Safety and Efficacy of Bexagliflozin in Subjects With Moderate Hepatic Impairment

A Phase 1, Open-label, Parallel-group Study to Evaluate the Effect of Moderate Hepatic Impairment on the Pharmacokinetics and Pharmacodynamics of Bexagliflozin

The purpose of this study is to examine the drug exposure and drug effects on subjects with moderate hepatic impairment after a single oral dose of bexagliflozin tablets, 20mg. The study will also evaluate how safe the study drug is and how well the study drug is tolerated in subjects with moderate hepatic impairment.

This was a Phase 1, open-label, parallel-group study designed to assess the effect of moderate hepatic impairment on the PK and PD of orally administered bexagliflozin tablets. A total of 16 subjects comprising eight with moderate hepatic impairment (Child Pugh total score 7 to 9) and eight healthy, matched controls, were enrolled and received a single oral dose of bexagliflozin tablets, 20 mg, after an overnight fast. Food was withheld for at least 2 h after dosing. Water was allowed as desired except within 1 h of drug administration.

Blood samples were collected prior to dosing, and at 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, and 48 h post-dose.

The unbound fraction of bexagliflozin at 24 h post dose and at the maximum plasma concentration for each subject was determined by equilibrium dialysis.

Urine samples for PD analysis were collected for the 12 h interval preceding dosing and for the 0 - 12 h, 12 - 24 h, 24 - 36 h, and 36 - 48 h intervals following dosing.

Each subject had to meet the following criteria to be eligible for the study:

1. Be male or female adults between the age of 18 and 75 years

2. Have a body mass index (BMI) of 18.0 kg/m2 to 40.0 kg/m2

3. Have adequate venous access at multiple sites in both arms

4. Be willing to be confined to the clinical research facility as required by the protocol

5. Be able to comprehend the explanation of the informed consent and be willing to provide written informed consent in accordance with institutional and regulatory guidelines

6. For subjects in the hepatic impairment group only: Be diagnosed with moderate hepatic impairment with a Child-Pugh score 7 to 9 and be in stable general health apart from hepatic impairment and its related conditions.

7. For subjects in the healthy control group only:

   • Be in general good health with matching demographics and baseline characteristics to individual subjects in the hepatic impairment group by age (± 10 years), weight (± 10%), sex, and smoking status
   • Exhibit neither evidence of an active infection nor undergoing any treatment with antibiotics at the time of Screening.

Prospective subjects who met any of the following criteria were ineligible to participate:

1. A clinically significant history of allergy to drugs or latex

2. A positive alcohol or drug result based on urine sample or breathalyzer testing at Screening or at clinic admission

3. A donation of 400 mL of whole blood within two months, 200 mL of whole blood within one month, or blood components or plasma within 14 days prior to Day 0

4. A history of exposure to an investigational drug within 30 days or 5 half-lives of the investigational drug prior to Day 0, whichever was longer

5. A history of exposure to any SGLT2 inhibitor within 3 months prior to Day 0 or participation in previous bexagliflozin clinical trials

6. A history of exposure to probenecid, rifampin, or any potential strong UGT1A9 inducers or inhibitors within 2 months of Day 0

7. A clinically significant abnormal electrocardiogram (ECG) that includes but is not limited to: heart rate < 40 or > 110 bpm, QRS> 160 ms, QTc> 480 ms (corrected by Bazett's formula), or any clinically significant arrhythmia including Mobitz type II 2nd Degree Heart block and bifascicular block

8. A history of human immunodeficiency virus (HIV) infection or a positive titer for HIV antibody

9. A history of vaccination (with the exception of the flu vaccine) within 30 days prior to Day 0

10. An estimated glomerular filtration rate (eGFR) < 60 mL·min-1 per 1.73 m2 as calculated by the modification of diet in renal disease study equation

11. Severe or moderate renal dysfunction or a history of kidney, other organ, bone marrow, or stem cell transplant

12. If male, unwilling to refrain from donating sperm or to use appropriate birth control when engaging in sexual intercourse for the duration of the study and a period of 14 days after discharge from the clinic. Surgically sterile male subjects were eligible

13. If female and of childbearing potential, unwilling to use an adequate method of contraception to avoid or prevent pregnancy for the duration of the study and 14 days after discharge from the clinic. Surgically sterile (as a result of hysterectomy or bilateral oophorectomy), or postmenopausal (absence of menses greater than 12 months and age > 45 years) female subjects were eligible. All females were to have had a negative pregnancy test at Screening and at clinic admission

14. Unwillingness to forgo consumption of grapefruit and grapefruit products from 7 days prior to Day 0 through discharge from the clinic

15. Pre existing thrombocytopenia (platelet blood count < 30,000 platelets) at Screening or other clinically significant findings in complete blood count (CBC) test.

16. A history of current febrile illness, hepatocellular carcinoma, acute liver disease, severe hepatic encephalopathy, or biliary liver cirrhosis.

17. A history of significant acute medical illness (new conditions and/or exacerbation of pre existing conditions or major surgery within 4 weeks of study drug administration), active alcoholic hepatitis, current or recent (within 2 months before Day 0) history of significant gastrointestinal disease

18. Clinical evidence of severe ascites, as judged by the Investigator

19. A history of surgical portosystemic shunt

20. For subjects in the healthy control group only:

    • A seated systolic blood pressure (SBP) of < 90 or > 140 mmHg, confirmed by repeat measurement
    • A seated diastolic blood pressure (DBP) of < 40 or > 90 mmHg
    • A history of vitamin preparation or supplement use (including St. John's Wort and ginseng) within 7 days prior to Day 0, or caffeine and methylxanthine (e.g., tea, chocolate) containing foods/beverages within 48 h prior to Day 0
    • A history of prescription or over-the-counter (OTC) drug use within 7 days or 5 half lives of the drug, whichever was longer, prior to Day 0
    • A history of liver disease or liver injury as indicated by an alanine aminotransferase (ALT), aspartate aminotransferase (AST), > 2.5 × the upper limit of normal (ULN) at Screening, or serum bilirubin > 1.5 × ULN
    • Evidence of hepatitis B virus (HBV) or hepatitis C virus (HCV) infection

21. For subjects in the hepatic impairment group only:

    • A seated SBP of < 80 or > 160 mmHg, confirmed by repeat measurement
    • A seated DBP of < 40 or > 100 mmHg
    • A history of any new prescription medication within 30 days prior to Day 0
    • A history of fluctuating or rapidly deteriorating hepatic function or the production of widely varying or worsening clinical and/or laboratory signs of hepatic impairment within the screening period

22. Any other serious medical condition that, in the opinion of the Investigator, would pose a significant risk to the subject or interfere with the interpretation of safety, PK, or PD data