Pharmacokinetic (PK) and Safety Study of Iptacopan (LNP023) in Participants With Mild, Moderate, and Severe Hepatic Impairment Compared to Matched Control Healthy Participants With Normal Hepatic Function.

• Status: Not yet recruiting
• Trial end date: 2022-06-01
• Target enrollment: 0
• Participant gender: All

Summary

This is a an open-label, single dose, parallel group study to evaluate the PK of iptacopan in participants with mild, moderate, or severe hepatic impairment compared to matched healthy control participants

• Phase: Phase 1
• Accepts Healthy Volunteers?: Accepts Healthy Volunteers

Details

• Lead Sponsor: Novartis Pharmaceuticals

Criteria

Inclusion Criteria:

All participants:

1. Signed informed consent must be obtained prior to participation in the study.

2. Male participants and female participants of non-childbearing potential 18 to 75 years of age (inclusive)

3. Participants must weigh at least 55 kg to participate in the study and must have a body mass index (BMI) within the range of 18 to 35 kg/m2 for healthy participants. For hepatic impairment participants without overt ascites, the BMI should be within the range of 18 to 40 kg/m2. For hepatic impairment participants with overt ascites, the BMI should be within the range of 18 to 45 kg/m2.

4. Ability to communicate well with the investigator, to understand and comply with the requirements of the study.

5. Participant must be willing to remain in the clinical research unit as required by the protocol.

Group 1 (healthy participants)

6. Each participant must match in age (± 10 years), gender, weight (± 15%), and smoking status to an individual participant in Group 2, 3, or 4.

7. Participants must be in good health as determined by medical history, physical examination, vital signs, ECG, and laboratory tests

• At Screening and Baseline, vital signs (systolic and diastolic blood pressure, and pulse rate) will be assessed after sitting 3 minutes and must be within the following ranges:

• Oral body temperature, 35.0 to 37.5°C.

• Systolic blood pressure, 89 to 139 mmHg.

• Diastolic blood pressure, 50 to 89 mmHg.

• Pulse rate, 50-100 bpm. Groups 2, 3, and 4 (participants with mild, moderate, or severe hepatic impairment)

8. Vital signs will be assessed after sitting 3 minutes and must be within the following ranges:

• Oral body temperature, 35.0 to 37.5°C.

• Systolic blood pressure, 85 to 160 mmHg.

• Diastolic blood pressure, 50 to 100 mmHg.

• Pulse rate, 50-100 bpm.

9. A Child-Pugh score clinically determined and calculated as per the Child-Pugh classification (see Section 8.4.4, Table 8-2) in line with the hepatic impairment of each Group, i.e., Group 2, 3, and 4 (participants with mild, moderate, or severe hepatic impairment).

• Group 2; mild; Child-Pugh score 5-6; Class A.

• Group 3; moderate; Child-Pugh score 7-9; Class B.

• Group 4; severe; Child-Pugh score 10-15; Class C.

10. Stable Child-Pugh status within 28 days prior to dosing per investigator's discretion

11. Participants with impaired hepatic function with other stable medical disorders such as controlled diabetes, hyperlipidemia, hypothyroidism, etc., may be eligible if they are considered appropriate for enrollment as determined by the investigator by past medical history, physical examination, vital signs, ECG, and laboratory tests at Screening

Exclusion Criteria:

All participants

1. Use of other investigational drugs within the last 30 days or 5 half-lives prior to dosing, whichever is longer

2. History of hypersensitivity to the investigational compound/compound class or its excipients being used in this study.

3. Pregnant or nursing (lactating) women. Pregnancy is defined as the state of a female after conception and until termination of gestation, confirmed by a positive human chorionic gonadotropin (hCG) laboratory test.

4. Women of childbearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing of study treatment. Women are considered post-menopausal and not of childbearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g., age-appropriate history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy or bilateral tubal ligation at least 6 weeks prior to the first dosing. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow-up hormone level assessment is, she considered not of childbearing potential.

5. Known history of, or current clinically significant arrhythmias, history of prolonged QTcF interval or QTcF > 450 msec (males) or QTcF > 460 msec (females) at Screening in healthy participants and history of prolonged QTcF interval QTcF > 470 msec (males) or QTcF > 480 msec (females) at Screening in participants with hepatic impairment.

6. History of immunodeficiency diseases, or a positive human immunodeficiency virus (HIV) test result at Screening.

7. Acute hepatitis B or C infection at Screening or active infection requiring therapy that will not be completed before screening.

8. History or presence of malignancy of any organ system (other than localized basal cell carcinoma of the skin or in-situ cervical cancer), treated or untreated, within 3 years of screening, regardless of whether there is evidence of local recurrence or metastases.

9. Donation or loss of 500 mL or more of blood within 8 weeks from Screening.

10. History of drug abuse within the last 12 months prior to dosing of study treatment or evidence of such abuse as indicated by the laboratory assays at Screening or Baseline..

11. History of unhealthy alcohol use within 12 months prior to dosing of study treatment, or evidence of such abuse as indicated by the laboratory assays conducted at Screening or Baseline. Excessive intake of alcohol defined as the regular consumption of more than 24 g of alcohol per day for men or 12 g of alcohol per day for women.

12. Any surgical or medical condition which might significantly alter the absorption, distribution, metabolism, or excretion of drugs (apart from cholecystectomy), or which may jeopardize the participants in case of participation in the study. The investigator should make this determination in consideration of the participant's medical history and/or clinical or laboratory evidence of any of the following:

• Inflammatory bowel disease, peptic ulcers, gastrointestinal including rectal bleeding within 3 months prior to Screening.

• Major gastrointestinal tract surgery such as gastrectomy, gastroenterostomy, or bowel resection.

• Pancreatic injury or pancreatitis.

13. Unwillingness or inability (e.g., physical or cognitive) to comply with study procedures and medication administration (injections) and schedule.

14. History of invasive infections caused by meningococci.

15. Participant has clinical signs and symptoms consistent with COVID-19, e.g., fever, dry cough, dyspnea, sore throat, fatigue or confirmed infection by appropriate laboratory test within the last 4 weeks prior to Screening or on admission.

16. Participant who had severe course of COVID-19 (e.g., hospitalization and/or extracorporeal membrane oxygenation, mechanically ventilated).

17. COVID-19 vaccines given 2 weeks prior to dosing. Group 1 (healthy participants)

18. Significant illness which has not resolved within 2 weeks prior to dosing.

19. Any single parameter of ALT, AST, γ GT, or ALP exceeding 1.2 × upper limit of normal (ULN) or ≥ 1.5 × ULN total bilirubin OR any elevation above ULN of more than one parameter of ALT, AST, GGT, ALP, or serum bilirubin at Screening or Baseline.

20. Hemoglobin levels ≤ LLN at Screening or Baseline

21. Platelet count ≤ LLN at Screening or Baseline (unless deemed not clinically significant by the investigator).

22. Participants known to have Gilbert's syndrome.

23. Chronic hepatitis B or hepatitis C infection. A positive Hepatitis B surface antigen (HBsAg) test, or if standard local practice, a positive Hepatitis B Virus (HBV) core antigen test, is an exclusion. Participants with a positive Hepatitis C Virus (HCV) Ab test should have HCV RNA levels measured. Participants with positive (detectable) HCV RNA should be excluded.

24. Use of any prescription drugs or herbal supplements within the last 4 weeks of dosing

25. Use of any counter (OTC) medication, dietary supplement (vitamins included) within last 2 weeks prior to dosing. Limited use of acetaminophen is acceptable but must be documented in the Concomitant medications/Significant non-drug therapies page of the electronic Case Report Forms (eCRF).

26. Impaired renal function as indicated by clinically significantly abnormal creatinine or blood urea nitrogen (BUN) and/or urea values, or abnormal urinary constituents at Screening or Baseline.

Groups 2 and 3 (participants with mild or moderate hepatic impairment)

27. Participants with hepatic impairment with abnormal laboratory values for the following parameters at Screening or Baseline:

• Hemoglobin < 9 g/dL.

• Platelet count < 30 × 109/L.

• White blood cell count < 2.5 × 109/L.

• Absolute neutrophil count < 1.5 × 109/L.

• Lymphocytes < 0.8 × 109/L.

• Total bilirubin > 8 mg/dL.

• Serum amylase > 5 × ULN with no abdominal symptoms (>2 x ULN with abdominal symptoms)

• International standardized ratio (INR) > 2.3.

• Corrected serum calcium < 8.6 or > 10.2 mg/dL.

28. Severe complications of liver disease within the preceding 3 months prior to dosing.

29. Hospitalization due to liver disease within the preceding 1 month prior to dosing.

30. Participants has received liver transplant at any time in the past and is on immunosuppressant therapy.

31. Participants requiring paracentesis more than every 3 weeks for the management of ascites are excluded. Participants who are receiving diuretics to manage ascites can be enrolled and will be assigned the Child-Pugh score for the degree of ascites while on diuretic treatment. The diuretic dose must have been stable for 7 days prior to dosing.

32. Transjugular intrahepatic portosystemic shunt and/or have undergone portacaval shunting.

33. Clinically significant abnormal findings in physical examination, ECG, or laboratory evaluations, not consistent with known clinical disease. Participants having myocardial infarction ≥ 5 years ago are eligible to participate.

34. Use of any prescription or non-prescription medication, dietary supplements, or vitamins that have the potential to interact with iptacopan during the study from dosing until the End of Study visit (Day 11) has been conducted. Participants with hepatic impairment should be excluded if there have been changes in dose regimen of medically required medication within 2 weeks prior to Screening or if there has been a significant change or addition to their routine medication (prescribed) within 1 month prior to drug administration. Minor changes to medication that require frequent dose adjustments, such as insulin or analgesia, can be made up to 2 weeks prior to drug administration, as agreed between the Investigator and Novartis.

35. Presence of moderate to severe impaired renal function as indicated by any or all of the following criteria:

• Creatinine clearance < 45 mL/min as calculated using the Cockcroft-Gault formula or eGFR < 45 mL/min/1.73 m2 based on MDRD calculation.

• Serum creatinine > 1.5 × ULN.

36. Encephalopathy Grade 3 or worse within 28 days of planned dosing.

37. Primary biliary cholangitis or biliary obstruction.

38. History of gastrointestinal bleeding requiring hospitalization within the past 3 months prior to Screening.

39. Clinically significant abnormal findings in physical examination or clinical laboratory evaluations not consistent with known liver disease.

40. Clinically significant illness within 2 weeks prior to initial dosing that may jeopardize safety of the study participant and/or alter the study results as judged by the investigator

Group 4 (participants with severe hepatic impairment)

41. Participants with hepatic impairment with abnormal laboratory values for the following parameters at Screening or Baseline:

• Hemoglobin < 8.5 g/dL.

• Platelet count < 30 × 109/L.

• White blood cell count < 2.5 × 109/L.

• Total bilirubin > 8 mg/dL.

• Serum amylase > 5 × ULN with no abdominal symptoms (>2 x ULN with abdominal symptoms).

• International standardized ratio (INR) > 2.3.

42. Severe complications of liver disease within the preceding 3 months prior to dosing.

43. Hospitalization due to liver disease within the preceding 1 month prior to dosing.

44. Participant has received liver transplant at any time in the past and is on immunosuppressant therapy.

45. Participants requiring paracentesis more than every 3 weeks for the management of ascites are excluded. Participants who are receiving diuretics to manage ascites can be enrolled and will be assigned the Child-Pugh score for the degree of ascites while on diuretic treatment. The diuretic dose must have been stable for 7 days prior to dosing.

46. Transjugular intrahepatic portosystemic shunt and/or have undergone portacaval shunting.

47. Clinically significant abnormal findings in physical examination, ECG, or laboratory evaluations, not consistent with known clinical disease. Participants having myocardial infarction ≥ 5 years ago are eligible to participate.

48. Use of any prescription medications that have the potential to interact with iptacopan during the study from dosing until the EOS visit (Day 11) has been conducted. Participants with hepatic impairment should be excluded if there have been changes in the dose or schedule of medically-required medication within 2 weeks prior to Screening or if there has been a change or addition to their routine medication (prescribed) within 1 month prior to drug administration, except for changes to medication that require frequent dose adjustments, such as insulin or analgesia, which can be made within 2 weeks prior to drug administration, as agreed between the Investigator and Novartis.

49. Presence of moderate to severe impaired renal function as indicated by any or all of the following criteria:

• Creatinine clearance < 45 mL/min as calculated using the Cockroft-Gault formula or eGFR < 45 mL/min/1.73 m2 based on MDRD calculation.

• Serum creatinine > 1.5 × ULN.

50. Encephalopathy Grade 3 or worse within 28 days of planned dosing.

51. Primary biliary cholangitis or biliary obstruction.

52. History of gastrointestinal bleeding requiring hospitalization within the past 3 months prior to Screening.