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

Inclusion Criteria:

1. Males or females aged 18 through 65 years (Parts A-D) or 75 years (Part E) at thetime of screening.

2. Parts A, B, C only: Participants with or without T2DM. If participants have adiagnosis of T2DM, the glucose control managed with diabetes diet and in addition tometformin treatment no more than two treatment options (with a stable dose 3 monthsprior to screening). Part D only: Participants who are diagnosed with T2DM, have inadequate glycaemiccontrol with diet and exercise. Participants who are prescribed an oralanti-diabetic agent such as metformin, a DPP IV inhibitor, sulphonylurea, glinides,alphaglucosidase inhibitors, and an SGLT2 inhibitor may be eligible to enter thestudy following a washout of 4-weeks or 5-half lives (whichever is longer) washoutperiod. Part E only: Participants are eligible to be included in the Part E only if theymeet all of the following criteria at screening:

3. Diagnosed with T2DM.

4. Are treated with diet and exercise only, or any combination of OAD with stabledoses in the 3 months prior to dosing.

5. Participants prescribed a DPP IV inhibitor or a GLP-1RA-containing medicine,alone or in combination with other OADs, may be eligible to enter the study ifthey have not been treated with any of these drugs for at least 35 days or 5drug half-lives (whichever is longer) prior to randomisation.

6. Participants with a screening HbA1c value within the target range of

• ≥ 42 to ≤ 86 mmol/mol (6% to 10%).

4. Body mass index from ≥27 (≥25 in Part D) to ≤39.9 kg/m2 (inclusive) (Part A-D) or ≥ 27 kg/m2 (Part E).

5. Contraceptive use by males or females should be consistent with local regulationsregarding the methods of contraception for those participating in clinical studies.

6. Written informed consent and any locally required authorization (eg, European UnionData Privacy Directive) obtained from the participant prior to performing anyprotocol-related procedures, including screening evaluations

7. Ability to complete and meet all eligibility requirements for randomisation within 60 days after signing the ICF.

8. Venous access suitable for multiple cannulations.

9. Willing and able to self-administer weekly SC injections (Parts C, D and E only).

Exclusion Criteria:

1. Participants with T2DM treated with insulin.

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

3. Participants with or without T2DM treated with a GLP-1RA or GLP-1RA/GIPRA within 3months of screening (Parts A to D only) or within 35 days of randomisation or fivehalf-lives (whichever is shorter) of dosing (Part E only).

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

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

6. History or presence of GI, renal, or hepatic disease (with the exception ofGilbert'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 skincancer.

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 thediscretion 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 takingantiretroviral medications as determined by medical history or participant's verbalreport.

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 clinicallysignificant haematological abnormality as judged by the investigator.

• Total serum calcium, albumin-corrected calcium or ionised calcium < LLN atscreening (Part E).

14. Impaired renal function defined as estimated glomerular filtration rate (eGFR) ≤ 60mL/minute/1.73m2 as defined by Chronic Kidney Disease Epidemiology Collaboration (2021) (Part A to D); or ≤ 45 mL/minute/1.73 m2 (Part E).

15. Any clinically important abnormalities in clinical chemistry, haematology,coagulation, or urinalysis results other than those specifically described asexclusion criteria herein, as judged by the investigator.

16. Significant late diabetic complications (macroangiopathy with symptoms of congestiveheart disease or peripheral arterial disease, microangiopathy with symptoms ofneuropathy, gastroparesis, retinopathy requiring treatment, nephropathy) detected inlaboratory results or in clinical history/documentation as judged by theinvestigator.

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

• 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 theinvestigator's judgement, they are not representative of the participant.

18. Any clinically important abnormalities in rhythm, conduction, or morphology of theresting ECG and any abnormalities in the 12-lead ECG that, as considered by theinvestigator, 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, andparticipants with symptomatic tachy- or brady-arrhythmias.

20. Participants with unstable angina pectoris or stable angina pectoris classifiedhigher than Canadian Cardiovascular Society class II or an acute coronarysyndrome/acute myocardial infarction or coronary intervention with percutaneouscoronary 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 ofheart failure. In Part E, severe congestive heart failure (New York HeartAssociation Class III or IV) or recent (< 6 months) hospitalisation due to heartfailure.

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

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

24. Whole blood or red blood cell donation, or any blood loss > 500 mL (or > 400 mL inPart 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 ordepression, where the participant is deemed to be clinically unstable as judged bythe investigator.

27. Previous hospitalisation for any psychiatric reason.

28. PHQ-9 score ≥ 15 within the 2 years prior to screening or at screening.

29. Received another new chemical entity (defined as a compound that has not beenapproved for marketing), or has participated in any other clinical study thatincluded drug treatment within at least 30 days or 5 half-lives prior to the firstadministration of study intervention in this study (whichever is longer). The periodof exclusion to begin 30 days or 5 halflives of IMP after the final dose, or afterthe last visit, whichever is longest. Participants consented and screened, but notrandomised 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 ofbody 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 weeksprior to the first administration of study intervention.

33. Received another new chemical entity (defined as a compound that has not beenapproved for marketing), or has participated in any other clinical study thatincluded drug treatment within at least 30 days or 5 half-lives prior to the firstadministration of study intervention in this study (whichever is longer). The periodof exclusion to begin 30 days or 5 half-lives of IMP after the final dose, or afterthe last visit, whichever is longest. Participants consented and screened, but notrandomised into this study or previous AZD9550, AZD6234, or AZD9550/AZD6234combination 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 thediet or treatment has been stopped at least 3 months prior to screening and theparticipant has had a stable body weight (± 5%) during the 3 months prior toscreening.

37. Participants who are vegans, ones with medical dietary restrictions, or participantswho are willingly conducting any diet likely to increase ketone levels (Atkins orany similar diet based on increased protein consummation or low carbohydratecontent) (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 (includinge-cigarettes) within the previous 3 months prior to screening (Part A-D only).

40. Participants who cannot communicate reliably with the investigator or vulnerableparticipants (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 CRO, or the study site, regardless of the employee's role.

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

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

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

45. History of use of marijuana or THC-containing products within 3 months prior toscreening or unwillingness to abstain from marijuana or THC-containing products useduring the study (Part E only).