Study to Assess the Efficacy and Safety of Atuliflapon in Moderate-to-Severe Uncontrolled Asthma (FLASH)

This is an interventional treatment trial for Asthma focused on measuring Efficacy, Safety, Multiple Dose Levels, Adults Read More

Inclusion Criteria

Lead-in PK Cohort:

• 18 to 55 years of age inclusive at the time of signing the informed consent at Visit 1.
• Bodyweight 50 to 120 kg (inclusive) and BMI 18 to 32 kg/m^2 (inclusive) at Visit 1.
• Documented asthma diagnosis ≥12 months prior to Visit 1.
• Able to perform acceptable lung function testing for FEV1 according to American Thoracic Society / European Respiratory Society (ATS/ERS) 2019 acceptability criteria.
• Morning pre- bronchodilator (BD) forced expiratory volume (FEV)1 ≥ 40% predicted at Visit 1 and Visit 2.
• Treated with low dose inhaled corticosteroid plus long-acting β2-agonist (ICS-LABA) or medium-high dose ICS alone or in combination with LABA at a stable dose for at least 3 months prior to Visit 1. Also, treatment with additional asthma controller therapies (eg, LAMA) at a stable dose ≥ 3 months prior to Visit 1 is allowed.
• Participant's influenza/pneumonia vaccination is up to date as per local guidelines prior to Visit 2.

Part 1 and Part 2: Specific Inclusion Criteria for Pre-Screening:

• Participant must be 18 to 80 years of age inclusive at the time of signing the informed consent
• Treated with low dose ICS-LABA or medium-high dose ICS alone or in combination with LABA at a stable dose for at least 3 months prior to Visit 1.
• Documented history of ≥ 1 severe asthma exacerbation within 3 years prior to Visit 0.
• Morning pre-BD FEV1 between ≥ 40% and ≤ 85% predicted at Visit 0.
• Able to perform acceptable lung function testing for FEV1 according to ATS/ERS 2019 acceptability criteria.

Specific Biomarker Inclusion Criteria for Part 1:

- Test for prospective biomarkers will be performed at visit 0 or 1.

General Inclusion Criteria for Part 1 and Part 2:

• Body weight ≥ 40 kg and body mass index (BMI) < 35 kg/m^2.
• Documented history of ≥ 1 severe asthma exacerbation within 3 years prior to Visit 1.
• Able to perform acceptable lung function testing for FEV1 according to ATS/ERS 2019 acceptability criteria.
• Morning pre-BD FEV1 between ≥ 40% and ≤ 85% predicted at Visit 1 and at Visit 3.
• An Asthma Control Questionnaire (ACQ)-6 score ≥ 1.5 at Visit 1 and at Visit 3.
• Participant's influenza/pneumonia vaccination is up to date as per local guidelines prior to Visit 2.

Additional Specific Criteria for Visit 3 (randomisation):

• Pre-bronchodilator FEV1 between ≥ 40% and ≤ 85% predicted.
• ACQ-6 score of ≥ 1.5.
• At least 80% compliance with usual asthma background medication during run-in period (from Visit 2 to Visit 3) based on the daily asthma electronic patient-reported outcome (ePROs).

Exclusion Criteria

• A severe asthma exacerbation within 8 weeks of randomisation.
• A positive test result of an approved antigen test (confirmed by a positive RT-PCR test) or a positive RT-PCR test for SARS-CoV-2, the virus responsible for COVID-19, at Visit 1 or at Visit 2 for the PK Lead-in cohort or at Visit 1 or at Visit 3 for Part 1 and Part 2. Results from the mandatory tests at Visit 2 (PK Lead-in cohort) and Visit 3 (Part 1, Part 2) must not be older than 48 hours and must be available before randomisation.
• Participants with a significant COVID-19 illness within 6 months of enrolment.
• Clinically important pulmonary disease other than asthma.
• Galactose intolerance, Lapp lactase deficiency, or glucose-galactose metabolism.
• Any disorder, including, but not limited to, cardiovascular, gastrointestinal, hepatic, renal, neurological, musculoskeletal, infectious, endocrine, metabolic, haematological, psychiatric, or major physical impairment that is not stable.
• Any clinically significant cardiac disease.
• History of severe renal disease or history of creatinine clearance < 30 mL/min × m2 calculated using Cockcroft-Gault equation.
• Severe hepatic impairment (Child-Pugh class C).
• Previous hepatotoxicity related to zileuton or leukotriene receptor antagonist (LTRAs) (eg montelukast).
• Participants with a recent history of, or who have a positive test for, infective hepatitis or unexplained jaundice, or participants who have been treated for hepatitis B, hepatitis C, or human immunodeficiency virus (HIV).
• Evidence of active or untreated latent tuberculosis (TB).
• Current or history of alcohol or drug abuse (including marijuana).
• Current diagnosis of cancer, not including in-situ or non-melanoma skin cancer or other previous malignancies where curative therapy was completed at least 5 years prior to Visit 1.
• Clinically important ongoing or previous psychiatric disease, especially suicidal behaviour, that in the opinion of the investigator might compromise the safety of the participant in the study.
• Treatment with any serum creatinine-altering drugs within 1 month prior to Visit 1 including but not limited to amphotericin, cimetidine, clofibrate, dronedarone, ketoconazole, probenecid, ranolazine, trimethoprim, aminoglycosides, or cephalosporins.
• Treatment with systemic corticosteroid use within 8 weeks (oral) or 12 weeks (intramuscular) before Visit 1.
• Treatment with marketed biologics including benralizumab, mepolizumab, reslizumab, omalizumab, and dupilumab within 6 months of Visit 0 and within 6 months of Visit 1 or 5 half-lives whichever is longer.
• Treatment with 5-lipoxygenase inhibitors (eg zileuton or other 5-LO inhibiting supplements) within 6 weeks prior to Visit 0 and within 8 weeks prior to Visit 1).Treatment with LTRAs (eg, montelukast) within 2 weeks prior to Visit 0 and within 4 weeks prior to Visit 1)
• Inhaled corticosteroid + fast-acting β2 agonist as a reliever (eg Symbicort or Fostair Maintenance and Reliever Treatment) is not allowed 15 days prior to Visit 1, during screening/run-in and the treatment period and preferably 1 week after the last dose of study intervention.
• Live or attenuated vaccines within 4 weeks of Visit 1.
• Immunoglobulin or blood products within 4 weeks of Visit 1.
• Treatment with Gemfibrozil within 4 weeks of Visit 1.
• Any immunotherapy within 6 months of Visit 1, except for stable maintenance dose allergen-specific immunotherapy started at least 4 weeks prior to Visit 1 and expected to continue through to the end of the follow-up period.
• Potent inducers/inhibitors of cytochrome P450 3A4 within 4 weeks of Visit 1.
• Treatment with simvastatin, lovastatin, and atorvastatin at doses > 40 mg per day within 1 month prior to Visit 1. Treatment with sensitive cytochrome 3A substrates with narrow therapeutic window should be avoided from randomization to study drug.
• For female participants on ethinyl oestradiol containing combined oral contraceptives.
• Concurrent enrolment in another clinical study.
• Participant treated with any investigational drug within 4 months prior to Visit 1.
• Known history of allergy or reaction to any component of the study intervention formulation.
• For female participants only: Currently pregnant or breast-feeding.
• Smokers with smoking history of < 10 pack-years or users of vaping or e-cigarettes, must have stopped at least 6 months prior to Visit 1.
• Involvement in the planning and/or conduct of the study.
• Donation of blood (≥ 450 mL) within 3 months or donation of plasma within 14 days before Visit 1.
• Major surgery within 8 weeks prior to Visit 1, or planned inpatient surgery, major dental procedure or hospitalisation during the screening, treatment or follow-up periods.