A Study to Investigate the Pharmacokinetics and Safety of Remibrutinib in Participants With Hepatic Impairment Compared With Matched Healthy Participants

Study Overview
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Brief Summary
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This study will be conducted in 2 parts. Part 1 will comprise of participants with mild and moderate HI and matching healthy control participants with normal hepatic function. Part 2 will comprise of participants with severe HI and matching healthy control participants with normal hepatic function. Each study part will comprise of a screening period of up to 28 days, a baseline evaluation on Day -1, and a treatment period including up to 8 days of safety and PK data collection. Participants will be domiciled from Day -1 through Day 8. All participants will receive 25 mg remibrutinib b.i.d. orally on Days 1 and 2, and a morning oral dose of 25 mg remibrutinib on Day 3. PK samples will be collected pre dose on Day 3 and until 72 hours post Day 3 dosing. Throughout the study, safety assessments will include physical examinations, ECGs, vital signs, clinical laboratory evaluations (hematology, chemistry, urinalysis and coagulation) and AE / serious adverse event (SAE) monitoring. The Investigator and Novartis will conduct a joint interim review of safety and PK data from Part 1 before proceeding to Part 2. Part 2 will only begin if administration of remibrutinib in Part 1 is deemed safe and tolerable by the Investigator and Novartis to proceed in participants with severe HI. Depending on the outcome of the interim review, administration of a lower dose of remibrutinib in severe HI participants and their matching healthy control participants may be considered. Part 2 will also include sentinel dosing where one participant with severe HI will receive the first dose of remibrutinib at least 1 week before the remaining participants. If the Investigator concludes that there are no emergent safety concerns for the sentinel participant, then dosing will commence for the remaining participants. Study Completion evaluations will occur on Day 8, followed by a post-study safety follow up contact (e.g. follow-up telephone call, email) approximately 30 days after the last administration of study treatment. The total study duration for each participant is expected to be up to approximately 62 days, including the Screening period and the follow-up contact.

Official Title
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A Phase 1, Open-label, Study to Investigate the Pharmacokinetics and Safety of Remibrutinib (LOU064) in Participants With Hepatic Impairment Compared to Matched Healthy Participants With Normal Hepatic Function

Conditions
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Hepatic Impairment

Intervention / Treatment
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* Drug: Part 1; LOU064 (Remibrutinib)
* Drug: Part 2; LOU064 (Remibrutinib)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: All participants Male and non-childbearing potential female participants 18 to 70 years of age, inclusive, at Screening. Must be a non-smoker or a light smoker who smokes no more than 10 cigarettes (or equivalent) per day, at Screening. Smokers must agree to smoke no more than 5 cigarettes (or equivalent) per day from check-in until after Study Completion evaluations. Participants with mild, moderate and severe HI (Groups 1, 2 and 3) Must weigh at least 50 kg to participate in the study, and must have a body mass index (BMI) within the range of 18.0 to 35.0 kg/m2, inclusive, at Screening. Has impaired hepatic function as defined by the Child-Pugh classification for severity of liver disease and has a Child-Pugh score in line with one of the following HI groups at Screening: Group 1; mild (Class A); Child-Pugh score 5-6, inclusive. Group 2; moderate (Class B); Child-Pugh score 7-9, inclusive. Group 3; severe (Class C); Child-Pugh score 10-15, inclusive. Participants with other stable medical disorders such as controlled diabetes, hyperlipidemia, hypothyroidism, etc., may be eligible as long as they are considered appropriate for enrollment as determined by the Investigator by past medical history, physical examination, ECG and clinical laboratory tests at Screening. Healthy control participants (Group 4) Each healthy participant must match the age (± 10 years) and body weight (± 20%) of participants in Groups 1 and 2 (Part 1) and/or Group 3 (Part 2). Must be in good health as determined by medical history, physical examination, ECG and clinical laboratory tests at Screening. Exclusion Criteria: All participants History of hypersensitivity to the study treatment or its excipients or to drugs of similar chemical classes. History or presence of malignancy of any organ system (other than treated localized basal cell or squamous cell carcinoma of the skin or in-situ cervical cancer), treated or untreated, within the past 5 years of Screening, regardless of whether there is evidence of local recurrence or metastases. History or presence of any ongoing, chronic or recurrent infectious disease (including tuberculosis, atypical mycobacterioses, listeriosis, aspergillosis). Participants with mild and moderate HI (Groups 1 and 2) Severe complications of liver disease within the preceding 3 months of Screening. Emergency room visit or hospitalization due to liver disease within the preceding 3 months of Screening. Has received liver transplant at any time in the past and/or is on immunosuppressant therapy at Screening. Clinically significant abnormal findings in physical examination, ECG or clinical laboratory evaluations, not consistent with known liver disease. Participants having had myocardial infarction < 5 years of Screening are not eligible to participate, participants having had myocardial infarction ≥ 5 years of Screening can be eligible to participate. Participants with severe HI (Group 3) Severe complications of liver disease within the preceding 3 months of Screening. Emergency room visit or hospitalization due to liver disease within the preceding 1 month of Screening. Has received liver transplant at any time in the past and/or is on immunosuppressant therapy at Screening. Clinically significant abnormal findings in physical examination, ECG or clinical laboratory evaluations, not consistent with known liver disease. Participants having had myocardial infarction < 5 years of Screening are not eligible to participate, participants having had myocardial infarction ≥ 5 years of Screening can be eligible to participate. Encephalopathy Grade 3 or worse within 28 days of planned first dosing of study treatment. Serum ammonia level > 200 μg/dL at Screening or Baseline. INR > 2.3 at Screening or Baseline. Transjugular intrahepatic portosystemic shunt and/or have undergone portacaval shunting.Documented presence of esophagus varices (stage III or IV) based on the evaluation of the participant's medical history at Screening and Baseline. History, clinical evidence or suspicion of a hepato-cellular carcinoma (HCC) based on sonographical and/or laboratory results (i.e. α-Fetoprotein (AFP) > 12 IU/mL [2 × upper limit of normal [ULN] at screening). Severe ascites and/or pleural effusion. Participants with clinical evidence or suspected acute liver failure as judged by the Investigator. Healthy control participants (Group 4) Significant illness which has not resolved within 2 weeks prior to first dosing of study treatment. Liver disease or liver injury as indicated by abnormal liver function tests at Screening. Any single parameter of alanine aminotransferase (ALT), AST, gamma-glutamyl transferase (GGT) or alkaline phosphatase (ALP) exceeding 1.2 x upper limit of normal (ULN) or ≥ 1.5 x ULN total bilirubin (TBL) OR any elevation above ULN of more than one parameter of ALT, AST, GGT, ALP or TBL. Hemoglobin levels below 11.0 g/dL for males and 10.0 g/dL for females at Screening or Baseline.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1; LOU064 (Remibrutinib)<br>Mild and Moderate HI participants and matching healthy participants | Drug: Part 1; LOU064 (Remibrutinib)<br>* 25 mg remibrutinib (5.5 days)<br>|
| Experimental: Part 2; LOU064 (Remibrutinib)<br>Severe HI participants and matching healthy participants | Drug: Part 2; LOU064 (Remibrutinib)<br>* 25 mg remibrutinib (5.5 days)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cmax | The maximum (peak) observed concentration following multiple-dose administration (mass/volume) | 72 hours | 
| AUCtau | The AUC from time zero to the end of the dosing interval (tau) following multiple-dose administration (mass*time/volume) | 72 hours | 
| AUClast | The area under the curve (AUC) from time zero to the last measurable concentration sampling time (mass*time/volume) | 72 hours | 
| Tmax | The time to reach maximum (peak)concentration following multiple-dose administration (time) | 72 hours | 
| T1/2 | The elimination half-life associated with the terminal slope (lambda_z) of a semi logarithmic concentration-time curve (time) | 72 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Unbound fraction; Cmax | The maximum (peak) observed concentration following multiple-dose administration (mass/volume) | 8 days | 
| Number of participants with adverse events | An adverse event (AE) is any untoward medical occurrence (e.g. any unfavorable and unintended sign [including abnormal laboratory findings], symptom or disease) in a clinical investigation participant after providing written informed consent for participation in the study. | 8 days | 
| Unbound fraction; AUCtau | The AUC from time zero to the end of the dosing interval (tau) following multiple-dose administration (mass*time/volume) | 8 days | 
| Unbound fraction; AUClast | The area under the curve (AUC) from time zero to the last measurable concentration sampling time (mass*time/volume) | 8 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Remibrutinib (LOU064), hepatic impairment, PK, safety, tolerability, Child-Pugh