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

Prior treatment

• major surgery within 30 days;
• functioning organ transplant or anticipated within 2 months; prior porto systemic shunt/TIPS;
• 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:
• 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).

Other illness

• Any clinically significant disease; Diabetes;
• severe allergy/hypersensitivity;
• HIV positive; HBV surface/core Ab or HCV Ab positive; drug/alcohol abuse within 1 year.
  • Hepatically impaired only:
• Unstable medical/psychological conditions or uncontrolled systemic disease;
• oesophageal banding within 3 months or GI bleeding within 6 months;
• acute liver disease due to infection/drug; hepatic impairment due to non liver disease;
• 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;
• 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.

Lab values

• lab values i) ALT/AST/ALP \>1.5×ULN; ii) WBC/platelets \<LLN; 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);
• pancreatitis or pancreatic enzymes \>2×ULN;
• triglycerides \>500 mg/dL (5.6 mmol/L);
• low corrected or ionised calcium;
• eGFR \<50 mL/min/1.73 m² (CKD EPI 2021);
• platelets \<35×10⁹/L; neutrophils \<1.2×10⁹/L; haemoglobin \<85 g/L; HbA1c ≥10%;
• ascites requiring paracentesis and albumin ≤4 week intervals; paracentesis within 30 days;
• pancreatitis or pancreatic enzymes \>2×ULN;
• 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 \<LLN;
• 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:

Other

• Healthy controls only:
• abnormal resting vital signs i) SBP \>150 or \<90 mmHg, ii) DBP \>95 or \<50 mmHg, iii) pulse ≥100 or ≤45 bpm;
• QTcF \>450 ms or clinically significant ECG abnormalities;
• calcitonin \>50 ng/L (50 pg/mL);
• severe vitamin D deficiency (\<12 ng/mL, 30 nmol/L);
• Abnormal resting vital signs i) SBP \>160 or \<100 mmHg, ii) DBP \>110 or \<65 mmHg, iii) pulse ≥100 or ≤50 bpm;
• fluctuating/worsening hepatic function during screening; hepatocellular carcinoma;
• biliary obstruction or non parenchymal causes; hepatic encephalopathy Grade ≥2;
• QTcF \>480 ms or clinically significant ECG abnormalities;
• 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:

• Age 18-85 years at consent.
• Groups:
  • Healthy controls: Medically healthy; no clinically significant findings in history, exam, labs, vitals, or 12 lead ECG (per investigator).
  • Hepatic impairment: Chronic (≥6 months), stable; documented Child Pugh B (Group 2) or C (Group 1).
• Stable concomitant regimen ≥2 weeks before screening (Groups 1-2).
• T2DM allowed if HbA1c \<10% and no severe hypo/hyperglycaemia or hospitalisation within 6 months.
• Body weight ≥50 kg; BMI 18-42 kg/m².
• 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.
• Written informed consent; separate consent for optional genomics.