A Phase I Study to Investigate the Effect of Hepatic Impairment of AZD9550 and AZD6234

Inclusion Criteria

• Inclusion Criteria
• 1. Age 18–85 years at consent.
• 2. Groups:
• o Healthy controls: Medically healthy; no clinically significant findings in history, exam, labs, vitals, or 12 lead ECG (per investigator).
• o Hepatic impairment: Chronic (≥6 months), stable; documented Child Pugh B (Group 2) or C (Group 1).
• 3. Stable concomitant regimen ≥2 weeks before screening (Groups 1–2).
• 4. T2DM allowed if HbA1c <10% and no severe hypo/hyperglycaemia or hospitalisation within 6 months.
• 5. Body weight ≥50 kg; BMI 18–42 kg/m².
• 6. Sex assigned at birth (male/female); contraception per local regulations. Females of child bearing potential: negative pregnancy tests and condoms plus one highly effective method through 54 days post last dose. Males: condom use; no sperm donation through 54 days post last dose.
• 7. Written informed consent; separate consent for optional genomics.
• Exclusion Criteria
• Healthy controls only:
• 1. Any clinically significant disease; Diabetes;
• 2. lab values
• i) ALT/AST/ALP >1.5×ULN;
• ii) WBC/platelets
• iii) haemoglobin <11.0 g/dL (female) or <12.0 g/dL (male); aPTT or PT/INR >1.2×ULN;
• iv) total bilirubin >1.5×ULN (or Gilbert’s);
• 3. abnormal resting vital signs
• i) SBP >150 or <90 mmHg,
• ii) DBP >95 or <50 mmHg,
• iii) pulse ≥100 or ≤45 bpm;
• 4. QTcF >450 ms or clinically significant ECG abnormalities;
• 5. severe allergy/hypersensitivity;
• 6. major surgery within 30 days;
• 7. pancreatitis or pancreatic enzymes >2×ULN;
• 8. triglycerides >500 mg/dL (5.6 mmol/L);
• 9. calcitonin >50 ng/L (50 pg/mL);
• 10. severe vitamin D deficiency (<12 ng/mL, 30 nmol/L);
• 11. low corrected or ionised calcium;
• 12. HIV positive; HBV surface/core Ab or HCV Ab positive; drug/alcohol abuse within 1 year.
• Hepatically impaired only:
• 13. Unstable medical/psychological conditions or uncontrolled systemic disease;
• 14. eGFR <50 mL/min/1.73 m² (CKD EPI 2021);
• 15. Abnormal resting vital signs
• i) SBP >160 or <100 mmHg,
• ii) DBP >110 or <65 mmHg,
• iii) pulse ≥100 or ≤50 bpm;
• 16. platelets <35×10⁹/L; neutrophils <1.2×10⁹/L; haemoglobin <85 g/L; HbA1c ≥10%;
• 17. oesophageal banding within 3 months or GI bleeding within 6 months;
• 18. ascites requiring paracentesis and albumin ≤4 week intervals; paracentesis within 30 days;
• 19. fluctuating/worsening hepatic function during screening; hepatocellular carcinoma;
• 20. acute liver disease due to infection/drug; hepatic impairment due to non liver disease;
• 21. biliary obstruction or non parenchymal causes; hepatic encephalopathy Grade ≥2;
• 22. functioning organ transplant or anticipated within 2 months; prior porto systemic shunt/TIPS;
• 23. QTcF >480 ms or clinically significant ECG abnormalities;
• 24. pancreatitis or pancreatic enzymes >2×ULN;
• 25. triglycerides >500 mg/dL (5.6 mmol/L); calcitonin >50 ng/L (50 pg/mL); severe vitamin D deficiency (<12 ng/mL, 30 nmol/L); ionised calcium
• 26. neoplastic disease within 10 years (except adequately treated BCC/SCC or in situ cervical); MEN2 or medullary thyroid carcinoma (personal or first degree relative); significant gastric emptying abnormality;
• 27. HIV positive; HBV surface/core Ab or HCV Ab positive (may be included if HBV DNA or HCV RNA negative on follow up); drug/alcohol abuse within 1 year.
• 28. Exposure to a new chemical entity within 30 days or 5 half lives (whichever longer) before intervention; prior exposure to AZD9550 or AZD6234;
• Prior/concomitant therapy:
• Healthy controls:
• 29. use of prescription/non prescription/supplements within 7 days (or 14 days for enzyme inducers) or 5 half lives before intervention unless judged non interfering; current oral contraceptives or oestrogen HRT.
• Hepatically impaired:
• 30. prohibited—weight loss medicines (including GLP 1), agents causing significant weight gain (e.g., systemic glucocorticoids, antipsychotics), GLP 1 RAs for diabetes, QT prolonging/prokinetic agents, oral contraceptives for contraception; restricted—short systemic glucocorticoids (≤7 days), 5HT 3 antiemetics at lowest effective dose, combined oral contraceptives for non contraceptive indications. If diabetes develops and requires insulin/SU/GLP 1 RA, discontinue from study.
• Other:
• 31. prior enrolment in this study (screened without dosing permitted). Positive drugs of abuse and/or alcohol screen (except prescribed meds in hepatic impairment); recent blood products/donation per protocol thresholds; employees or close relatives; vulnerable populations; unlikely to comply (investigator judgement).