Safety and Pharmacokinetics Study of Linzagolix in Female Subjects With Normal and Impaired Hepatic Function

Study Overview
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Brief Summary
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The primary objective of this study is to assess the pharmacokinetics (PK) of linzagolix in subjects with varying degrees of impaired hepatic function compared to match control subjects with normal hepatic function

Detailed Description
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This is a Phase 1, non-randomized, open label, single-dose study to evaluate the effect of varying degrees of impaired hepatic function (i.e., mild, moderate, and severe Hepatic Impairment (HI)) on the PK, safety, and tolerability of linzagolix and its major metabolite, KP017. Up to 28 adult female participants will be enrolled.

Official Title
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Evaluation of the Safety and Pharmacokinetics of a Single Dose of Linzagolix in Female Subjects With Normal and Impaired Hepatic Function

Conditions
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Hepatic Impairment, Healthy Participants

Intervention / Treatment
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* Drug: Linzagolix


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Hepatic Impaired Subjects Adult female, 18-75 years of age, inclusive, at screening Has a BMI ≥ 18.0 and ≤ 42.0 kg/m^2 and weight ≥ 40 kg, at screening Aside from HI, be sufficiently healthy for study participation based upon medical history, physical examination, vital signs, electrocardiograms (ECGs), and screening clinical laboratory profiles, as deemed by the Principal Investigator (PI) or designee Has a score on the Child-Pugh scale at screening as follows: Severe HI: ≥ 10 and ≤ 15 Moderate HI: ≥ 7 and ≤ 9 Mild HI: ≥ 5 and ≤ 6 Has a diagnosis of chronic (> 6 months), stable (no acute episodes of illness within the previous 2 months due to deterioration in hepatic function) hepatic insufficiency with features of cirrhosis due to any etiology Healthy Subjects Healthy adult female will be matched based upon age and BMI Medically healthy with no clinically significant medical history, physical examination, laboratory profiles, vital signs or ECGs, as deemed by the PI or designee. Key Exclusion Criteria: Hepatic Impaired Subjects Has a clinically active Grade 3 or 4 encephalopathy Has fluctuating or rapidly deteriorating hepatic function within the screening period, and up to 30 days prior to Day 1, in the opinion of the PI and Sponsor Has history of liver or other solid organ transplant Had any major surgery within 4 weeks prior to dosing Has a surgical (e.g., hepatectomy, nephrectomy, digestive organ resection) or medical condition other than HI which might significantly alter the absorption, distribution, metabolism, or excretion of linzagolix and its metabolites, or which may jeopardize the subject's safety in case of participation in the study in the opinion of the PI or designee Healthy Subjects Has any clinically significant illness, as judged by the PI or designee, within 4 weeks prior to dosing Has laboratory values at screening or check-in which are deemed to be clinically significant (especially derangement within liver function test), unless agreed in advance by the PI and the Sponsor

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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Female

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: Basic Science
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Normal Hepatic Function<br>Healthy participants with Normal Hepatic Function | Drug: Linzagolix<br>* A single dose of 200 mg linzagolix (2 tablets of 100 mg) will be administered orally under fasting conditions<br>|
| Experimental: Mild Hepatic Impairment<br>Presence of Mild Hepatic Impairment (score of 5 to 6, on the Child Pugh scale and with features of cirrhosis due to any etiology) | Drug: Linzagolix<br>* A single dose of 200 mg linzagolix (2 tablets of 100 mg) will be administered orally under fasting conditions<br>|
| Experimental: Moderate Hepatic Impairment<br>Presence of Moderate Hepatic Impairment (score of 7 to 9, on the Child Pugh scale and with features of cirrhosis due to any etiology) | Drug: Linzagolix<br>* A single dose of 200 mg linzagolix (2 tablets of 100 mg) will be administered orally under fasting conditions<br>|
| Experimental: Severe Hepatic Impairment<br>Presence of Severe Hepatic Impairment (score of 10 to 15 on the Child Pugh scale and with features of cirrhosis due to any etiology) | Drug: Linzagolix<br>* A single dose of 200 mg linzagolix (2 tablets of 100 mg) will be administered orally under fasting conditions<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma pharmacokinetic (PK) parameter Cmax of linzagolix and of KP017 | Measurement of effect of hepatic impairment on PK of linzagolix and its metabolite KP017 by assessment of the maximum plasma concentration (Cmax). Cmax directly determined from the plasma concentration-time profiles | predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120 hours post-dose | 
| Plasma PK parameter Tmax of linzagolix and of KP017 | Measurement of effect of hepatic impairment on PK of linzagolix and its metabolite KP017 by assessment of the Time to reach Cmax (Tmax) | predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120 hours post-dose | 
| Plasma PK parameter AUC0-t of linzagolix and of KP017 | Measurement of effect of hepatic impairment on PK of linzagolix and its metabolite KP017 by assessment of the AUC0-t (area under the concentration time curve, from time 0 to the last observed non-zero concentration) | predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120 hours post-dose | 
| Plasma PK parameter T1/2 of linzagolix and of KP017 | Measurement of effect of hepatic impairment on PK of linzagolix and its metabolite KP017 by assessment of the T1/2 (Terminal half life) | predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120 hours post-dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment emergent Adverse Events | Assessment of safety and tolerability of a single dose of linzagolix in hepatic impaired subjects compared with healthy control subjects by assessing the number, frequency and severity of treatment emergent Adverse Events | Day 1 to 14 days post-dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Linzagolix, OBE2109, Hepatic Impairment, Hepatic Insufficiency, Liver Diseases, Clinical pharmacology study