A Phase 2a, Randomised, Double-Blind, Placebo Controlled Study to Assess Efficacy and Safety of Atuliflapon Given Orally Once Daily for Twelve Weeks in Adults with Moderate-to-Severe Uncontrolled Asthma

Part 1 and Part 2 protocol 5.1.2.

General Inclusion Criteria for Part 1 and Part 2
10. Capable of giving signed informed consent
11. Provision of signed and dated written Optional Genetic Research Information
informed
consent prior to collection of samples for optional genetic research that
supports Genomic
Initiative.
12. Participant is willing and able to follow study procedures and restrictions.
13. Participant must be 18 to 80 years of age inclusive, at the time of signing
the ICF.
14. Body weight 50 - 120 kg and body mass index (BMI) 18 -35 kg/m2.
15. Documented physician-diagnosed asthma >= 12 months prior to Visit 1.
16. Able to perform acceptable lung function testing for FEV1 according to
ATS/ERS 2019
acceptability criteria.
17. Documented evidence of asthma as demonstrated by either:
* Post-BD reversibility of FEV1 >= 12% and >= 200 within 5 years prior to Visit
1, or at Visit 1, or
* PEF average daily variability > 10% over a 2-week period within 5 years prior
to Visit 1, or
* Variability of FEV1 > 12% and 200 mL between any two clinical visits within 5
years prior to Visit 1, or
* Positive methacholine challenge test within the 5 years prior to Visit 1. A
positive result is defined as a PC20 <= 8 mg/mL.
18. Morning pre-BD FEV1 between >= 40% and <= 80% predicted at Visit 1.
19. Documented history of >= 1 severe asthma exacerbation within 3 years prior
to Visit 1.
20. Treated with low dose ICS-LABA or medium-high dose ICS (as per GINA 2021 ICS
equivalence table - Appendix C) alone or in combination with LABA at a stable
dose for
at least 3 months prior to Visit 1. (The ICS can be contained within an
ICS-LABA fixed
dose combination product).
* Treatment with additional asthma controller therapies (eg, LAMA) at a stable
dose
>= 3 months prior to Visit 1 is allowed. (Treatment with LTRAs or 5-LO
inhibitors is not allowed.
21. An ACQ-6 score >= 1.5 at Visit 1 and at Visit 3.
22. Able and willing to comply with the requirements of the protocol including
ability to
read, write, be fluent in the translated language of all participant facing
questionnaires
used at site, and use electronic devices, eg, eCOA device and spirometry.
28. At least 80% compliance with usual asthma background medication during
run-in period
(from Visit 2 to Visit 3) based on the daily asthma ePROs.
29. Minimum 80% compliance with daily eCOA assessments.
24. For female participants, a negative serum pregnancy test.
25. Contraceptive use by female participants should be consistent with local
regulations
regarding the methods of contraception for those participating in clinical
studies. There
are no restrictions on male participants or their female partners.

Protocol 5.2.1. 1. A severe asthma exacerbation within 8 weeks of
randomisation. 2. A positive nucleic acid test (eg RT-PCR) at Visit 1 or at
Visit 3 for SARS-CoV-2, the virus responsible for COVID-19. 3. Participants
with a significant COVID-19 illness within 6 months of enrolment: *
Participants with a diagnosis of COVID-19 pneumonia based on radiological
assessment. * Participants with a diagnosis of COVID-19 requiring
hospitalisation and/or oxygen supplementation therapy. 4. Clinically important
pulmonary disease other than asthma eg, active lung infection, COPD,
bronchiectasis, pulmonary fibrosis, cystic fibrosis, hypoventilation syndrome
associated with obesity, lung cancer, history or planned lung lobectomy,
alpha-1 anti-trypsin deficiency, primary ciliary dyskinesia, Churg-Strauss
syndrome, allergic bronchopulmonary aspergillosis and hyper-eosinophilic
syndrome. 6. 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 in the opinion of the investigator and could: * Affect the
safety of the participant throughout the study. * Influence the findings of the
study or the interpretation. * Impede the participant's ability to complete the
entire duration of study. 7. Any clinically significant cardiac disease: *
Acute coronary syndrome (acute myocardial infarction, unstable angina),
coronary intervention with percutaneous coronary intervention/coronary artery
bypass surgery or stroke within 6 months. * Heart failure NYHA II-IV. *
Untreated high degree atrioventricular-block (>= 3:1 conduction rate/Grade III
block)/ significant sinus node dysfunction/pause or therapy requiring
tachyarrhythmia. * History or family history of long QT-syndrome. * History of
QT prolongation associated with other medications that required discontinuation
of that medication. * Hypertrophic cardiomyopathy or clinically significant
valvular heart disease. * Stroke within 3 months of Visit 1. 8. History of
severe renal disease (CKD stage 4 or 5) or history of creatinine clearance < 30
mL/min × m2 calculated using Cockcroft-Gault equation. 9. Severe hepatic
impairment (Child-Pugh class C). 10. Previous hepatotoxicity related to
zileuton or LTRAs (eg montelukast) 11. 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 HIV. For
the hepatitis B testing (HbsAg, anti-HBs, and anti-HBc), any of the following
would exclude the participant from the study: * Participants positive for
HbsAg. * Participants positive for anti-HBc. 12. Evidence of active or
untreated latent TB: * Positive IGRA, or repeated indeterminate IGRAs, no
evidence of active TB and untreated for LTBI, unable to be treated for, or
declines treatment of LTBI. * Participants newly diagnosed with LTBI at Visit 1
could be considered for rescreening if they complete a full course of treatment
for LTBI in accordance with recommended treatment guidelines prior to
rescreening. In this situation, repeat IGRA test is not required after
completion of treatment for LTBI. * Participants with an indeterminate IGRA
should undergo a repeat test and if still indeterminate may be enrolled only
after being treated for LTBI. 13. Any other clinically relevant abnormal
findings on physical examination or laboratory testing including haematology,
coagulation, serum chemistry, urinalysis, or ECG between Visit 1 and Visit 3
(randomisation), that in the opinion of the investigator or medical monitor
might compromise the safety of the participant in the study or interfere with
evaluation of the study intervention. Abnormal findings include, but are not
limited to: * ALT or AST >= 2 × ULN. * TBL >= 1.5 × ULN (unless due to Gilbert*s
disease). * Evidence of chronic liver disease. * Abnormal vital signs, after 5
minutes of supine or sitting rest (confirmed by one controlled measurement),
defined as any of the following: o SBP < 80 mmHg or >= 150 mmHg. o DBP < 50 mmHg
or >= 95 mmHg. o Pulse < 45 or > 100 beats per minute. * Signs of pulmonary
oedema or volume overload. * Any clinically significant rhythm, conduction, or
morphology abnormalities in the ECG including but not limited to QTcF > 450 ms.
34. 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 Please refer
to the protocol for the full list of exclusion criteria.