Trial Outcomes & Findings for First-Time-in-Human (FTIH) Study to Evaluate the Safety, Tolerability and Pharmacokinetics (PK) of VH4004280 in Healthy Participants (NCT NCT05163522)

Last Updated: 2025-07-30

Results Overview

An AE was defined as any untoward medical occurrence in a participant, temporally associated with the use of a study intervention whether or not considered related to the study intervention. The Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric AE was used for all AE severity grading, where Grade 1=Mild symptoms causing no or minimal interference with usual social \& functional activities with intervention not indicated, 2=Moderate symptoms causing greater than minimal interference with usual social \& functional activities with intervention indicated, 3=Severe symptoms causing inability to perform usual social \& functional activities with intervention or hospitalization indicated, 4=Potentially life-threatening symptoms causing inability to perform basic self-care functions with intervention indicated to prevent permanent impairment, persistent disability or death, 5=Death.

Recruitment status

COMPLETED

Study phase

PHASE1

Target enrollment

73 participants

Primary outcome timeframe

Up to Day 49

Results posted on

2025-07-30

Participant Flow

Participant milestones

Participant milestones
Measure	Part 1 Single Ascending Dose (SAD): Placebo Powder-in-bottle (PiB) Healthy participants were given a single oral dose of placebo on Day 1 and were followed up to approximately Day 49.	Part 1 (SAD): VH4004280 10 mg PiB Healthy participants were given a single oral dose of 10 mg VH4004280 PiB on Day 1 and were followed up to approximately Day 49.	Part 1 (SAD): VH4004280 50 mg PiB Healthy participants were given a single oral dose of 50 mg VH4004280 PiB on Day 1 and were followed up to approximately Day 49.	Part 1 (SAD): VH4004280 150 mg PiB Healthy participants were given a single oral dose of 150 mg VH4004280 PiB on Day 1 and were followed up to approximately Day 49.	Part 1 (SAD): VH4004280 450 mg PiB Healthy participants were given a single oral dose of 450 mg VH4004280 PiB on Day 1 and were followed up to approximately Day 49.	Part 1 (SAD): VH4004280 900 mg PiB Healthy participants were given a single oral dose of 900 mg VH4004280 PiB on Day 1 and were followed up to approximately Day 49.	Part 2 Multiple Ascending Dose (MAD): Placebo PiB Healthy participants were given a dose of placebo once daily (QD) for a 14-day period and were followed up to approximately Day 63.	Part 2 (MAD): VH4004280 100 mg PiB Healthy participants were given a dose of 100 mg VH4004280 PiB QD for a 14-day period and were followed up to approximately Day 63.	Part 2 (MAD): VH4004280 250 mg + Midazolam (MDZ) PiB Healthy participants were given a dose of 250 mg VH4004280 PiB QD for a 14-day period, and a single dose of Midazolam on days 1, 2, and 15, and were followed up to approximately Day 63.	Part 2 (MAD): VH4004280 350 mg PiB Healthy participants were given a dose of 350 mg VH4004280 PiB QD for a 14-day period and were followed up to approximately Day 63.	Part 3 (Single Dose): VH4004280 450 mg Tablet Healthy participants were given a single oral dose of VH4004280 450 mg tablet at Day 1 and were followed up to approximately Day 49.
Overall Study STARTED	10	6	7	6	6	6	6	6	8	6	6
Overall Study COMPLETED	10	6	6	6	6	6	6	6	8	6	6
Overall Study NOT COMPLETED	0	0	1	0	0	0	0	0	0	0	0

Reasons for withdrawal

Reasons for withdrawal
Measure	Part 1 Single Ascending Dose (SAD): Placebo Powder-in-bottle (PiB) Healthy participants were given a single oral dose of placebo on Day 1 and were followed up to approximately Day 49.	Part 1 (SAD): VH4004280 10 mg PiB Healthy participants were given a single oral dose of 10 mg VH4004280 PiB on Day 1 and were followed up to approximately Day 49.	Part 1 (SAD): VH4004280 50 mg PiB Healthy participants were given a single oral dose of 50 mg VH4004280 PiB on Day 1 and were followed up to approximately Day 49.	Part 1 (SAD): VH4004280 150 mg PiB Healthy participants were given a single oral dose of 150 mg VH4004280 PiB on Day 1 and were followed up to approximately Day 49.	Part 1 (SAD): VH4004280 450 mg PiB Healthy participants were given a single oral dose of 450 mg VH4004280 PiB on Day 1 and were followed up to approximately Day 49.	Part 1 (SAD): VH4004280 900 mg PiB Healthy participants were given a single oral dose of 900 mg VH4004280 PiB on Day 1 and were followed up to approximately Day 49.	Part 2 Multiple Ascending Dose (MAD): Placebo PiB Healthy participants were given a dose of placebo once daily (QD) for a 14-day period and were followed up to approximately Day 63.	Part 2 (MAD): VH4004280 100 mg PiB Healthy participants were given a dose of 100 mg VH4004280 PiB QD for a 14-day period and were followed up to approximately Day 63.	Part 2 (MAD): VH4004280 250 mg + Midazolam (MDZ) PiB Healthy participants were given a dose of 250 mg VH4004280 PiB QD for a 14-day period, and a single dose of Midazolam on days 1, 2, and 15, and were followed up to approximately Day 63.	Part 2 (MAD): VH4004280 350 mg PiB Healthy participants were given a dose of 350 mg VH4004280 PiB QD for a 14-day period and were followed up to approximately Day 63.	Part 3 (Single Dose): VH4004280 450 mg Tablet Healthy participants were given a single oral dose of VH4004280 450 mg tablet at Day 1 and were followed up to approximately Day 49.
Overall Study Withdrawal by Subject	0	0	1	0	0	0	0	0	0	0	0

Baseline Characteristics

First-Time-in-Human (FTIH) Study to Evaluate the Safety, Tolerability and Pharmacokinetics (PK) of VH4004280 in Healthy Participants

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Part 1 Single Ascending Dose (SAD): Placebo Powder-in-bottle (PiB) n=10 Participants Healthy participants were given a single oral dose of placebo on Day 1 and were followed up to approximately Day 49.	Part 1 (SAD): VH4004280 10 mg PiB n=6 Participants Healthy participants were given a single oral dose of 10 mg VH4004280 PiB on Day 1 and were followed up to approximately Day 49.	Part 1 (SAD): VH4004280 50 mg PiB n=7 Participants Healthy participants were given a single oral dose of 50 mg VH4004280 PiB on Day 1 and were followed up to approximately Day 49.	Part 1 (SAD): VH4004280 150 mg PiB n=6 Participants Healthy participants were given a single oral dose of 150 mg VH4004280 PiB on Day 1 and were followed up to approximately Day 49.	Part 1 (SAD): VH4004280 450 mg PiB n=6 Participants Healthy participants were given a single oral dose of 450 mg VH4004280 PiB on Day 1 and were followed up to approximately Day 49.	Part 1 (SAD): VH4004280 900 mg PiB n=6 Participants Healthy participants were given a single oral dose of 900 mg VH4004280 PiB on Day 1 and were followed up to approximately Day 49.	Part 2 Multiple Ascending Dose (MAD): Placebo PiB n=6 Participants Healthy participants were given a dose of placebo once daily (QD) for a 14-day period and were followed up to approximately Day 63.	Part 2 (MAD): VH4004280 100 mg PiB n=6 Participants Healthy participants were given a dose of 100 mg VH4004280 PiB QD for a 14-day period and were followed up to approximately Day 63.	Part 2 (MAD): VH4004280 250 mg + Midazolam (MDZ) PiB n=8 Participants Healthy participants were given a dose of 250 mg VH4004280 PiB QD for a 14-day period, and a single dose of Midazolam on days 1, 2, and 15, and were followed up to approximately Day 63.	Part 2 (MAD): VH4004280 350 mg PiB n=6 Participants Healthy participants were given a dose of 350 mg VH4004280 PiB QD for a 14-day period and were followed up to approximately Day 63.	Part 3 (Single Dose): VH4004280 450 mg Tablet n=6 Participants Healthy participants were given a single oral dose of VH4004280 450 mg tablet at Day 1 and were followed up to approximately Day 49.	Total n=73 Participants Total of all reporting groups
Age, Continuous	34.0 YEARS STANDARD_DEVIATION 7.21 • n=5 Participants	33.8 YEARS STANDARD_DEVIATION 8.13 • n=7 Participants	30.0 YEARS STANDARD_DEVIATION 9.36 • n=5 Participants	31.5 YEARS STANDARD_DEVIATION 6.28 • n=4 Participants	27.7 YEARS STANDARD_DEVIATION 6.44 • n=21 Participants	31.5 YEARS STANDARD_DEVIATION 6.02 • n=8 Participants	36.2 YEARS STANDARD_DEVIATION 7.68 • n=8 Participants	33.5 YEARS STANDARD_DEVIATION 9.09 • n=24 Participants	34.0 YEARS STANDARD_DEVIATION 10.74 • n=42 Participants	42.3 YEARS STANDARD_DEVIATION 11.08 • n=42 Participants	43.5 YEARS STANDARD_DEVIATION 7.06 • n=42 Participants	34.27 YEARS STANDARD_DEVIATION 8.898 • n=42 Participants
Sex/Gender, Customized Male	10 Participants n=5 Participants	6 Participants n=7 Participants	7 Participants n=5 Participants	6 Participants n=4 Participants	6 Participants n=21 Participants	6 Participants n=8 Participants	6 Participants n=8 Participants	6 Participants n=24 Participants	8 Participants n=42 Participants	6 Participants n=42 Participants	5 Participants n=42 Participants	72 Participants n=42 Participants
Sex/Gender, Customized Female	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	0 Participants n=8 Participants	0 Participants n=8 Participants	0 Participants n=24 Participants	0 Participants n=42 Participants	0 Participants n=42 Participants	1 Participants n=42 Participants	1 Participants n=42 Participants
Race/Ethnicity, Customized Asian	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	0 Participants n=8 Participants	0 Participants n=8 Participants	2 Participants n=24 Participants	1 Participants n=42 Participants	0 Participants n=42 Participants	2 Participants n=42 Participants	7 Participants n=42 Participants
Race/Ethnicity, Customized Black or African American	3 Participants n=5 Participants	2 Participants n=7 Participants	1 Participants n=5 Participants	3 Participants n=4 Participants	5 Participants n=21 Participants	2 Participants n=8 Participants	2 Participants n=8 Participants	4 Participants n=24 Participants	6 Participants n=42 Participants	3 Participants n=42 Participants	3 Participants n=42 Participants	34 Participants n=42 Participants
Race/Ethnicity, Customized Native Hawaiian or other Pacific Islander	1 Participants n=5 Participants	1 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	0 Participants n=8 Participants	0 Participants n=8 Participants	0 Participants n=24 Participants	0 Participants n=42 Participants	0 Participants n=42 Participants	0 Participants n=42 Participants	2 Participants n=42 Participants
Race/Ethnicity, Customized White	4 Participants n=5 Participants	2 Participants n=7 Participants	5 Participants n=5 Participants	3 Participants n=4 Participants	1 Participants n=21 Participants	4 Participants n=8 Participants	4 Participants n=8 Participants	0 Participants n=24 Participants	1 Participants n=42 Participants	3 Participants n=42 Participants	1 Participants n=42 Participants	28 Participants n=42 Participants
Race/Ethnicity, Customized Multiple	1 Participants n=5 Participants	1 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	0 Participants n=8 Participants	0 Participants n=8 Participants	0 Participants n=24 Participants	0 Participants n=42 Participants	0 Participants n=42 Participants	0 Participants n=42 Participants	2 Participants n=42 Participants

PRIMARY outcome

Timeframe: Up to Day 49

Outcome measures

Outcome measures
Measure	Part 2 (MAD): VH4004280 100 mg PiB n=6 Participants Healthy participants were given a dose of 100 mg VH4004280 PiB QD for a 14-day period and were followed up to approximately Day 63.	Part 2 (MAD): VH4004280 250 mg + Midazolam (MDZ) PiB n=7 Participants Healthy participants were given a dose of 250 mg VH4004280 PiB QD for a 14-day period, and a single dose of Midazolam on days 1, 2, and 15, and were followed up to approximately Day 63.	Part 2 (MAD): VH4004280 350 mg PiB n=6 Participants Healthy participants were given a dose of 350 mg VH4004280 PiB QD for a 14-day period and were followed up to approximately Day 63.	Part 3 (Single Dose): VH4004280 450 mg Tablet n=10 Participants Healthy participants were given a single oral dose of VH4004280 450 mg tablet at Day 1 and were followed up to approximately Day 49.	Part 1 (SAD): VH4004280 450 mg PiB n=6 Participants Healthy participants were given a single oral dose of 450 mg VH4004280 PiB on Day 1 and were followed up to approximately Day 49.	Part 1 (SAD): VH4004280 900 mg PiB n=6 Participants Healthy participants were given a single oral dose of 900 mg VH4004280 PiB on Day 1 and were followed up to approximately Day 49.
Part 1: Number of Participants With Any Adverse Events (AEs) and by Severity Any AEs	2 Participants	3 Participants	0 Participants	4 Participants	0 Participants	1 Participants
Part 1: Number of Participants With Any Adverse Events (AEs) and by Severity Grade 2 AEs	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Part 1: Number of Participants With Any Adverse Events (AEs) and by Severity Grade 1 AEs	2 Participants	3 Participants	0 Participants	3 Participants	0 Participants	1 Participants
Part 1: Number of Participants With Any Adverse Events (AEs) and by Severity Grade 3 AEs	0 Participants	0 Participants	0 Participants	1 Participants	0 Participants	0 Participants
Part 1: Number of Participants With Any Adverse Events (AEs) and by Severity Grade 4 AEs	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Part 1: Number of Participants With Any Adverse Events (AEs) and by Severity Grade 5 AEs	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants

PRIMARY outcome

Timeframe: Up to Day 63

The DAIDS Table for Grading the Severity of Adult and Pediatric AE was used for all AE severity grading, where Grade 1=Mild symptoms causing no or minimal interference with usual social \& functional activities with intervention not indicated, 2=Moderate symptoms causing greater than minimal interference with usual social \& functional activities with intervention indicated, 3=Severe symptoms causing inability to perform usual social \& functional activities with intervention or hospitalization indicated, 4=Potentially life-threatening symptoms causing inability to perform basic self-care functions with intervention indicated to prevent permanent impairment, persistent disability or death, 5=Death.

Outcome measures

Outcome measures
Measure	Part 2 (MAD): VH4004280 100 mg PiB n=6 Participants Healthy participants were given a dose of 100 mg VH4004280 PiB QD for a 14-day period and were followed up to approximately Day 63.	Part 2 (MAD): VH4004280 250 mg + Midazolam (MDZ) PiB n=8 Participants Healthy participants were given a dose of 250 mg VH4004280 PiB QD for a 14-day period, and a single dose of Midazolam on days 1, 2, and 15, and were followed up to approximately Day 63.	Part 2 (MAD): VH4004280 350 mg PiB n=6 Participants Healthy participants were given a dose of 350 mg VH4004280 PiB QD for a 14-day period and were followed up to approximately Day 63.	Part 3 (Single Dose): VH4004280 450 mg Tablet n=6 Participants Healthy participants were given a single oral dose of VH4004280 450 mg tablet at Day 1 and were followed up to approximately Day 49.	Part 1 (SAD): VH4004280 450 mg PiB Healthy participants were given a single oral dose of 450 mg VH4004280 PiB on Day 1 and were followed up to approximately Day 49.	Part 1 (SAD): VH4004280 900 mg PiB Healthy participants were given a single oral dose of 900 mg VH4004280 PiB on Day 1 and were followed up to approximately Day 49.
Part 2: Number of Participants With Any AEs and by Severity Grade 1 AEs	4 Participants	4 Participants	2 Participants	3 Participants	—	—
Part 2: Number of Participants With Any AEs and by Severity Grade 2 AEs	0 Participants	3 Participants	0 Participants	0 Participants	—	—
Part 2: Number of Participants With Any AEs and by Severity Grade 3 AEs	0 Participants	0 Participants	1 Participants	0 Participants	—	—
Part 2: Number of Participants With Any AEs and by Severity Grade 4 AEs	0 Participants	0 Participants	1 Participants	0 Participants	—	—
Part 2: Number of Participants With Any AEs and by Severity Grade 5 AEs	0 Participants	0 Participants	0 Participants	0 Participants	—	—
Part 2: Number of Participants With Any AEs and by Severity Any AEs	4 Participants	7 Participants	4 Participants	3 Participants	—	—

PRIMARY outcome

Timeframe: Up to Day 49

Population: The analysis was performed on the Safety Set which included all enrolled participants in Part 3 (Single Dose) who received 1 single dose of study treatment. The participants were analyzed according to the treatment they actually received.

Outcome measures

Outcome measures
Measure	Part 2 (MAD): VH4004280 100 mg PiB Healthy participants were given a dose of 100 mg VH4004280 PiB QD for a 14-day period and were followed up to approximately Day 63.	Part 2 (MAD): VH4004280 250 mg + Midazolam (MDZ) PiB Healthy participants were given a dose of 250 mg VH4004280 PiB QD for a 14-day period, and a single dose of Midazolam on days 1, 2, and 15, and were followed up to approximately Day 63.	Part 2 (MAD): VH4004280 350 mg PiB Healthy participants were given a dose of 350 mg VH4004280 PiB QD for a 14-day period and were followed up to approximately Day 63.	Part 3 (Single Dose): VH4004280 450 mg Tablet n=6 Participants Healthy participants were given a single oral dose of VH4004280 450 mg tablet at Day 1 and were followed up to approximately Day 49.	Part 1 (SAD): VH4004280 450 mg PiB Healthy participants were given a single oral dose of 450 mg VH4004280 PiB on Day 1 and were followed up to approximately Day 49.	Part 1 (SAD): VH4004280 900 mg PiB Healthy participants were given a single oral dose of 900 mg VH4004280 PiB on Day 1 and were followed up to approximately Day 49.
Part 3: Number of Participants With Any AEs and by Severity Any AEs	—	—	—	3 Participants	—	—
Part 3: Number of Participants With Any AEs and by Severity Grade 2 AEs	—	—	—	0 Participants	—	—
Part 3: Number of Participants With Any AEs and by Severity Grade 3 AEs	—	—	—	1 Participants	—	—
Part 3: Number of Participants With Any AEs and by Severity Grade 4 AEs	—	—	—	0 Participants	—	—
Part 3: Number of Participants With Any AEs and by Severity Grade 5 AEs	—	—	—	0 Participants	—	—
Part 3: Number of Participants With Any AEs and by Severity Grade 1 AEs	—	—	—	2 Participants	—	—

PRIMARY outcome

Timeframe: Up to Day 63

Number of participants who discontinued treatment due to AEs are presented.

Outcome measures

Outcome measures
Measure	Part 2 (MAD): VH4004280 100 mg PiB n=6 Participants Healthy participants were given a dose of 100 mg VH4004280 PiB QD for a 14-day period and were followed up to approximately Day 63.	Part 2 (MAD): VH4004280 250 mg + Midazolam (MDZ) PiB n=8 Participants Healthy participants were given a dose of 250 mg VH4004280 PiB QD for a 14-day period, and a single dose of Midazolam on days 1, 2, and 15, and were followed up to approximately Day 63.	Part 2 (MAD): VH4004280 350 mg PiB n=6 Participants Healthy participants were given a dose of 350 mg VH4004280 PiB QD for a 14-day period and were followed up to approximately Day 63.	Part 3 (Single Dose): VH4004280 450 mg Tablet n=6 Participants Healthy participants were given a single oral dose of VH4004280 450 mg tablet at Day 1 and were followed up to approximately Day 49.	Part 1 (SAD): VH4004280 450 mg PiB Healthy participants were given a single oral dose of 450 mg VH4004280 PiB on Day 1 and were followed up to approximately Day 49.	Part 1 (SAD): VH4004280 900 mg PiB Healthy participants were given a single oral dose of 900 mg VH4004280 PiB on Day 1 and were followed up to approximately Day 49.
Part 2: Number of Participants Discontinuing Treatment Due to AEs	0 Participants	0 Participants	0 Participants	0 Participants	—	—

PRIMARY outcome

Timeframe: Up to Day 49

Population: The analysis was performed on the Safety Set which included all enrolled participants in Part 1 (SAD) who received 1 full dose of study treatment. The participants were analyzed according to the treatment they actually received. Only those participants with data available at specified time points were analyzed for the specific category titles.

Blood samples were collected as assessed by protocol, at specific time points for laboratory analysis of bilirubin. Standard Deviation (SD)=0.0000 is defined as following: if all participants analyzed for a specific parameter at a specific time point have the same value, then SD is equal with 0.0000.

Outcome measures

Outcome measures
Measure	Part 2 (MAD): VH4004280 100 mg PiB n=6 Participants Healthy participants were given a dose of 100 mg VH4004280 PiB QD for a 14-day period and were followed up to approximately Day 63.	Part 2 (MAD): VH4004280 250 mg + Midazolam (MDZ) PiB n=7 Participants Healthy participants were given a dose of 250 mg VH4004280 PiB QD for a 14-day period, and a single dose of Midazolam on days 1, 2, and 15, and were followed up to approximately Day 63.	Part 2 (MAD): VH4004280 350 mg PiB n=6 Participants Healthy participants were given a dose of 350 mg VH4004280 PiB QD for a 14-day period and were followed up to approximately Day 63.	Part 3 (Single Dose): VH4004280 450 mg Tablet n=10 Participants Healthy participants were given a single oral dose of VH4004280 450 mg tablet at Day 1 and were followed up to approximately Day 49.	Part 1 (SAD): VH4004280 450 mg PiB n=6 Participants Healthy participants were given a single oral dose of 450 mg VH4004280 PiB on Day 1 and were followed up to approximately Day 49.	Part 1 (SAD): VH4004280 900 mg PiB n=6 Participants Healthy participants were given a single oral dose of 900 mg VH4004280 PiB on Day 1 and were followed up to approximately Day 49.
Part 1: Absolute Values of Liver Panel Parameters: Direct Bilirubin and Total Bilirubin Direct Bilirubin, Baseline (Day 1)	1.9950 Micromoles per liter (μmol/L) Standard Deviation 0.69810	2.9314 Micromoles per liter (μmol/L) Standard Deviation 0.83439	2.2800 Micromoles per liter (μmol/L) Standard Deviation 1.39621	2.5650 Micromoles per liter (μmol/L) Standard Deviation 1.20915	2.2800 Micromoles per liter (μmol/L) Standard Deviation 0.88304	2.8500 Micromoles per liter (μmol/L) Standard Deviation 0.88304
Part 1: Absolute Values of Liver Panel Parameters: Direct Bilirubin and Total Bilirubin Direct Bilirubin, Day 2	2.5080 Micromoles per liter (μmol/L) Standard Deviation 0.59891	2.9559 Micromoles per liter (μmol/L) Standard Deviation 1.17113	2.0520 Micromoles per liter (μmol/L) Standard Deviation 1.03734	2.7170 Micromoles per liter (μmol/L) Standard Deviation 1.24620	2.7360 Micromoles per liter (μmol/L) Standard Deviation 0.93661	3.0780 Micromoles per liter (μmol/L) Standard Deviation 1.27507
Part 1: Absolute Values of Liver Panel Parameters: Direct Bilirubin and Total Bilirubin Direct Bilirubin, Day 3	2.4795 Micromoles per liter (μmol/L) Standard Deviation 0.51584	2.7075 Micromoles per liter (μmol/L) Standard Deviation 0.98776	1.8525 Micromoles per liter (μmol/L) Standard Deviation 1.07834	2.7018 Micromoles per liter (μmol/L) Standard Deviation 1.15078	2.3655 Micromoles per liter (μmol/L) Standard Deviation 0.87472	3.0495 Micromoles per liter (μmol/L) Standard Deviation 1.23033
Part 1: Absolute Values of Liver Panel Parameters: Direct Bilirubin and Total Bilirubin Direct Bilirubin, Day 4	2.0235 Micromoles per liter (μmol/L) Standard Deviation 0.79043	2.7360 Micromoles per liter (μmol/L) Standard Deviation 0.87193	1.9836 Micromoles per liter (μmol/L) Standard Deviation 0.73151	2.4966 Micromoles per liter (μmol/L) Standard Deviation 1.36847	2.2515 Micromoles per liter (μmol/L) Standard Deviation 1.11566	2.6790 Micromoles per liter (μmol/L) Standard Deviation 1.02410
Part 1: Absolute Values of Liver Panel Parameters: Direct Bilirubin and Total Bilirubin Direct Bilirubin, Day 5	2.6505 Micromoles per liter (μmol/L) Standard Deviation 0.63753	2.5080 Micromoles per liter (μmol/L) Standard Deviation 0.73085	1.9665 Micromoles per liter (μmol/L) Standard Deviation 0.81472	2.7360 Micromoles per liter (μmol/L) Standard Deviation 1.18198	2.8215 Micromoles per liter (μmol/L) Standard Deviation 0.75512	2.8215 Micromoles per liter (μmol/L) Standard Deviation 0.98381
Part 1: Absolute Values of Liver Panel Parameters: Direct Bilirubin and Total Bilirubin Direct Bilirubin, Day 6	2.6505 Micromoles per liter (μmol/L) Standard Deviation 0.69038	2.3085 Micromoles per liter (μmol/L) Standard Deviation 0.77045	1.7955 Micromoles per liter (μmol/L) Standard Deviation 0.89673	2.5650 Micromoles per liter (μmol/L) Standard Deviation 0.68400	2.3655 Micromoles per liter (μmol/L) Standard Deviation 0.98182	2.8785 Micromoles per liter (μmol/L) Standard Deviation 1.17190
Part 1: Absolute Values of Liver Panel Parameters: Direct Bilirubin and Total Bilirubin Direct Bilirubin, Day 7	2.4795 Micromoles per liter (μmol/L) Standard Deviation 0.63753	2.2800 Micromoles per liter (μmol/L) Standard Deviation 0.70643	1.9095 Micromoles per liter (μmol/L) Standard Deviation 0.75253	2.8899 Micromoles per liter (μmol/L) Standard Deviation 1.24216	2.3370 Micromoles per liter (μmol/L) Standard Deviation 1.26894	2.5935 Micromoles per liter (μmol/L) Standard Deviation 0.95770
Part 1: Absolute Values of Liver Panel Parameters: Direct Bilirubin and Total Bilirubin Direct Bilirubin, Day 14	1.7100 Micromoles per liter (μmol/L) Standard Deviation 0.00000	1.5732 Micromoles per liter (μmol/L) Standard Deviation 0.37072	1.6245 Micromoles per liter (μmol/L) Standard Deviation 0.86351	2.3598 Micromoles per liter (μmol/L) Standard Deviation 0.77234	2.2230 Micromoles per liter (μmol/L) Standard Deviation 0.29618	2.6790 Micromoles per liter (μmol/L) Standard Deviation 1.60291
Part 1: Absolute Values of Liver Panel Parameters: Direct Bilirubin and Total Bilirubin Direct Bilirubin, Day 21	2.1375 Micromoles per liter (μmol/L) Standard Deviation 0.95974	2.3085 Micromoles per liter (μmol/L) Standard Deviation 0.94747	1.4250 Micromoles per liter (μmol/L) Standard Deviation 0.49166	2.5308 Micromoles per liter (μmol/L) Standard Deviation 1.19238	2.4795 Micromoles per liter (μmol/L) Standard Deviation 0.83598	2.0520 Micromoles per liter (μmol/L) Standard Deviation 0.98529
Part 1: Absolute Values of Liver Panel Parameters: Direct Bilirubin and Total Bilirubin Direct Bilirubin, Day 28	2.0805 Micromoles per liter (μmol/L) Standard Deviation 0.97585	2.3256 Micromoles per liter (μmol/L) Standard Deviation 0.81651	1.6530 Micromoles per liter (μmol/L) Standard Deviation 0.51490	2.8215 Micromoles per liter (μmol/L) Standard Deviation 1.67400	3.2490 Micromoles per liter (μmol/L) Standard Deviation 1.34646	2.3370 Micromoles per liter (μmol/L) Standard Deviation 0.88304
Part 1: Absolute Values of Liver Panel Parameters: Direct Bilirubin and Total Bilirubin Direct Bilirubin, Day 35	2.1090 Micromoles per liter (μmol/L) Standard Deviation 0.69810	2.2800 Micromoles per liter (μmol/L) Standard Deviation 0.91556	1.7385 Micromoles per liter (μmol/L) Standard Deviation 0.83364	2.3598 Micromoles per liter (μmol/L) Standard Deviation 1.25348	2.2800 Micromoles per liter (μmol/L) Standard Deviation 1.00682	1.9494 Micromoles per liter (μmol/L) Standard Deviation 0.76090
Part 1: Absolute Values of Liver Panel Parameters: Direct Bilirubin and Total Bilirubin Direct Bilirubin, Day 42	—	—	1.6530 Micromoles per liter (μmol/L) Standard Deviation 0.69810	2.9355 Micromoles per liter (μmol/L) Standard Deviation 2.10105	2.7360 Micromoles per liter (μmol/L) Standard Deviation 1.38499	2.7645 Micromoles per liter (μmol/L) Standard Deviation 1.44053
Part 1: Absolute Values of Liver Panel Parameters: Direct Bilirubin and Total Bilirubin Direct Bilirubin, Day 49	—	—	1.5675 Micromoles per liter (μmol/L) Standard Deviation 0.58657	2.9355 Micromoles per liter (μmol/L) Standard Deviation 1.48452	2.6505 Micromoles per liter (μmol/L) Standard Deviation 1.15852	2.6505 Micromoles per liter (μmol/L) Standard Deviation 1.49759
Part 1: Absolute Values of Liver Panel Parameters: Direct Bilirubin and Total Bilirubin Total Bilirubin, Baseline (Day 1)	12.5400 Micromoles per liter (μmol/L) Standard Deviation 3.84908	14.9014 Micromoles per liter (μmol/L) Standard Deviation 3.65613	12.2550 Micromoles per liter (μmol/L) Standard Deviation 8.47558	13.1670 Micromoles per liter (μmol/L) Standard Deviation 6.84237	11.6850 Micromoles per liter (μmol/L) Standard Deviation 5.00498	10.8300 Micromoles per liter (μmol/L) Standard Deviation 5.26132
Part 1: Absolute Values of Liver Panel Parameters: Direct Bilirubin and Total Bilirubin Total Bilirubin, Day 2	11.9130 Micromoles per liter (μmol/L) Standard Deviation 3.49052	13.4357 Micromoles per liter (μmol/L) Standard Deviation 4.91245	10.7730 Micromoles per liter (μmol/L) Standard Deviation 6.63074	14.8770 Micromoles per liter (μmol/L) Standard Deviation 7.69405	17.9835 Micromoles per liter (μmol/L) Standard Deviation 7.41865	16.2735 Micromoles per liter (μmol/L) Standard Deviation 7.49161
Part 1: Absolute Values of Liver Panel Parameters: Direct Bilirubin and Total Bilirubin Total Bilirubin, Day 3	11.7705 Micromoles per liter (μmol/L) Standard Deviation 3.38635	12.1410 Micromoles per liter (μmol/L) Standard Deviation 4.37573	10.4595 Micromoles per liter (μmol/L) Standard Deviation 7.28983	14.2956 Micromoles per liter (μmol/L) Standard Deviation 6.79530	15.5040 Micromoles per liter (μmol/L) Standard Deviation 7.42594	15.5895 Micromoles per liter (μmol/L) Standard Deviation 6.56018
Part 1: Absolute Values of Liver Panel Parameters: Direct Bilirubin and Total Bilirubin Total Bilirubin, Day 4	9.4620 Micromoles per liter (μmol/L) Standard Deviation 3.81091	14.2215 Micromoles per liter (μmol/L) Standard Deviation 6.54322	10.6704 Micromoles per liter (μmol/L) Standard Deviation 7.32172	13.6287 Micromoles per liter (μmol/L) Standard Deviation 8.26482	15.8460 Micromoles per liter (μmol/L) Standard Deviation 5.98125	13.5090 Micromoles per liter (μmol/L) Standard Deviation 6.44718
Part 1: Absolute Values of Liver Panel Parameters: Direct Bilirubin and Total Bilirubin Total Bilirubin, Day 5	11.6565 Micromoles per liter (μmol/L) Standard Deviation 3.15571	11.8275 Micromoles per liter (μmol/L) Standard Deviation 4.79461	10.6875 Micromoles per liter (μmol/L) Standard Deviation 5.85984	13.5603 Micromoles per liter (μmol/L) Standard Deviation 6.89113	15.7320 Micromoles per liter (μmol/L) Standard Deviation 7.04470	14.7345 Micromoles per liter (μmol/L) Standard Deviation 5.17813
Part 1: Absolute Values of Liver Panel Parameters: Direct Bilirubin and Total Bilirubin Total Bilirubin, Day 6	12.1125 Micromoles per liter (μmol/L) Standard Deviation 3.92990	9.6330 Micromoles per liter (μmol/L) Standard Deviation 3.97319	9.3480 Micromoles per liter (μmol/L) Standard Deviation 6.12902	12.9618 Micromoles per liter (μmol/L) Standard Deviation 4.88926	13.9365 Micromoles per liter (μmol/L) Standard Deviation 7.53701	14.3640 Micromoles per liter (μmol/L) Standard Deviation 5.24388
Part 1: Absolute Values of Liver Panel Parameters: Direct Bilirubin and Total Bilirubin Total Bilirubin, Day 7	10.6020 Micromoles per liter (μmol/L) Standard Deviation 3.25350	9.9465 Micromoles per liter (μmol/L) Standard Deviation 2.53730	10.7160 Micromoles per liter (μmol/L) Standard Deviation 5.72854	13.8510 Micromoles per liter (μmol/L) Standard Deviation 7.21180	16.6725 Micromoles per liter (μmol/L) Standard Deviation 8.20640	12.5400 Micromoles per liter (μmol/L) Standard Deviation 4.43239
Part 1: Absolute Values of Liver Panel Parameters: Direct Bilirubin and Total Bilirubin Total Bilirubin, Day 14	6.7545 Micromoles per liter (μmol/L) Standard Deviation 3.25125	7.2846 Micromoles per liter (μmol/L) Standard Deviation 2.33087	7.9515 Micromoles per liter (μmol/L) Standard Deviation 4.34050	10.4139 Micromoles per liter (μmol/L) Standard Deviation 2.46942	11.1150 Micromoles per liter (μmol/L) Standard Deviation 0.91289	11.7990 Micromoles per liter (μmol/L) Standard Deviation 7.42857
Part 1: Absolute Values of Liver Panel Parameters: Direct Bilirubin and Total Bilirubin Total Bilirubin, Day 21	9.6045 Micromoles per liter (μmol/L) Standard Deviation 5.04078	10.2885 Micromoles per liter (μmol/L) Standard Deviation 3.37424	7.5525 Micromoles per liter (μmol/L) Standard Deviation 3.38980	12.4317 Micromoles per liter (μmol/L) Standard Deviation 5.82742	12.4830 Micromoles per liter (μmol/L) Standard Deviation 4.36636	8.9205 Micromoles per liter (μmol/L) Standard Deviation 3.94920
Part 1: Absolute Values of Liver Panel Parameters: Direct Bilirubin and Total Bilirubin Total Bilirubin, Day 28	9.1200 Micromoles per liter (μmol/L) Standard Deviation 4.86394	10.1916 Micromoles per liter (μmol/L) Standard Deviation 4.40238	7.9800 Micromoles per liter (μmol/L) Standard Deviation 2.95720	13.1670 Micromoles per liter (μmol/L) Standard Deviation 9.01537	16.7580 Micromoles per liter (μmol/L) Standard Deviation 9.74550	11.4000 Micromoles per liter (μmol/L) Standard Deviation 3.21674
Part 1: Absolute Values of Liver Panel Parameters: Direct Bilirubin and Total Bilirubin Total Bilirubin, Day 35	8.5785 Micromoles per liter (μmol/L) Standard Deviation 3.90002	10.0605 Micromoles per liter (μmol/L) Standard Deviation 3.87143	8.4360 Micromoles per liter (μmol/L) Standard Deviation 4.45476	12.0042 Micromoles per liter (μmol/L) Standard Deviation 7.37960	11.3715 Micromoles per liter (μmol/L) Standard Deviation 7.28046	8.7552 Micromoles per liter (μmol/L) Standard Deviation 2.95786
Part 1: Absolute Values of Liver Panel Parameters: Direct Bilirubin and Total Bilirubin Total Bilirubin, Day 42	—	—	8.2080 Micromoles per liter (μmol/L) Standard Deviation 4.29070	14.8485 Micromoles per liter (μmol/L) Standard Deviation 12.01166	15.5895 Micromoles per liter (μmol/L) Standard Deviation 10.02324	12.9675 Micromoles per liter (μmol/L) Standard Deviation 6.50917
Part 1: Absolute Values of Liver Panel Parameters: Direct Bilirubin and Total Bilirubin Total Bilirubin, Day 49	—	—	8.8350 Micromoles per liter (μmol/L) Standard Deviation 3.94512	14.0505 Micromoles per liter (μmol/L) Standard Deviation 7.95429	14.8200 Micromoles per liter (μmol/L) Standard Deviation 6.47967	12.7680 Micromoles per liter (μmol/L) Standard Deviation 8.27588

PRIMARY outcome

Timeframe: Up to Day 49

Blood samples were collected as assessed by protocol, at specific time points for laboratory analysis of ALP, ALT and AST.

Outcome measures

Outcome measures
Measure	Part 2 (MAD): VH4004280 100 mg PiB n=6 Participants Healthy participants were given a dose of 100 mg VH4004280 PiB QD for a 14-day period and were followed up to approximately Day 63.	Part 2 (MAD): VH4004280 250 mg + Midazolam (MDZ) PiB n=7 Participants Healthy participants were given a dose of 250 mg VH4004280 PiB QD for a 14-day period, and a single dose of Midazolam on days 1, 2, and 15, and were followed up to approximately Day 63.	Part 2 (MAD): VH4004280 350 mg PiB n=6 Participants Healthy participants were given a dose of 350 mg VH4004280 PiB QD for a 14-day period and were followed up to approximately Day 63.	Part 3 (Single Dose): VH4004280 450 mg Tablet n=10 Participants Healthy participants were given a single oral dose of VH4004280 450 mg tablet at Day 1 and were followed up to approximately Day 49.	Part 1 (SAD): VH4004280 450 mg PiB n=6 Participants Healthy participants were given a single oral dose of 450 mg VH4004280 PiB on Day 1 and were followed up to approximately Day 49.	Part 1 (SAD): VH4004280 900 mg PiB n=6 Participants Healthy participants were given a single oral dose of 900 mg VH4004280 PiB on Day 1 and were followed up to approximately Day 49.
Part 1: Absolute Values of Liver Panel Parameters: Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) AST, Day 35	20.5 International units per liter (IU/L) Standard Deviation 6.19	18.3 International units per liter (IU/L) Standard Deviation 7.50	21.7 International units per liter (IU/L) Standard Deviation 4.50	17.4 International units per liter (IU/L) Standard Deviation 4.70	18.5 International units per liter (IU/L) Standard Deviation 4.32	18.0 International units per liter (IU/L) Standard Deviation 2.65
Part 1: Absolute Values of Liver Panel Parameters: Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) AST, Day 42	—	—	22.8 International units per liter (IU/L) Standard Deviation 2.99	14.8 International units per liter (IU/L) Standard Deviation 1.72	16.3 International units per liter (IU/L) Standard Deviation 2.58	16.8 International units per liter (IU/L) Standard Deviation 3.19
Part 1: Absolute Values of Liver Panel Parameters: Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) ALP, Baseline (Day 1)	64.7 International units per liter (IU/L) Standard Deviation 10.88	67.1 International units per liter (IU/L) Standard Deviation 27.91	69.0 International units per liter (IU/L) Standard Deviation 25.04	51.8 International units per liter (IU/L) Standard Deviation 9.39	64.0 International units per liter (IU/L) Standard Deviation 11.10	61.8 International units per liter (IU/L) Standard Deviation 15.41
Part 1: Absolute Values of Liver Panel Parameters: Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) ALP, Day 2	59.0 International units per liter (IU/L) Standard Deviation 10.86	60.4 International units per liter (IU/L) Standard Deviation 23.56	63.5 International units per liter (IU/L) Standard Deviation 21.68	48.6 International units per liter (IU/L) Standard Deviation 7.52	58.2 International units per liter (IU/L) Standard Deviation 10.61	54.5 International units per liter (IU/L) Standard Deviation 9.73
Part 1: Absolute Values of Liver Panel Parameters: Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) ALP, Day 3	58.8 International units per liter (IU/L) Standard Deviation 11.20	56.2 International units per liter (IU/L) Standard Deviation 21.44	63.0 International units per liter (IU/L) Standard Deviation 21.25	48.2 International units per liter (IU/L) Standard Deviation 4.57	55.8 International units per liter (IU/L) Standard Deviation 10.76	52.5 International units per liter (IU/L) Standard Deviation 10.29
Part 1: Absolute Values of Liver Panel Parameters: Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) ALP, Day 4	60.5 International units per liter (IU/L) Standard Deviation 12.08	60.5 International units per liter (IU/L) Standard Deviation 19.36	58.6 International units per liter (IU/L) Standard Deviation 18.84	49.3 International units per liter (IU/L) Standard Deviation 6.60	63.2 International units per liter (IU/L) Standard Deviation 10.57	52.8 International units per liter (IU/L) Standard Deviation 11.86
Part 1: Absolute Values of Liver Panel Parameters: Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) ALP, Day 5	59.2 International units per liter (IU/L) Standard Deviation 10.32	54.7 International units per liter (IU/L) Standard Deviation 20.65	63.3 International units per liter (IU/L) Standard Deviation 21.16	48.1 International units per liter (IU/L) Standard Deviation 8.16	60.5 International units per liter (IU/L) Standard Deviation 9.57	57.7 International units per liter (IU/L) Standard Deviation 9.16
Part 1: Absolute Values of Liver Panel Parameters: Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) ALP, Day 6	62.5 International units per liter (IU/L) Standard Deviation 10.99	56.3 International units per liter (IU/L) Standard Deviation 21.10	63.0 International units per liter (IU/L) Standard Deviation 19.15	48.8 International units per liter (IU/L) Standard Deviation 6.44	62.3 International units per liter (IU/L) Standard Deviation 10.01	54.5 International units per liter (IU/L) Standard Deviation 7.40
Part 1: Absolute Values of Liver Panel Parameters: Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) ALP, Day 7	64.3 International units per liter (IU/L) Standard Deviation 13.60	61.7 International units per liter (IU/L) Standard Deviation 17.18	64.3 International units per liter (IU/L) Standard Deviation 20.25	51.7 International units per liter (IU/L) Standard Deviation 7.30	66.3 International units per liter (IU/L) Standard Deviation 11.41	56.8 International units per liter (IU/L) Standard Deviation 7.44
Part 1: Absolute Values of Liver Panel Parameters: Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) ALP, Day 14	62.2 International units per liter (IU/L) Standard Deviation 6.97	59.6 International units per liter (IU/L) Standard Deviation 19.49	65.0 International units per liter (IU/L) Standard Deviation 21.48	54.8 International units per liter (IU/L) Standard Deviation 11.85	66.4 International units per liter (IU/L) Standard Deviation 12.72	61.3 International units per liter (IU/L) Standard Deviation 8.62
Part 1: Absolute Values of Liver Panel Parameters: Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) ALP, Day 21	58.7 International units per liter (IU/L) Standard Deviation 9.50	62.2 International units per liter (IU/L) Standard Deviation 29.88	66.0 International units per liter (IU/L) Standard Deviation 22.33	53.0 International units per liter (IU/L) Standard Deviation 11.18	61.5 International units per liter (IU/L) Standard Deviation 12.05	59.2 International units per liter (IU/L) Standard Deviation 8.70
Part 1: Absolute Values of Liver Panel Parameters: Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) ALP, Day 28	57.5 International units per liter (IU/L) Standard Deviation 7.97	66.2 International units per liter (IU/L) Standard Deviation 43.85	65.5 International units per liter (IU/L) Standard Deviation 22.95	53.9 International units per liter (IU/L) Standard Deviation 12.35	63.5 International units per liter (IU/L) Standard Deviation 10.82	65.5 International units per liter (IU/L) Standard Deviation 11.33
Part 1: Absolute Values of Liver Panel Parameters: Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) ALP, Day 35	66.3 International units per liter (IU/L) Standard Deviation 12.80	62.3 International units per liter (IU/L) Standard Deviation 28.22	63.8 International units per liter (IU/L) Standard Deviation 23.56	52.9 International units per liter (IU/L) Standard Deviation 8.69	64.7 International units per liter (IU/L) Standard Deviation 9.14	62.8 International units per liter (IU/L) Standard Deviation 8.07
Part 1: Absolute Values of Liver Panel Parameters: Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) ALP, Day 42	—	—	63.3 International units per liter (IU/L) Standard Deviation 25.31	53.7 International units per liter (IU/L) Standard Deviation 9.75	66.2 International units per liter (IU/L) Standard Deviation 9.54	63.2 International units per liter (IU/L) Standard Deviation 9.79
Part 1: Absolute Values of Liver Panel Parameters: Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) ALP, Day 49	—	—	67.2 International units per liter (IU/L) Standard Deviation 27.21	54.3 International units per liter (IU/L) Standard Deviation 7.53	66.7 International units per liter (IU/L) Standard Deviation 11.50	59.7 International units per liter (IU/L) Standard Deviation 6.41
Part 1: Absolute Values of Liver Panel Parameters: Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) ALT, Baseline (Day 1)	22.8 International units per liter (IU/L) Standard Deviation 11.72	15.1 International units per liter (IU/L) Standard Deviation 4.85	20.7 International units per liter (IU/L) Standard Deviation 8.07	18.4 International units per liter (IU/L) Standard Deviation 5.60	14.8 International units per liter (IU/L) Standard Deviation 2.93	16.0 International units per liter (IU/L) Standard Deviation 4.34
Part 1: Absolute Values of Liver Panel Parameters: Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) ALT, Day 2	22.0 International units per liter (IU/L) Standard Deviation 16.60	15.6 International units per liter (IU/L) Standard Deviation 5.47	21.3 International units per liter (IU/L) Standard Deviation 9.61	18.3 International units per liter (IU/L) Standard Deviation 7.78	15.7 International units per liter (IU/L) Standard Deviation 3.61	15.3 International units per liter (IU/L) Standard Deviation 3.08
Part 1: Absolute Values of Liver Panel Parameters: Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) ALT, Day 3	22.2 International units per liter (IU/L) Standard Deviation 17.23	15.8 International units per liter (IU/L) Standard Deviation 7.65	20.7 International units per liter (IU/L) Standard Deviation 9.09	18.6 International units per liter (IU/L) Standard Deviation 7.15	15.8 International units per liter (IU/L) Standard Deviation 3.60	16.0 International units per liter (IU/L) Standard Deviation 4.52
Part 1: Absolute Values of Liver Panel Parameters: Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) ALT, Day 4	23.2 International units per liter (IU/L) Standard Deviation 17.47	16.7 International units per liter (IU/L) Standard Deviation 8.94	22.4 International units per liter (IU/L) Standard Deviation 12.52	19.2 International units per liter (IU/L) Standard Deviation 6.60	14.3 International units per liter (IU/L) Standard Deviation 3.20	16.2 International units per liter (IU/L) Standard Deviation 4.12
Part 1: Absolute Values of Liver Panel Parameters: Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) ALT, Day 5	21.7 International units per liter (IU/L) Standard Deviation 16.74	17.0 International units per liter (IU/L) Standard Deviation 10.84	24.5 International units per liter (IU/L) Standard Deviation 13.77	18.1 International units per liter (IU/L) Standard Deviation 6.30	15.0 International units per liter (IU/L) Standard Deviation 2.68	16.0 International units per liter (IU/L) Standard Deviation 4.77
Part 1: Absolute Values of Liver Panel Parameters: Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) ALT, Day 6	22.5 International units per liter (IU/L) Standard Deviation 16.15	18.0 International units per liter (IU/L) Standard Deviation 12.98	24.2 International units per liter (IU/L) Standard Deviation 13.27	18.9 International units per liter (IU/L) Standard Deviation 7.96	14.5 International units per liter (IU/L) Standard Deviation 3.02	18.8 International units per liter (IU/L) Standard Deviation 7.96
Part 1: Absolute Values of Liver Panel Parameters: Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) ALT, Day 14	27.3 International units per liter (IU/L) Standard Deviation 17.90	18.0 International units per liter (IU/L) Standard Deviation 8.86	29.8 International units per liter (IU/L) Standard Deviation 21.29	26.1 International units per liter (IU/L) Standard Deviation 21.07	22.0 International units per liter (IU/L) Standard Deviation 11.51	22.7 International units per liter (IU/L) Standard Deviation 13.87
Part 1: Absolute Values of Liver Panel Parameters: Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) ALT, Day 21	23.5 International units per liter (IU/L) Standard Deviation 13.98	20.2 International units per liter (IU/L) Standard Deviation 10.61	24.5 International units per liter (IU/L) Standard Deviation 10.54	23.4 International units per liter (IU/L) Standard Deviation 15.94	19.2 International units per liter (IU/L) Standard Deviation 7.41	22.2 International units per liter (IU/L) Standard Deviation 15.66
Part 1: Absolute Values of Liver Panel Parameters: Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) ALT, Day 35	28.5 International units per liter (IU/L) Standard Deviation 15.42	17.8 International units per liter (IU/L) Standard Deviation 8.35	23.5 International units per liter (IU/L) Standard Deviation 5.75	19.8 International units per liter (IU/L) Standard Deviation 10.78	21.3 International units per liter (IU/L) Standard Deviation 15.71	16.8 International units per liter (IU/L) Standard Deviation 3.70
Part 1: Absolute Values of Liver Panel Parameters: Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) ALT, Day 42	—	—	25.5 International units per liter (IU/L) Standard Deviation 6.02	14.2 International units per liter (IU/L) Standard Deviation 3.60	16.3 International units per liter (IU/L) Standard Deviation 4.23	17.5 International units per liter (IU/L) Standard Deviation 4.76
Part 1: Absolute Values of Liver Panel Parameters: Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) ALT, Day 49	—	—	27.8 International units per liter (IU/L) Standard Deviation 9.85	15.0 International units per liter (IU/L) Standard Deviation 4.34	18.7 International units per liter (IU/L) Standard Deviation 10.23	17.2 International units per liter (IU/L) Standard Deviation 5.23
Part 1: Absolute Values of Liver Panel Parameters: Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) AST, Baseline (Day 1)	17.3 International units per liter (IU/L) Standard Deviation 5.82	15.1 International units per liter (IU/L) Standard Deviation 4.14	17.5 International units per liter (IU/L) Standard Deviation 3.62	17.3 International units per liter (IU/L) Standard Deviation 5.03	15.0 International units per liter (IU/L) Standard Deviation 3.03	16.5 International units per liter (IU/L) Standard Deviation 3.51
Part 1: Absolute Values of Liver Panel Parameters: Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) AST, Day 2	16.3 International units per liter (IU/L) Standard Deviation 8.31	14.3 International units per liter (IU/L) Standard Deviation 3.40	16.5 International units per liter (IU/L) Standard Deviation 3.78	17.3 International units per liter (IU/L) Standard Deviation 7.97	15.0 International units per liter (IU/L) Standard Deviation 2.97	15.8 International units per liter (IU/L) Standard Deviation 2.71
Part 1: Absolute Values of Liver Panel Parameters: Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) AST, Day 3	16.0 International units per liter (IU/L) Standard Deviation 7.56	14.8 International units per liter (IU/L) Standard Deviation 4.07	16.7 International units per liter (IU/L) Standard Deviation 3.44	16.4 International units per liter (IU/L) Standard Deviation 4.33	14.7 International units per liter (IU/L) Standard Deviation 2.80	15.2 International units per liter (IU/L) Standard Deviation 2.14
Part 1: Absolute Values of Liver Panel Parameters: Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) AST, Day 4	16.7 International units per liter (IU/L) Standard Deviation 7.76	15.3 International units per liter (IU/L) Standard Deviation 3.83	18.4 International units per liter (IU/L) Standard Deviation 5.46	15.8 International units per liter (IU/L) Standard Deviation 3.82	13.3 International units per liter (IU/L) Standard Deviation 2.42	15.5 International units per liter (IU/L) Standard Deviation 2.81
Part 1: Absolute Values of Liver Panel Parameters: Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) AST, Day 5	14.8 International units per liter (IU/L) Standard Deviation 6.34	14.8 International units per liter (IU/L) Standard Deviation 3.92	18.5 International units per liter (IU/L) Standard Deviation 5.05	14.8 International units per liter (IU/L) Standard Deviation 2.90	13.7 International units per liter (IU/L) Standard Deviation 1.63	15.8 International units per liter (IU/L) Standard Deviation 2.14
Part 1: Absolute Values of Liver Panel Parameters: Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) AST, Day 6	16.0 International units per liter (IU/L) Standard Deviation 6.42	15.7 International units per liter (IU/L) Standard Deviation 5.43	17.7 International units per liter (IU/L) Standard Deviation 5.57	15.6 International units per liter (IU/L) Standard Deviation 3.13	14.3 International units per liter (IU/L) Standard Deviation 1.21	16.7 International units per liter (IU/L) Standard Deviation 2.34
Part 1: Absolute Values of Liver Panel Parameters: Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) AST, Day 7	16.8 International units per liter (IU/L) Standard Deviation 5.38	15.8 International units per liter (IU/L) Standard Deviation 4.36	18.2 International units per liter (IU/L) Standard Deviation 5.49	16.5 International units per liter (IU/L) Standard Deviation 3.84	15.3 International units per liter (IU/L) Standard Deviation 2.16	18.0 International units per liter (IU/L) Standard Deviation 3.10
Part 1: Absolute Values of Liver Panel Parameters: Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) AST, Day 14	18.0 International units per liter (IU/L) Standard Deviation 6.13	14.2 International units per liter (IU/L) Standard Deviation 5.22	20.7 International units per liter (IU/L) Standard Deviation 7.81	40.0 International units per liter (IU/L) Standard Deviation 71.85	20.0 International units per liter (IU/L) Standard Deviation 7.97	17.5 International units per liter (IU/L) Standard Deviation 3.62
Part 1: Absolute Values of Liver Panel Parameters: Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) AST, Day 21	18.7 International units per liter (IU/L) Standard Deviation 5.28	18.3 International units per liter (IU/L) Standard Deviation 8.09	19.5 International units per liter (IU/L) Standard Deviation 3.78	17.9 International units per liter (IU/L) Standard Deviation 6.82	17.3 International units per liter (IU/L) Standard Deviation 2.94	18.2 International units per liter (IU/L) Standard Deviation 5.38
Part 1: Absolute Values of Liver Panel Parameters: Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) AST, Day 49	—	—	23.3 International units per liter (IU/L) Standard Deviation 6.15	15.2 International units per liter (IU/L) Standard Deviation 2.04	18.2 International units per liter (IU/L) Standard Deviation 2.93	18.0 International units per liter (IU/L) Standard Deviation 5.22
Part 1: Absolute Values of Liver Panel Parameters: Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) ALT, Day 7	23.5 International units per liter (IU/L) Standard Deviation 15.59	18.2 International units per liter (IU/L) Standard Deviation 12.83	24.7 International units per liter (IU/L) Standard Deviation 14.90	19.9 International units per liter (IU/L) Standard Deviation 9.97	15.3 International units per liter (IU/L) Standard Deviation 3.20	20.8 International units per liter (IU/L) Standard Deviation 10.28
Part 1: Absolute Values of Liver Panel Parameters: Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) ALT, Day 28	33.7 International units per liter (IU/L) Standard Deviation 22.25	17.6 International units per liter (IU/L) Standard Deviation 8.50	24.2 International units per liter (IU/L) Standard Deviation 9.50	20.1 International units per liter (IU/L) Standard Deviation 10.02	16.8 International units per liter (IU/L) Standard Deviation 6.37	20.8 International units per liter (IU/L) Standard Deviation 10.63
Part 1: Absolute Values of Liver Panel Parameters: Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) AST, Day 28	23.0 International units per liter (IU/L) Standard Deviation 6.54	17.0 International units per liter (IU/L) Standard Deviation 6.04	20.3 International units per liter (IU/L) Standard Deviation 4.08	16.8 International units per liter (IU/L) Standard Deviation 3.39	16.3 International units per liter (IU/L) Standard Deviation 1.75	16.8 International units per liter (IU/L) Standard Deviation 1.94

PRIMARY outcome

Timeframe: Up to Day 63

Population: The analysis was performed on the Safety Set which included all enrolled participants in Part 2 (MAD) who received at least 1 full or partial dose of study treatment. The participants were analyzed according to the treatment they actually received. Only those participants with data available at specified time points were analyzed for the specific category titles.

Blood samples were collected as assessed by protocol, at specific time points for laboratory analysis of bilirubin. Standard Deviation (SD)=0.00000 is defined as following: if all participants analyzed for a specific parameter at a specific time point have the same value, then SD is equal with 0.00000.

Outcome measures

Outcome measures
Measure	Part 2 (MAD): VH4004280 100 mg PiB n=6 Participants Healthy participants were given a dose of 100 mg VH4004280 PiB QD for a 14-day period and were followed up to approximately Day 63.	Part 2 (MAD): VH4004280 250 mg + Midazolam (MDZ) PiB n=8 Participants Healthy participants were given a dose of 250 mg VH4004280 PiB QD for a 14-day period, and a single dose of Midazolam on days 1, 2, and 15, and were followed up to approximately Day 63.	Part 2 (MAD): VH4004280 350 mg PiB n=6 Participants Healthy participants were given a dose of 350 mg VH4004280 PiB QD for a 14-day period and were followed up to approximately Day 63.	Part 3 (Single Dose): VH4004280 450 mg Tablet n=6 Participants Healthy participants were given a single oral dose of VH4004280 450 mg tablet at Day 1 and were followed up to approximately Day 49.	Part 1 (SAD): VH4004280 450 mg PiB Healthy participants were given a single oral dose of 450 mg VH4004280 PiB on Day 1 and were followed up to approximately Day 49.	Part 1 (SAD): VH4004280 900 mg PiB Healthy participants were given a single oral dose of 900 mg VH4004280 PiB on Day 1 and were followed up to approximately Day 49.
Part 2: Absolute Values of Liver Panel Parameters: Direct Bilirubin and Total Bilirubin Direct Bilirubin, Baseline (Day 1)	2.8500 μmol/L Standard Deviation 1.39621	2.1375 μmol/L Standard Deviation 0.79158	1.7100 μmol/L Standard Deviation 0.00000	2.2800 μmol/L Standard Deviation 0.88304	—	—
Part 2: Absolute Values of Liver Panel Parameters: Direct Bilirubin and Total Bilirubin Direct Bilirubin, Day 2	3.1065 μmol/L Standard Deviation 1.34826	—	2.1375 μmol/L Standard Deviation 0.40103	2.1803 μmol/L Standard Deviation 0.47090	—	—
Part 2: Absolute Values of Liver Panel Parameters: Direct Bilirubin and Total Bilirubin Direct Bilirubin, Day 3	—	2.1589 μmol/L Standard Deviation 0.78595	—	2.2230 μmol/L Standard Deviation 0.24183	—	—
Part 2: Absolute Values of Liver Panel Parameters: Direct Bilirubin and Total Bilirubin Direct Bilirubin, Day 5	3.1635 μmol/L Standard Deviation 1.82498	—	2.1945 μmol/L Standard Deviation 0.54524	2.0948 μmol/L Standard Deviation 0.35253	—	—
Part 2: Absolute Values of Liver Panel Parameters: Direct Bilirubin and Total Bilirubin Direct Bilirubin, Day 6	—	2.3940 μmol/L Standard Deviation 0.99289	—	2.2230 μmol/L Standard Deviation 0.00000	—	—
Part 2: Absolute Values of Liver Panel Parameters: Direct Bilirubin and Total Bilirubin Direct Bilirubin, Day 7	2.9070 μmol/L Standard Deviation 1.75056	—	2.5650 μmol/L Standard Deviation 0.47141	1.8383 μmol/L Standard Deviation 0.37917	—	—
Part 2: Absolute Values of Liver Panel Parameters: Direct Bilirubin and Total Bilirubin Direct Bilirubin, Day 8	—	2.4795 μmol/L Standard Deviation 0.83272	—	2.3940 μmol/L Standard Deviation 0.72549	—	—
Part 2: Absolute Values of Liver Panel Parameters: Direct Bilirubin and Total Bilirubin Direct Bilirubin, Day 11	2.6505 μmol/L Standard Deviation 1.04948	—	2.4795 μmol/L Standard Deviation 0.58989	2.2230 μmol/L Standard Deviation 0.72549	—	—
Part 2: Absolute Values of Liver Panel Parameters: Direct Bilirubin and Total Bilirubin Direct Bilirubin, Day 12	—	2.5436 μmol/L Standard Deviation 0.76712	—	1.9665 μmol/L Standard Deviation 0.60458	—	—
Part 2: Absolute Values of Liver Panel Parameters: Direct Bilirubin and Total Bilirubin Direct Bilirubin, Day 14	2.6220 μmol/L Standard Deviation 1.07426	—	1.9950 μmol/L Standard Deviation 0.33625	1.5818 μmol/L Standard Deviation 0.29204	—	—
Part 2: Absolute Values of Liver Panel Parameters: Direct Bilirubin and Total Bilirubin Direct Bilirubin, Day 15	—	2.8856 μmol/L Standard Deviation 0.78329	—	2.7360 μmol/L Standard Deviation 0.24183	—	—
Part 2: Absolute Values of Liver Panel Parameters: Direct Bilirubin and Total Bilirubin Direct Bilirubin, Day 21	2.7360 μmol/L Standard Deviation 1.17978	—	2.5935 μmol/L Standard Deviation 0.34905	1.7100 μmol/L Standard Deviation 0.46307	—	—
Part 2: Absolute Values of Liver Panel Parameters: Direct Bilirubin and Total Bilirubin Direct Bilirubin, Day 22	—	3.2276 μmol/L Standard Deviation 0.93409	—	3.5055 μmol/L Standard Deviation 0.12092	—	—
Part 2: Absolute Values of Liver Panel Parameters: Direct Bilirubin and Total Bilirubin Direct Bilirubin, Day 28	2.0235 μmol/L Standard Deviation 0.64362	2.0948 μmol/L Standard Deviation 0.61145	1.8810 μmol/L Standard Deviation 0.49561	1.5732 μmol/L Standard Deviation 0.44262	—	—
Part 2: Absolute Values of Liver Panel Parameters: Direct Bilirubin and Total Bilirubin Direct Bilirubin, Day 35	1.8810 μmol/L Standard Deviation 0.63982	2.1375 μmol/L Standard Deviation 0.59937	1.7955 μmol/L Standard Deviation 0.41536	1.7955 μmol/L Standard Deviation 0.28098	—	—
Part 2: Absolute Values of Liver Panel Parameters: Direct Bilirubin and Total Bilirubin Direct Bilirubin, Day 42	2.0805 μmol/L Standard Deviation 0.77549	2.0306 μmol/L Standard Deviation 0.57401	1.5960 μmol/L Standard Deviation 0.35322	2.0520 μmol/L Standard Deviation 0.58241	—	—
Part 2: Absolute Values of Liver Panel Parameters: Direct Bilirubin and Total Bilirubin Direct Bilirubin, Day 49	2.2230 μmol/L Standard Deviation 0.80206	2.2016 μmol/L Standard Deviation 0.59544	1.9095 μmol/L Standard Deviation 0.59646	2.1204 μmol/L Standard Deviation 0.66887	—	—
Part 2: Absolute Values of Liver Panel Parameters: Direct Bilirubin and Total Bilirubin Direct Bilirubin, Day 56	2.2914 μmol/L Standard Deviation 1.08555	1.8810 μmol/L Standard Deviation 0.51706	1.7955 μmol/L Standard Deviation 0.49265	1.9095 μmol/L Standard Deviation 0.47656	—	—
Part 2: Absolute Values of Liver Panel Parameters: Direct Bilirubin and Total Bilirubin Direct Bilirubin, Day 63	1.9095 μmol/L Standard Deviation 0.69601	1.8596 μmol/L Standard Deviation 0.83990	1.9665 μmol/L Standard Deviation 0.51584	1.7670 μmol/L Standard Deviation 0.38491	—	—
Part 2: Absolute Values of Liver Panel Parameters: Direct Bilirubin and Total Bilirubin Total Bilirubin, Baseline (Day 1)	15.1050 μmol/L Standard Deviation 6.87553	9.6188 μmol/L Standard Deviation 3.53265	8.2650 μmol/L Standard Deviation 1.28724	11.9700 μmol/L Standard Deviation 3.42000	—	—
Part 2: Absolute Values of Liver Panel Parameters: Direct Bilirubin and Total Bilirubin Total Bilirubin, Day 2	17.9550 μmol/L Standard Deviation 8.54521	—	11.6565 μmol/L Standard Deviation 2.67858	10.6020 μmol/L Standard Deviation 2.39807	—	—
Part 2: Absolute Values of Liver Panel Parameters: Direct Bilirubin and Total Bilirubin Total Bilirubin, Day 3	—	12.2051 μmol/L Standard Deviation 3.59151	—	16.3305 μmol/L Standard Deviation 6.40851	—	—
Part 2: Absolute Values of Liver Panel Parameters: Direct Bilirubin and Total Bilirubin Total Bilirubin, Day 5	18.8670 μmol/L Standard Deviation 10.05775	—	13.0815 μmol/L Standard Deviation 4.18409	10.6020 μmol/L Standard Deviation 2.08498	—	—
Part 2: Absolute Values of Liver Panel Parameters: Direct Bilirubin and Total Bilirubin Total Bilirubin, Day 6	—	13.2525 μmol/L Standard Deviation 4.38546	—	15.1335 μmol/L Standard Deviation 4.71570	—	—
Part 2: Absolute Values of Liver Panel Parameters: Direct Bilirubin and Total Bilirubin Total Bilirubin, Day 7	16.5015 μmol/L Standard Deviation 9.02436	—	14.8770 μmol/L Standard Deviation 3.05894	9.0203 μmol/L Standard Deviation 1.14604	—	—
Part 2: Absolute Values of Liver Panel Parameters: Direct Bilirubin and Total Bilirubin Total Bilirubin, Day 8	—	14.4281 μmol/L Standard Deviation 3.99249	—	16.5870 μmol/L Standard Deviation 8.94773	—	—
Part 2: Absolute Values of Liver Panel Parameters: Direct Bilirubin and Total Bilirubin Total Bilirubin, Day 11	15.2190 μmol/L Standard Deviation 5.69715	—	13.0530 μmol/L Standard Deviation 2.43917	9.4050 μmol/L Standard Deviation 3.62746	—	—
Part 2: Absolute Values of Liver Panel Parameters: Direct Bilirubin and Total Bilirubin Total Bilirubin, Day 12	—	15.6893 μmol/L Standard Deviation 3.63062	—	11.4570 μmol/L Standard Deviation 0.72549	—	—
Part 2: Absolute Values of Liver Panel Parameters: Direct Bilirubin and Total Bilirubin Total Bilirubin, Day 14	14.2500 μmol/L Standard Deviation 4.70504	—	13.9650 μmol/L Standard Deviation 2.37109	7.3958 μmol/L Standard Deviation 1.36354	—	—
Part 2: Absolute Values of Liver Panel Parameters: Direct Bilirubin and Total Bilirubin Total Bilirubin, Day 15	—	14.9839 μmol/L Standard Deviation 4.61559	—	15.5610 μmol/L Standard Deviation 4.11112	—	—
Part 2: Absolute Values of Liver Panel Parameters: Direct Bilirubin and Total Bilirubin Total Bilirubin, Day 21	15.8175 μmol/L Standard Deviation 5.32110	—	14.9625 μmol/L Standard Deviation 2.61076	7.6095 μmol/L Standard Deviation 1.74666	—	—
Part 2: Absolute Values of Liver Panel Parameters: Direct Bilirubin and Total Bilirubin Total Bilirubin, Day 22	—	18.0833 μmol/L Standard Deviation 4.97435	—	19.9215 μmol/L Standard Deviation 5.92485	—	—
Part 2: Absolute Values of Liver Panel Parameters: Direct Bilirubin and Total Bilirubin Total Bilirubin, Day 28	10.3170 μmol/L Standard Deviation 3.52221	9.7256 μmol/L Standard Deviation 2.84298	9.7755 μmol/L Standard Deviation 2.53499	8.3106 μmol/L Standard Deviation 2.41710	—	—
Part 2: Absolute Values of Liver Panel Parameters: Direct Bilirubin and Total Bilirubin Total Bilirubin, Day 35	10.7730 μmol/L Standard Deviation 3.04361	10.3028 μmol/L Standard Deviation 2.29739	9.1200 μmol/L Standard Deviation 1.86591	9.2910 μmol/L Standard Deviation 1.47365	—	—
Part 2: Absolute Values of Liver Panel Parameters: Direct Bilirubin and Total Bilirubin Total Bilirubin, Day 42	10.7445 μmol/L Standard Deviation 3.45304	10.2173 μmol/L Standard Deviation 3.00208	8.8920 μmol/L Standard Deviation 3.09505	10.6305 μmol/L Standard Deviation 4.12024	—	—
Part 2: Absolute Values of Liver Panel Parameters: Direct Bilirubin and Total Bilirubin Total Bilirubin, Day 49	12.1410 μmol/L Standard Deviation 3.91885	11.1791 μmol/L Standard Deviation 2.73896	9.7755 μmol/L Standard Deviation 3.40872	11.5254 μmol/L Standard Deviation 4.75214	—	—
Part 2: Absolute Values of Liver Panel Parameters: Direct Bilirubin and Total Bilirubin Total Bilirubin, Day 56	11.0466 μmol/L Standard Deviation 4.41233	8.3149 μmol/L Standard Deviation 1.86413	8.8065 μmol/L Standard Deviation 2.41770	10.1175 μmol/L Standard Deviation 5.17248	—	—
Part 2: Absolute Values of Liver Panel Parameters: Direct Bilirubin and Total Bilirubin Total Bilirubin, Day 63	10.3455 μmol/L Standard Deviation 3.58815	8.9775 μmol/L Standard Deviation 3.69817	10.1745 μmol/L Standard Deviation 2.83829	8.9205 μmol/L Standard Deviation 2.27993	—	—

PRIMARY outcome

Timeframe: Up to Day 63

Blood samples were collected as assessed by protocol, at specific time points for laboratory analysis of ALP, ALT and AST.

Outcome measures

Outcome measures
Measure	Part 2 (MAD): VH4004280 100 mg PiB n=6 Participants Healthy participants were given a dose of 100 mg VH4004280 PiB QD for a 14-day period and were followed up to approximately Day 63.	Part 2 (MAD): VH4004280 250 mg + Midazolam (MDZ) PiB n=8 Participants Healthy participants were given a dose of 250 mg VH4004280 PiB QD for a 14-day period, and a single dose of Midazolam on days 1, 2, and 15, and were followed up to approximately Day 63.	Part 2 (MAD): VH4004280 350 mg PiB n=6 Participants Healthy participants were given a dose of 350 mg VH4004280 PiB QD for a 14-day period and were followed up to approximately Day 63.	Part 3 (Single Dose): VH4004280 450 mg Tablet n=6 Participants Healthy participants were given a single oral dose of VH4004280 450 mg tablet at Day 1 and were followed up to approximately Day 49.	Part 1 (SAD): VH4004280 450 mg PiB Healthy participants were given a single oral dose of 450 mg VH4004280 PiB on Day 1 and were followed up to approximately Day 49.	Part 1 (SAD): VH4004280 900 mg PiB Healthy participants were given a single oral dose of 900 mg VH4004280 PiB on Day 1 and were followed up to approximately Day 49.
Part 2: Absolute Values of Liver Panel Parameters: ALP, ALT and AST ALP, Baseline (Day 1)	53.7 IU/L Standard Deviation 10.01	57.5 IU/L Standard Deviation 21.37	56.7 IU/L Standard Deviation 11.41	66.2 IU/L Standard Deviation 16.75	—	—
Part 2: Absolute Values of Liver Panel Parameters: ALP, ALT and AST ALP, Day 2	52.0 IU/L Standard Deviation 8.97	—	56.2 IU/L Standard Deviation 10.23	69.0 IU/L Standard Deviation 27.47	—	—
Part 2: Absolute Values of Liver Panel Parameters: ALP, ALT and AST ALP, Day 3	—	58.4 IU/L Standard Deviation 20.88	—	68.0 IU/L Standard Deviation 5.66	—	—
Part 2: Absolute Values of Liver Panel Parameters: ALP, ALT and AST ALP, Day 6	—	55.6 IU/L Standard Deviation 19.78	—	64.0 IU/L Standard Deviation 4.24	—	—
Part 2: Absolute Values of Liver Panel Parameters: ALP, ALT and AST ALP, Day 7	48.8 IU/L Standard Deviation 7.39	—	56.5 IU/L Standard Deviation 7.12	64.8 IU/L Standard Deviation 25.16	—	—
Part 2: Absolute Values of Liver Panel Parameters: ALP, ALT and AST ALP, Day 8	—	55.8 IU/L Standard Deviation 18.98	—	68.5 IU/L Standard Deviation 9.19	—	—
Part 2: Absolute Values of Liver Panel Parameters: ALP, ALT and AST ALP, Day 11	47.5 IU/L Standard Deviation 4.20	—	54.3 IU/L Standard Deviation 11.47	72.0 IU/L Standard Deviation 2.83	—	—
Part 2: Absolute Values of Liver Panel Parameters: ALP, ALT and AST ALP, Day 12	—	58.3 IU/L Standard Deviation 21.97	—	71.0 IU/L Standard Deviation 4.24	—	—
Part 2: Absolute Values of Liver Panel Parameters: ALP, ALT and AST ALP, Day 14	47.7 IU/L Standard Deviation 7.53	—	58.0 IU/L Standard Deviation 12.20	69.5 IU/L Standard Deviation 24.52	—	—
Part 2: Absolute Values of Liver Panel Parameters: ALP, ALT and AST ALP, Day 15	—	58.0 IU/L Standard Deviation 19.09	—	66.0 IU/L Standard Deviation 5.66	—	—
Part 2: Absolute Values of Liver Panel Parameters: ALP, ALT and AST ALP, Day 21	50.5 IU/L Standard Deviation 5.21	—	57.5 IU/L Standard Deviation 11.64	62.0 IU/L Standard Deviation 19.41	—	—
Part 2: Absolute Values of Liver Panel Parameters: ALP, ALT and AST ALP, Day 22	—	62.6 IU/L Standard Deviation 19.53	—	70.5 IU/L Standard Deviation 4.95	—	—
Part 2: Absolute Values of Liver Panel Parameters: ALP, ALT and AST ALP, Day 28	49.2 IU/L Standard Deviation 11.69	59.8 IU/L Standard Deviation 19.20	59.5 IU/L Standard Deviation 10.73	61.4 IU/L Standard Deviation 15.98	—	—
Part 2: Absolute Values of Liver Panel Parameters: ALP, ALT and AST ALP, Day 35	53.0 IU/L Standard Deviation 15.26	59.9 IU/L Standard Deviation 17.10	53.0 IU/L Standard Deviation 11.56	64.2 IU/L Standard Deviation 17.88	—	—
Part 2: Absolute Values of Liver Panel Parameters: ALP, ALT and AST ALP, Day 42	51.3 IU/L Standard Deviation 11.76	62.1 IU/L Standard Deviation 19.58	57.7 IU/L Standard Deviation 12.09	67.7 IU/L Standard Deviation 19.31	—	—
Part 2: Absolute Values of Liver Panel Parameters: ALP, ALT and AST ALP, Day 49	51.0 IU/L Standard Deviation 12.36	58.8 IU/L Standard Deviation 18.48	54.0 IU/L Standard Deviation 12.71	64.2 IU/L Standard Deviation 16.81	—	—
Part 2: Absolute Values of Liver Panel Parameters: ALP, ALT and AST ALP, Day 56	51.6 IU/L Standard Deviation 11.15	62.8 IU/L Standard Deviation 20.42	56.5 IU/L Standard Deviation 7.20	69.0 IU/L Standard Deviation 19.71	—	—
Part 2: Absolute Values of Liver Panel Parameters: ALP, ALT and AST ALP, Day 63	53.8 IU/L Standard Deviation 11.75	58.8 IU/L Standard Deviation 18.97	57.3 IU/L Standard Deviation 11.08	66.5 IU/L Standard Deviation 17.44	—	—
Part 2: Absolute Values of Liver Panel Parameters: ALP, ALT and AST ALT, Baseline (Day 1)	19.0 IU/L Standard Deviation 6.93	16.3 IU/L Standard Deviation 5.04	19.5 IU/L Standard Deviation 7.69	18.7 IU/L Standard Deviation 11.98	—	—
Part 2: Absolute Values of Liver Panel Parameters: ALP, ALT and AST ALT, Day 2	19.2 IU/L Standard Deviation 5.12	—	19.8 IU/L Standard Deviation 7.65	16.0 IU/L Standard Deviation 9.42	—	—
Part 2: Absolute Values of Liver Panel Parameters: ALP, ALT and AST ALT, Day 3	—	18.3 IU/L Standard Deviation 4.43	—	19.0 IU/L Standard Deviation 8.49	—	—
Part 2: Absolute Values of Liver Panel Parameters: ALP, ALT and AST ALT, Day 5	19.5 IU/L Standard Deviation 5.32	—	16.7 IU/L Standard Deviation 6.28	19.0 IU/L Standard Deviation 8.76	—	—
Part 2: Absolute Values of Liver Panel Parameters: ALP, ALT and AST ALT, Day 6	—	18.3 IU/L Standard Deviation 5.26	—	15.0 IU/L Standard Deviation 5.66	—	—
Part 2: Absolute Values of Liver Panel Parameters: ALP, ALT and AST ALT, Day 7	24.7 IU/L Standard Deviation 9.14	—	16.5 IU/L Standard Deviation 6.47	22.3 IU/L Standard Deviation 12.50	—	—
Part 2: Absolute Values of Liver Panel Parameters: ALP, ALT and AST ALT, Day 8	—	16.8 IU/L Standard Deviation 5.39	—	15.0 IU/L Standard Deviation 7.07	—	—
Part 2: Absolute Values of Liver Panel Parameters: ALP, ALT and AST ALT, Day 11	20.8 IU/L Standard Deviation 3.86	—	14.8 IU/L Standard Deviation 5.34	21.0 IU/L Standard Deviation 11.31	—	—
Part 2: Absolute Values of Liver Panel Parameters: ALP, ALT and AST ALT, Day 12	—	19.1 IU/L Standard Deviation 8.81	—	19.0 IU/L Standard Deviation 8.49	—	—
Part 2: Absolute Values of Liver Panel Parameters: ALP, ALT and AST ALT, Day 14	29.5 IU/L Standard Deviation 14.01	—	16.7 IU/L Standard Deviation 6.77	33.3 IU/L Standard Deviation 31.36	—	—
Part 2: Absolute Values of Liver Panel Parameters: ALP, ALT and AST ALT, Day 15	—	21.5 IU/L Standard Deviation 10.04	—	20.0 IU/L Standard Deviation 7.07	—	—
Part 2: Absolute Values of Liver Panel Parameters: ALP, ALT and AST ALT, Day 21	32.8 IU/L Standard Deviation 15.35	—	23.2 IU/L Standard Deviation 9.28	24.5 IU/L Standard Deviation 11.39	—	—
Part 2: Absolute Values of Liver Panel Parameters: ALP, ALT and AST ALT, Day 22	—	24.1 IU/L Standard Deviation 8.46	—	21.5 IU/L Standard Deviation 3.54	—	—
Part 2: Absolute Values of Liver Panel Parameters: ALP, ALT and AST ALT, Day 28	27.5 IU/L Standard Deviation 13.10	26.6 IU/L Standard Deviation 8.02	33.7 IU/L Standard Deviation 34.31	31.2 IU/L Standard Deviation 28.37	—	—
Part 2: Absolute Values of Liver Panel Parameters: ALP, ALT and AST ALT, Day 35	36.8 IU/L Standard Deviation 31.13	23.8 IU/L Standard Deviation 6.45	22.8 IU/L Standard Deviation 9.33	25.0 IU/L Standard Deviation 12.76	—	—
Part 2: Absolute Values of Liver Panel Parameters: ALP, ALT and AST ALT, Day 42	27.8 IU/L Standard Deviation 10.65	20.3 IU/L Standard Deviation 8.36	21.2 IU/L Standard Deviation 8.86	26.7 IU/L Standard Deviation 20.29	—	—
Part 2: Absolute Values of Liver Panel Parameters: ALP, ALT and AST ALT, Day 49	24.2 IU/L Standard Deviation 12.19	18.5 IU/L Standard Deviation 7.41	17.0 IU/L Standard Deviation 6.10	19.4 IU/L Standard Deviation 12.76	—	—
Part 2: Absolute Values of Liver Panel Parameters: ALP, ALT and AST ALP, Day 5	49.8 IU/L Standard Deviation 6.79	—	57.2 IU/L Standard Deviation 9.60	64.3 IU/L Standard Deviation 23.14	—	—
Part 2: Absolute Values of Liver Panel Parameters: ALP, ALT and AST ALT, Day 56	21.2 IU/L Standard Deviation 11.45	18.0 IU/L Standard Deviation 6.14	14.7 IU/L Standard Deviation 5.50	19.0 IU/L Standard Deviation 9.49	—	—
Part 2: Absolute Values of Liver Panel Parameters: ALP, ALT and AST ALT, Day 63	19.3 IU/L Standard Deviation 7.69	18.4 IU/L Standard Deviation 7.71	15.2 IU/L Standard Deviation 2.64	15.2 IU/L Standard Deviation 5.85	—	—
Part 2: Absolute Values of Liver Panel Parameters: ALP, ALT and AST AST, Baseline (Day 1)	19.2 IU/L Standard Deviation 4.12	14.9 IU/L Standard Deviation 3.14	17.8 IU/L Standard Deviation 3.54	16.2 IU/L Standard Deviation 2.99	—	—
Part 2: Absolute Values of Liver Panel Parameters: ALP, ALT and AST AST, Day 2	17.2 IU/L Standard Deviation 2.64	—	17.5 IU/L Standard Deviation 3.99	14.8 IU/L Standard Deviation 2.06	—	—
Part 2: Absolute Values of Liver Panel Parameters: ALP, ALT and AST AST, Day 3	—	16.3 IU/L Standard Deviation 2.25	—	15.5 IU/L Standard Deviation 3.54	—	—
Part 2: Absolute Values of Liver Panel Parameters: ALP, ALT and AST AST, Day 5	18.5 IU/L Standard Deviation 4.14	—	15.7 IU/L Standard Deviation 2.94	18.8 IU/L Standard Deviation 3.69	—	—
Part 2: Absolute Values of Liver Panel Parameters: ALP, ALT and AST AST, Day 6	—	15.3 IU/L Standard Deviation 3.01	—	15.0 IU/L Standard Deviation 1.41	—	—
Part 2: Absolute Values of Liver Panel Parameters: ALP, ALT and AST AST, Day 7	24.5 IU/L Standard Deviation 10.88	—	16.0 IU/L Standard Deviation 2.83	19.8 IU/L Standard Deviation 6.40	—	—
Part 2: Absolute Values of Liver Panel Parameters: ALP, ALT and AST AST, Day 8	—	15.5 IU/L Standard Deviation 2.14	—	15.0 IU/L Standard Deviation 2.83	—	—
Part 2: Absolute Values of Liver Panel Parameters: ALP, ALT and AST AST, Day 11	19.5 IU/L Standard Deviation 3.11	—	13.8 IU/L Standard Deviation 1.94	17.0 IU/L Standard Deviation 2.83	—	—
Part 2: Absolute Values of Liver Panel Parameters: ALP, ALT and AST AST, Day 12	—	16.3 IU/L Standard Deviation 3.33	—	16.5 IU/L Standard Deviation 2.12	—	—
Part 2: Absolute Values of Liver Panel Parameters: ALP, ALT and AST AST, Day 14	22.8 IU/L Standard Deviation 6.55	—	15.7 IU/L Standard Deviation 2.73	24.8 IU/L Standard Deviation 17.50	—	—
Part 2: Absolute Values of Liver Panel Parameters: ALP, ALT and AST AST, Day 15	—	16.0 IU/L Standard Deviation 3.59	—	16.0 IU/L Standard Deviation 2.83	—	—
Part 2: Absolute Values of Liver Panel Parameters: ALP, ALT and AST AST, Day 21	23.3 IU/L Standard Deviation 5.79	—	18.8 IU/L Standard Deviation 4.26	17.0 IU/L Standard Deviation 3.83	—	—
Part 2: Absolute Values of Liver Panel Parameters: ALP, ALT and AST AST, Day 22	—	17.9 IU/L Standard Deviation 2.47	—	17.5 IU/L Standard Deviation 2.12	—	—
Part 2: Absolute Values of Liver Panel Parameters: ALP, ALT and AST AST, Day 28	21.5 IU/L Standard Deviation 5.13	21.9 IU/L Standard Deviation 18.76	49.5 IU/L Standard Deviation 80.64	23.6 IU/L Standard Deviation 12.20	—	—
Part 2: Absolute Values of Liver Panel Parameters: ALP, ALT and AST AST, Day 35	24.7 IU/L Standard Deviation 10.03	19.5 IU/L Standard Deviation 6.63	18.8 IU/L Standard Deviation 5.19	20.0 IU/L Standard Deviation 5.51	—	—
Part 2: Absolute Values of Liver Panel Parameters: ALP, ALT and AST AST, Day 42	22.3 IU/L Standard Deviation 2.66	15.9 IU/L Standard Deviation 2.95	18.0 IU/L Standard Deviation 3.35	21.5 IU/L Standard Deviation 10.29	—	—
Part 2: Absolute Values of Liver Panel Parameters: ALP, ALT and AST AST, Day 49	19.5 IU/L Standard Deviation 5.28	16.1 IU/L Standard Deviation 5.41	16.5 IU/L Standard Deviation 1.97	18.2 IU/L Standard Deviation 4.97	—	—
Part 2: Absolute Values of Liver Panel Parameters: ALP, ALT and AST AST, Day 56	20.8 IU/L Standard Deviation 4.09	16.9 IU/L Standard Deviation 6.17	16.5 IU/L Standard Deviation 2.17	18.0 IU/L Standard Deviation 3.63	—	—
Part 2: Absolute Values of Liver Panel Parameters: ALP, ALT and AST AST, Day 63	19.8 IU/L Standard Deviation 6.34	16.1 IU/L Standard Deviation 3.72	17.0 IU/L Standard Deviation 3.41	15.2 IU/L Standard Deviation 1.72	—	—

PRIMARY outcome

Timeframe: Up to Day 49

Blood samples were collected as assessed by protocol, at specific time points for laboratory analysis of bilirubin.

Outcome measures

Outcome measures
Measure	Part 2 (MAD): VH4004280 100 mg PiB Healthy participants were given a dose of 100 mg VH4004280 PiB QD for a 14-day period and were followed up to approximately Day 63.	Part 2 (MAD): VH4004280 250 mg + Midazolam (MDZ) PiB Healthy participants were given a dose of 250 mg VH4004280 PiB QD for a 14-day period, and a single dose of Midazolam on days 1, 2, and 15, and were followed up to approximately Day 63.	Part 2 (MAD): VH4004280 350 mg PiB Healthy participants were given a dose of 350 mg VH4004280 PiB QD for a 14-day period and were followed up to approximately Day 63.	Part 3 (Single Dose): VH4004280 450 mg Tablet n=6 Participants Healthy participants were given a single oral dose of VH4004280 450 mg tablet at Day 1 and were followed up to approximately Day 49.	Part 1 (SAD): VH4004280 450 mg PiB Healthy participants were given a single oral dose of 450 mg VH4004280 PiB on Day 1 and were followed up to approximately Day 49.	Part 1 (SAD): VH4004280 900 mg PiB Healthy participants were given a single oral dose of 900 mg VH4004280 PiB on Day 1 and were followed up to approximately Day 49.
Part 3: Absolute Values of Liver Panel Parameters: Direct Bilirubin, Total Bilirubin Direct Bilirubin, Baseline (Day 1)	—	—	—	1.9950 μmol/L Standard Deviation 0.69810	—	—
Part 3: Absolute Values of Liver Panel Parameters: Direct Bilirubin, Total Bilirubin Direct Bilirubin, Day 2	—	—	—	2.3085 μmol/L Standard Deviation 0.68186	—	—
Part 3: Absolute Values of Liver Panel Parameters: Direct Bilirubin, Total Bilirubin Direct Bilirubin, Day 3	—	—	—	2.2515 μmol/L Standard Deviation 0.59646	—	—
Part 3: Absolute Values of Liver Panel Parameters: Direct Bilirubin, Total Bilirubin Direct Bilirubin, Day 4	—	—	—	2.1660 μmol/L Standard Deviation 0.66375	—	—
Part 3: Absolute Values of Liver Panel Parameters: Direct Bilirubin, Total Bilirubin Direct Bilirubin, Day 5	—	—	—	1.9380 μmol/L Standard Deviation 0.57905	—	—
Part 3: Absolute Values of Liver Panel Parameters: Direct Bilirubin, Total Bilirubin Direct Bilirubin, Day 6	—	—	—	2.2800 μmol/L Standard Deviation 0.55848	—	—
Part 3: Absolute Values of Liver Panel Parameters: Direct Bilirubin, Total Bilirubin Direct Bilirubin, Day 7	—	—	—	1.7670 μmol/L Standard Deviation 0.69810	—	—
Part 3: Absolute Values of Liver Panel Parameters: Direct Bilirubin, Total Bilirubin Direct Bilirubin, Day 14	—	—	—	1.7385 μmol/L Standard Deviation 0.77549	—	—
Part 3: Absolute Values of Liver Panel Parameters: Direct Bilirubin, Total Bilirubin Direct Bilirubin, Day 21	—	—	—	1.9380 μmol/L Standard Deviation 1.02979	—	—
Part 3: Absolute Values of Liver Panel Parameters: Direct Bilirubin, Total Bilirubin Direct Bilirubin, Day 28	—	—	—	1.8525 μmol/L Standard Deviation 0.79043	—	—
Part 3: Absolute Values of Liver Panel Parameters: Direct Bilirubin, Total Bilirubin Direct Bilirubin, Day 35	—	—	—	1.8525 μmol/L Standard Deviation 0.72077	—	—
Part 3: Absolute Values of Liver Panel Parameters: Direct Bilirubin, Total Bilirubin Direct Bilirubin, Day 42	—	—	—	1.9494 μmol/L Standard Deviation 0.56196	—	—
Part 3: Absolute Values of Liver Panel Parameters: Direct Bilirubin, Total Bilirubin Direct Bilirubin, Day 49	—	—	—	1.6530 μmol/L Standard Deviation 0.39981	—	—
Part 3: Absolute Values of Liver Panel Parameters: Direct Bilirubin, Total Bilirubin Total Bilirubin, Baseline (Day 1)	—	—	—	9.9750 μmol/L Standard Deviation 4.24640	—	—
Part 3: Absolute Values of Liver Panel Parameters: Direct Bilirubin, Total Bilirubin Total Bilirubin, Day 2	—	—	—	12.2550 μmol/L Standard Deviation 4.31200	—	—
Part 3: Absolute Values of Liver Panel Parameters: Direct Bilirubin, Total Bilirubin Total Bilirubin, Day 3	—	—	—	11.0580 μmol/L Standard Deviation 3.23487	—	—
Part 3: Absolute Values of Liver Panel Parameters: Direct Bilirubin, Total Bilirubin Total Bilirubin, Day 4	—	—	—	10.4025 μmol/L Standard Deviation 2.63898	—	—
Part 3: Absolute Values of Liver Panel Parameters: Direct Bilirubin, Total Bilirubin Total Bilirubin, Day 5	—	—	—	10.7730 μmol/L Standard Deviation 3.30875	—	—
Part 3: Absolute Values of Liver Panel Parameters: Direct Bilirubin, Total Bilirubin Total Bilirubin, Day 6	—	—	—	11.3715 μmol/L Standard Deviation 2.69888	—	—
Part 3: Absolute Values of Liver Panel Parameters: Direct Bilirubin, Total Bilirubin Total Bilirubin, Day 7	—	—	—	8.8635 μmol/L Standard Deviation 3.39669	—	—
Part 3: Absolute Values of Liver Panel Parameters: Direct Bilirubin, Total Bilirubin Total Bilirubin, Day 14	—	—	—	8.7780 μmol/L Standard Deviation 5.31551	—	—
Part 3: Absolute Values of Liver Panel Parameters: Direct Bilirubin, Total Bilirubin Total Bilirubin, Day 21	—	—	—	9.0915 μmol/L Standard Deviation 5.22647	—	—
Part 3: Absolute Values of Liver Panel Parameters: Direct Bilirubin, Total Bilirubin Total Bilirubin, Day 28	—	—	—	8.8920 μmol/L Standard Deviation 4.03357	—	—
Part 3: Absolute Values of Liver Panel Parameters: Direct Bilirubin, Total Bilirubin Total Bilirubin, Day 35	—	—	—	10.0890 μmol/L Standard Deviation 5.11859	—	—
Part 3: Absolute Values of Liver Panel Parameters: Direct Bilirubin, Total Bilirubin Total Bilirubin, Day 42	—	—	—	8.8920 μmol/L Standard Deviation 2.25240	—	—
Part 3: Absolute Values of Liver Panel Parameters: Direct Bilirubin, Total Bilirubin Total Bilirubin, Day 49	—	—	—	8.4645 μmol/L Standard Deviation 2.29866	—	—

PRIMARY outcome

Timeframe: Up to Day 49

Blood samples were collected as assessed by protocol, at specific time points for laboratory analysis of ALP, ALT and AST.

Outcome measures

Outcome measures
Measure	Part 2 (MAD): VH4004280 100 mg PiB Healthy participants were given a dose of 100 mg VH4004280 PiB QD for a 14-day period and were followed up to approximately Day 63.	Part 2 (MAD): VH4004280 250 mg + Midazolam (MDZ) PiB Healthy participants were given a dose of 250 mg VH4004280 PiB QD for a 14-day period, and a single dose of Midazolam on days 1, 2, and 15, and were followed up to approximately Day 63.	Part 2 (MAD): VH4004280 350 mg PiB Healthy participants were given a dose of 350 mg VH4004280 PiB QD for a 14-day period and were followed up to approximately Day 63.	Part 3 (Single Dose): VH4004280 450 mg Tablet n=6 Participants Healthy participants were given a single oral dose of VH4004280 450 mg tablet at Day 1 and were followed up to approximately Day 49.	Part 1 (SAD): VH4004280 450 mg PiB Healthy participants were given a single oral dose of 450 mg VH4004280 PiB on Day 1 and were followed up to approximately Day 49.	Part 1 (SAD): VH4004280 900 mg PiB Healthy participants were given a single oral dose of 900 mg VH4004280 PiB on Day 1 and were followed up to approximately Day 49.
Part 3: Absolute Values of Liver Panel Parameters: ALP, ALT and AST AST, Day 42	—	—	—	28.2 IU/L Standard Deviation 27.31	—	—
Part 3: Absolute Values of Liver Panel Parameters: ALP, ALT and AST AST, Day 49	—	—	—	19.5 IU/L Standard Deviation 9.71	—	—
Part 3: Absolute Values of Liver Panel Parameters: ALP, ALT and AST ALP, Baseline (Day 1)	—	—	—	55.7 IU/L Standard Deviation 11.78	—	—
Part 3: Absolute Values of Liver Panel Parameters: ALP, ALT and AST ALP, Day 2	—	—	—	47.8 IU/L Standard Deviation 10.76	—	—
Part 3: Absolute Values of Liver Panel Parameters: ALP, ALT and AST ALP, Day 3	—	—	—	50.2 IU/L Standard Deviation 10.63	—	—
Part 3: Absolute Values of Liver Panel Parameters: ALP, ALT and AST ALP, Day 4	—	—	—	50.8 IU/L Standard Deviation 9.68	—	—
Part 3: Absolute Values of Liver Panel Parameters: ALP, ALT and AST ALP, Day 5	—	—	—	48.8 IU/L Standard Deviation 7.94	—	—
Part 3: Absolute Values of Liver Panel Parameters: ALP, ALT and AST ALP, Day 6	—	—	—	49.7 IU/L Standard Deviation 10.84	—	—
Part 3: Absolute Values of Liver Panel Parameters: ALP, ALT and AST ALP, Day 7	—	—	—	50.3 IU/L Standard Deviation 9.29	—	—
Part 3: Absolute Values of Liver Panel Parameters: ALP, ALT and AST ALP, Day 14	—	—	—	60.2 IU/L Standard Deviation 18.27	—	—
Part 3: Absolute Values of Liver Panel Parameters: ALP, ALT and AST ALP, Day 21	—	—	—	58.0 IU/L Standard Deviation 15.47	—	—
Part 3: Absolute Values of Liver Panel Parameters: ALP, ALT and AST ALP, Day 28	—	—	—	59.7 IU/L Standard Deviation 18.99	—	—
Part 3: Absolute Values of Liver Panel Parameters: ALP, ALT and AST ALP, Day 35	—	—	—	59.5 IU/L Standard Deviation 16.43	—	—
Part 3: Absolute Values of Liver Panel Parameters: ALP, ALT and AST ALP, Day 42	—	—	—	58.2 IU/L Standard Deviation 8.81	—	—
Part 3: Absolute Values of Liver Panel Parameters: ALP, ALT and AST ALP, Day 49	—	—	—	55.8 IU/L Standard Deviation 13.39	—	—
Part 3: Absolute Values of Liver Panel Parameters: ALP, ALT and AST ALT, Baseline (Day 1)	—	—	—	24.3 IU/L Standard Deviation 17.07	—	—
Part 3: Absolute Values of Liver Panel Parameters: ALP, ALT and AST ALT, Day 2	—	—	—	19.2 IU/L Standard Deviation 13.04	—	—
Part 3: Absolute Values of Liver Panel Parameters: ALP, ALT and AST ALT, Day 3	—	—	—	19.2 IU/L Standard Deviation 11.00	—	—
Part 3: Absolute Values of Liver Panel Parameters: ALP, ALT and AST ALT, Day 4	—	—	—	19.2 IU/L Standard Deviation 8.80	—	—
Part 3: Absolute Values of Liver Panel Parameters: ALP, ALT and AST ALT, Day 5	—	—	—	18.7 IU/L Standard Deviation 8.36	—	—
Part 3: Absolute Values of Liver Panel Parameters: ALP, ALT and AST ALT, Day 6	—	—	—	20.3 IU/L Standard Deviation 9.20	—	—
Part 3: Absolute Values of Liver Panel Parameters: ALP, ALT and AST ALT, Day 7	—	—	—	21.3 IU/L Standard Deviation 10.78	—	—
Part 3: Absolute Values of Liver Panel Parameters: ALP, ALT and AST ALT, Day 14	—	—	—	44.7 IU/L Standard Deviation 64.91	—	—
Part 3: Absolute Values of Liver Panel Parameters: ALP, ALT and AST ALT, Day 21	—	—	—	31.3 IU/L Standard Deviation 34.51	—	—
Part 3: Absolute Values of Liver Panel Parameters: ALP, ALT and AST ALT, Day 28	—	—	—	41.8 IU/L Standard Deviation 57.78	—	—
Part 3: Absolute Values of Liver Panel Parameters: ALP, ALT and AST ALT, Day 35	—	—	—	26.7 IU/L Standard Deviation 22.90	—	—
Part 3: Absolute Values of Liver Panel Parameters: ALP, ALT and AST ALT, Day 42	—	—	—	34.6 IU/L Standard Deviation 47.24	—	—
Part 3: Absolute Values of Liver Panel Parameters: ALP, ALT and AST ALT, Day 49	—	—	—	26.3 IU/L Standard Deviation 30.80	—	—
Part 3: Absolute Values of Liver Panel Parameters: ALP, ALT and AST AST, Baseline (Day 1)	—	—	—	17.5 IU/L Standard Deviation 4.28	—	—
Part 3: Absolute Values of Liver Panel Parameters: ALP, ALT and AST AST, Day 2	—	—	—	15.2 IU/L Standard Deviation 3.49	—	—
Part 3: Absolute Values of Liver Panel Parameters: ALP, ALT and AST AST, Day 3	—	—	—	15.2 IU/L Standard Deviation 3.37	—	—
Part 3: Absolute Values of Liver Panel Parameters: ALP, ALT and AST AST, Day 4	—	—	—	15.7 IU/L Standard Deviation 2.42	—	—
Part 3: Absolute Values of Liver Panel Parameters: ALP, ALT and AST AST, Day 5	—	—	—	15.3 IU/L Standard Deviation 2.80	—	—
Part 3: Absolute Values of Liver Panel Parameters: ALP, ALT and AST AST, Day 6	—	—	—	17.5 IU/L Standard Deviation 4.68	—	—
Part 3: Absolute Values of Liver Panel Parameters: ALP, ALT and AST AST, Day 7	—	—	—	17.2 IU/L Standard Deviation 5.23	—	—
Part 3: Absolute Values of Liver Panel Parameters: ALP, ALT and AST AST, Day 14	—	—	—	24.3 IU/L Standard Deviation 19.58	—	—
Part 3: Absolute Values of Liver Panel Parameters: ALP, ALT and AST AST, Day 21	—	—	—	20.0 IU/L Standard Deviation 7.97	—	—
Part 3: Absolute Values of Liver Panel Parameters: ALP, ALT and AST AST, Day 28	—	—	—	24.5 IU/L Standard Deviation 16.72	—	—
Part 3: Absolute Values of Liver Panel Parameters: ALP, ALT and AST AST, Day 35	—	—	—	21.2 IU/L Standard Deviation 7.91	—	—

PRIMARY outcome

Timeframe: From Baseline (Day 1) and up to Day 49

Change from baseline was calculated by subtracting the baseline value from the post-dose visit value. Standard Deviation (SD)=0.0000 is defined as following: if all participants analyzed for a specific parameter at a specific time point have the same value, then SD is equal with 0.0000.

Outcome measures

Outcome measures
Measure	Part 2 (MAD): VH4004280 100 mg PiB n=6 Participants Healthy participants were given a dose of 100 mg VH4004280 PiB QD for a 14-day period and were followed up to approximately Day 63.	Part 2 (MAD): VH4004280 250 mg + Midazolam (MDZ) PiB n=7 Participants Healthy participants were given a dose of 250 mg VH4004280 PiB QD for a 14-day period, and a single dose of Midazolam on days 1, 2, and 15, and were followed up to approximately Day 63.	Part 2 (MAD): VH4004280 350 mg PiB n=6 Participants Healthy participants were given a dose of 350 mg VH4004280 PiB QD for a 14-day period and were followed up to approximately Day 63.	Part 3 (Single Dose): VH4004280 450 mg Tablet n=10 Participants Healthy participants were given a single oral dose of VH4004280 450 mg tablet at Day 1 and were followed up to approximately Day 49.	Part 1 (SAD): VH4004280 450 mg PiB n=6 Participants Healthy participants were given a single oral dose of 450 mg VH4004280 PiB on Day 1 and were followed up to approximately Day 49.	Part 1 (SAD): VH4004280 900 mg PiB n=6 Participants Healthy participants were given a single oral dose of 900 mg VH4004280 PiB on Day 1 and were followed up to approximately Day 49.
Part 1: Change From Baseline in Liver Panel Parameters: Direct Bilirubin, Total Bilirubin Total Bilirubin, Day 6	-0.4275 μmol/L Standard Deviation 0.98973	-5.4720 μmol/L Standard Deviation 3.74330	-2.9070 μmol/L Standard Deviation 2.84087	-0.2052 μmol/L Standard Deviation 6.38797	2.2515 μmol/L Standard Deviation 4.45049	3.5340 μmol/L Standard Deviation 2.75234
Part 1: Change From Baseline in Liver Panel Parameters: Direct Bilirubin, Total Bilirubin Total Bilirubin, Day 7	-1.9380 μmol/L Standard Deviation 1.87841	-5.1585 μmol/L Standard Deviation 3.43777	-1.5390 μmol/L Standard Deviation 2.91002	0.6840 μmol/L Standard Deviation 5.49629	4.9875 μmol/L Standard Deviation 4.06738	1.7100 μmol/L Standard Deviation 3.37351
Part 1: Change From Baseline in Liver Panel Parameters: Direct Bilirubin, Total Bilirubin Total Bilirubin, Day 14	-5.7855 μmol/L Standard Deviation 1.36978	-6.7374 μmol/L Standard Deviation 3.07705	-4.3035 μmol/L Standard Deviation 5.00001	-2.7531 μmol/L Standard Deviation 6.09471	1.1970 μmol/L Standard Deviation 2.11861	0.9690 μmol/L Standard Deviation 7.12039
Part 1: Change From Baseline in Liver Panel Parameters: Direct Bilirubin, Total Bilirubin Total Bilirubin, Day 28	-3.4200 μmol/L Standard Deviation 1.69626	-3.8304 μmol/L Standard Deviation 2.83984	-4.2750 μmol/L Standard Deviation 5.88995	0.0000 μmol/L Standard Deviation 4.73683	5.0730 μmol/L Standard Deviation 5.72446	0.5700 μmol/L Standard Deviation 6.01635
Part 1: Change From Baseline in Liver Panel Parameters: Direct Bilirubin, Total Bilirubin Direct Bilirubin, Baseline (Day 1)	1.9950 μmol/L Standard Deviation 0.69810	2.9314 μmol/L Standard Deviation 0.83439	2.2800 μmol/L Standard Deviation 1.39621	2.5650 μmol/L Standard Deviation 1.20915	2.2800 μmol/L Standard Deviation 0.88304	2.8500 μmol/L Standard Deviation 0.88304
Part 1: Change From Baseline in Liver Panel Parameters: Direct Bilirubin, Total Bilirubin Direct Bilirubin, Day 2	0.5130 μmol/L Standard Deviation 0.47141	0.0244 μmol/L Standard Deviation 0.96948	-0.2280 μmol/L Standard Deviation 0.46726	0.0570 μmol/L Standard Deviation 0.80206	0.4560 μmol/L Standard Deviation 0.69810	0.2280 μmol/L Standard Deviation 1.00100
Part 1: Change From Baseline in Liver Panel Parameters: Direct Bilirubin, Total Bilirubin Direct Bilirubin, Day 3	0.4845 μmol/L Standard Deviation 0.47656	-0.1425 μmol/L Standard Deviation 0.62518	-0.4275 μmol/L Standard Deviation 0.51584	0.1368 μmol/L Standard Deviation 0.87861	0.0855 μmol/L Standard Deviation 0.57989	0.1995 μmol/L Standard Deviation 0.96379
Part 1: Change From Baseline in Liver Panel Parameters: Direct Bilirubin, Total Bilirubin Direct Bilirubin, Day 4	0.0285 μmol/L Standard Deviation 0.39614	-0.1140 μmol/L Standard Deviation 0.69810	-0.4104 μmol/L Standard Deviation 0.84295	-0.0684 μmol/L Standard Deviation 1.09107	-0.0285 μmol/L Standard Deviation 0.65264	-0.1710 μmol/L Standard Deviation 0.85841
Part 1: Change From Baseline in Liver Panel Parameters: Direct Bilirubin, Total Bilirubin Direct Bilirubin, Day 5	0.6555 μmol/L Standard Deviation 0.36542	-0.3420 μmol/L Standard Deviation 0.83072	-0.3135 μmol/L Standard Deviation 0.62518	0.1710 μmol/L Standard Deviation 1.19564	0.5415 μmol/L Standard Deviation 0.42464	-0.0285 μmol/L Standard Deviation 0.58657
Part 1: Change From Baseline in Liver Panel Parameters: Direct Bilirubin, Total Bilirubin Direct Bilirubin, Day 6	0.6555 μmol/L Standard Deviation 0.45134	-0.5415 μmol/L Standard Deviation 0.45134	-0.4845 μmol/L Standard Deviation 0.54524	0.0000 μmol/L Standard Deviation 1.01004	0.0855 μmol/L Standard Deviation 0.87695	0.0285 μmol/L Standard Deviation 0.95158
Part 1: Change From Baseline in Liver Panel Parameters: Direct Bilirubin, Total Bilirubin Direct Bilirubin, Day 7	0.4845 μmol/L Standard Deviation 0.60619	-0.5700 μmol/L Standard Deviation 0.70643	-0.3705 μmol/L Standard Deviation 0.67033	0.3249 μmol/L Standard Deviation 1.18869	0.0570 μmol/L Standard Deviation 0.66375	-0.2565 μmol/L Standard Deviation 0.69880
Part 1: Change From Baseline in Liver Panel Parameters: Direct Bilirubin, Total Bilirubin Direct Bilirubin, Day 14	-0.2850 μmol/L Standard Deviation 0.69810	-1.1628 μmol/L Standard Deviation 1.04995	-0.6555 μmol/L Standard Deviation 0.68755	-0.2052 μmol/L Standard Deviation 1.04109	0.1710 μmol/L Standard Deviation 0.72549	-0.1710 μmol/L Standard Deviation 1.72023
Part 1: Change From Baseline in Liver Panel Parameters: Direct Bilirubin, Total Bilirubin Direct Bilirubin, Day 21	0.1425 μmol/L Standard Deviation 0.80509	-0.5415 μmol/L Standard Deviation 0.86125	-0.8550 μmol/L Standard Deviation 0.93034	-0.0342 μmol/L Standard Deviation 1.03168	0.1995 μmol/L Standard Deviation 0.55586	-0.7980 μmol/L Standard Deviation 0.76218
Part 1: Change From Baseline in Liver Panel Parameters: Direct Bilirubin, Total Bilirubin Direct Bilirubin, Day 28	0.0855 μmol/L Standard Deviation 0.63753	-0.4104 μmol/L Standard Deviation 0.44591	-0.6270 μmol/L Standard Deviation 0.98331	0.2565 μmol/L Standard Deviation 1.37570	0.9690 μmol/L Standard Deviation 0.60859	-0.5130 μmol/L Standard Deviation 1.23310
Part 1: Change From Baseline in Liver Panel Parameters: Direct Bilirubin, Total Bilirubin Total Bilirubin, Day 4	-3.0780 μmol/L Standard Deviation 1.47100	-0.8835 μmol/L Standard Deviation 3.77816	-1.6416 μmol/L Standard Deviation 2.98785	0.4617 μmol/L Standard Deviation 5.19048	4.1610 μmol/L Standard Deviation 2.59033	2.5650 μmol/L Standard Deviation 3.61332
Part 1: Change From Baseline in Liver Panel Parameters: Direct Bilirubin, Total Bilirubin Total Bilirubin, Day 5	-0.8835 μmol/L Standard Deviation 0.97585	-3.2775 μmol/L Standard Deviation 4.31980	-1.5675 μmol/L Standard Deviation 2.78350	0.3933 μmol/L Standard Deviation 5.87628	4.0470 μmol/L Standard Deviation 3.19851	3.9045 μmol/L Standard Deviation 2.63233
Part 1: Change From Baseline in Liver Panel Parameters: Direct Bilirubin, Total Bilirubin Total Bilirubin, Day 21	-2.9355 μmol/L Standard Deviation 2.88664	-4.8165 μmol/L Standard Deviation 3.47667	-4.7025 μmol/L Standard Deviation 5.15927	-0.7353 μmol/L Standard Deviation 3.99004	0.7980 μmol/L Standard Deviation 2.90532	-1.9095 μmol/L Standard Deviation 4.55440
Part 1: Change From Baseline in Liver Panel Parameters: Direct Bilirubin, Total Bilirubin Total Bilirubin, Day 35	-3.9615 μmol/L Standard Deviation 1.41183	-5.0445 μmol/L Standard Deviation 4.68272	-3.8190 μmol/L Standard Deviation 5.34403	-1.1628 μmol/L Standard Deviation 4.21939	-0.3135 μmol/L Standard Deviation 3.91200	-2.1888 μmol/L Standard Deviation 4.84024
Part 1: Change From Baseline in Liver Panel Parameters: Direct Bilirubin, Total Bilirubin Total Bilirubin, Day 42	—	—	-4.0470 μmol/L Standard Deviation 4.70877	0.0285 μmol/L Standard Deviation 5.67701	3.9045 μmol/L Standard Deviation 5.91316	2.1375 μmol/L Standard Deviation 2.03985
Part 1: Change From Baseline in Liver Panel Parameters: Direct Bilirubin, Total Bilirubin Total Bilirubin, Day 49	—	—	-3.4200 μmol/L Standard Deviation 4.88354	-0.7695 μmol/L Standard Deviation 4.69270	3.1350 μmol/L Standard Deviation 2.76717	1.9380 μmol/L Standard Deviation 8.15487
Part 1: Change From Baseline in Liver Panel Parameters: Direct Bilirubin, Total Bilirubin Direct Bilirubin, Day 49	—	—	-0.7125 μmol/L Standard Deviation 0.96379	0.0855 μmol/L Standard Deviation 1.19333	0.3705 μmol/L Standard Deviation 0.84756	-0.1995 μmol/L Standard Deviation 0.95770
Part 1: Change From Baseline in Liver Panel Parameters: Direct Bilirubin, Total Bilirubin Total Bilirubin, Baseline (Day 1)	12.5400 μmol/L Standard Deviation 3.84908	14.9014 μmol/L Standard Deviation 3.65613	12.2550 μmol/L Standard Deviation 8.47558	13.1670 μmol/L Standard Deviation 6.84237	11.6850 μmol/L Standard Deviation 5.00498	10.8300 μmol/L Standard Deviation 5.26132
Part 1: Change From Baseline in Liver Panel Parameters: Direct Bilirubin, Total Bilirubin Direct Bilirubin, Day 35	0.1140 μmol/L Standard Deviation 0.27924	-0.5700 μmol/L Standard Deviation 0.84928	-0.5415 μmol/L Standard Deviation 1.02267	-0.2052 μmol/L Standard Deviation 1.10174	0.0000 μmol/L Standard Deviation 0.76474	-0.7866 μmol/L Standard Deviation 0.67971
Part 1: Change From Baseline in Liver Panel Parameters: Direct Bilirubin, Total Bilirubin Direct Bilirubin, Day 42	—	—	-0.6270 μmol/L Standard Deviation 0.84928	0.0855 μmol/L Standard Deviation 1.41321	0.4560 μmol/L Standard Deviation 0.97134	-0.0855 μmol/L Standard Deviation 0.77045
Part 1: Change From Baseline in Liver Panel Parameters: Direct Bilirubin, Total Bilirubin Total Bilirubin, Day 2	-0.6270 μmol/L Standard Deviation 1.14285	-1.4657 μmol/L Standard Deviation 2.08465	-1.4820 μmol/L Standard Deviation 1.96662	1.5770 μmol/L Standard Deviation 4.50462	6.2985 μmol/L Standard Deviation 3.89252	5.4435 μmol/L Standard Deviation 4.21426
Part 1: Change From Baseline in Liver Panel Parameters: Direct Bilirubin, Total Bilirubin Total Bilirubin, Day 3	-0.7695 μmol/L Standard Deviation 1.10159	-2.9640 μmol/L Standard Deviation 1.07426	-1.7955 μmol/L Standard Deviation 1.66407	1.1286 μmol/L Standard Deviation 4.54801	3.8190 μmol/L Standard Deviation 4.03164	4.7595 μmol/L Standard Deviation 4.71342

PRIMARY outcome

Timeframe: From Baseline (Day 1) and up to Day 49

Change from baseline was calculated by subtracting the baseline value from the post-dose visit value.

Outcome measures

Outcome measures
Measure	Part 2 (MAD): VH4004280 100 mg PiB n=6 Participants Healthy participants were given a dose of 100 mg VH4004280 PiB QD for a 14-day period and were followed up to approximately Day 63.	Part 2 (MAD): VH4004280 250 mg + Midazolam (MDZ) PiB n=7 Participants Healthy participants were given a dose of 250 mg VH4004280 PiB QD for a 14-day period, and a single dose of Midazolam on days 1, 2, and 15, and were followed up to approximately Day 63.	Part 2 (MAD): VH4004280 350 mg PiB n=6 Participants Healthy participants were given a dose of 350 mg VH4004280 PiB QD for a 14-day period and were followed up to approximately Day 63.	Part 3 (Single Dose): VH4004280 450 mg Tablet n=10 Participants Healthy participants were given a single oral dose of VH4004280 450 mg tablet at Day 1 and were followed up to approximately Day 49.	Part 1 (SAD): VH4004280 450 mg PiB n=6 Participants Healthy participants were given a single oral dose of 450 mg VH4004280 PiB on Day 1 and were followed up to approximately Day 49.	Part 1 (SAD): VH4004280 900 mg PiB n=6 Participants Healthy participants were given a single oral dose of 900 mg VH4004280 PiB on Day 1 and were followed up to approximately Day 49.
Part 1: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST ALP, Day 6	-2.2 IU/L Standard Deviation 3.66	-9.3 IU/L Standard Deviation 11.66	-6.0 IU/L Standard Deviation 6.63	-3.0 IU/L Standard Deviation 4.92	-1.7 IU/L Standard Deviation 2.80	-7.3 IU/L Standard Deviation 10.56
Part 1: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST ALP, Day 7	-0.3 IU/L Standard Deviation 5.79	-4.0 IU/L Standard Deviation 14.86	-4.7 IU/L Standard Deviation 5.50	-0.1 IU/L Standard Deviation 6.95	2.3 IU/L Standard Deviation 4.23	-5.0 IU/L Standard Deviation 9.49
Part 1: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST ALT, Day 4	0.3 IU/L Standard Deviation 6.38	2.3 IU/L Standard Deviation 7.37	2.6 IU/L Standard Deviation 3.85	0.8 IU/L Standard Deviation 7.13	-0.5 IU/L Standard Deviation 3.73	0.2 IU/L Standard Deviation 2.14
Part 1: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST ALT, Day 5	-1.2 IU/L Standard Deviation 6.18	2.7 IU/L Standard Deviation 9.37	3.8 IU/L Standard Deviation 6.43	-0.3 IU/L Standard Deviation 7.97	0.2 IU/L Standard Deviation 2.93	0.0 IU/L Standard Deviation 2.83
Part 1: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST ALT, Day 28	10.8 IU/L Standard Deviation 20.21	4.8 IU/L Standard Deviation 5.63	3.5 IU/L Standard Deviation 4.09	1.7 IU/L Standard Deviation 10.22	2.0 IU/L Standard Deviation 4.34	4.8 IU/L Standard Deviation 6.88
Part 1: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST ALT, Day 35	5.7 IU/L Standard Deviation 9.54	3.5 IU/L Standard Deviation 4.76	2.8 IU/L Standard Deviation 5.49	1.4 IU/L Standard Deviation 9.88	6.5 IU/L Standard Deviation 15.36	2.4 IU/L Standard Deviation 2.41
Part 1: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST AST, Baseline (Day 1)	17.3 IU/L Standard Deviation 5.82	15.1 IU/L Standard Deviation 4.14	17.5 IU/L Standard Deviation 3.62	17.3 IU/L Standard Deviation 5.03	15.0 IU/L Standard Deviation 3.03	16.5 IU/L Standard Deviation 3.51
Part 1: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST AST, Day 2	-1.0 IU/L Standard Deviation 3.10	-0.9 IU/L Standard Deviation 4.34	-1.0 IU/L Standard Deviation 0.89	-0.1 IU/L Standard Deviation 3.69	0.0 IU/L Standard Deviation 3.29	-0.7 IU/L Standard Deviation 1.51
Part 1: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST AST, Day 49	—	—	5.8 IU/L Standard Deviation 4.07	-0.7 IU/L Standard Deviation 1.75	3.2 IU/L Standard Deviation 4.71	1.5 IU/L Standard Deviation 5.82
Part 1: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST ALP, Baseline (Day 1)	64.7 IU/L Standard Deviation 10.88	67.1 IU/L Standard Deviation 27.91	69.0 IU/L Standard Deviation 25.04	51.8 IU/L Standard Deviation 9.39	64.0 IU/L Standard Deviation 11.10	61.8 IU/L Standard Deviation 15.41
Part 1: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST ALP, Day 2	-5.7 IU/L Standard Deviation 2.88	-6.7 IU/L Standard Deviation 5.53	-5.5 IU/L Standard Deviation 5.09	-4.2 IU/L Standard Deviation 5.74	-5.8 IU/L Standard Deviation 3.97	-7.3 IU/L Standard Deviation 7.23
Part 1: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST ALP, Day 3	-5.8 IU/L Standard Deviation 3.97	-9.5 IU/L Standard Deviation 9.54	-6.0 IU/L Standard Deviation 6.20	-3.6 IU/L Standard Deviation 5.97	-8.2 IU/L Standard Deviation 4.36	-9.3 IU/L Standard Deviation 6.47
Part 1: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST ALP, Day 4	-4.2 IU/L Standard Deviation 4.92	-5.2 IU/L Standard Deviation 12.46	-5.4 IU/L Standard Deviation 7.30	-2.5 IU/L Standard Deviation 6.19	-0.8 IU/L Standard Deviation 2.86	-9.0 IU/L Standard Deviation 5.06
Part 1: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST ALP, Day 5	-5.5 IU/L Standard Deviation 4.42	-11.0 IU/L Standard Deviation 10.33	-5.7 IU/L Standard Deviation 8.04	-3.7 IU/L Standard Deviation 3.47	-3.5 IU/L Standard Deviation 3.62	-4.2 IU/L Standard Deviation 9.20
Part 1: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST ALP, Day 14	-2.5 IU/L Standard Deviation 5.61	-6.8 IU/L Standard Deviation 15.22	-4.0 IU/L Standard Deviation 5.18	3.0 IU/L Standard Deviation 5.96	2.0 IU/L Standard Deviation 7.04	-0.5 IU/L Standard Deviation 8.29
Part 1: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST ALP, Day 21	-6.0 IU/L Standard Deviation 2.28	-3.5 IU/L Standard Deviation 6.80	-3.0 IU/L Standard Deviation 9.55	1.2 IU/L Standard Deviation 3.49	-2.5 IU/L Standard Deviation 4.59	-2.7 IU/L Standard Deviation 10.01
Part 1: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST ALP, Day 28	-7.2 IU/L Standard Deviation 7.33	-0.2 IU/L Standard Deviation 12.72	-3.5 IU/L Standard Deviation 5.89	2.1 IU/L Standard Deviation 7.29	-0.5 IU/L Standard Deviation 4.51	3.7 IU/L Standard Deviation 17.44
Part 1: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST ALP, Day 35	1.7 IU/L Standard Deviation 5.54	-3.3 IU/L Standard Deviation 6.83	-5.2 IU/L Standard Deviation 7.11	1.1 IU/L Standard Deviation 4.07	0.7 IU/L Standard Deviation 7.20	-0.6 IU/L Standard Deviation 9.07
Part 1: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST ALP, Day 42	—	—	-5.7 IU/L Standard Deviation 3.67	-1.8 IU/L Standard Deviation 5.78	2.2 IU/L Standard Deviation 6.74	1.3 IU/L Standard Deviation 6.44
Part 1: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST ALP, Day 49	—	—	-1.8 IU/L Standard Deviation 5.85	-1.2 IU/L Standard Deviation 4.45	2.7 IU/L Standard Deviation 9.35	-2.2 IU/L Standard Deviation 10.46
Part 1: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST ALT, Baseline (Day 1)	22.8 IU/L Standard Deviation 11.72	15.1 IU/L Standard Deviation 4.85	20.7 IU/L Standard Deviation 8.07	18.4 IU/L Standard Deviation 5.60	14.8 IU/L Standard Deviation 2.93	16.0 IU/L Standard Deviation 4.34
Part 1: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST ALT, Day 2	-0.8 IU/L Standard Deviation 5.64	0.4 IU/L Standard Deviation 4.28	0.7 IU/L Standard Deviation 1.75	-0.1 IU/L Standard Deviation 4.81	0.8 IU/L Standard Deviation 3.66	-0.7 IU/L Standard Deviation 1.86
Part 1: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST ALT, Day 3	-0.7 IU/L Standard Deviation 6.44	1.5 IU/L Standard Deviation 6.09	0.0 IU/L Standard Deviation 1.26	0.2 IU/L Standard Deviation 6.34	1.0 IU/L Standard Deviation 3.79	0.0 IU/L Standard Deviation 1.79
Part 1: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST ALT, Day 6	-0.3 IU/L Standard Deviation 5.85	3.7 IU/L Standard Deviation 11.29	3.5 IU/L Standard Deviation 6.72	0.5 IU/L Standard Deviation 9.57	-0.3 IU/L Standard Deviation 3.98	2.8 IU/L Standard Deviation 4.96
Part 1: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST ALT, Day 7	0.7 IU/L Standard Deviation 5.61	3.8 IU/L Standard Deviation 10.87	4.0 IU/L Standard Deviation 7.97	1.5 IU/L Standard Deviation 11.65	0.5 IU/L Standard Deviation 4.51	4.8 IU/L Standard Deviation 7.03
Part 1: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST ALT, Day 14	4.5 IU/L Standard Deviation 11.26	5.2 IU/L Standard Deviation 6.72	9.2 IU/L Standard Deviation 14.58	7.7 IU/L Standard Deviation 16.96	6.2 IU/L Standard Deviation 11.63	6.7 IU/L Standard Deviation 10.03
Part 1: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST ALT, Day 21	0.7 IU/L Standard Deviation 4.76	5.8 IU/L Standard Deviation 8.42	3.8 IU/L Standard Deviation 4.54	5.0 IU/L Standard Deviation 14.54	4.3 IU/L Standard Deviation 5.16	6.2 IU/L Standard Deviation 11.63
Part 1: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST ALT, Day 42	—	—	4.8 IU/L Standard Deviation 7.70	-1.7 IU/L Standard Deviation 3.78	1.5 IU/L Standard Deviation 3.62	1.5 IU/L Standard Deviation 2.74
Part 1: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST ALT, Day 49	—	—	7.2 IU/L Standard Deviation 8.50	-0.8 IU/L Standard Deviation 2.64	3.8 IU/L Standard Deviation 9.75	1.2 IU/L Standard Deviation 4.22
Part 1: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST AST, Day 3	-1.3 IU/L Standard Deviation 2.94	1.0 IU/L Standard Deviation 3.69	-0.8 IU/L Standard Deviation 2.23	-0.9 IU/L Standard Deviation 3.25	-0.3 IU/L Standard Deviation 2.50	-1.3 IU/L Standard Deviation 2.42
Part 1: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST AST, Day 4	-0.7 IU/L Standard Deviation 3.01	1.5 IU/L Standard Deviation 2.81	1.0 IU/L Standard Deviation 2.83	-1.5 IU/L Standard Deviation 3.95	-1.7 IU/L Standard Deviation 2.07	-1.0 IU/L Standard Deviation 3.22
Part 1: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST AST, Day 5	-2.5 IU/L Standard Deviation 2.43	1.0 IU/L Standard Deviation 3.22	1.0 IU/L Standard Deviation 2.83	-2.5 IU/L Standard Deviation 4.48	-1.3 IU/L Standard Deviation 2.07	-0.7 IU/L Standard Deviation 2.34
Part 1: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST AST, Day 6	-1.3 IU/L Standard Deviation 2.34	1.8 IU/L Standard Deviation 4.92	0.2 IU/L Standard Deviation 4.17	-1.7 IU/L Standard Deviation 5.12	-0.7 IU/L Standard Deviation 2.50	0.2 IU/L Standard Deviation 3.54
Part 1: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST AST, Day 7	-0.5 IU/L Standard Deviation 2.95	2.0 IU/L Standard Deviation 3.22	0.7 IU/L Standard Deviation 2.73	-0.8 IU/L Standard Deviation 5.87	0.3 IU/L Standard Deviation 1.63	1.5 IU/L Standard Deviation 4.23
Part 1: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST AST, Day 14	0.7 IU/L Standard Deviation 3.50	0.6 IU/L Standard Deviation 3.05	3.2 IU/L Standard Deviation 5.12	22.7 IU/L Standard Deviation 70.63	4.6 IU/L Standard Deviation 6.11	1.0 IU/L Standard Deviation 1.79
Part 1: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST AST, Day 21	1.3 IU/L Standard Deviation 1.75	4.5 IU/L Standard Deviation 6.35	2.0 IU/L Standard Deviation 3.63	0.6 IU/L Standard Deviation 7.37	2.3 IU/L Standard Deviation 3.01	1.7 IU/L Standard Deviation 7.20
Part 1: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST AST, Day 28	5.7 IU/L Standard Deviation 6.56	3.4 IU/L Standard Deviation 3.97	2.8 IU/L Standard Deviation 3.31	-0.5 IU/L Standard Deviation 4.88	1.3 IU/L Standard Deviation 3.27	0.3 IU/L Standard Deviation 4.68
Part 1: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST AST, Day 35	3.2 IU/L Standard Deviation 5.31	4.5 IU/L Standard Deviation 5.58	4.2 IU/L Standard Deviation 5.34	0.1 IU/L Standard Deviation 2.96	3.5 IU/L Standard Deviation 6.57	1.0 IU/L Standard Deviation 1.58
Part 1: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST AST, Day 42	—	—	5.3 IU/L Standard Deviation 4.72	-1.0 IU/L Standard Deviation 2.53	1.3 IU/L Standard Deviation 1.37	0.3 IU/L Standard Deviation 3.61

PRIMARY outcome

Timeframe: From Baseline (Day 1) and up to Day 63

Outcome measures

Outcome measures
Measure	Part 2 (MAD): VH4004280 100 mg PiB n=6 Participants Healthy participants were given a dose of 100 mg VH4004280 PiB QD for a 14-day period and were followed up to approximately Day 63.	Part 2 (MAD): VH4004280 250 mg + Midazolam (MDZ) PiB n=8 Participants Healthy participants were given a dose of 250 mg VH4004280 PiB QD for a 14-day period, and a single dose of Midazolam on days 1, 2, and 15, and were followed up to approximately Day 63.	Part 2 (MAD): VH4004280 350 mg PiB n=6 Participants Healthy participants were given a dose of 350 mg VH4004280 PiB QD for a 14-day period and were followed up to approximately Day 63.	Part 3 (Single Dose): VH4004280 450 mg Tablet n=6 Participants Healthy participants were given a single oral dose of VH4004280 450 mg tablet at Day 1 and were followed up to approximately Day 49.	Part 1 (SAD): VH4004280 450 mg PiB Healthy participants were given a single oral dose of 450 mg VH4004280 PiB on Day 1 and were followed up to approximately Day 49.	Part 1 (SAD): VH4004280 900 mg PiB Healthy participants were given a single oral dose of 900 mg VH4004280 PiB on Day 1 and were followed up to approximately Day 49.
Part 2: Change From Baseline in Liver Panel Parameters: Direct Bilirubin, Total Bilirubin Direct Bilirubin, Baseline (Day 1)	2.8500 μmol/L Standard Deviation 1.39621	2.1375 μmol/L Standard Deviation 0.79158	1.7100 μmol/L Standard Deviation 0.00000	2.2800 μmol/L Standard Deviation 0.88304	—	—
Part 2: Change From Baseline in Liver Panel Parameters: Direct Bilirubin, Total Bilirubin Direct Bilirubin, Day 5	0.3135 μmol/L Standard Deviation 0.97585	—	0.4845 μmol/L Standard Deviation 0.54524	-0.0428 μmol/L Standard Deviation 1.13750	—	—
Part 2: Change From Baseline in Liver Panel Parameters: Direct Bilirubin, Total Bilirubin Direct Bilirubin, Day 8	—	0.3420 μmol/L Standard Deviation 0.69611	—	-0.1710 μmol/L Standard Deviation 0.48366	—	—
Part 2: Change From Baseline in Liver Panel Parameters: Direct Bilirubin, Total Bilirubin Direct Bilirubin, Day 11	0.5130 μmol/L Standard Deviation 0.60859	—	0.7695 μmol/L Standard Deviation 0.58989	0.5130 μmol/L Standard Deviation 0.72549	—	—
Part 2: Change From Baseline in Liver Panel Parameters: Direct Bilirubin, Total Bilirubin Direct Bilirubin, Day 14	-0.2280 μmol/L Standard Deviation 0.95923	—	0.2850 μmol/L Standard Deviation 0.33625	-0.5558 μmol/L Standard Deviation 0.68932	—	—
Part 2: Change From Baseline in Liver Panel Parameters: Direct Bilirubin, Total Bilirubin Direct Bilirubin, Day 28	-0.8265 μmol/L Standard Deviation 0.87472	-0.0428 μmol/L Standard Deviation 0.67632	0.1710 μmol/L Standard Deviation 0.49561	-0.8208 μmol/L Standard Deviation 1.13041	—	—
Part 2: Change From Baseline in Liver Panel Parameters: Direct Bilirubin, Total Bilirubin Total Bilirubin, Day 5	3.7620 μmol/L Standard Deviation 4.99952	—	4.8165 μmol/L Standard Deviation 3.79823	-0.0855 μmol/L Standard Deviation 2.68748	—	—
Part 2: Change From Baseline in Liver Panel Parameters: Direct Bilirubin, Total Bilirubin Total Bilirubin, Day 11	3.6765 μmol/L Standard Deviation 2.12893	—	4.7880 μmol/L Standard Deviation 1.89494	-0.8550 μmol/L Standard Deviation 3.62746	—	—
Part 2: Change From Baseline in Liver Panel Parameters: Direct Bilirubin, Total Bilirubin Total Bilirubin, Day 12	—	6.0705 μmol/L Standard Deviation 2.04180	—	-3.0780 μmol/L Standard Deviation 6.77125	—	—
Part 2: Change From Baseline in Liver Panel Parameters: Direct Bilirubin, Total Bilirubin Total Bilirubin, Day 35	-4.3320 μmol/L Standard Deviation 5.66489	0.6840 μmol/L Standard Deviation 1.99837	0.8550 μmol/L Standard Deviation 1.00294	-2.6790 μmol/L Standard Deviation 2.91336	—	—
Part 2: Change From Baseline in Liver Panel Parameters: Direct Bilirubin, Total Bilirubin Total Bilirubin, Day 56	-6.0534 μmol/L Standard Deviation 4.17394	-1.3039 μmol/L Standard Deviation 2.45421	0.5415 μmol/L Standard Deviation 1.86199	-1.8525 μmol/L Standard Deviation 2.73047	—	—
Part 2: Change From Baseline in Liver Panel Parameters: Direct Bilirubin, Total Bilirubin Total Bilirubin, Day 63	-4.7595 μmol/L Standard Deviation 5.86150	-0.6413 μmol/L Standard Deviation 2.44536	1.9095 μmol/L Standard Deviation 2.35811	-3.0495 μmol/L Standard Deviation 1.72504	—	—
Part 2: Change From Baseline in Liver Panel Parameters: Direct Bilirubin, Total Bilirubin Direct Bilirubin, Day 2	0.2565 μmol/L Standard Deviation 0.67323	—	0.4275 μmol/L Standard Deviation 0.40103	0.0428 μmol/L Standard Deviation 0.84208	—	—
Part 2: Change From Baseline in Liver Panel Parameters: Direct Bilirubin, Total Bilirubin Direct Bilirubin, Day 3	—	0.0214 μmol/L Standard Deviation 0.51249	—	-0.3420 μmol/L Standard Deviation 0.96732	—	—
Part 2: Change From Baseline in Liver Panel Parameters: Direct Bilirubin, Total Bilirubin Direct Bilirubin, Day 6	—	0.2565 μmol/L Standard Deviation 0.78095	—	-0.3420 μmol/L Standard Deviation 1.20915	—	—
Part 2: Change From Baseline in Liver Panel Parameters: Direct Bilirubin, Total Bilirubin Direct Bilirubin, Day 7	0.0570 μmol/L Standard Deviation 0.82837	—	0.8550 μmol/L Standard Deviation 0.47141	-0.2993 μmol/L Standard Deviation 1.01044	—	—
Part 2: Change From Baseline in Liver Panel Parameters: Direct Bilirubin, Total Bilirubin Direct Bilirubin, Day 12	—	0.4061 μmol/L Standard Deviation 0.78062	—	-0.5985 μmol/L Standard Deviation 1.81373	—	—
Part 2: Change From Baseline in Liver Panel Parameters: Direct Bilirubin, Total Bilirubin Direct Bilirubin, Day 15	—	0.7481 μmol/L Standard Deviation 0.46551	—	0.1710 μmol/L Standard Deviation 0.96732	—	—
Part 2: Change From Baseline in Liver Panel Parameters: Direct Bilirubin, Total Bilirubin Direct Bilirubin, Day 21	-0.1140 μmol/L Standard Deviation 1.00100	—	0.8835 μmol/L Standard Deviation 0.34905	-0.4275 μmol/L Standard Deviation 0.86632	—	—
Part 2: Change From Baseline in Liver Panel Parameters: Direct Bilirubin, Total Bilirubin Direct Bilirubin, Day 22	—	1.0901 μmol/L Standard Deviation 0.85225	—	0.9405 μmol/L Standard Deviation 1.08824	—	—
Part 2: Change From Baseline in Liver Panel Parameters: Direct Bilirubin, Total Bilirubin Direct Bilirubin, Day 35	-0.9690 μmol/L Standard Deviation 0.91556	0.0000 μmol/L Standard Deviation 0.80725	0.0855 μmol/L Standard Deviation 0.41536	-0.4845 μmol/L Standard Deviation 0.79043	—	—
Part 2: Change From Baseline in Liver Panel Parameters: Direct Bilirubin, Total Bilirubin Direct Bilirubin, Day 42	-0.7695 μmol/L Standard Deviation 0.80024	-0.1069 μmol/L Standard Deviation 1.08896	-0.1140 μmol/L Standard Deviation 0.35322	-0.2280 μmol/L Standard Deviation 0.54791	—	—
Part 2: Change From Baseline in Liver Panel Parameters: Direct Bilirubin, Total Bilirubin Direct Bilirubin, Day 49	-0.6270 μmol/L Standard Deviation 0.84928	0.0641 μmol/L Standard Deviation 0.45645	0.1995 μmol/L Standard Deviation 0.59646	-0.2736 μmol/L Standard Deviation 0.35459	—	—
Part 2: Change From Baseline in Liver Panel Parameters: Direct Bilirubin, Total Bilirubin Direct Bilirubin, Day 56	-0.7866 μmol/L Standard Deviation 0.82542	-0.2565 μmol/L Standard Deviation 0.62663	0.0855 μmol/L Standard Deviation 0.49265	-0.3705 μmol/L Standard Deviation 0.83364	—	—
Part 2: Change From Baseline in Liver Panel Parameters: Direct Bilirubin, Total Bilirubin Direct Bilirubin, Day 63	-0.9405 μmol/L Standard Deviation 1.25542	-0.2779 μmol/L Standard Deviation 0.80174	0.2565 μmol/L Standard Deviation 0.51584	-0.5130 μmol/L Standard Deviation 0.64890	—	—
Part 2: Change From Baseline in Liver Panel Parameters: Direct Bilirubin, Total Bilirubin Total Bilirubin, Baseline (Day 1)	15.1050 μmol/L Standard Deviation 6.87553	9.6188 μmol/L Standard Deviation 3.53265	8.2650 μmol/L Standard Deviation 1.28724	11.9700 μmol/L Standard Deviation 3.42000	—	—
Part 2: Change From Baseline in Liver Panel Parameters: Direct Bilirubin, Total Bilirubin Total Bilirubin, Day 2	2.8500 μmol/L Standard Deviation 3.18017	—	3.3915 μmol/L Standard Deviation 2.22541	-0.0855 μmol/L Standard Deviation 2.38789	—	—
Part 2: Change From Baseline in Liver Panel Parameters: Direct Bilirubin, Total Bilirubin Total Bilirubin, Day 3	—	2.5864 μmol/L Standard Deviation 2.03655	—	1.7955 μmol/L Standard Deviation 0.36275	—	—
Part 2: Change From Baseline in Liver Panel Parameters: Direct Bilirubin, Total Bilirubin Total Bilirubin, Day 6	—	3.6338 μmol/L Standard Deviation 2.33168	—	0.5985 μmol/L Standard Deviation 1.33007	—	—
Part 2: Change From Baseline in Liver Panel Parameters: Direct Bilirubin, Total Bilirubin Total Bilirubin, Day 7	1.3965 μmol/L Standard Deviation 4.31166	—	6.6120 μmol/L Standard Deviation 2.54018	-1.6673 μmol/L Standard Deviation 1.34192	—	—
Part 2: Change From Baseline in Liver Panel Parameters: Direct Bilirubin, Total Bilirubin Total Bilirubin, Day 8	—	4.8094 μmol/L Standard Deviation 3.07316	—	2.0520 μmol/L Standard Deviation 2.90197	—	—
Part 2: Change From Baseline in Liver Panel Parameters: Direct Bilirubin, Total Bilirubin Total Bilirubin, Day 14	-0.8550 μmol/L Standard Deviation 5.47307	—	5.7000 μmol/L Standard Deviation 1.55099	-3.2918 μmol/L Standard Deviation 0.94050	—	—
Part 2: Change From Baseline in Liver Panel Parameters: Direct Bilirubin, Total Bilirubin Total Bilirubin, Day 15	—	5.3651 μmol/L Standard Deviation 2.82455	—	1.0260 μmol/L Standard Deviation 1.93464	—	—
Part 2: Change From Baseline in Liver Panel Parameters: Direct Bilirubin, Total Bilirubin Total Bilirubin, Day 21	0.7125 μmol/L Standard Deviation 4.72334	—	6.6975 μmol/L Standard Deviation 1.87139	-3.0780 μmol/L Standard Deviation 1.45769	—	—
Part 2: Change From Baseline in Liver Panel Parameters: Direct Bilirubin, Total Bilirubin Total Bilirubin, Day 22	—	8.4645 μmol/L Standard Deviation 4.99216	—	5.3865 μmol/L Standard Deviation 0.12092	—	—
Part 2: Change From Baseline in Liver Panel Parameters: Direct Bilirubin, Total Bilirubin Total Bilirubin, Day 28	-4.7880 μmol/L Standard Deviation 6.47907	0.1069 μmol/L Standard Deviation 3.43820	1.5105 μmol/L Standard Deviation 3.13339	-4.0014 μmol/L Standard Deviation 3.67869	—	—
Part 2: Change From Baseline in Liver Panel Parameters: Direct Bilirubin, Total Bilirubin Total Bilirubin, Day 42	-4.3605 μmol/L Standard Deviation 5.70510	0.5985 μmol/L Standard Deviation 4.89669	0.6270 μmol/L Standard Deviation 2.71598	-1.3395 μmol/L Standard Deviation 1.08913	—	—
Part 2: Change From Baseline in Liver Panel Parameters: Direct Bilirubin, Total Bilirubin Total Bilirubin, Day 49	-2.9640 μmol/L Standard Deviation 4.81803	1.5604 μmol/L Standard Deviation 2.81789	1.5105 μmol/L Standard Deviation 2.40233	-0.7866 μmol/L Standard Deviation 1.70400	—	—

PRIMARY outcome

Timeframe: From Baseline (Day 1) and up to Day 63

Change from baseline was calculated by subtracting the baseline value from the post-dose visit value.

Outcome measures

Outcome measures
Measure	Part 2 (MAD): VH4004280 100 mg PiB n=6 Participants Healthy participants were given a dose of 100 mg VH4004280 PiB QD for a 14-day period and were followed up to approximately Day 63.	Part 2 (MAD): VH4004280 250 mg + Midazolam (MDZ) PiB n=8 Participants Healthy participants were given a dose of 250 mg VH4004280 PiB QD for a 14-day period, and a single dose of Midazolam on days 1, 2, and 15, and were followed up to approximately Day 63.	Part 2 (MAD): VH4004280 350 mg PiB n=6 Participants Healthy participants were given a dose of 350 mg VH4004280 PiB QD for a 14-day period and were followed up to approximately Day 63.	Part 3 (Single Dose): VH4004280 450 mg Tablet n=6 Participants Healthy participants were given a single oral dose of VH4004280 450 mg tablet at Day 1 and were followed up to approximately Day 49.	Part 1 (SAD): VH4004280 450 mg PiB Healthy participants were given a single oral dose of 450 mg VH4004280 PiB on Day 1 and were followed up to approximately Day 49.	Part 1 (SAD): VH4004280 900 mg PiB Healthy participants were given a single oral dose of 900 mg VH4004280 PiB on Day 1 and were followed up to approximately Day 49.
Part 2: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST ALP, Day 28	-4.5 IU/L Standard Deviation 6.69	2.3 IU/L Standard Deviation 5.70	2.8 IU/L Standard Deviation 3.76	-2.0 IU/L Standard Deviation 4.85	—	—
Part 2: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST ALP, Day 35	-0.7 IU/L Standard Deviation 8.62	2.4 IU/L Standard Deviation 7.41	-3.7 IU/L Standard Deviation 3.61	-2.0 IU/L Standard Deviation 5.83	—	—
Part 2: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST ALT, Baseline (Day 1)	19.0 IU/L Standard Deviation 6.93	16.3 IU/L Standard Deviation 5.04	19.5 IU/L Standard Deviation 7.69	18.7 IU/L Standard Deviation 11.98	—	—
Part 2: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST ALT, Day 7	5.7 IU/L Standard Deviation 7.81	—	-3.0 IU/L Standard Deviation 3.79	4.8 IU/L Standard Deviation 8.38	—	—
Part 2: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST ALT, Day 35	17.8 IU/L Standard Deviation 26.69	7.5 IU/L Standard Deviation 7.29	3.3 IU/L Standard Deviation 12.23	6.3 IU/L Standard Deviation 5.50	—	—
Part 2: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST AST, Day 7	5.3 IU/L Standard Deviation 9.73	—	-1.8 IU/L Standard Deviation 3.06	3.8 IU/L Standard Deviation 4.11	—	—
Part 2: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST AST, Day 8	—	0.6 IU/L Standard Deviation 2.88	—	-1.5 IU/L Standard Deviation 0.71	—	—
Part 2: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST AST, Day 5	-0.7 IU/L Standard Deviation 3.50	—	-2.2 IU/L Standard Deviation 2.04	2.8 IU/L Standard Deviation 3.86	—	—
Part 2: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST AST, Day 6	—	0.4 IU/L Standard Deviation 3.89	—	-1.5 IU/L Standard Deviation 0.71	—	—
Part 2: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST AST, Day 11	2.0 IU/L Standard Deviation 6.06	—	-4.0 IU/L Standard Deviation 2.53	2.0 IU/L Standard Deviation 1.41	—	—
Part 2: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST ALP, Baseline (Day 1)	53.7 IU/L Standard Deviation 10.01	57.5 IU/L Standard Deviation 21.37	56.7 IU/L Standard Deviation 11.41	66.2 IU/L Standard Deviation 16.75	—	—
Part 2: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST ALP, Day 2	-1.7 IU/L Standard Deviation 3.33	—	-0.5 IU/L Standard Deviation 2.81	4.0 IU/L Standard Deviation 8.45	—	—
Part 2: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST ALP, Day 3	—	0.9 IU/L Standard Deviation 3.31	—	-0.5 IU/L Standard Deviation 4.95	—	—
Part 2: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST ALP, Day 5	-3.8 IU/L Standard Deviation 5.98	—	0.5 IU/L Standard Deviation 4.85	-0.8 IU/L Standard Deviation 4.50	—	—
Part 2: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST ALP, Day 6	—	-1.9 IU/L Standard Deviation 3.40	—	-4.5 IU/L Standard Deviation 3.54	—	—
Part 2: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST ALP, Day 7	-4.8 IU/L Standard Deviation 7.47	—	-0.2 IU/L Standard Deviation 5.27	-0.3 IU/L Standard Deviation 5.56	—	—
Part 2: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST ALP, Day 8	—	-1.8 IU/L Standard Deviation 3.77	—	0.0 IU/L Standard Deviation 8.49	—	—
Part 2: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST ALP, Day 11	-2.0 IU/L Standard Deviation 5.48	—	-2.3 IU/L Standard Deviation 5.05	-7.5 IU/L Standard Deviation 3.54	—	—
Part 2: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST ALP, Day 12	—	0.8 IU/L Standard Deviation 3.24	—	2.5 IU/L Standard Deviation 4.95	—	—
Part 2: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST ALP, Day 14	-6.0 IU/L Standard Deviation 6.16	—	1.3 IU/L Standard Deviation 4.37	4.5 IU/L Standard Deviation 14.57	—	—
Part 2: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST ALP, Day 15	—	0.5 IU/L Standard Deviation 4.99	—	-2.5 IU/L Standard Deviation 6.36	—	—
Part 2: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST ALP, Day 21	-3.2 IU/L Standard Deviation 9.02	—	0.8 IU/L Standard Deviation 4.62	-3.0 IU/L Standard Deviation 3.16	—	—
Part 2: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST ALP, Day 22	—	5.1 IU/L Standard Deviation 3.94	—	2.0 IU/L Standard Deviation 5.66	—	—
Part 2: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST ALP, Day 42	-2.3 IU/L Standard Deviation 5.43	4.6 IU/L Standard Deviation 9.64	1.0 IU/L Standard Deviation 4.73	1.5 IU/L Standard Deviation 6.47	—	—
Part 2: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST ALP, Day 49	-2.7 IU/L Standard Deviation 7.03	1.3 IU/L Standard Deviation 6.76	-2.7 IU/L Standard Deviation 4.55	0.8 IU/L Standard Deviation 7.89	—	—
Part 2: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST ALP, Day 56	-3.6 IU/L Standard Deviation 3.21	5.3 IU/L Standard Deviation 6.90	-0.2 IU/L Standard Deviation 4.96	2.8 IU/L Standard Deviation 9.20	—	—
Part 2: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST ALP, Day 63	0.2 IU/L Standard Deviation 5.95	1.3 IU/L Standard Deviation 4.37	0.7 IU/L Standard Deviation 2.88	0.3 IU/L Standard Deviation 5.05	—	—
Part 2: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST ALT, Day 2	0.2 IU/L Standard Deviation 2.64	—	0.3 IU/L Standard Deviation 2.07	-1.5 IU/L Standard Deviation 5.80	—	—
Part 2: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST ALT, Day 3	—	2.0 IU/L Standard Deviation 2.33	—	-2.0 IU/L Standard Deviation 1.41	—	—
Part 2: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST ALT, Day 5	0.5 IU/L Standard Deviation 3.83	—	-2.8 IU/L Standard Deviation 2.64	1.5 IU/L Standard Deviation 8.96	—	—
Part 2: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST ALT, Day 6	—	2.0 IU/L Standard Deviation 5.45	—	-6.0 IU/L Standard Deviation 4.24	—	—
Part 2: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST ALT, Day 8	—	0.5 IU/L Standard Deviation 6.02	—	-6.0 IU/L Standard Deviation 2.83	—	—
Part 2: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST ALT, Day 11	4.0 IU/L Standard Deviation 11.28	—	-4.7 IU/L Standard Deviation 4.72	9.0 IU/L Standard Deviation 5.66	—	—
Part 2: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST ALT, Day 12	—	2.9 IU/L Standard Deviation 9.48	—	-2.0 IU/L Standard Deviation 1.41	—	—
Part 2: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST ALT, Day 14	10.5 IU/L Standard Deviation 13.85	—	-2.8 IU/L Standard Deviation 5.53	15.8 IU/L Standard Deviation 17.21	—	—
Part 2: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST ALT, Day 15	—	5.3 IU/L Standard Deviation 10.74	—	-1.0 IU/L Standard Deviation 2.83	—	—
Part 2: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST ALT, Day 21	13.8 IU/L Standard Deviation 15.28	—	3.7 IU/L Standard Deviation 9.48	7.0 IU/L Standard Deviation 4.69	—	—
Part 2: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST ALT, Day 22	—	7.9 IU/L Standard Deviation 10.29	—	0.5 IU/L Standard Deviation 6.36	—	—
Part 2: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST ALT, Day 28	8.5 IU/L Standard Deviation 9.65	10.4 IU/L Standard Deviation 9.38	14.2 IU/L Standard Deviation 37.02	12.0 IU/L Standard Deviation 15.98	—	—
Part 2: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST ALT, Day 42	8.8 IU/L Standard Deviation 7.19	4.0 IU/L Standard Deviation 6.74	1.7 IU/L Standard Deviation 8.07	8.0 IU/L Standard Deviation 8.65	—	—
Part 2: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST ALT, Day 49	5.2 IU/L Standard Deviation 7.60	2.3 IU/L Standard Deviation 6.34	-2.5 IU/L Standard Deviation 5.96	0.2 IU/L Standard Deviation 1.10	—	—
Part 2: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST ALT, Day 56	0.8 IU/L Standard Deviation 8.44	1.8 IU/L Standard Deviation 6.71	-4.8 IU/L Standard Deviation 2.48	0.3 IU/L Standard Deviation 3.33	—	—
Part 2: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST ALT, Day 63	0.3 IU/L Standard Deviation 3.88	2.1 IU/L Standard Deviation 6.31	-4.3 IU/L Standard Deviation 5.92	-3.5 IU/L Standard Deviation 6.53	—	—
Part 2: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST AST, Baseline (Day 1)	19.2 IU/L Standard Deviation 4.12	14.9 IU/L Standard Deviation 3.14	17.8 IU/L Standard Deviation 3.54	16.2 IU/L Standard Deviation 2.99	—	—
Part 2: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST AST, Day 2	-2.0 IU/L Standard Deviation 2.68	—	-0.3 IU/L Standard Deviation 1.51	-1.3 IU/L Standard Deviation 2.06	—	—
Part 2: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST AST, Day 3	—	1.4 IU/L Standard Deviation 3.02	—	-1.0 IU/L Standard Deviation 1.41	—	—
Part 2: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST AST, Day 12	—	1.4 IU/L Standard Deviation 4.44	—	0.0 IU/L Standard Deviation 0.00	—	—
Part 2: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST AST, Day 14	3.7 IU/L Standard Deviation 6.35	—	-2.2 IU/L Standard Deviation 2.93	8.8 IU/L Standard Deviation 14.36	—	—
Part 2: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST AST, Day 15	—	1.1 IU/L Standard Deviation 4.79	—	-0.5 IU/L Standard Deviation 0.71	—	—
Part 2: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST AST, Day 21	4.2 IU/L Standard Deviation 5.81	—	1.0 IU/L Standard Deviation 3.10	1.0 IU/L Standard Deviation 1.15	—	—
Part 2: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST AST, Day 22	—	3.0 IU/L Standard Deviation 3.02	—	1.0 IU/L Standard Deviation 0.00	—	—
Part 2: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST AST, Day 28	2.3 IU/L Standard Deviation 6.22	7.0 IU/L Standard Deviation 17.57	31.7 IU/L Standard Deviation 81.01	7.8 IU/L Standard Deviation 9.31	—	—
Part 2: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST AST, Day 35	5.5 IU/L Standard Deviation 7.29	4.6 IU/L Standard Deviation 5.68	1.0 IU/L Standard Deviation 6.42	3.8 IU/L Standard Deviation 4.67	—	—
Part 2: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST AST, Day 42	3.2 IU/L Standard Deviation 5.27	1.0 IU/L Standard Deviation 2.27	0.2 IU/L Standard Deviation 3.87	5.3 IU/L Standard Deviation 7.71	—	—
Part 2: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST AST, Day 49	0.3 IU/L Standard Deviation 4.03	1.3 IU/L Standard Deviation 3.20	-1.3 IU/L Standard Deviation 4.13	2.4 IU/L Standard Deviation 2.41	—	—
Part 2: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST AST, Day 56	0.4 IU/L Standard Deviation 3.85	2.0 IU/L Standard Deviation 7.46	-1.3 IU/L Standard Deviation 1.63	1.8 IU/L Standard Deviation 2.64	—	—
Part 2: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST AST, Day 63	0.7 IU/L Standard Deviation 4.03	1.3 IU/L Standard Deviation 4.30	-0.8 IU/L Standard Deviation 3.54	-1.0 IU/L Standard Deviation 1.41	—	—

PRIMARY outcome

Timeframe: From Baseline (Day 1) and up to Day 49

Change from baseline was calculated by subtracting the baseline value from the post-dose visit value.

Outcome measures

Outcome measures
Measure	Part 2 (MAD): VH4004280 100 mg PiB Healthy participants were given a dose of 100 mg VH4004280 PiB QD for a 14-day period and were followed up to approximately Day 63.	Part 2 (MAD): VH4004280 250 mg + Midazolam (MDZ) PiB Healthy participants were given a dose of 250 mg VH4004280 PiB QD for a 14-day period, and a single dose of Midazolam on days 1, 2, and 15, and were followed up to approximately Day 63.	Part 2 (MAD): VH4004280 350 mg PiB Healthy participants were given a dose of 350 mg VH4004280 PiB QD for a 14-day period and were followed up to approximately Day 63.	Part 3 (Single Dose): VH4004280 450 mg Tablet n=6 Participants Healthy participants were given a single oral dose of VH4004280 450 mg tablet at Day 1 and were followed up to approximately Day 49.	Part 1 (SAD): VH4004280 450 mg PiB Healthy participants were given a single oral dose of 450 mg VH4004280 PiB on Day 1 and were followed up to approximately Day 49.	Part 1 (SAD): VH4004280 900 mg PiB Healthy participants were given a single oral dose of 900 mg VH4004280 PiB on Day 1 and were followed up to approximately Day 49.
Part 3: Change From Baseline in Liver Panel Parameters: Direct Bilirubin, Total Bilirubin Direct Bilirubin, Day 6	—	—	—	0.2850 μmol/L Standard Deviation 0.50341	—	—
Part 3: Change From Baseline in Liver Panel Parameters: Direct Bilirubin, Total Bilirubin Direct Bilirubin, Day 7	—	—	—	-0.2280 μmol/L Standard Deviation 0.65488	—	—
Part 3: Change From Baseline in Liver Panel Parameters: Direct Bilirubin, Total Bilirubin Direct Bilirubin, Baseline (Day 1)	—	—	—	1.9950 μmol/L Standard Deviation 0.69810	—	—
Part 3: Change From Baseline in Liver Panel Parameters: Direct Bilirubin, Total Bilirubin Direct Bilirubin, Day 2	—	—	—	0.3135 μmol/L Standard Deviation 0.43820	—	—
Part 3: Change From Baseline in Liver Panel Parameters: Direct Bilirubin, Total Bilirubin Direct Bilirubin, Day 3	—	—	—	0.2565 μmol/L Standard Deviation 0.40103	—	—
Part 3: Change From Baseline in Liver Panel Parameters: Direct Bilirubin, Total Bilirubin Direct Bilirubin, Day 4	—	—	—	0.1710 μmol/L Standard Deviation 0.55146	—	—
Part 3: Change From Baseline in Liver Panel Parameters: Direct Bilirubin, Total Bilirubin Direct Bilirubin, Day 5	—	—	—	-0.0570 μmol/L Standard Deviation 0.62752	—	—
Part 3: Change From Baseline in Liver Panel Parameters: Direct Bilirubin, Total Bilirubin Direct Bilirubin, Day 14	—	—	—	-0.2565 μmol/L Standard Deviation 0.23571	—	—
Part 3: Change From Baseline in Liver Panel Parameters: Direct Bilirubin, Total Bilirubin Direct Bilirubin, Day 21	—	—	—	-0.0570 μmol/L Standard Deviation 0.54791	—	—
Part 3: Change From Baseline in Liver Panel Parameters: Direct Bilirubin, Total Bilirubin Direct Bilirubin, Day 28	—	—	—	-0.1425 μmol/L Standard Deviation 0.39614	—	—
Part 3: Change From Baseline in Liver Panel Parameters: Direct Bilirubin, Total Bilirubin Direct Bilirubin, Day 35	—	—	—	-0.1425 μmol/L Standard Deviation 0.22729	—	—
Part 3: Change From Baseline in Liver Panel Parameters: Direct Bilirubin, Total Bilirubin Direct Bilirubin, Day 42	—	—	—	-0.1026 μmol/L Standard Deviation 0.72145	—	—
Part 3: Change From Baseline in Liver Panel Parameters: Direct Bilirubin, Total Bilirubin Direct Bilirubin, Day 49	—	—	—	-0.3420 μmol/L Standard Deviation 0.50727	—	—
Part 3: Change From Baseline in Liver Panel Parameters: Direct Bilirubin, Total Bilirubin Total Bilirubin, Baseline (Day 1)	—	—	—	9.9750 μmol/L Standard Deviation 4.24640	—	—
Part 3: Change From Baseline in Liver Panel Parameters: Direct Bilirubin, Total Bilirubin Total Bilirubin, Day 2	—	—	—	2.2800 μmol/L Standard Deviation 1.65673	—	—
Part 3: Change From Baseline in Liver Panel Parameters: Direct Bilirubin, Total Bilirubin Total Bilirubin, Day 3	—	—	—	1.0830 μmol/L Standard Deviation 2.10730	—	—
Part 3: Change From Baseline in Liver Panel Parameters: Direct Bilirubin, Total Bilirubin Total Bilirubin, Day 4	—	—	—	0.4275 μmol/L Standard Deviation 2.53346	—	—
Part 3: Change From Baseline in Liver Panel Parameters: Direct Bilirubin, Total Bilirubin Total Bilirubin, Day 5	—	—	—	0.7980 μmol/L Standard Deviation 2.64396	—	—
Part 3: Change From Baseline in Liver Panel Parameters: Direct Bilirubin, Total Bilirubin Total Bilirubin, Day 6	—	—	—	1.3965 μmol/L Standard Deviation 2.58072	—	—
Part 3: Change From Baseline in Liver Panel Parameters: Direct Bilirubin, Total Bilirubin Total Bilirubin, Day 7	—	—	—	-1.1115 μmol/L Standard Deviation 3.11530	—	—
Part 3: Change From Baseline in Liver Panel Parameters: Direct Bilirubin, Total Bilirubin Total Bilirubin, Day 14	—	—	—	-1.1970 μmol/L Standard Deviation 2.45193	—	—
Part 3: Change From Baseline in Liver Panel Parameters: Direct Bilirubin, Total Bilirubin Total Bilirubin, Day 21	—	—	—	-0.8835 μmol/L Standard Deviation 2.28249	—	—
Part 3: Change From Baseline in Liver Panel Parameters: Direct Bilirubin, Total Bilirubin Total Bilirubin, Day 28	—	—	—	-1.0830 μmol/L Standard Deviation 2.22344	—	—
Part 3: Change From Baseline in Liver Panel Parameters: Direct Bilirubin, Total Bilirubin Total Bilirubin, Day 35	—	—	—	0.1140 μmol/L Standard Deviation 3.42285	—	—
Part 3: Change From Baseline in Liver Panel Parameters: Direct Bilirubin, Total Bilirubin Total Bilirubin, Day 42	—	—	—	-2.0520 μmol/L Standard Deviation 4.26987	—	—
Part 3: Change From Baseline in Liver Panel Parameters: Direct Bilirubin, Total Bilirubin Total Bilirubin, Day 49	—	—	—	-1.5105 μmol/L Standard Deviation 2.99795	—	—

PRIMARY outcome

Timeframe: From Baseline (Day 1) and up to Day 49

Change from baseline was calculated by subtracting the baseline value from the post-dose visit value.

Outcome measures

Outcome measures
Measure	Part 2 (MAD): VH4004280 100 mg PiB Healthy participants were given a dose of 100 mg VH4004280 PiB QD for a 14-day period and were followed up to approximately Day 63.	Part 2 (MAD): VH4004280 250 mg + Midazolam (MDZ) PiB Healthy participants were given a dose of 250 mg VH4004280 PiB QD for a 14-day period, and a single dose of Midazolam on days 1, 2, and 15, and were followed up to approximately Day 63.	Part 2 (MAD): VH4004280 350 mg PiB Healthy participants were given a dose of 350 mg VH4004280 PiB QD for a 14-day period and were followed up to approximately Day 63.	Part 3 (Single Dose): VH4004280 450 mg Tablet n=6 Participants Healthy participants were given a single oral dose of VH4004280 450 mg tablet at Day 1 and were followed up to approximately Day 49.	Part 1 (SAD): VH4004280 450 mg PiB Healthy participants were given a single oral dose of 450 mg VH4004280 PiB on Day 1 and were followed up to approximately Day 49.	Part 1 (SAD): VH4004280 900 mg PiB Healthy participants were given a single oral dose of 900 mg VH4004280 PiB on Day 1 and were followed up to approximately Day 49.
Part 3: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST AST, Day 21	—	—	—	2.5 IU/L Standard Deviation 4.04	—	—
Part 3: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST AST, Day 28	—	—	—	7.0 IU/L Standard Deviation 12.59	—	—
Part 3: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST ALP, Baseline (Day 1)	—	—	—	55.7 IU/L Standard Deviation 11.78	—	—
Part 3: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST ALP, Day 2	—	—	—	-7.8 IU/L Standard Deviation 3.13	—	—
Part 3: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST ALP, Day 3	—	—	—	-5.5 IU/L Standard Deviation 3.02	—	—
Part 3: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST ALP, Day 4	—	—	—	-4.8 IU/L Standard Deviation 2.86	—	—
Part 3: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST ALP, Day 5	—	—	—	-6.8 IU/L Standard Deviation 5.64	—	—
Part 3: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST ALP, Day 6	—	—	—	-6.0 IU/L Standard Deviation 2.61	—	—
Part 3: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST ALP, Day 7	—	—	—	-5.3 IU/L Standard Deviation 4.89	—	—
Part 3: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST ALP, Day 14	—	—	—	4.5 IU/L Standard Deviation 9.81	—	—
Part 3: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST ALP, Day 21	—	—	—	2.3 IU/L Standard Deviation 9.87	—	—
Part 3: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST ALP, Day 28	—	—	—	4.0 IU/L Standard Deviation 12.20	—	—
Part 3: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST ALP, Day 35	—	—	—	3.8 IU/L Standard Deviation 8.16	—	—
Part 3: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST ALP, Day 42	—	—	—	-0.2 IU/L Standard Deviation 5.93	—	—
Part 3: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST ALP, Day 49	—	—	—	0.2 IU/L Standard Deviation 6.05	—	—
Part 3: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST ALT, Baseline (Day 1)	—	—	—	24.3 IU/L Standard Deviation 17.07	—	—
Part 3: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST ALT, Day 2	—	—	—	-5.2 IU/L Standard Deviation 4.49	—	—
Part 3: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST ALT, Day 3	—	—	—	-5.2 IU/L Standard Deviation 6.40	—	—
Part 3: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST ALT, Day 4	—	—	—	-5.2 IU/L Standard Deviation 8.57	—	—
Part 3: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST ALT, Day 5	—	—	—	-5.7 IU/L Standard Deviation 8.87	—	—
Part 3: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST ALT, Day 6	—	—	—	-4.0 IU/L Standard Deviation 8.44	—	—
Part 3: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST ALT, Day 7	—	—	—	-3.0 IU/L Standard Deviation 7.32	—	—
Part 3: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST ALT, Day 14	—	—	—	20.3 IU/L Standard Deviation 48.50	—	—
Part 3: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST ALT, Day 21	—	—	—	7.0 IU/L Standard Deviation 17.85	—	—
Part 3: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST ALT, Day 28	—	—	—	17.5 IU/L Standard Deviation 41.15	—	—
Part 3: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST ALT, Day 35	—	—	—	2.3 IU/L Standard Deviation 6.53	—	—
Part 3: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST ALT, Day 42	—	—	—	10.2 IU/L Standard Deviation 28.44	—	—
Part 3: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST ALT, Day 49	—	—	—	2.0 IU/L Standard Deviation 15.07	—	—
Part 3: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST AST, Baseline (Day 1)	—	—	—	17.5 IU/L Standard Deviation 4.28	—	—
Part 3: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST AST, Day 2	—	—	—	-2.3 IU/L Standard Deviation 2.58	—	—
Part 3: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST AST, Day 3	—	—	—	-2.3 IU/L Standard Deviation 3.33	—	—
Part 3: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST AST, Day 4	—	—	—	-1.8 IU/L Standard Deviation 3.13	—	—
Part 3: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST AST, Day 5	—	—	—	-2.2 IU/L Standard Deviation 2.79	—	—
Part 3: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST AST, Day 6	—	—	—	0.0 IU/L Standard Deviation 3.63	—	—
Part 3: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST AST, Day 7	—	—	—	-0.3 IU/L Standard Deviation 3.08	—	—
Part 3: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST AST, Day 14	—	—	—	6.8 IU/L Standard Deviation 15.46	—	—
Part 3: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST AST, Day 35	—	—	—	3.7 IU/L Standard Deviation 6.35	—	—
Part 3: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST AST, Day 42	—	—	—	10.6 IU/L Standard Deviation 22.61	—	—
Part 3: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST AST, Day 49	—	—	—	2.0 IU/L Standard Deviation 6.87	—	—

PRIMARY outcome

Timeframe: Up to Day 49

Blood samples were collected as assessed by protocol, at specific time points for laboratory analysis of the liver panel parameters: ALT, ALP, AST, total bilirubin and direct bilirubin. The number of participants with any grade increase (from grade 1 \[mild\] to grade 4 \[potentially life-threatening\]) have been presented.

Outcome measures

Outcome measures
Measure	Part 2 (MAD): VH4004280 100 mg PiB n=6 Participants Healthy participants were given a dose of 100 mg VH4004280 PiB QD for a 14-day period and were followed up to approximately Day 63.	Part 2 (MAD): VH4004280 250 mg + Midazolam (MDZ) PiB n=7 Participants Healthy participants were given a dose of 250 mg VH4004280 PiB QD for a 14-day period, and a single dose of Midazolam on days 1, 2, and 15, and were followed up to approximately Day 63.	Part 2 (MAD): VH4004280 350 mg PiB n=6 Participants Healthy participants were given a dose of 350 mg VH4004280 PiB QD for a 14-day period and were followed up to approximately Day 63.	Part 3 (Single Dose): VH4004280 450 mg Tablet n=10 Participants Healthy participants were given a single oral dose of VH4004280 450 mg tablet at Day 1 and were followed up to approximately Day 49.	Part 1 (SAD): VH4004280 450 mg PiB n=6 Participants Healthy participants were given a single oral dose of 450 mg VH4004280 PiB on Day 1 and were followed up to approximately Day 49.	Part 1 (SAD): VH4004280 900 mg PiB n=6 Participants Healthy participants were given a single oral dose of 900 mg VH4004280 PiB on Day 1 and were followed up to approximately Day 49.
Part 1: Number of Participants With Maximum Toxicity Grade Increase From Baseline for Liver Panel Parameters ALT, Increase to Grade 1	1 Participants	0 Participants	1 Participants	1 Participants	0 Participants	0 Participants
Part 1: Number of Participants With Maximum Toxicity Grade Increase From Baseline for Liver Panel Parameters ALT, Increase to Grade 3	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Part 1: Number of Participants With Maximum Toxicity Grade Increase From Baseline for Liver Panel Parameters ALT, Increase to Grade 4	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Part 1: Number of Participants With Maximum Toxicity Grade Increase From Baseline for Liver Panel Parameters ALP, Increase to Grade 3	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Part 1: Number of Participants With Maximum Toxicity Grade Increase From Baseline for Liver Panel Parameters AST, Increase to Grade 3	0 Participants	0 Participants	0 Participants	1 Participants	0 Participants	0 Participants
Part 1: Number of Participants With Maximum Toxicity Grade Increase From Baseline for Liver Panel Parameters Total Bilirubin, Increase to Grade 1	0 Participants	0 Participants	0 Participants	0 Participants	1 Participants	0 Participants
Part 1: Number of Participants With Maximum Toxicity Grade Increase From Baseline for Liver Panel Parameters Total Bilirubin, Increase to Grade 2	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Part 1: Number of Participants With Maximum Toxicity Grade Increase From Baseline for Liver Panel Parameters Total Bilirubin, Increase to Grade 3	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Part 1: Number of Participants With Maximum Toxicity Grade Increase From Baseline for Liver Panel Parameters Total Bilirubin, Increase to Grade 4	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Part 1: Number of Participants With Maximum Toxicity Grade Increase From Baseline for Liver Panel Parameters Direct Bilirubin, Increase to Grade 2	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Part 1: Number of Participants With Maximum Toxicity Grade Increase From Baseline for Liver Panel Parameters Direct Bilirubin, Increase to Grade 4	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Part 1: Number of Participants With Maximum Toxicity Grade Increase From Baseline for Liver Panel Parameters ALT, Increase to Grade 2	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Part 1: Number of Participants With Maximum Toxicity Grade Increase From Baseline for Liver Panel Parameters ALP, Increase to Grade 1	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Part 1: Number of Participants With Maximum Toxicity Grade Increase From Baseline for Liver Panel Parameters ALP, Increase to Grade 2	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Part 1: Number of Participants With Maximum Toxicity Grade Increase From Baseline for Liver Panel Parameters ALP, Increase to Grade 4	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Part 1: Number of Participants With Maximum Toxicity Grade Increase From Baseline for Liver Panel Parameters AST, Increase to Grade 1	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Part 1: Number of Participants With Maximum Toxicity Grade Increase From Baseline for Liver Panel Parameters AST, Increase to Grade 2	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Part 1: Number of Participants With Maximum Toxicity Grade Increase From Baseline for Liver Panel Parameters AST, Increase to Grade 4	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Part 1: Number of Participants With Maximum Toxicity Grade Increase From Baseline for Liver Panel Parameters Direct Bilirubin, Increase to Grade 1	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Part 1: Number of Participants With Maximum Toxicity Grade Increase From Baseline for Liver Panel Parameters Direct Bilirubin, Increase to Grade 3	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants

PRIMARY outcome

Timeframe: Up to Day 63

Outcome measures

Outcome measures
Measure	Part 2 (MAD): VH4004280 100 mg PiB n=6 Participants Healthy participants were given a dose of 100 mg VH4004280 PiB QD for a 14-day period and were followed up to approximately Day 63.	Part 2 (MAD): VH4004280 250 mg + Midazolam (MDZ) PiB n=8 Participants Healthy participants were given a dose of 250 mg VH4004280 PiB QD for a 14-day period, and a single dose of Midazolam on days 1, 2, and 15, and were followed up to approximately Day 63.	Part 2 (MAD): VH4004280 350 mg PiB n=6 Participants Healthy participants were given a dose of 350 mg VH4004280 PiB QD for a 14-day period and were followed up to approximately Day 63.	Part 3 (Single Dose): VH4004280 450 mg Tablet n=6 Participants Healthy participants were given a single oral dose of VH4004280 450 mg tablet at Day 1 and were followed up to approximately Day 49.	Part 1 (SAD): VH4004280 450 mg PiB Healthy participants were given a single oral dose of 450 mg VH4004280 PiB on Day 1 and were followed up to approximately Day 49.	Part 1 (SAD): VH4004280 900 mg PiB Healthy participants were given a single oral dose of 900 mg VH4004280 PiB on Day 1 and were followed up to approximately Day 49.
Part 2: Number of Participants With Maximum Toxicity Grade Increase From Baseline for Liver Panel Parameters ALP, Increase to Grade 3	0 Participants	0 Participants	0 Participants	0 Participants	—	—
Part 2: Number of Participants With Maximum Toxicity Grade Increase From Baseline for Liver Panel Parameters ALP, Increase to Grade 4	0 Participants	0 Participants	0 Participants	0 Participants	—	—
Part 2: Number of Participants With Maximum Toxicity Grade Increase From Baseline for Liver Panel Parameters ALT, Increase to Grade 2	0 Participants	0 Participants	0 Participants	0 Participants	—	—
Part 2: Number of Participants With Maximum Toxicity Grade Increase From Baseline for Liver Panel Parameters ALT, Increase to Grade 3	0 Participants	0 Participants	0 Participants	0 Participants	—	—
Part 2: Number of Participants With Maximum Toxicity Grade Increase From Baseline for Liver Panel Parameters ALT, Increase to Grade 4	0 Participants	0 Participants	0 Participants	0 Participants	—	—
Part 2: Number of Participants With Maximum Toxicity Grade Increase From Baseline for Liver Panel Parameters ALP, Increase to Grade 2	0 Participants	0 Participants	0 Participants	0 Participants	—	—
Part 2: Number of Participants With Maximum Toxicity Grade Increase From Baseline for Liver Panel Parameters AST, Increase to Grade 1	0 Participants	1 Participants	0 Participants	1 Participants	—	—
Part 2: Number of Participants With Maximum Toxicity Grade Increase From Baseline for Liver Panel Parameters AST, Increase to Grade 2	0 Participants	0 Participants	0 Participants	0 Participants	—	—
Part 2: Number of Participants With Maximum Toxicity Grade Increase From Baseline for Liver Panel Parameters AST, Increase to Grade 3	0 Participants	0 Participants	1 Participants	0 Participants	—	—
Part 2: Number of Participants With Maximum Toxicity Grade Increase From Baseline for Liver Panel Parameters AST, Increase to Grade 4	0 Participants	0 Participants	0 Participants	0 Participants	—	—
Part 2: Number of Participants With Maximum Toxicity Grade Increase From Baseline for Liver Panel Parameters Total Bilirubin, Increase to Grade 1	0 Participants	0 Participants	0 Participants	0 Participants	—	—
Part 2: Number of Participants With Maximum Toxicity Grade Increase From Baseline for Liver Panel Parameters Total Bilirubin, Increase to Grade 2	0 Participants	0 Participants	0 Participants	0 Participants	—	—
Part 2: Number of Participants With Maximum Toxicity Grade Increase From Baseline for Liver Panel Parameters Total Bilirubin, Increase to Grade 3	0 Participants	0 Participants	0 Participants	0 Participants	—	—
Part 2: Number of Participants With Maximum Toxicity Grade Increase From Baseline for Liver Panel Parameters Total Bilirubin, Increase to Grade 4	0 Participants	0 Participants	0 Participants	0 Participants	—	—
Part 2: Number of Participants With Maximum Toxicity Grade Increase From Baseline for Liver Panel Parameters Direct Bilirubin, Increase to Grade 2	0 Participants	0 Participants	0 Participants	0 Participants	—	—
Part 2: Number of Participants With Maximum Toxicity Grade Increase From Baseline for Liver Panel Parameters Direct Bilirubin, Increase to Grade 4	0 Participants	0 Participants	0 Participants	0 Participants	—	—
Part 2: Number of Participants With Maximum Toxicity Grade Increase From Baseline for Liver Panel Parameters Direct Bilirubin, Increase to Grade 3	0 Participants	0 Participants	0 Participants	0 Participants	—	—
Part 2: Number of Participants With Maximum Toxicity Grade Increase From Baseline for Liver Panel Parameters ALT, Increase to Grade 1	1 Participants	0 Participants	1 Participants	1 Participants	—	—
Part 2: Number of Participants With Maximum Toxicity Grade Increase From Baseline for Liver Panel Parameters ALP, Increase to Grade 1	0 Participants	0 Participants	0 Participants	0 Participants	—	—
Part 2: Number of Participants With Maximum Toxicity Grade Increase From Baseline for Liver Panel Parameters Direct Bilirubin, Increase to Grade 1	0 Participants	0 Participants	0 Participants	0 Participants	—	—

PRIMARY outcome

Timeframe: Up to Day 49

Outcome measures

Outcome measures
Measure	Part 2 (MAD): VH4004280 100 mg PiB Healthy participants were given a dose of 100 mg VH4004280 PiB QD for a 14-day period and were followed up to approximately Day 63.	Part 2 (MAD): VH4004280 250 mg + Midazolam (MDZ) PiB Healthy participants were given a dose of 250 mg VH4004280 PiB QD for a 14-day period, and a single dose of Midazolam on days 1, 2, and 15, and were followed up to approximately Day 63.	Part 2 (MAD): VH4004280 350 mg PiB Healthy participants were given a dose of 350 mg VH4004280 PiB QD for a 14-day period and were followed up to approximately Day 63.	Part 3 (Single Dose): VH4004280 450 mg Tablet n=6 Participants Healthy participants were given a single oral dose of VH4004280 450 mg tablet at Day 1 and were followed up to approximately Day 49.	Part 1 (SAD): VH4004280 450 mg PiB Healthy participants were given a single oral dose of 450 mg VH4004280 PiB on Day 1 and were followed up to approximately Day 49.	Part 1 (SAD): VH4004280 900 mg PiB Healthy participants were given a single oral dose of 900 mg VH4004280 PiB on Day 1 and were followed up to approximately Day 49.
Part 3: Number of Participants With Maximum Toxicity Grade Increase From Baseline for Liver Panel Parameters ALT, Increase to Grade 1	—	—	—	0 Participants	—	—
Part 3: Number of Participants With Maximum Toxicity Grade Increase From Baseline for Liver Panel Parameters ALT, Increase to Grade 2	—	—	—	1 Participants	—	—
Part 3: Number of Participants With Maximum Toxicity Grade Increase From Baseline for Liver Panel Parameters ALT, Increase to Grade 3	—	—	—	0 Participants	—	—
Part 3: Number of Participants With Maximum Toxicity Grade Increase From Baseline for Liver Panel Parameters ALT, Increase to Grade 4	—	—	—	0 Participants	—	—
Part 3: Number of Participants With Maximum Toxicity Grade Increase From Baseline for Liver Panel Parameters ALP, Increase to Grade 1	—	—	—	0 Participants	—	—
Part 3: Number of Participants With Maximum Toxicity Grade Increase From Baseline for Liver Panel Parameters ALP, Increase to Grade 2	—	—	—	0 Participants	—	—
Part 3: Number of Participants With Maximum Toxicity Grade Increase From Baseline for Liver Panel Parameters ALP, Increase to Grade 3	—	—	—	0 Participants	—	—
Part 3: Number of Participants With Maximum Toxicity Grade Increase From Baseline for Liver Panel Parameters ALP, Increase to Grade 4	—	—	—	0 Participants	—	—
Part 3: Number of Participants With Maximum Toxicity Grade Increase From Baseline for Liver Panel Parameters AST, Increase to Grade 1	—	—	—	1 Participants	—	—
Part 3: Number of Participants With Maximum Toxicity Grade Increase From Baseline for Liver Panel Parameters AST, Increase to Grade 2	—	—	—	0 Participants	—	—
Part 3: Number of Participants With Maximum Toxicity Grade Increase From Baseline for Liver Panel Parameters AST, Increase to Grade 3	—	—	—	0 Participants	—	—
Part 3: Number of Participants With Maximum Toxicity Grade Increase From Baseline for Liver Panel Parameters AST, Increase to Grade 4	—	—	—	0 Participants	—	—
Part 3: Number of Participants With Maximum Toxicity Grade Increase From Baseline for Liver Panel Parameters Total Bilirubin, Increase to Grade 1	—	—	—	0 Participants	—	—
Part 3: Number of Participants With Maximum Toxicity Grade Increase From Baseline for Liver Panel Parameters Total Bilirubin, Increase to Grade 2	—	—	—	0 Participants	—	—
Part 3: Number of Participants With Maximum Toxicity Grade Increase From Baseline for Liver Panel Parameters Total Bilirubin, Increase to Grade 3	—	—	—	0 Participants	—	—
Part 3: Number of Participants With Maximum Toxicity Grade Increase From Baseline for Liver Panel Parameters Total Bilirubin, Increase to Grade 4	—	—	—	0 Participants	—	—
Part 3: Number of Participants With Maximum Toxicity Grade Increase From Baseline for Liver Panel Parameters Direct Bilirubin, Increase to Grade 1	—	—	—	0 Participants	—	—
Part 3: Number of Participants With Maximum Toxicity Grade Increase From Baseline for Liver Panel Parameters Direct Bilirubin, Increase to Grade 2	—	—	—	0 Participants	—	—
Part 3: Number of Participants With Maximum Toxicity Grade Increase From Baseline for Liver Panel Parameters Direct Bilirubin, Increase to Grade 3	—	—	—	0 Participants	—	—
Part 3: Number of Participants With Maximum Toxicity Grade Increase From Baseline for Liver Panel Parameters Direct Bilirubin, Increase to Grade 4	—	—	—	0 Participants	—	—

PRIMARY outcome

Timeframe: At Day 1

Population: The analysis was performed on the VH4004280 PK Set which included all participants in the Part 1 (SAD) Safety Set who received 1 full dose of study treatment with at least one non-missing PK assessment. The participants were analyzed according to the treatment they received.

Blood samples were collected as assessed by protocol, at specific time points for pharmacokinetic (PK) analysis to determine AUC(0-inf). For AUC, a linear trapezoidal method was employed for all incremental trapezoids arising from increasing concentrations and the logarithmic trapezoidal method was used for those arising from decreasing concentrations. Geometric Coefficient of Variation was expressed in percentages.

Outcome measures

Outcome measures
Measure	Part 2 (MAD): VH4004280 100 mg PiB n=7 Participants Healthy participants were given a dose of 100 mg VH4004280 PiB QD for a 14-day period and were followed up to approximately Day 63.	Part 2 (MAD): VH4004280 250 mg + Midazolam (MDZ) PiB n=6 Participants Healthy participants were given a dose of 250 mg VH4004280 PiB QD for a 14-day period, and a single dose of Midazolam on days 1, 2, and 15, and were followed up to approximately Day 63.	Part 2 (MAD): VH4004280 350 mg PiB n=6 Participants Healthy participants were given a dose of 350 mg VH4004280 PiB QD for a 14-day period and were followed up to approximately Day 63.	Part 3 (Single Dose): VH4004280 450 mg Tablet n=6 Participants Healthy participants were given a single oral dose of VH4004280 450 mg tablet at Day 1 and were followed up to approximately Day 49.	Part 1 (SAD): VH4004280 450 mg PiB n=6 Participants Healthy participants were given a single oral dose of 450 mg VH4004280 PiB on Day 1 and were followed up to approximately Day 49.	Part 1 (SAD): VH4004280 900 mg PiB Healthy participants were given a single oral dose of 900 mg VH4004280 PiB on Day 1 and were followed up to approximately Day 49.
Part 1: Area Under the Plasma Concentration Time Curve From Time Zero to Infinity (AUC[0-infinity]) Following Single Dose Administration of VH4004280	16829.76 Hour nanogram per milliliter (h*ng/mL) Geometric Coefficient of Variation 17.59	51168.22 Hour nanogram per milliliter (h*ng/mL) Geometric Coefficient of Variation 51.76	174441.72 Hour nanogram per milliliter (h*ng/mL) Geometric Coefficient of Variation 33.21	1396.25 Hour nanogram per milliliter (h*ng/mL) Geometric Coefficient of Variation 28.02	215339.87 Hour nanogram per milliliter (h*ng/mL) Geometric Coefficient of Variation 42.90	—

PRIMARY outcome

Timeframe: At Days 1 and 14 for Part 2 (MAD): VH4004280 100 mg PiB and Part 2 (MAD): VH4004280 350 mg PiB groups, and at Days 2 and 15 for Part 2 (MAD): VH4004280 250 mg + Midazolam (MDZ) PiB group

Population: The analysis was performed on the VH4004280 PK Set which included all participants in the Part 2 (MAD) Safety Set who received at least 1 full dose of study treatment with at least one non-missing PK assessment. The participants were analyzed according to the treatment they received.

Blood samples were collected as assessed by protocol, at specific time points for PK analysis to determine AUC(0-t). For AUC, a linear trapezoidal method was employed for all incremental trapezoids arising from increasing concentrations and the logarithmic trapezoidal method was used for those arising from decreasing concentrations.

Outcome measures

Outcome measures
Measure	Part 2 (MAD): VH4004280 100 mg PiB n=8 Participants Healthy participants were given a dose of 100 mg VH4004280 PiB QD for a 14-day period and were followed up to approximately Day 63.	Part 2 (MAD): VH4004280 250 mg + Midazolam (MDZ) PiB n=6 Participants Healthy participants were given a dose of 250 mg VH4004280 PiB QD for a 14-day period, and a single dose of Midazolam on days 1, 2, and 15, and were followed up to approximately Day 63.	Part 2 (MAD): VH4004280 350 mg PiB Healthy participants were given a dose of 350 mg VH4004280 PiB QD for a 14-day period and were followed up to approximately Day 63.	Part 3 (Single Dose): VH4004280 450 mg Tablet n=6 Participants Healthy participants were given a single oral dose of VH4004280 450 mg tablet at Day 1 and were followed up to approximately Day 49.	Part 1 (SAD): VH4004280 450 mg PiB Healthy participants were given a single oral dose of 450 mg VH4004280 PiB on Day 1 and were followed up to approximately Day 49.	Part 1 (SAD): VH4004280 900 mg PiB Healthy participants were given a single oral dose of 900 mg VH4004280 PiB on Day 1 and were followed up to approximately Day 49.
Part 2: AUC Over a Dosing Interval From Time of Dosing to the Time of the Subsequent Dose (AUC[0-t]) Following Repeat Dose Administration of VH4004280 Day 1	—	14869.75 h*ng/mL Geometric Coefficient of Variation 23.49	—	6268.14 h*ng/mL Geometric Coefficient of Variation 17.35	—	—
Part 2: AUC Over a Dosing Interval From Time of Dosing to the Time of the Subsequent Dose (AUC[0-t]) Following Repeat Dose Administration of VH4004280 Day 2	15157.94 h*ng/mL Geometric Coefficient of Variation 26.00	—	—	—	—	—
Part 2: AUC Over a Dosing Interval From Time of Dosing to the Time of the Subsequent Dose (AUC[0-t]) Following Repeat Dose Administration of VH4004280 Day 14	—	1882862.73 h*ng/mL Geometric Coefficient of Variation 37.66	—	449239.54 h*ng/mL Geometric Coefficient of Variation 53.50	—	—
Part 2: AUC Over a Dosing Interval From Time of Dosing to the Time of the Subsequent Dose (AUC[0-t]) Following Repeat Dose Administration of VH4004280 Day 15	1527149.1 h*ng/mL Geometric Coefficient of Variation 26.00	—	—	—	—	—

PRIMARY outcome

Timeframe: At Day 1

Blood samples were collected as assessed by protocol, at specific time points for PK analysis to determine Cmax.

Outcome measures

Outcome measures
Measure	Part 2 (MAD): VH4004280 100 mg PiB n=7 Participants Healthy participants were given a dose of 100 mg VH4004280 PiB QD for a 14-day period and were followed up to approximately Day 63.	Part 2 (MAD): VH4004280 250 mg + Midazolam (MDZ) PiB n=6 Participants Healthy participants were given a dose of 250 mg VH4004280 PiB QD for a 14-day period, and a single dose of Midazolam on days 1, 2, and 15, and were followed up to approximately Day 63.	Part 2 (MAD): VH4004280 350 mg PiB n=6 Participants Healthy participants were given a dose of 350 mg VH4004280 PiB QD for a 14-day period and were followed up to approximately Day 63.	Part 3 (Single Dose): VH4004280 450 mg Tablet n=6 Participants Healthy participants were given a single oral dose of VH4004280 450 mg tablet at Day 1 and were followed up to approximately Day 49.	Part 1 (SAD): VH4004280 450 mg PiB n=6 Participants Healthy participants were given a single oral dose of 450 mg VH4004280 PiB on Day 1 and were followed up to approximately Day 49.	Part 1 (SAD): VH4004280 900 mg PiB Healthy participants were given a single oral dose of 900 mg VH4004280 PiB on Day 1 and were followed up to approximately Day 49.
Part 1: Maximum Observed Plasma Concentration (Cmax) Following Single Dose Administration of VH4004280	149.77 nanogram per milliliter (ng/mL) Geometric Coefficient of Variation 27.34	438.80 nanogram per milliliter (ng/mL) Geometric Coefficient of Variation 53.60	1342.72 nanogram per milliliter (ng/mL) Geometric Coefficient of Variation 30.74	13.49 nanogram per milliliter (ng/mL) Geometric Coefficient of Variation 23.59	1630.95 nanogram per milliliter (ng/mL) Geometric Coefficient of Variation 27.05	—

PRIMARY outcome

Timeframe: At Day 1

Population: The analysis was performed on the VH4004280 PK Set which included all participants in the Part 1 (SAD) Safety Set who received at least 1 full dose of study treatment with at least one non-missing PK assessment. The participants were analyzed according to the treatment they received.

Blood samples were collected as assessed by protocol, at specific time points for PK analysis to determine Tmax.

Outcome measures

Outcome measures
Measure	Part 2 (MAD): VH4004280 100 mg PiB n=7 Participants Healthy participants were given a dose of 100 mg VH4004280 PiB QD for a 14-day period and were followed up to approximately Day 63.	Part 2 (MAD): VH4004280 250 mg + Midazolam (MDZ) PiB n=6 Participants Healthy participants were given a dose of 250 mg VH4004280 PiB QD for a 14-day period, and a single dose of Midazolam on days 1, 2, and 15, and were followed up to approximately Day 63.	Part 2 (MAD): VH4004280 350 mg PiB n=6 Participants Healthy participants were given a dose of 350 mg VH4004280 PiB QD for a 14-day period and were followed up to approximately Day 63.	Part 3 (Single Dose): VH4004280 450 mg Tablet n=6 Participants Healthy participants were given a single oral dose of VH4004280 450 mg tablet at Day 1 and were followed up to approximately Day 49.	Part 1 (SAD): VH4004280 450 mg PiB n=6 Participants Healthy participants were given a single oral dose of 450 mg VH4004280 PiB on Day 1 and were followed up to approximately Day 49.	Part 1 (SAD): VH4004280 900 mg PiB Healthy participants were given a single oral dose of 900 mg VH4004280 PiB on Day 1 and were followed up to approximately Day 49.
Part 1: Time to Maximum Observed Plasma Concentration (Tmax) Following Single Dose Administration of VH4004280	9.90 hours Geometric Coefficient of Variation 16.62	11.15 hours Geometric Coefficient of Variation 40.09	10.31 hours Geometric Coefficient of Variation 7.45	9.63 hours Geometric Coefficient of Variation 9.13	8.53 hours Geometric Coefficient of Variation 20.71	—

PRIMARY outcome

Timeframe: Day 1 to Day 49

Blood samples were collected as assessed by protocol, at specific time points for PK analysis to determine T1/2.

Outcome measures

Outcome measures
Measure	Part 2 (MAD): VH4004280 100 mg PiB n=7 Participants Healthy participants were given a dose of 100 mg VH4004280 PiB QD for a 14-day period and were followed up to approximately Day 63.	Part 2 (MAD): VH4004280 250 mg + Midazolam (MDZ) PiB n=6 Participants Healthy participants were given a dose of 250 mg VH4004280 PiB QD for a 14-day period, and a single dose of Midazolam on days 1, 2, and 15, and were followed up to approximately Day 63.	Part 2 (MAD): VH4004280 350 mg PiB n=6 Participants Healthy participants were given a dose of 350 mg VH4004280 PiB QD for a 14-day period and were followed up to approximately Day 63.	Part 3 (Single Dose): VH4004280 450 mg Tablet n=6 Participants Healthy participants were given a single oral dose of VH4004280 450 mg tablet at Day 1 and were followed up to approximately Day 49.	Part 1 (SAD): VH4004280 450 mg PiB n=6 Participants Healthy participants were given a single oral dose of 450 mg VH4004280 PiB on Day 1 and were followed up to approximately Day 49.	Part 1 (SAD): VH4004280 900 mg PiB Healthy participants were given a single oral dose of 900 mg VH4004280 PiB on Day 1 and were followed up to approximately Day 49.
Part 1: Apparent Terminal Half-life (T1/2) Following Single Dose Administration of VH4004280	149.91 hours Geometric Coefficient of Variation 40.40	149.94 hours Geometric Coefficient of Variation 43.47	177.58 hours Geometric Coefficient of Variation 18.23	145.82 hours Geometric Coefficient of Variation 40.60	172.66 hours Geometric Coefficient of Variation 29.45	—

PRIMARY outcome

Timeframe: At Days 1 and 14 for Part 2 (MAD): VH4004280 100 mg PiB and Part 2 (MAD): VH4004280 350 mg PiB groups, and at Days 2 and 15 for Part 2 (MAD): VH4004280 250 mg + Midazolam (MDZ) PiB group

Blood samples were collected as assessed by protocol, at specific time points for PK analysis to determine Cmax.

Outcome measures

Outcome measures
Measure	Part 2 (MAD): VH4004280 100 mg PiB n=8 Participants Healthy participants were given a dose of 100 mg VH4004280 PiB QD for a 14-day period and were followed up to approximately Day 63.	Part 2 (MAD): VH4004280 250 mg + Midazolam (MDZ) PiB n=6 Participants Healthy participants were given a dose of 250 mg VH4004280 PiB QD for a 14-day period, and a single dose of Midazolam on days 1, 2, and 15, and were followed up to approximately Day 63.	Part 2 (MAD): VH4004280 350 mg PiB Healthy participants were given a dose of 350 mg VH4004280 PiB QD for a 14-day period and were followed up to approximately Day 63.	Part 3 (Single Dose): VH4004280 450 mg Tablet n=6 Participants Healthy participants were given a single oral dose of VH4004280 450 mg tablet at Day 1 and were followed up to approximately Day 49.	Part 1 (SAD): VH4004280 450 mg PiB Healthy participants were given a single oral dose of 450 mg VH4004280 PiB on Day 1 and were followed up to approximately Day 49.	Part 1 (SAD): VH4004280 900 mg PiB Healthy participants were given a single oral dose of 900 mg VH4004280 PiB on Day 1 and were followed up to approximately Day 49.
Part 2: Cmax Following Repeat Dose Administration of VH4004280 Day 1	—	957.92 ng/mL Geometric Coefficient of Variation 21.70	—	422.68 ng/mL Geometric Coefficient of Variation 15.53	—	—
Part 2: Cmax Following Repeat Dose Administration of VH4004280 Day 2	972.51 ng/mL Geometric Coefficient of Variation 26.49	—	—	—	—	—
Part 2: Cmax Following Repeat Dose Administration of VH4004280 Day 14	—	7573.63 ng/mL Geometric Coefficient of Variation 66.10	—	1725.63 ng/mL Geometric Coefficient of Variation 36.64	—	—
Part 2: Cmax Following Repeat Dose Administration of VH4004280 Day 15	4487.14 ng/mL Geometric Coefficient of Variation 42.27	—	—	—	—	—

PRIMARY outcome

Timeframe: Day 14 to Day 63 for Part 2 (MAD): VH4004280 100 mg PiB and Part 2 (MAD): VH4004280 350 mg PiB groups, and Day 15 to Day 63 for Part 2 (MAD): VH4004280 250 mg + Midazolam (MDZ) PiB group

Blood samples were collected as assessed by protocol, at specific time points for PK analysis to determine T1/2.

Outcome measures

Outcome measures
Measure	Part 2 (MAD): VH4004280 100 mg PiB n=8 Participants Healthy participants were given a dose of 100 mg VH4004280 PiB QD for a 14-day period and were followed up to approximately Day 63.	Part 2 (MAD): VH4004280 250 mg + Midazolam (MDZ) PiB n=6 Participants Healthy participants were given a dose of 250 mg VH4004280 PiB QD for a 14-day period, and a single dose of Midazolam on days 1, 2, and 15, and were followed up to approximately Day 63.	Part 2 (MAD): VH4004280 350 mg PiB Healthy participants were given a dose of 350 mg VH4004280 PiB QD for a 14-day period and were followed up to approximately Day 63.	Part 3 (Single Dose): VH4004280 450 mg Tablet n=6 Participants Healthy participants were given a single oral dose of VH4004280 450 mg tablet at Day 1 and were followed up to approximately Day 49.	Part 1 (SAD): VH4004280 450 mg PiB Healthy participants were given a single oral dose of 450 mg VH4004280 PiB on Day 1 and were followed up to approximately Day 49.	Part 1 (SAD): VH4004280 900 mg PiB Healthy participants were given a single oral dose of 900 mg VH4004280 PiB on Day 1 and were followed up to approximately Day 49.
Part 2: T1/2 Following Repeat Dose Administration of VH4004280 Day 14 to Day 63	—	147.93 hours Geometric Coefficient of Variation 56.42	—	166.29 hours Geometric Coefficient of Variation 34.95	—	—
Part 2: T1/2 Following Repeat Dose Administration of VH4004280 Day 15 to Day 63	207.76 hours Geometric Coefficient of Variation 35.36	—	—	—	—	—

PRIMARY outcome

Timeframe: At Days 1 and 14 for Part 2 (MAD): VH4004280 100 mg PiB and Part 2 (MAD): VH4004280 350 mg PiB groups, and at Days 2 and 15 for Part 2 (MAD): VH4004280 250 mg + Midazolam (MDZ) PiB group

Blood samples were collected as assessed by protocol, at specific time points for PK analysis to determine Tmax.