Need for evaluation of emerging pre-clinical toxicology findings

This study is intended to evaluate the systemic pharmacokinetic (PK) characteristics and the safety of AZD8154 following administration of the Monodose DPI formulation compared with the administration of the nebuliser suspension.

This study will be a randomised, open-label, 3-period, single-dose, single-centre, crossover study in healthy males and healthy females of non-childbearing potential.

The study will comprise:

• A Screening Period of maximum 28 days;
• Three treatment periods during which subjects will be resident at the Clinical Unit from the morning of the day before dosing with AZD8154 or placebo (Day 1) until 72 hours following dosing for collection of PK samples; discharged on the morning of Day 4 of each treatment period;
• A Follow up Visit within 6 ± 1 days after last dose administration of investigational medicinal products (IMPs) (i.e., AZD8154 or placebo).

A total of 15 healthy subjects will be randomised in this study to ensure that at least 12 subjects are evaluable.

Each subject will be involved in the study for approximately 9 weeks.

Inclusion Criteria:

1. Provision of signed and dated, written informed consent prior to any study specific procedures.

2. Healthy male and/or healthy female subjects of non childbearing potential aged 18 to 55 years (inclusive at the Screening Visit) with suitable veins for cannulation or repeated venipuncture.

3. Females must have a negative pregnancy test at Screening Visit and on admission to the Clinical Unit, must not be lactating and must be of non childbearing potential, confirmed at Screening by fulfilling 1 of the following criteria (i) Females are considered postmenopausal if they have had amenorrhea for at least 12 months without an alternative medical cause. The following age specific requirements apply: Women under 50 years old are considered postmenopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments and with luteinising hormone and follicle stimulating hormone levels are in the postmenopausal range.

   Women over 50 years of age would be considered postmenopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments.

   (ii) Documentation of irreversible surgical sterilization by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation.

4. Have a body mass index (BMI) between 18 and 30 kg/m2 inclusive and weigh at least 60 kg and no more than 100 kg inclusive.

5. Subject has a forced expiratory volume in 1 second ≥ 80% of the predicted value regarding age, height, gender and ethnicity at the Screening Visit.

Exclusion Criteria:

1. History of any clinically significant disease or disorder which, in the opinion of the Principal Investigator, may either put the volunteer at risk because of participation in the study, or influence the results or the volunteer's ability to participate in the study.

2. Subject is immune compromised.

3. History of diabetes, impaired fasting glucose, metabolic syndrome, hypertriglyceridemia or familial lipid disorders.

4. Current or previous history of malignancy of any kind except cutaneous basal or squamous cell carcinoma successful treated with therapy.

5. History of any respiratory disorders such as asthma, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis (IPF), or infantile bronchiolitis.

6. Subject with latent or active tuberculosis, as confirmed by a positive QuantiFERON® TB Gold test or as judged by the Investigator at the Screening Visit.

7. History or presence of gastrointestinal, hepatic or renal disease or any other condition known to interfere with absorption, distribution, metabolism or excretion of drugs, or bowel disorders not otherwise specified.

8. Any clinically important illness, medical/surgical procedure or trauma within 4 weeks of the first administration of the IMP.

9. Any clinically important abnormalities in clinical chemistry, haematology or urinalysis results, defined as the following:

   (i) Alanine aminotransferase and/or aspartate aminotransferase > 1.5 x the upper limit of the normal (ULN) laboratory range.

   (ii) Bilirubin > 1.5 times the ULN laboratory range. (iii) Absolute neutrophil count < lower limit of normal (LLN). (iv) Absolute lymphocyte count < LLN.

10. Any positive result at the Screening Visit for serum hepatitis B surface antigen OR hepatitis B core antibodies, hepatitis C virus antibody (anti HCV) and human immunodeficiency virus.

11. Abnormal vital signs, after 5 minutes supine rest, defined as any of the following:

    (i) Systolic blood pressure (BP) < 90 mmHg or > 140 mmHg. (ii) Diastolic BP < 50 mmHg or > 90 mmHg. (iii) Pulse < 50 or > 90 beats per minute (bpm).

12. Any clinically important abnormalities in rhythm, conduction or morphology of the 12 lead safety ECG as judged by the Investigator.

    (i) Prolonged QT interval corrected for heart rate using Fridericia's formula (QTcF) > 450 ms or shortened QTcF < 340 ms or family history of long QT syndrome.

    (ii) PR (PQ) interval shortening < 120 ms (PR > 110 ms but < 120 ms is acceptable if there is no evidence of ventricular pre excitation).

    (iii) PR (PQ) interval prolongation (> 220 ms) intermittent second (Wenckebach block while asleep is not exclusive) or third degree atrioventricular (AV) block, or AV dissociation.

    (iv) Persistent or intermittent complete bundle branch block (BBB), incomplete bundle branch block (IBBB), or intraventricular conduction delay (IVCD) with QRS > 110 ms. Subjects with QRS > 110 ms but < 115 ms are acceptable if there is no evidence of e.g., ventricular hypertrophy or pre excitation.

13. Previous use of a mechanistic target of rapamycin (mTOR) antagonist (e.g., rapamycin, everolimus) or PI3K inhibitor (selective or non selective PI3K inhibitors).

14. Known or suspected history of drug abuse as judged by the Investigator.

15. Current smokers or those who have smoked or used nicotine products (including e cigarettes) within the previous 3 months.

16. History of alcohol abuse or excessive intake of alcohol as judged by the Investigator.

17. Positive screen for drugs of abuse or cotinine (nicotine) at the Screening Visit or admission to the Clinical Unit or positive screen for alcohol on admission to the Clinical Unit before the first administration of the IMP.

18. History of severe allergy/hypersensitivity or ongoing clinically important allergy/hypersensitivity, as judged by the Investigator or history of hypersensitivity to drugs with a similar chemical structure or class to AZD8154.

19. Receipt of live attenuated vaccines 2 months before first administration of the IMP and 3 months after the last IMP administration.

20. Excessive intake of caffeine-containing drinks or food (e.g., coffee, tea, chocolate) as judged by the Investigator.

21. Use of drugs with cytochrome P450 (CYP) 3A enzyme inducing or inhibition properties within 3 weeks before first administration of IMP.

22. Use of any prescribed or nonprescribed medication including antacids, analgesics (other than paracetamol/acetaminophen), herbal remedies, megadose vitamins (intake of 20 to 600 times the recommended daily dose) and minerals during the 2 weeks before the first administration of the IMP or longer if the medication has a long half life.

23. Plasma donation within 1 month of the Screening Visit or any blood donation/blood loss > 500 mL during the 2 months before the Screening Visit.

24. Has received another new chemical entity (defined as a compound which has not been approved for marketing) within 3 months of the first administration the IMP in this study. The period of exclusion begins 3 months after the final dose or 1 month after the last visit whichever is the longest.

25. Involvement of any Astra Zeneca or study site employee or their close relatives.

26. Judgement by the Investigator that the subject should not participate in the study if they have any ongoing or recent (i.e., during the Screening Period) minor medical complaints that may interfere with the interpretation of study data or are considered unlikely to comply with study procedures, restrictions and requirements.

27. Subjects who cannot communicate reliably with the Investigator and/or is not able to read speak and understand the German language.

28. Vulnerable subjects, e.g., kept in detention, protected adults under guardianship, trusteeship or committed to an institution by governmental or juridical order.

29. Subject has a positive test result for SARS-CoV-2 RT-PCR before randomisation.

30. Subject has clinical signs and symptoms consistent with COVID-19, e.g., fever, dry cough, dyspnoea, sore throat, fatigue, or confirmed infection by appropriate laboratory test within the last 4 weeks prior to screening or on first admission.

31. History of severe COVID-19 (hospitalisation, extracorporeal membrane oxygenation, mechanically ventilated).

32. Subjects who are regularly exposed to COVID-19 as part of their daily life (e.g., health care professionals working in COVID-19 wards or at emergency departments).

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request will be evaluated as per the AZ disclosure commitment:

https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure. Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared.

AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

When a request has been approved AstraZeneca will provide access to the de-identified individual patient-level data in an approved sponsored tool. Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.