A Study to Investigate the Repeat-dose Pharmacokinetics of a Combined Oral Contraceptive When Given Alone and in Combination With Ganfeborole in Female Participants of Non-childbearing Potential

A Phase 1, Open-Label, Fixed Sequence, 1-Way Drug-Drug Interaction Study to Investigate the Repeat-Dose Pharmacokinetics of Microgynon, an Oral Contraceptive Containing Ethinyl Estradiol and Levonorgestrel, When Administered Alone and in Combination With Ganfeborole in Healthy Female Participants of Non-Childbearing Potential Aged 18-65 Years Old

This study is designed to assess the pharmacokinetics (PK), safety, and tolerability of Ganfeborole and Microgynon, an oral contraceptive containing ethinylestradiol (EE) and levonorgestrel (LNG), when Microgynon is administered alone and in combination with Ganfeborole in healthy female participants of non-childbearing potential.

Inclusion Criteria:

1. Participant is 18 to <65 years of age, inclusive, at the time of signing the informed consent.

2. Participants who are healthy as determined by the investigator or medically qualified designee based on a medical evaluation including medical history, physical examination, laboratory tests, and cardiac monitoring (history and ECG).

3. A creatinine clearance of >=75 mL/min.

4. Normal echocardiogram or echocardiogram with normal left ventricular function with at most trace to mild valvular regurgitation is allowed and no valvular stenosis.

5. Body weight >=40.0 kg (99 pounds [lbs]) and body mass index within the range 18.5 up to 30.0 kg/m^2 (inclusive).

6. Participant of Non-childbearing Potential. Participants in the following categories are considered female PONCBP: Postmenopausal female.

   A postmenopausal state is defined as no menses for 12 months without an alternative medical cause.

   • A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a postmenopausal state in individuals not using hormonal contraception or hormonal replacement therapy (HRT). However, in the absence of 12 months of amenorrhea, confirmation with more than one FSH measurement is required, within the Screening period.
   • Females on HRT and whose menopausal status is in doubt must discontinue HRT at least 30 days prior to the start of Treatment Period 1 to allow confirmation of postmenopausal status before study enrollment.

7. Participant is capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the Informed Consent Form (ICF) and in the protocol.

8. Additional inclusion criteria:

   • Two FSH tests
   • Negative pregnancy test

Exclusion Criteria:

1. History of known cardiac valve abnormalities

2. Medical history of fatty liver disease

3. Major health conditions (including ovarian, endometrial, cervical, and breast tumours as per the Microgynon label)

4. History of ovarian, endometrial, cervical and breast cancer

5. History of deep vein thrombosis (DVT)

6. Presence of hepatitis B surface antigen at Screening or within 3 months prior to starting study treatment.

7. Positive hepatitis C antibody test result at Screening or within 3 months prior to starting study treatment AND positive on reflex to hepatitis C RNA.

8. Positive HIV-1 and/or -2 antigen/antibody immunoassay at Screening.

9. Alanine aminotransferase (ALT) >1.5×ULN. A single repeat of ALT is allowed within a single screening period to determine eligibility.

10. Bilirubin >1.5×ULN (isolated bilirubin >1.5×ULN is acceptable if bilirubin was fractionated and direct bilirubin <35%).

11. Any acute laboratory abnormality at Screening which, in the opinion of the investigator, should preclude participation in the study of an investigational compound.

12. Participants with haemoglobin <8.0 g/dL.

13. Any Grade 3 to 4 laboratory abnormality at Screening, inclusive of creatine phosphokinase and lipid abnormalities and ALT, excludes a participant from the study unless the investigator provided a compelling explanation for the laboratory result(s) and has the assent of the sponsor. A single repeat of any laboratory abnormality is allowed within a single screening period to determine eligibility.

14. A positive test result for drugs of abuse (including marijuana), alcohol, or cotinine (indicating active current smoking) at Screening or before the first dose of study treatment.

15. Unable to refrain from the use of prescription (including HRT), or non-prescription drugs including vitamins, herbal and dietary supplements (including St John's wort) within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) prior to the first dose of study treatment and for the duration of the study. Concomitant medications may be permitted on a case by case basis on the discretion of the medical monitor and the GSK Ganfeborole team.

16. Treatment with any vaccine within 30 days prior to receiving study treatment.

17. Unwillingness to abstain from excessive consumption of any food or drink containing caffeine, grapefruit or grapefruit juice, Seville oranges, blood oranges, or pomelos or their fruit juices within 7 days prior to the first dose of study treatment(s) until the end of the study.

18. The study will exclude participants who have undergone IVF or other assisted reproductive techniques within 9 months prior to screening or are participating in such programs at the time of screening, or who plan to undergo IVF or other assisted reproductive techniques during the following year.

19. Participation in another concurrent clinical study or prior clinical study (with the exception of imaging trials) prior to the first dosing day in the current study: 30 days, 5 half-lives plus 10 days, or twice the duration of the biological effect of the investigational product (whichever is longer).

20. Where participation in the study results in donation of blood or blood products in excess of 500 mL within 56 days.

21. Any significant arrhythmia or ECG finding which would interfere with the safety for the individual participant

22. Exclusion criteria for screening ECG (a single repeat is allowed for eligibility determination): Heart rate: <50 or >100 beats per minute; QTcF interval: >450 milliseconds; QTcF interval (Bundle Branch Block): >480 milliseconds.

23. Participants with vitiligo.

24. Participants with hypertension or Type 2 diabetes that cannot be controlled with diet and exercise alone.

25. History of regular alcohol consumption within 6 months of the study defined as: an average weekly intake of >14 units. One unit is equivalent to 8 g of alcohol: a half pint (~240 mL) of beer, 1 glass (125 mL) of wine or 1 (25 mL) measure of spirits.

26. Unable to refrain from tobacco- or nicotine-containing products.

27. History of sensitivity to any of the study medications, or components thereof, or a history of drug or other allergy that, in the opinion of the investigator or medical monitor, contraindicates their participation.

28. Liver safety exclusion criteria:

    • ALT >1.5xULN.
    • Total bilirubin >1.5xULN; Participants with Gilbert's syndrome can be included with total bilirubin >1.5xULN if direct bilirubin is <=1.5xULN.
    • Current or chronic history of liver disease (including fatty liver disease) or known hepatic or biliary abnormalities (except for Gilbert's syndrome or asymptomatic gallstones).
    • Presence of hepatitis B surface antigen (HBsAg) at screening or within 3 months prior to first dose of study intervention.
    • Positive hepatitis C antibody test result at screening or within 3 months prior to first dose of study intervention.
    • Positive hepatitis C RNA test result at screening or within 3 months prior to first dose of study intervention.

29. Cardiac safety exclusion criteria:

    • QTcF >450 milliseconds or QTcF >480 milliseconds for patients with bundle branch block.