A Trial to Learn How Safe AZD9550 Monotherapy and Combined With AZD6234 is in People With or Without Type 2 Diabetes Who Are Living With Obesity and Overweight

1. Participants with T2DM (Part F) and participants with T2DM treated with insulin (Parts A-E).

2. Participants with T2DM treated with more than 3 anti-diabetic therapies (Parts A-D only).

3. Treatment with GLP-1RA or GLP-1RA/GIPRA within 3 months of screening (Parts A to C only) or within 35 days of randomisation or five half-lives (whichever is shorter) of dosing (Parts E and F only).

4. History of any clinically important disease or disorder which may either put the participant at risk because of participation in the study, or influence the results or the participant's ability to participate in the study.

5. Serum calcitonin suggestive of thyroid C-cell hyperplasia (calcitonin level \> 50 ng/L), medullary thyroid carcinoma, or history or family history of multiple endocrine neoplasia at screening.

6. History or presence of GI, renal, or hepatic disease (with the exception of Gilbert's syndrome), or any other condition known to interfere with absorption, distribution, metabolism, or excretion of drugs, as judged by the investigator.

7. History of cancer within the last 10 years, with the exception of non-melanoma skin cancer.

8. Any clinically important illness (apart from T2DM), as judged by the investigator.

9. Any medical/surgical procedure, or trauma within 4 weeks prior to screening, at the discretion of the investigator.

10. Symptoms of insulinopenia or poor blood glucose control (eg, significant thirst, nocturia, polyuria, polydipsia, or weight loss).

11. Positive hepatitis B or hepatitis C virus serology at screening.

12. Positive human immunodeficiency virus test at screening or participant taking antiretroviral medications as determined by medical history or participant's verbal report.

13. At screening blood tests, any of the following:

* AST ≥ 1.5 × ULN

* ALT ≥ 1.5 × ULN

* TBL ≥ 1.5 × ULN (with the exception of Gilbert's syndrome)

* Haemoglobin below the lower limit of the normal range or any other clinically significant haematological abnormality as judged by the investigator.

* Total serum calcium, albumin-corrected calcium or ionised calcium \< LLN at screening (Part E).

14. Impaired renal function defined as eGFR ≤ 60 mL/minute/1.73 m2 as defined by Chronic Kidney Disease Epidemiology Collaboration (2021) (Part A to C); or ≤ 45 mL/minute/1.73 m2 (Parts E and F).

16. Significant late diabetic complications (macroangiopathy with symptoms of congestive heart disease or peripheral arterial disease, microangiopathy with symptoms of neuropathy, gastroparesis, retinopathy requiring treatment, nephropathy) detected in laboratory results or in clinical history/documentation as judged by the investigator.

17. Abnormal vital signs, after 10 minutes of supine rest, defined as any of the following:

* Systolic BP \< 90 mmHg or ≥ 150 mmHg

* Diastolic BP \< 50 mmHg or ≥ 90 mmHg

* HR \< 50 or \> 85 bpm at resting state

* Participants may be re-tested for the vital signs criteria only once if, in the investigator's judgement, they are not representative of the participant.

18. Any clinically important abnormalities in rhythm, conduction, or morphology of the resting ECG and any abnormalities in the 12-lead ECG that, as considered by the investigator, may interfere with the interpretation of QTc interval changes, including abnormal ST-T-wave morphology or left ventricular hypertrophy.

19. Participants with implantable cardiac defibrillator or a permanent pacemaker, and participants with symptomatic tachy- or brady-arrhythmias.

20. Participants with unstable angina pectoris or stable angina pectoris classified higher than Canadian Cardiovascular Society class II or an acute coronary syndrome/acute myocardial infarction or coronary intervention with percutaneous coronary intervention or coronary artery bypass grafting or stroke within 6 months.

21. In Parts A-D: History of hospitalisation caused by heart failure or a diagnosis of heart failure. In Part E, severe congestive heart failure (New York Heart Association Class III or IV) or recent (\< 6 months) hospitalisation due to heart failure.

22. Known or suspected history of drug abuse within the past 3 years as judged by the investigator (Parts A-F) and/or a positive screen for drugs of abuse at screening (Parts A-C only).

23. History of severe allergy/hypersensitivity or ongoing clinically important allergy/hypersensitivity as judged by the investigator.

24. Whole blood or red blood cell donation, or any blood loss \> 500 mL (or \> 400 mL in Part D) during the 3 months prior to screening.

25. History of psychosis or bipolar disorder.

26. History of major depressive disorder within the 2 years prior to screening or depression, where the participant is deemed to be clinically unstable as judged by the investigator.

27. Previous hospitalisation for any psychiatric reason.

28. Questionnaire score ≥ xx within the x years prior to screening or at screening (Parts E and F only).

29. Received another new chemical entity (defined as a compound that has not been approved for marketing), or has participated in any other clinical study that included drug treatment within at least 30 days or 5 half-lives prior to the first administration of study intervention in this study (whichever is longer). The period of exclusion to begin 30 days or 5 halflives of IMP after the final dose, or after the last visit, whichever is longest. Participants consented and screened, but not randomised into this study or a previous Phase 1 study, are not excluded.

30. History of lactic acidosis

31. Use of any of the following medicinal products:

* Use of systemic corticosteroids within 28 days prior to screening.

* Use of compounds known to prolong the QTc interval.

* Use of any herbal preparations or medicinal products licensed for control of body weight or appetite within 3 months prior to screening.

32. Use of drugs with enzyme inducing properties such as St John's Wort within 3 weeks prior to the first administration of study intervention.

33. Received another new chemical entity (defined as a compound that has not been approved for marketing), or has participated in any other clinical study that included drug treatment within at least 30 days or 5 half-lives prior to the first administration of study intervention in this study (whichever is longer). The period of exclusion to begin 30 days or 5 half-lives of IMP after the final dose, or after the last visit, whichever is longest. Participants consented and screened, but not randomised into this study or previous AZD9550, AZD6234, or AZD9550/AZD6234 combination studies, are not excluded from Part E.

34. Previous enrolment or randomisation in the present study.

35. Concurrent participation in another study of any kind is prohibited.

36. Ongoing weight loss diet (hypocaloric diet) or use of weight loss agents, unless the diet or treatment has been stopped at least 3 months prior to screening and the participant has had a stable body weight (± 5%) during the 3 months prior to screening.

37. Participants who are vegans, ones with medical dietary restrictions, or participants who are willingly conducting any diet likely to increase ketone levels (Atkins or any similar diet based on increased protein consummation or low carbohydrate content) (Part A-D only).

38. Excessive intake of caffeine-containing drinks or food (eg, coffee, tea, Coca-Cola/Pepsi or similar drink type, chocolate) as judged by the investigator (Part A-D only).

39. Current smokers or those who have smoked or used nicotine products (including e-cigarettes) within the previous 3 months prior to screening (Part A-D only).

40. Participants who cannot communicate reliably with the investigator or vulnerable participants (eg, kept in detention, protected adults under guardianship, trusteeship, or committed to an institution by governmental or juridical order).

41. The participant is an employee, or close relative of an employee, of AstraZeneca, the Service Provider, or the study site, regardless of the employee's role.

42. Judgement by the investigator that the participant should not participate in the study if the participant is unlikely to comply with study procedures, restrictions, and requirements.

43. Contra-indication to MRI: such as participants with pacemakers, metallic cardiac valves, magnetic material such as surgical clips, implanted electronic infusion pumps or other conditions that would preclude proximity to a strong magnetic field; participants with history of extreme claustrophobia or participant cannot fit inside the MRI scanner cavity (Parts B and C only).

44. Serum triglyceride concentrations \> 500 mg/dL (5.6 mmol/L) at screening or any other metabolic condition judged by the investigator as likely to precipitate acute pancreatitis (Part E only).

45. History of use of marijuana or THC-containing products within 3 months prior to screening or unwillingness to abstain from marijuana or THC-containing products use during the study (Parts E and F only).

What this study is about