A Multiple-Dose Study of Bulevirtide in Participants With Normal and Impaired Renal Function

Phase 1

Completed

Conditions: Chronic Hepatitis D Infection

Interventions: Drug: Bulevirtide (BLV)

Registration Number: NCT05760300

Lead Sponsor: Gilead Sciences

Brief Summary: The goals of this study are to compare the amount of study drug, bulevirtide (BLV), that gets into the bloodstream and how long it takes for the body to eliminate it, measure the effect of BLV on bile acids, and evaluate the safety and tolerability of multiple doses of BLV in participants with normal or impaired renal (kidney) function.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 41

Inclusion Criteria

All Individuals:

Body mass index (BMI) of at least ≥ 18.0 kg/m^2 and ≤ 40.0 kg/m^2 at screening.
No clinically significant abnormalities on electrocardiogram (ECG)
No known Liver Disease (Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT)) ≤ 3 x upper limit of normal (ULN) at screening.

Individuals with Renal Impairment (RI):

Have RI classification at screening that has been unchanged during the 90 days prior to study drug dosing.
Estimated Glomerular Filtration Rate (eGFR) must be the following (using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation (Inker 2021)) based on serum creatinine as measured at the screening evaluation:
- Severe RI (Groups A and B): eGFR ≥ 15 to ≤ 29 mL/min/1.73 m^2
- Moderate RI (Group C): eGFR ≥ 30 to ≤ 59 mL/min/1.73 m^2
- Mild RI (Group D): eGFR ≥ 60 to ≤ 89 mL/min/1.73 m^2
Hemoglobin ≥ 9 g/dL at screening.
Individuals with cardiovascular disease, hypertension, diabetes mellitus, hyperlipidemia, hypothyroidism, osteoporosis, and many others) may be included provided that these diseases/conditions are clinically stable.

Matched Control Individuals:

Have an eGFR of at least 90 mL/min/1.73 m^2 (using the CKD-EPI equation) based on serum creatinine as measured at screening evaluation.
Matched for sex, age (± 10 years), and BMI (± 20%, 18.0 ≤ BMI ≤ 40.0 kg/m^2) with the respective participant in the RI group.

Key

Exclusion Criteria

All Individuals:

Positive human immunodeficiency virus (HIV) test, hepatitis B surface antigen (HBsAg), or hepatitis C virus (HCV) antibody with detectable HCV viral ribonucleic acid (RNA) at screening.
Have any serious or active medical or psychiatric illness (including depression) that, in the opinion of the investigator, would interfere with participant treatment, assessment, or compliance with the protocol.

Individuals with RI:

Recent history of reception of any blood or blood products or history of major bleeding within 4 weeks of dosing.
Positive test for drugs of abuse, including alcohol at screening or admission, with the exception of opioids and tetrahydrocannabinol (THC, marijuana) under prescription and verified by the investigator as for pain management.
Received treatment with trimethoprim or cimetidine or tenofovir prodrugs (tenofovir disoproxil fumarate (TDF) or tenofovir alafenamide (TAF)) (affects elimination of creatinine) or with competitors of renal tubular excretion (eg, probenecid, chronic high-dose nonsteroidal anti-inflammatory drugs) within 28 days of Day -1.
Received known nephrotoxic drugs (eg, aminoglycosides, amphotericin B, vancomycin, cidofovir, foscarnet, cisplatin, pentamidine, cyclosporine, tacrolimus, herbal remedies (eg, compounds with aristolochic acid)) within 28 days of Day -1.
Individuals requiring or anticipated to require dialysis within 90 days of study entry.
Serum albumin concentration <25 g/L.
Uncontrolled treated/untreated hypertension (defined as a mean of 3 repeated measurements for systolic blood pressure ≥180 mmHg and/or diastolic blood pressure ≥110 mmHg); current or documented history of repeated clinically significant hypotension or severe episodes of orthostatic hypotension (systolic blood pressure <90 mmHg and/or diastolic blood pressure <50 mmHg).

Matched Control Individuals:

Have taken any prescription medications or over-the-counter medications, including herbal products, within 28 days prior to start of study drug dosing, with the exception of vitamins

Note: Other protocol defined Inclusion/Exclusion criteria may apply

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Group A: BLV 2 mg (Severe RI Group)	Bulevirtide (BLV)	Participants with severe renal impairment (RI) \[estimated glomerular filtration rate (eGFR) ≥ 15 to ≤ 29 mL/min/1.73 m\^2\] will receive bulevirtide (BLV) 2 mg, administered subcutaneously (SC), once daily (QD), for 6 days.
Group A: BLV 2 mg (Matched Control)	Bulevirtide (BLV)	Participants with normal renal function (matched control group) \[eGFR ≥ 90 mL/min/1.73 m\^2\] will receive BLV 2 mg, administered SC, QD, for 6 days.
Group B: BLV 10 mg (Severe RI Group)	Bulevirtide (BLV)	Participants with severe RI \[eGFR ≥ 15 to ≤ 29 mL/min/1.73 m\^2\] will receive BLV 10 mg, administered SC, QD, for 6 days.
Group B: BLV 10 mg (Matched Control)	Bulevirtide (BLV)	Participants with normal renal function (matched control group) \[eGFR ≥ 90 mL/min/1.73 m\^2\] will receive BLV 10 mg, administered SC, QD, for 6 days.

Primary Outcome Measures

Name	Time	Method
Pharmacokinetic (PK) Parameter for Bulevirtide (BLV): AUCtau	Day 6: Predose (≤ 30 minutes before dose), 0.5, 1, 1.5, 2, 3, 4, 6, 9, 12, and 24 hours postdose	AUCtau is defined as the area under the concentration versus time curve over the dosing interval at steady state at Day 6.
PK Parameter for BLV: Cmax ss	Day 6: Predose (≤ 30 minutes before dose), 0.5, 1, 1.5, 2, 3, 4, 6, 9, 12, and 24 hours postdose	Cmax is defined as the maximum observed concentration of drug at steady state at Day 6.

Secondary Outcome Measures

Name	Time	Method
PK Parameter for BLV: AUC0-24	Day 1: Predose (≤ 30 minutes before dose), 0.5, 1, 1.5, 2, 3, 4, 6, 9, 12, and 24 hours postdose	AUC0-24 is defined as the concentration of drug over time between time 0 hour and time 24 hours.
PK Parameter for BLV: Cmax	Day 1: Predose (≤ 30 minutes before dose), 0.5, 1, 1.5, 2, 3, 4, 6, 9, 12, and 24 hours postdose	Cmax is defined as the maximum observed concentration of drug.
PK Parameter for BLV: Tmax	Day 1: Predose (≤ 30 minutes before dose), 0.5, 1, 1.5, 2, 3, 4, 6, 9, 12, and 24 hours postdose; Day 6: Predose (≤ 30 minutes before dose), 0.5, 1, 1.5, 2, 3, 4, 6, 9, 12, 24, and 48 hours postdose	Tmax is defined as the time (observed time point) of Cmax.
PK Parameter for BLV: t1/2	Day 1: Predose (≤ 30 minutes before dose), 0.5, 1, 1.5, 2, 3, 4, 6, 9, 12, and 24 hours postdose; Day 6: Predose (≤ 30 minutes before dose), 0.5, 1, 1.5, 2, 3, 4, 6, 9, 12, 24, and 48 hours postdose	t1/2 is defined as the estimate of the terminal elimination half-life of the drug.
PK Parameter for BLV: CLss/F	Day 6: Predose (≤ 30 minutes before dose), 0.5, 1, 1.5, 2, 3, 4, 6, 9, 12, 24, and 48 hours postdose	CLss/F is defined as the apparent clearance at steady state at Day 6. CLss/F = Dose/AUCtau, where "Dose" is the dose of the drug per interval.
PK Parameter for BLV: Vss/F	Day 6: Predose (≤ 30 minutes before dose), 0.5, 1, 1.5, 2, 3, 4, 6, 9, 12, 24, and 48 hours postdose	Vss/F is defined as the apparent volume of distribution at steady state at Day 6.
Pharmacodynamic (PD) Parameter for Total Bile Acids (BA): Cmax	Day 1: Predose (≤ 30 minutes before dose), 0.5, 1, 1.5, 2, 3, 4, 6, 9, 12, and 24 hours postdose; Day 6: Predose (≤ 30 minutes before dose), 0.5, 1, 1.5, 2, 3, 4, 6, 9, 12, 24, and 48 hours postdose	The PD effect of BLV was evaluated on plasma BA in participants with RI compared to matched control participants with normal renal function. Cmax is defined as the maximum observed concentration of total BA. The plasma bile acid panel includes 15 individual bile acids, and total BA is the sum of these 15 components.
PD Parameter for Total BA: AUC0-24	Days 1 and 6: Predose (≤ 30 minutes before dose), 0.5, 1, 1.5, 2, 3, 4, 6, 9, 12, and 24 hours postdose	The PD effect of BLV was evaluated on plasma BA in participants with RI compared to matched control participants with normal renal function. AUC0-24 is defined as the concentration of total BA over time between time 0 hour and time 24 hours. The plasma bile acid panel includes 15 individual bile acids, and total BA is the sum of these 15 components.
PD Parameter for Total BA: NetAUC	Day 1: Predose (≤ 30 minutes before dose), 0.5, 1, 1.5, 2, 3, 4, 6, 9, 12, and 24 hours postdose; Day 6: Predose (≤ 30 minutes before dose), 0.5, 1, 1.5, 2, 3, 4, 6, 9, 12, 24, and 48 hours postdose	The PD effect of BLV was evaluated on plasma BA in participants with RI compared to matched control participants with normal renal function. NetAUC is defined as positive portion of area under the baseline-adjusted biomarker concentration versus time curve over the dosing interval. The plasma bile acid panel includes 15 individual bile acids, and total BA is the sum of these 15 components.
Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs)	Up to 36 days	An adverse event (AE) was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. TEAEs were defined as any AEs with an onset date on or after the study drug start date and no later than 30 days after permanent discontinuation of study drug and/or if the AE onset date was the same as the date of study drug start date then the AE onset time must have been on or after the study drug start time. If the AE onset time was missing when the start dates was the same, the AE was considered treatment emergent.and/or any AEs leading to premature discontinuation of study drug.
Percentage of Participants Experiencing Laboratory Abnormalities	Up to 36 days	A treatment-emergent laboratory abnormality was any value that was outside the reference range at any time post baseline up to and including the date of last study drug dose plus 30 days. Grading categories are determined by Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Grade 1: mild, Grade 2: moderate, Grade 3: severe or medically significant, Grade 4: life-threatening; Grade 5: Death. Participants with at least a 1 grade increased from baseline for an individual laboratory test where the maximum post baseline laboratory abnormality was grade 1 or higher and grade 3 or higher were reported. The maximum post baseline toxicity grade across all tests for an individual participant was used in analysis.

Trial Locations

Locations (9): Velocity Clinical Research, New Smyrna Beach
🇺🇸
Edgewater, Florida, United States
Clinical Pharmacology of Miami, LLC
🇺🇸
Miami, Florida, United States
Advanced Pharma CR, LLC
🇺🇸
Miami, Florida, United States
Panax Clinical Research
🇺🇸
Miami Lakes, Florida, United States
Floridian Clinical Research, LLC
🇺🇸
Miami Lakes, Florida, United States
Global Clinical Professionals Research
🇺🇸
St. Petersburg, Florida, United States
Genesis Clinical Research, LLC
🇺🇸
Tampa, Florida, United States
Massachusetts General Hospital - Renal Associates Clinic
🇺🇸
Boston, Massachusetts, United States
Nucleus Network
🇺🇸
Saint Paul, Minnesota, United States
Velocity Clinical Research, New Smyrna Beach
🇺🇸Edgewater, Florida, United States