60 years at Screening, where applicable according to local regulation.
3. 3. Asthma Cohorts C1-C3: Physician-diagnosed 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 C1-C3: Asthma severity documented as mild or moderate (as defined by Global Initiative for Asthma [GINA] 2021 guidelines) for at least 6 months prior to Screening. Mild or moderate asthma includes patients well controlled on any of the following treatment regimens: a. As-needed bronchodilator or as-needed low- or medium-dose ICS-LABA; b. Scheduled low- or medium-dose ICS-LABA; c. Scheduled low- or medium-dose ICS; d. Scheduled leukotriene receptor antagonists or chromones. Patients who require high-dose ICS-LABA (with high-dose ICS defined as daily dose >500 mcg fluticasone propionate or equivalent) have severe asthma and thus do not qualify as mild or moderate asthma.
5. 5. Asthma Cohorts C1-C3: Prebronchodilator ppFEV1 ≥70% at Screening, prior to sputum induction.
6. 6. Asthma Cohorts C1-C3: Blood eosinophil count ≥200 cells/μL at Screening.
7. 7. Asthma Cohorts C1-C3: Stable dose of asthma controller medications for at least 4 weeks prior to Screening.
8. 8. Asthma Cohorts C1-C3: If on allergen-specific immunotherapy, patients must be on a stable maintenance dose for at least 3 months prior to first dose.
9. 9. Asthma Cohorts C1-C3: Chest x-ray taken at Screening that, according to the Investigator, excludes significant alternative respiratory disease.
10. 10. Asthma Cohorts C1-C3: Able and willing to provide written informed consent prior to the performance of any study-specific procedures.
11. 11. Asthma Cohorts C1-C3: BMI between 18.0 and 35.0 kg/m2 at Screening.
12. 12. Asthma Cohorts C1-C3: A 12-lead ECG at Screening with no abnormalities that may compromise the participant’s safety in this study.
13. 13. Asthma Cohorts C1-C3: 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.
14. 14. Asthma Cohorts C1-C3: Participants of childbearing potential must agree to use highly effective 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.
15. 15. Asthma Cohorts C1-C3: Able and willing to comply with all study assessments and adhere to the protocol schedule.
16. 16. Asthma Cohorts C1-C3: Able to produce an induced sputum sample at Screening that meets the criteria of acceptable quality.
17. 17. Asthma Cohorts D1 and D3: Male or nonpregnant, nonlactating female volunteers
18. 18. Asthma Cohorts D1 and D3: Age 18 to 65 years at Screening. Age 19 to 65 years at Screening, where applicable according to local regulation.
19. 19. Asthma Cohorts D1 and D3: Physician-diagnosed asthma, which must have been confirmed and documented (based on source verifiable medical record) for at least 12 months prior to Screening.
20. 20. Asthma Cohorts D1 and D3: Documented treatment with a daily maintenance asthma controller regimen that includes inhaled corticosteroid (ICS) for at least 3 months prior to Screening. ICS controller regimen may be either low, medium, or high dose ICS. Subjects who use ICS only on an as-needed basis do not qualify.
21. 21. Asthma Cohorts D1 and D3: Prebronchodilator ppFEV1 ≥40% at Screening.
22. 22. Asthma Cohorts D1 and D3: Stable dose of asthma controller medications for at least 28 days prior to Screening.
23. 23. Asthma Cohorts D1 and D3: FeNO ≥35 ppb at each visit during Screening.
24. 24. Asthma Cohorts D1 and D3: If on allergen-specific immunotherapy, patients must be on a stable maintenance dose for at least 3 months prior to first dose.
25. 25. Asthma Cohorts D1 and D3: Chest x-ray taken at Screening that, according to the Investigator, excludes significant alternative respiratory disease.
26. 26. Asthma Cohorts D1 and D3: Able and willing to provide written informed consent prior to the performance of any study-specific procedures.
27. 27. Asthma Cohorts D1 and D3: BMI between 18.0 and 35.0 kg/m2 at Screening.
28. 28. Asthma Cohorts D1 and D3: A 12-lead ECG at Screening with no abnormalities that may compromise the participant’s safety in this study.
29. 29. Asthma Cohorts D1 and D3: 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.
30. 30. Asthma Cohorts D1 and D3: Participants of childbearing potential must agree to use highly effective 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.
31. 31. Asthma Cohorts D1 and D3: Able and willing to comply with all study assessments and adhere to the protocol schedule.

Exclusion criteria 56

1. 1. Asthma Cohorts C1 to C3: Acute lower respiratory infection or asthma exacerbation within 30 days prior to first dose: Please note that a positive sputum bacterial culture from Study Day 1 does not meet this exclusion criterion.
2. 2. Asthma Cohorts C1 to C3: Acute upper respiratory infection within 7 days prior to first dose: 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 C1 to C3: Positive COVID-19 test during Screening window. Any record of a positive test during the Screening window, whether protocol-mandated antigen test or any NAAT or antigen test obtained outside of this study, serves as a potential exclusion criterion: 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 or #4), 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 (if such results are available), 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 C1 to C3: Chronic or acute infection that is clinically significant or requires treatment with systemic antibiotics, antivirals, antifungals, or antiparasitics within 30 days prior to first dose: Please note that a positive sputum bacterial culture from Study Day 1 does not meet this exclusion criterion.
5. 5. Asthma Cohorts C1 to C3: Use of systemic corticosteroid therapy within 90 days prior to first dose.
6. 6. Asthma Cohorts C1 to C3: Use of immunosuppressive medication (eg, methotrexate, cyclosporine, azathioprine, etc.) within 90 days prior to first dose.
7. 7. Asthma Cohorts C1 to C3: Use of biologic therapies for asthma (ie, anti-IgE, anti-IL5/IL5R, anti-IL4R, anti-TSLP) within 16 weeks prior to first dose.
8. 8. Asthma Cohorts C1 to C3: Prior history of bronchial thermoplasty treatment.
9. 9. Asthma Cohorts C1 to C3: Diagnosis of vocal cord dysfunction, reactive airways dysfunction syndrome, panic attacks with hyperventilation, or other mimics of asthma.
10. 10. Asthma Cohorts C1 to C3: Any concomitant pulmonary disease that, in the opinion of the Investigator and/or Medical Monitor, will interfere with the evaluation of the study drug or interpretation of patient safety or study results (including, but not limited to: COPD, interstitial lung disease, cystic fibrosis, allergic bronchopulmonary aspergillosis, bronchiectasis, tuberculosis, etc). Any concomitant pulmonary disease must be discussed with the Medical Monitor during Screening.
11. 11. Asthma Cohorts C1 to C3: Any history of organ transplant.
12. 12. Asthma Cohorts C1 to C3: Human immunodeficiency virus infection, as shown by presence of anti-HIV antibodies (seropositive).
13. 13. Asthma Cohorts C1 to C3: Seropositive for HBV or HCV (positive result for anti-HCV antibodies must be confirmed with positive HCV RNA test for exclusion).
14. 14. Asthma Cohorts C1 to C3: Uncontrolled hypertension (SBP >150 mmHg or DBP >100 mmHg) at Screening.
15. 15. Asthma Cohorts C1 to C3: 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 should be discussed with the Medical Monitor.
16. 16. Asthma Cohorts C1 to C3: A family history of congenital long QT syndrome or unexplained sudden cardiac death.
17. 17. Asthma Cohorts C1 to C3: Use of medications known to prolong the QTc interval within 30 days prior to first dose.
18. 18. Asthma Cohorts C1 to C3: Use of theophylline within 30 days prior to first dose.
19. 19. Asthma Cohorts C1 to C3: 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.
20. 20. Asthma Cohorts C1 to C3: History of malignancy within the past 2 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 >2-year disease-free interval may be entered following approval by the Medical Monitor.
21. 21. Asthma Cohorts C1 to C3: History of major surgery within 12 weeks prior to first dose.
22. 22. Asthma Cohorts C1 to C3: 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).
23. 23. Asthma Cohorts C1 to C3: Use of illicit drugs (such as cocaine or 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 THC/marijuana is acceptable and inclusion is at the discretion of the PI). Subjects who smoke or vape prescription THC/marijuana should be discussed with the Medical Monitor.
24. 24. Asthma Cohorts C1 to C3: 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.
25. 25. Asthma Cohorts C1 to C3: 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 to 499 mL of whole blood within 30 days or more than 499 mL of whole blood within 56 days prior to first dose.
26. 26. Asthma Cohorts C1 to C3: 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.
27. 27. Asthma Cohorts C1 to C3: Participants who are unable to return for all scheduled study visits.
28. 28. Asthma Cohorts C1 to C3: Any of the following laboratory values at Screening: a. ALT or AST >2× ULN; b. eGFR <60 mL/min/1.73m2
29. 29. Asthma Cohorts C1 to C3: Receipt of any intranasal vaccine (eg, live attenuated influenza vaccine) within 30 days prior to first dose.
30. 30. Asthma Cohorts D1 and D3: Acute lower respiratory infection or asthma exacerbation within 30 days prior to first dose.
31. 31. Asthma Cohorts D1 and D3: Acute upper respiratory infection within 7 days prior to first dose: 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 >35 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 >52 days.
32. 32. Asthma Cohorts D1 and D3: Positive COVID-19 test during Screening window. Any record of a positive test during the Screening window, whether protocol-mandated antigen test or any NAAT or antigen test obtained outside of this study, serves as a potential exclusion criterion: 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 or #4), 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 (if such results are available), whichever is later. If necessary, the Screening period may be extended to >35 days, but in no case will the Screening period be extended to >52 days.
33. 33. Asthma Cohorts D1 and D3: Chronic or acute infection that is clinically significant or requires treatment with systemic antibiotics, antivirals, antifungals, or antiparasitics within 30 days prior to first dose.
34. 34. Asthma Cohorts D1 and D3: Use of systemic corticosteroid therapy within 90 days prior to first dose.
35. 35. Asthma Cohorts D1 and D3: Use of immunosuppressive medication (eg, methotrexate, cyclosporine, azathioprine, etc.) within 90 days prior to first dose.
36. 36. Asthma Cohorts D1 and D3: Use of biologic therapies for asthma (ie, anti-IgE, anti-IL5/IL5R, anti-IL4R, anti-TSLP) within 16 weeks prior to first dose.
37. 37. Asthma Cohorts D1 and D3: Prior history of bronchial thermoplasty treatment.
38. 38. Asthma Cohorts D1 and D3: Diagnosis of vocal cord dysfunction, reactive airways dysfunction syndrome, panic attacks with hyperventilation, or other mimics of asthma.
39. 39. Asthma Cohorts D1 and D3: Any concomitant pulmonary disease that, in the opinion of the Investigator and/or Medical Monitor, will interfere with the evaluation of the study drug or interpretation of patient safety or study results (including, but not limited to: COPD, interstitial lung disease, cystic fibrosis, allergic bronchopulmonary aspergillosis, bronchiectasis, tuberculosis, etc). Any concomitant pulmonary disease must be discussed with the Medical Monitor during Screening.
40. 40. Asthma Cohorts D1 and D3: Any history of organ transplant.
41. 41. Asthma Cohorts D1 and D3: Human immunodeficiency virus infection, as shown by presence of anti-HIV antibodies (seropositive).
42. 42. Asthma Cohorts D1 and D3: Seropositive for HBV or HCV (positive result for anti-HCV antibodies must be confirmed with positive HCV RNA test for exclusion).
43. 43. Asthma Cohorts D1 and D3: Uncontrolled hypertension (SBP >150 mmHg or DBP >100 mmHg) at Screening.
44. 44. Asthma Cohorts D1 and D3: 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 should be discussed with the Medical Monitor. Participants with a history of cardiac rhythm abnormality that has been treated with a device (eg, pacemaker) should be discussed with Medical Monitor.
45. 45. Asthma Cohorts D1 and D3: A family history of congenital long QT syndrome or unexplained sudden cardiac death.
46. 46. Asthma Cohorts D1 and D3: 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.
47. 47. Asthma Cohorts D1 and D3: History of malignancy within the past 2 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 >2-year disease-free interval may be entered following approval by the Medical Monitor.
48. 48. Asthma Cohorts D1 and D3: History of major surgery within 12 weeks prior to first dose.
49. 49. Asthma Cohorts D1 and D3: 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).
50. 50. Asthma Cohorts D1 and D3: Use of illicit drugs (such as cocaine or 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 THC/marijuana is acceptable and inclusion is at the discretion of the PI). Subjects who smoke or vape prescription THC/marijuana should be discussed with the Medical Monitor.
51. 51. Asthma Cohorts D1 and D3: 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.
52. 52. Asthma Cohorts D1 and D3: 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 to 499 mL of whole blood within 30 days or more than 499 mL of whole blood within 56 days prior to first dose.
53. 53. Asthma Cohorts D1 and D3: 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.
54. 54. Asthma Cohorts D1 and D3: Participants who are unable to return for all scheduled study visits.
55. 55. Asthma Cohorts D1 and D3: Any of the following laboratory values at Screening: a. ALT or AST >2× ULN; b. eGFR <60 mL/min/1.73m2.
56. 56. Asthma Cohorts D1 and D3: Receipt of any intranasal vaccine (eg, live attenuated influenza vaccine) within 30 days prior to first dose.

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 4

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. Change from baseline over time through EOS in diffusing capacity for carbon monoxide (DLCO) as a safety assessment
4. 4. Plasma PK parameters of ARO-RAGE after each dose of study drug

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 · 7 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 29 files

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

Application history

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