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

Inclusion Criteria

Lead-in PK Cohort:

• 18 to 55 years of age inclusive at the time of signing the informed consent at screening Visit 1.

• Bodyweight 50 to 120 kg (inclusive) and BMI 18 to 32 kg/m^2 (inclusive) at screening Visit 1.

• Documented asthma diagnosis ≥12 months prior to screening 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 screening 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 screening Visit 1. Also, treatment with additional asthma controller therapies (eg, LAMA) at a stable dose ≥ 3 months prior to screening Visit 1 is allowed.

• Participant's influenza/pneumonia vaccination is up to date as per local guidelines prior to Visit 2.

General Inclusion Criteria for Part 1:

• Body weight ≥ 40 kg and body mass index (BMI) < 35 kg/m^2.

• Documented history of ≥ 1 severe asthma exacerbation within 1 year prior to screening 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 screening Visit 1 and Visit

• An Asthma Control Questionnaire (ACQ)-6 score ≥ 1.5 at screening Visit 1 and at Visit 3.

Exclusion Criteria

• A severe asthma exacerbation within 8 weeks of screening (visit 1) or within 12 weeks of randomisation (Visit 3).

• 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 screening Visit 1 or at Visit 2 for the PK Lead-in cohort. For Part 1 the testing will be done at Visit 3. Results from the mandatory tests at Visit 2 (PK Lead-in cohort) and Visit 3 (Part 1) 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.

• 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 tuberculosis (TB), either treated or untreated or latent 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 screening 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 screening 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 screening (Visit 1) or 12 weeks (oral) or 16 weeks (IM) before randomization (Visit 3).

• Treatment with marketed biologics including benralizumab, mepolizumab, reslizumab, omalizumab, and dupilumab within 6 months of screening 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 screening 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 screening Visit 1, during screening (Visit 1)/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 screening Visit 1.

• Immunoglobulin or blood products within 4 weeks of screening Visit 1.

• Treatment with Gemfibrozil within 4 weeks of screening Visit 1.

• Any immunotherapy within 6 months of screening Visit 1, except for stable maintenance dose allergen-specific immunotherapy started at least 4 weeks prior to screening 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 screening Visit

• Treatment with simvastatin, lovastatin, and atorvastatin at doses > 40 mg per day within 1 month prior to screening 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, the ethinyl oestradiol doses exceeding 20 mcg per day.

• Concurrent enrolment in another clinical study.

• Previous participation in the current clinical study.

• Participant treated with any investigational drug within 4 months prior to screening Visit 1.

• Known history of allergy or reaction to any component of the study intervention formulation.

• Smokers with smoking history of < 10 pack-years or users of vaping or e-cigarettes, must have stopped at least 6 months prior to screening 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 screening Visit 1.

• Major surgery within 8 weeks prior to screening Visit 1, or planned inpatient surgery, major dental procedure or hospitalisation during the screening (Visit 1), treatment or follow-up periods.