Trial Outcomes & Findings for Safety, Tolerability and Pharmacokinetic Profiles of MOTREM (LR12) in Healthy Male Subjects (NCT NCT03463044)

Last Updated: 2025-02-10

Results Overview

The number of subjects experiencing treatment emergent adverse events was collected to assess the safety and tolerability of MOTREM (LR12) in comparison with placebo.

Recruitment status

COMPLETED

Study phase

PHASE1

Target enrollment

27 participants

Primary outcome timeframe

30-44 days

Results posted on

2025-02-10

Participant Flow

The study was conducted in the UK. The first subject first visit was on 01 April 2016 and last subject last visit was on 25 August 2016.

Subjects were screened within 14 days and screening could be performed over multiple days prior to entering the study on Day -1. A total of 27 subjects were randomized and 26 subjects completed the study (1 subject was lost to follow-up and was prematurely withdrawn).

Participant milestones

Participant milestones
Measure	Placebo Placebo: Placebo	1 mg (Loading Dose) Nangibotide Part A, Cohort 1: 1 mg (loading dose) over 15 minutes i.v.	10 mg (Loading Dose) Nangibotide Part A, Cohort 2: 10 mg (loading dose) over 15 minutes i.v.	0.5 mg/kg (Loading Dose) and 0.03 mg/kg/h (Maintenance Dose) Nangibotide Part B, Cohort 3: 0.5 mg/kg i.v. loading dose and 0.03 mg/kg/h maintenance dose i.v. over 7 hours and 45 min	1 mg/kg (Loading Dose) and 0.1 mg/kg/h (Maintenance Dose) Nangibotide Part B, Cohort 4: 1 mg/kg i.v. loading dose and 0.1 mg/kg/h maintenance dose i.v. over 7 hours and 45 min	2 mg/kg (Loading Dose) and 0.3 mg/kg/h (Maintenance Dose) Nangibotide Part B, Cohort 5: 2 mg/kg i.v. loading dose and 0.3 mg/kg/h maintenance dose i.v. over 7 hours and 45 min	5 mg/kg (Loading Dose) and 1 mg/kg/h (Maintenance Dose) Nangibotide Part B, Cohort 6: 5 mg/kg i.v. loading dose and 1 mg/kg/h maintenance dose i.v. over 7 hours and 45 min	5 mg/kg (Loading Dose) and 3 mg/kg/h (Maintenance Dose) Nangibotide Part B, Cohort 7: 5 mg/kg i.v. loading dose and 3 mg/kg/h maintenance dose i.v. over 7 hours and 45 min	5 mg/kg (Loading Dose) and 6 mg/kg/h (Maintenance Dose) Nangibotide Part B, Cohort 8: 5 mg/kg i.v. loading dose and 6 mg/kg/h maintenance dose i.v. over 7 hours and 45 min
Overall Study STARTED	6	1	2	3	3	3	3	3	3
Overall Study COMPLETED	6	1	2	3	3	3	3	2	3
Overall Study NOT COMPLETED	0	0	0	0	0	0	0	1	0

Reasons for withdrawal

Reasons for withdrawal
Measure	Placebo Placebo: Placebo	1 mg (Loading Dose) Nangibotide Part A, Cohort 1: 1 mg (loading dose) over 15 minutes i.v.	10 mg (Loading Dose) Nangibotide Part A, Cohort 2: 10 mg (loading dose) over 15 minutes i.v.	0.5 mg/kg (Loading Dose) and 0.03 mg/kg/h (Maintenance Dose) Nangibotide Part B, Cohort 3: 0.5 mg/kg i.v. loading dose and 0.03 mg/kg/h maintenance dose i.v. over 7 hours and 45 min	1 mg/kg (Loading Dose) and 0.1 mg/kg/h (Maintenance Dose) Nangibotide Part B, Cohort 4: 1 mg/kg i.v. loading dose and 0.1 mg/kg/h maintenance dose i.v. over 7 hours and 45 min	2 mg/kg (Loading Dose) and 0.3 mg/kg/h (Maintenance Dose) Nangibotide Part B, Cohort 5: 2 mg/kg i.v. loading dose and 0.3 mg/kg/h maintenance dose i.v. over 7 hours and 45 min	5 mg/kg (Loading Dose) and 1 mg/kg/h (Maintenance Dose) Nangibotide Part B, Cohort 6: 5 mg/kg i.v. loading dose and 1 mg/kg/h maintenance dose i.v. over 7 hours and 45 min	5 mg/kg (Loading Dose) and 3 mg/kg/h (Maintenance Dose) Nangibotide Part B, Cohort 7: 5 mg/kg i.v. loading dose and 3 mg/kg/h maintenance dose i.v. over 7 hours and 45 min	5 mg/kg (Loading Dose) and 6 mg/kg/h (Maintenance Dose) Nangibotide Part B, Cohort 8: 5 mg/kg i.v. loading dose and 6 mg/kg/h maintenance dose i.v. over 7 hours and 45 min
Overall Study Lost to Follow-up	0	0	0	0	0	0	0	1	0

Baseline Characteristics

Safety, Tolerability and Pharmacokinetic Profiles of MOTREM (LR12) in Healthy Male Subjects

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Cohort 1 n=1 Participants 1 mg nangibotide over 15 minutes i.v.	Cohort 2 n=2 Participants 10 mg nangibotide over 15 minutes i.v.	Cohort 3 n=4 Participants 0.5 mg/kg i.v. and 0.03 mg/kg/h nangibotide i.v. over 7 hours and 45 min or placebo	Cohort 4 n=4 Participants 1 mg/kg i.v. and 0.1 mg/kg/h i.v. nangibotide over 7 hours and 45 min or placebo	Cohort 5 n=4 Participants 2 mg/kg i.v. and 0.3 mg/kg/h i.v. nangibotide over 7 hours and 45 min or placebo	Cohort 6 n=4 Participants 5 mg/kg i.v. and 1 mg/kg/h i.v. nangibotide over 7 hours and 45 min or placebo	Cohort 7 n=4 Participants 5 mg/kg i.v. and 3 mg/kg/h i.v. nangibotide over 7 hours and 45 min or placebo	Cohort 8 n=4 Participants 5 mg/kg i.v. and 6 mg/kg/h i.v. nangibotide over 7 hours and 45 min or placebo	Total n=27 Participants Total of all reporting groups
Age, Categorical <=18 years	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
Age, Categorical Between 18 and 65 years	1 Participants n=5 Participants	2 Participants n=7 Participants	4 Participants n=5 Participants	4 Participants n=4 Participants	4 Participants n=21 Participants	4 Participants n=8 Participants	4 Participants n=8 Participants	4 Participants n=24 Participants	27 Participants n=42 Participants
Age, Categorical >=65 years	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
Sex: Female, Male 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
Sex: Female, Male Male	1 Participants n=5 Participants	2 Participants n=7 Participants	4 Participants n=5 Participants	4 Participants n=4 Participants	4 Participants n=21 Participants	4 Participants n=8 Participants	4 Participants n=8 Participants	4 Participants n=24 Participants	27 Participants n=42 Participants
Race (NIH/OMB) American Indian or Alaska Native	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
Race (NIH/OMB) Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	1 Participants n=4 Participants	0 Participants n=21 Participants	0 Participants n=8 Participants	1 Participants n=8 Participants	1 Participants n=24 Participants	3 Participants n=42 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	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
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	2 Participants n=4 Participants	1 Participants n=21 Participants	0 Participants n=8 Participants	0 Participants n=8 Participants	0 Participants n=24 Participants	3 Participants n=42 Participants
Race (NIH/OMB) White	1 Participants n=5 Participants	2 Participants n=7 Participants	4 Participants n=5 Participants	1 Participants n=4 Participants	3 Participants n=21 Participants	4 Participants n=8 Participants	3 Participants n=8 Participants	3 Participants n=24 Participants	21 Participants n=42 Participants
Race (NIH/OMB) More than one race	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
Race (NIH/OMB) Unknown or Not Reported	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
Region of Enrollment United Kingdom	1 participants n=5 Participants	2 participants n=7 Participants	4 participants n=5 Participants	4 participants n=4 Participants	4 participants n=21 Participants	4 participants n=8 Participants	4 participants n=8 Participants	4 participants n=24 Participants	27 participants n=42 Participants
Weight	81.2 kg n=5 Participants	68.6 kg n=7 Participants	71.7 kg n=5 Participants	77.1 kg n=4 Participants	73.1 kg n=21 Participants	74.4 kg n=8 Participants	77.1 kg n=8 Participants	76.7 kg n=24 Participants	75.7 kg n=42 Participants
Height	189.0 cm n=5 Participants	169.5 cm n=7 Participants	178.0 cm n=5 Participants	180.0 cm n=4 Participants	183.0 cm n=21 Participants	178.0 cm n=8 Participants	179.5 cm n=8 Participants	182.0 cm n=24 Participants	180.0 cm n=42 Participants
BMI	22.7 kg/m² n=5 Participants	23.7 kg/m² n=7 Participants	22.3 kg/m² n=5 Participants	24.2 kg/m² n=4 Participants	21.9 kg/m² n=21 Participants	23.5 kg/m² n=8 Participants	24.1 kg/m² n=8 Participants	23.1 kg/m² n=24 Participants	23.4 kg/m² n=42 Participants

PRIMARY outcome

Timeframe: 30-44 days

The number of subjects experiencing treatment emergent adverse events was collected to assess the safety and tolerability of MOTREM (LR12) in comparison with placebo.

Outcome measures

Outcome measures
Measure	Placebo n=6 Participants Placebo: Placebo	1 mg (Loading Dose) Nangibotide n=1 Participants Part A, Cohort 1: 1 mg (loading dose) over 15 minutes i.v.	10 mg (Loading Dose) Nangibotide n=2 Participants Part A, Cohort 2: 10 mg (loading dose) over 15 minutes i.v.	0.5 mg/kg (Loading Dose) and 0.03 mg/kg/h (Maintenance Dose) Nangibotide n=3 Participants Part B, Cohort 3: 0.5 mg/kg i.v. loading dose and 0.03 mg/kg/h maintenance dose i.v. over 7 hours and 45 min	1 mg/kg (Loading Dose) and 0.1 mg/kg/h (Maintenance Dose) Nangibotide n=3 Participants Part B, Cohort 4: 1 mg/kg i.v. loading dose and 0.1 mg/kg/h maintenance dose i.v. over 7 hours and 45 min	2 mg/kg (Loading Dose) and 0.3 mg/kg/h (Maintenance Dose) Nangibotide n=3 Participants Part B, Cohort 5: 2 mg/kg i.v. loading dose and 0.3 mg/kg/h maintenance dose i.v. over 7 hours and 45 min	5 mg/kg (Loading Dose) and 1 mg/kg/h (Maintenance Dose) Nangibotide n=3 Participants Part B, Cohort 6: 5 mg/kg i.v. loading dose and 1 mg/kg/h maintenance dose i.v. over 7 hours and 45 min	5 mg/kg (Loading Dose) and 3 mg/kg/h (Maintenance Dose) Nangibotide n=3 Participants Part B, Cohort 7: 5 mg/kg i.v. loading dose and 3 mg/kg/h maintenance dose i.v. over 7 hours and 45 min	5 mg/kg (Loading Dose) and 6 mg/kg/h (Maintenance Dose) n=3 Participants Part B, Cohort 8: 5 mg/kg i.v. loading dose and 6 mg/kg/h maintenance dose i.v. over 7 hours and 45 min
Safety and Tolerability: the Number of Subjects Experiencing Treatment Emergent Adverse Events	1 Participants	0 Participants	1 Participants	1 Participants	1 Participants	0 Participants	0 Participants	1 Participants	1 Participants

SECONDARY outcome

Timeframe: Maximum Plasma Concentration (Cmax) was assessed only for Groups 3-8 who received loading dose over 15 min and maintenance dose over 7 h and 45 min. Cmax is determined over a period of time starting from predose to 10h after start of the loading dose.

Population: In cohort 1 and cohort 2, there was 1 subject per cohort and the subjects received only a loading dose. LR12 plasma concentrations were quantifiable only at 15 min post-start of the infusion. For this reason, no PK analysis was performed for these two cohorts and for this reason results were not presented.

Plasma concentrations of LR12 were measured by a validated liquid chromatography-mass spectrometry (LC-MS/MS) assay and analyzed using noncompartmental methods to obtain estimates of the pharmacokinetic parameter of Maximum Plasma Concentration (Cmax).

Outcome measures

Outcome measures
Measure	Placebo n=3 Participants Placebo: Placebo	1 mg (Loading Dose) Nangibotide n=3 Participants Part A, Cohort 1: 1 mg (loading dose) over 15 minutes i.v.	10 mg (Loading Dose) Nangibotide n=3 Participants Part A, Cohort 2: 10 mg (loading dose) over 15 minutes i.v.	0.5 mg/kg (Loading Dose) and 0.03 mg/kg/h (Maintenance Dose) Nangibotide n=3 Participants Part B, Cohort 3: 0.5 mg/kg i.v. loading dose and 0.03 mg/kg/h maintenance dose i.v. over 7 hours and 45 min	1 mg/kg (Loading Dose) and 0.1 mg/kg/h (Maintenance Dose) Nangibotide n=3 Participants Part B, Cohort 4: 1 mg/kg i.v. loading dose and 0.1 mg/kg/h maintenance dose i.v. over 7 hours and 45 min	2 mg/kg (Loading Dose) and 0.3 mg/kg/h (Maintenance Dose) Nangibotide n=3 Participants Part B, Cohort 5: 2 mg/kg i.v. loading dose and 0.3 mg/kg/h maintenance dose i.v. over 7 hours and 45 min	5 mg/kg (Loading Dose) and 1 mg/kg/h (Maintenance Dose) Nangibotide Part B, Cohort 6: 5 mg/kg i.v. loading dose and 1 mg/kg/h maintenance dose i.v. over 7 hours and 45 min	5 mg/kg (Loading Dose) and 3 mg/kg/h (Maintenance Dose) Nangibotide Part B, Cohort 7: 5 mg/kg i.v. loading dose and 3 mg/kg/h maintenance dose i.v. over 7 hours and 45 min	5 mg/kg (Loading Dose) and 6 mg/kg/h (Maintenance Dose) Part B, Cohort 8: 5 mg/kg i.v. loading dose and 6 mg/kg/h maintenance dose i.v. over 7 hours and 45 min
Pharmacokinetics (Maximum Plasma Concentration)	256.20 ng/mL Geometric Coefficient of Variation 39	638.04 ng/mL Geometric Coefficient of Variation 25	1643.25 ng/mL Geometric Coefficient of Variation 22	3818.94 ng/mL Geometric Coefficient of Variation 1	4185.47 ng/mL Geometric Coefficient of Variation 66	4200.05 ng/mL Geometric Coefficient of Variation 21	—	—	—

SECONDARY outcome

Timeframe: Cavg30-465 was assessed only for Groups 3-8 who received loading dose over 15 min and maintenance dose over 7 h and 45 min. Cavg30-465 is determined over a period of time starting from predose to 10h after start of the loading dose.

Plasma concentrations of LR12 were measured by a validated LC-MS/MS assay and analyzed using noncompartmental methods to obtain estimates of the PK parameter of steady state concentration during the maintenance infusion (Cavg30-465).

Outcome measures

Outcome measures
Measure	Placebo n=3 Participants Placebo: Placebo	1 mg (Loading Dose) Nangibotide n=3 Participants Part A, Cohort 1: 1 mg (loading dose) over 15 minutes i.v.	10 mg (Loading Dose) Nangibotide n=3 Participants Part A, Cohort 2: 10 mg (loading dose) over 15 minutes i.v.	0.5 mg/kg (Loading Dose) and 0.03 mg/kg/h (Maintenance Dose) Nangibotide n=3 Participants Part B, Cohort 3: 0.5 mg/kg i.v. loading dose and 0.03 mg/kg/h maintenance dose i.v. over 7 hours and 45 min	1 mg/kg (Loading Dose) and 0.1 mg/kg/h (Maintenance Dose) Nangibotide n=3 Participants Part B, Cohort 4: 1 mg/kg i.v. loading dose and 0.1 mg/kg/h maintenance dose i.v. over 7 hours and 45 min	2 mg/kg (Loading Dose) and 0.3 mg/kg/h (Maintenance Dose) Nangibotide n=3 Participants Part B, Cohort 5: 2 mg/kg i.v. loading dose and 0.3 mg/kg/h maintenance dose i.v. over 7 hours and 45 min	5 mg/kg (Loading Dose) and 1 mg/kg/h (Maintenance Dose) Nangibotide Part B, Cohort 6: 5 mg/kg i.v. loading dose and 1 mg/kg/h maintenance dose i.v. over 7 hours and 45 min	5 mg/kg (Loading Dose) and 3 mg/kg/h (Maintenance Dose) Nangibotide Part B, Cohort 7: 5 mg/kg i.v. loading dose and 3 mg/kg/h maintenance dose i.v. over 7 hours and 45 min	5 mg/kg (Loading Dose) and 6 mg/kg/h (Maintenance Dose) Part B, Cohort 8: 5 mg/kg i.v. loading dose and 6 mg/kg/h maintenance dose i.v. over 7 hours and 45 min
Statistical Analysis of LR12 PK Parameters: Steady State Concentration During the Maintenance Infusion (Cavg30-465)	NA ng/mL Geometric Coefficient of Variation NA For Cohort 3 values for Cavg30-465 were non-calculable because of missing values for some of the 3 patients because below the level of detection	13.46 ng/mL Geometric Coefficient of Variation 18	36.61 ng/mL Geometric Coefficient of Variation 14	152.41 ng/mL Geometric Coefficient of Variation 12	418.05 ng/mL Geometric Coefficient of Variation 22	983.19 ng/mL Geometric Coefficient of Variation 20	—	—	—

SECONDARY outcome

Timeframe: t1/2 was assessed only for Groups 3-8 who received loading dose over 15 min and maintenance dose over 7 h and 45 min. t1/2 is determined over a period of time starting from 7 h and 45 min to 10h after start of the loading dose (decaying period).

Population: Up to cohort 5, due to paucity of the data, t1/2 could not be determined, hence the results for these cohorts are not presented.

Plasma concentrations of LR12 were measured by a validated LC-MS/MS assay and analyzed using noncompartmental methods to obtain estimates of the PK parameter of terminal half-life (t1/2). Of note, apparent increase in half-life at increasing doses is explained by the detection of a slow elimination phase, which was below limit of quantification for the lower doses.

Outcome measures

Outcome measures
Measure	Placebo n=3 Participants Placebo: Placebo	1 mg (Loading Dose) Nangibotide n=3 Participants Part A, Cohort 1: 1 mg (loading dose) over 15 minutes i.v.	10 mg (Loading Dose) Nangibotide n=3 Participants Part A, Cohort 2: 10 mg (loading dose) over 15 minutes i.v.	0.5 mg/kg (Loading Dose) and 0.03 mg/kg/h (Maintenance Dose) Nangibotide n=3 Participants Part B, Cohort 3: 0.5 mg/kg i.v. loading dose and 0.03 mg/kg/h maintenance dose i.v. over 7 hours and 45 min	1 mg/kg (Loading Dose) and 0.1 mg/kg/h (Maintenance Dose) Nangibotide n=3 Participants Part B, Cohort 4: 1 mg/kg i.v. loading dose and 0.1 mg/kg/h maintenance dose i.v. over 7 hours and 45 min	2 mg/kg (Loading Dose) and 0.3 mg/kg/h (Maintenance Dose) Nangibotide n=3 Participants Part B, Cohort 5: 2 mg/kg i.v. loading dose and 0.3 mg/kg/h maintenance dose i.v. over 7 hours and 45 min	5 mg/kg (Loading Dose) and 1 mg/kg/h (Maintenance Dose) Nangibotide Part B, Cohort 6: 5 mg/kg i.v. loading dose and 1 mg/kg/h maintenance dose i.v. over 7 hours and 45 min	5 mg/kg (Loading Dose) and 3 mg/kg/h (Maintenance Dose) Nangibotide Part B, Cohort 7: 5 mg/kg i.v. loading dose and 3 mg/kg/h maintenance dose i.v. over 7 hours and 45 min	5 mg/kg (Loading Dose) and 6 mg/kg/h (Maintenance Dose) Part B, Cohort 8: 5 mg/kg i.v. loading dose and 6 mg/kg/h maintenance dose i.v. over 7 hours and 45 min
Statistical Analysis of LR12 PK Parameters: t1/2	NA minute Geometric Coefficient of Variation NA Up to cohort 5, due to paucity of the data (below the level of detection), t1/2 could not be determined	NA minute Geometric Coefficient of Variation NA Up to cohort 5, due to paucity of the data (below the level of detection), t1/2 could not be determined.	NA minute Geometric Coefficient of Variation NA Up to cohort 5, due to paucity of the data (below the level of detection), t1/2 could not be determined.	1.63 minute Geometric Coefficient of Variation 20	17.87 minute Geometric Coefficient of Variation 23	40.70 minute Geometric Coefficient of Variation 76	—	—	—

SECONDARY outcome

Timeframe: AUC0-t was assessed only for Groups 3-8 who received loading dose over 15 min and maintenance dose over 7 h and 45 min. AUC0-t is determined over a period of time starting time zero (predose) to the time of last observed concentration (t).

Population: There was 1 subject per cohort in cohort 1 and cohort 2 and the subjects received only a loading dose. LR12 (nangibotide) plasma concentrations were quantifiable only at 15 min post-start of the infusion. For this reason, no PK analysis was planned for these two cohorts and no results were presented.

Plasma concentrations of LR12 were measured by a validated LC-MS/MS assay and analyzed using noncompartmental methods to obtain estimates of the PK parameter of the area under the plasma concentration curve (h.ng/mL) from time zero (predose) to the time of last observed concentration (t) measured (which can go up to 10h post loading dose start) using a linear trapezoidal method (AUC0-t).

Outcome measures

Outcome measures
Measure	Placebo n=3 Participants Placebo: Placebo	1 mg (Loading Dose) Nangibotide n=3 Participants Part A, Cohort 1: 1 mg (loading dose) over 15 minutes i.v.	10 mg (Loading Dose) Nangibotide n=3 Participants Part A, Cohort 2: 10 mg (loading dose) over 15 minutes i.v.	0.5 mg/kg (Loading Dose) and 0.03 mg/kg/h (Maintenance Dose) Nangibotide n=3 Participants Part B, Cohort 3: 0.5 mg/kg i.v. loading dose and 0.03 mg/kg/h maintenance dose i.v. over 7 hours and 45 min	1 mg/kg (Loading Dose) and 0.1 mg/kg/h (Maintenance Dose) Nangibotide n=3 Participants Part B, Cohort 4: 1 mg/kg i.v. loading dose and 0.1 mg/kg/h maintenance dose i.v. over 7 hours and 45 min	2 mg/kg (Loading Dose) and 0.3 mg/kg/h (Maintenance Dose) Nangibotide n=3 Participants Part B, Cohort 5: 2 mg/kg i.v. loading dose and 0.3 mg/kg/h maintenance dose i.v. over 7 hours and 45 min	5 mg/kg (Loading Dose) and 1 mg/kg/h (Maintenance Dose) Nangibotide Part B, Cohort 6: 5 mg/kg i.v. loading dose and 1 mg/kg/h maintenance dose i.v. over 7 hours and 45 min	5 mg/kg (Loading Dose) and 3 mg/kg/h (Maintenance Dose) Nangibotide Part B, Cohort 7: 5 mg/kg i.v. loading dose and 3 mg/kg/h maintenance dose i.v. over 7 hours and 45 min	5 mg/kg (Loading Dose) and 6 mg/kg/h (Maintenance Dose) Part B, Cohort 8: 5 mg/kg i.v. loading dose and 6 mg/kg/h maintenance dose i.v. over 7 hours and 45 min
Statistical Analysis of LR12 PK Parameters: AUC0-t	101.98 h.ng/ml Geometric Coefficient of Variation 11	244.38 h.ng/ml Geometric Coefficient of Variation 14	661.60 h.ng/ml Geometric Coefficient of Variation 23	2153.14 h.ng/ml Geometric Coefficient of Variation 11	4208.65 h.ng/ml Geometric Coefficient of Variation 29	8556.69 h.ng/ml Geometric Coefficient of Variation 17	—	—	—

SECONDARY outcome

Timeframe: AUC0-∞ was assessed only for Groups 3-8 who received loading dose over 15 min and maintenance dose over 7 h and 45 min. AUC0-∞ is determined over a period of time starting time zero (predose) to infinity (cf. extrapolation formula in the above section).

Population: The percentage of extrapolation of AUC0-∞ was below 1% in subjects up to cohort 5, and due to this it was not determined for these subjects. For this reason, results were not presented for cohorts 1-5.

Plasma concentrations of LR12 were measured by a validated LC-MS/MS assay and analyzed using noncompartmental methods to obtain estimates of the PK parameter of AUC0-∞. AUC0-∞ represents the area under the plasma concentration-time curve (h.ng/mL) from time 0 to infinity (AUC0- ∞= AUC0-t + \[Ct/ke\], where Ct = the observed concentration of drug for the last sample on the PK profile in which drug was detected, and ke represents the terminal rate constant). The percentage of extrapolation of AUC0-∞ should not exceed 20%.

Outcome measures

Outcome measures
Measure	Placebo n=3 Participants Placebo: Placebo	1 mg (Loading Dose) Nangibotide n=3 Participants Part A, Cohort 1: 1 mg (loading dose) over 15 minutes i.v.	10 mg (Loading Dose) Nangibotide n=3 Participants Part A, Cohort 2: 10 mg (loading dose) over 15 minutes i.v.	0.5 mg/kg (Loading Dose) and 0.03 mg/kg/h (Maintenance Dose) Nangibotide n=3 Participants Part B, Cohort 3: 0.5 mg/kg i.v. loading dose and 0.03 mg/kg/h maintenance dose i.v. over 7 hours and 45 min	1 mg/kg (Loading Dose) and 0.1 mg/kg/h (Maintenance Dose) Nangibotide n=3 Participants Part B, Cohort 4: 1 mg/kg i.v. loading dose and 0.1 mg/kg/h maintenance dose i.v. over 7 hours and 45 min	2 mg/kg (Loading Dose) and 0.3 mg/kg/h (Maintenance Dose) Nangibotide n=3 Participants Part B, Cohort 5: 2 mg/kg i.v. loading dose and 0.3 mg/kg/h maintenance dose i.v. over 7 hours and 45 min	5 mg/kg (Loading Dose) and 1 mg/kg/h (Maintenance Dose) Nangibotide Part B, Cohort 6: 5 mg/kg i.v. loading dose and 1 mg/kg/h maintenance dose i.v. over 7 hours and 45 min	5 mg/kg (Loading Dose) and 3 mg/kg/h (Maintenance Dose) Nangibotide Part B, Cohort 7: 5 mg/kg i.v. loading dose and 3 mg/kg/h maintenance dose i.v. over 7 hours and 45 min	5 mg/kg (Loading Dose) and 6 mg/kg/h (Maintenance Dose) Part B, Cohort 8: 5 mg/kg i.v. loading dose and 6 mg/kg/h maintenance dose i.v. over 7 hours and 45 min
Statistical Analysis of LR12 PK Parameters: AUC0-∞	NA h.ng/ml Geometric Coefficient of Variation NA The percentage of extrapolation of AUC0-∞ was below the level of detection of 1% in subjects up to cohort 5, and due to this it was not determined for these subjects.	NA h.ng/ml Geometric Coefficient of Variation NA The percentage of extrapolation of AUC0-∞ was below the level of detection of 1% in subjects up to cohort 5, and due to this it was not determined for these subjects.	NA h.ng/ml Geometric Coefficient of Variation NA The percentage of extrapolation of AUC0-∞ was below the level of detection of 1% in subjects up to cohort 5, and due to this it was not determined for these subjects.	2153.38 h.ng/ml Geometric Coefficient of Variation 11	4211.90 h.ng/ml Geometric Coefficient of Variation 29	8565.30 h.ng/ml Geometric Coefficient of Variation 17	—	—	—

SECONDARY outcome

Timeframe: CL was assessed only for Groups 3-8 who received loading dose over 15 min and maintenance dose over 7 h and 45 min (465 min). CL is calculated based on the perfusion rate (ng/kg/h) and the concentration at the end of perfusion (7h45min = 465min).

Population: There was 1 subject per cohort and the subjects received only a loading dose in cohort 1 and cohort 2. LR12 (nangibotide) plasma concentrations were quantifiable only at 15 min post-start of the infusion. No PK analysis was planned for these two cohorts. Also, CL values for cohort 3 were non-calculable. For this reason, results for cohorts 1-3 are not presented.

Plasma concentrations of LR12 were measured by a validated LC-MS/MS assay and analyzed using noncompartmental methods to obtain estimates of the PK parameter of systemic clearance (CL). The systemic clearance was estimated using the formula: CL = K0/ Css where K0 is the perfusion rate (ng/kg/h) and Css is the concentration at the end of perfusion (C at 465 min). Of note, this narrow range of the clearance values indicates that the apparent increases in t1/2 and volume of distribution as a function of doses are not due to a non-linearity in the pharmacokinetics, but to the limit of quantification of the bioanalytical assay.

Outcome measures

Outcome measures
Measure	Placebo n=3 Participants Placebo: Placebo	1 mg (Loading Dose) Nangibotide n=3 Participants Part A, Cohort 1: 1 mg (loading dose) over 15 minutes i.v.	10 mg (Loading Dose) Nangibotide n=3 Participants Part A, Cohort 2: 10 mg (loading dose) over 15 minutes i.v.	0.5 mg/kg (Loading Dose) and 0.03 mg/kg/h (Maintenance Dose) Nangibotide n=3 Participants Part B, Cohort 3: 0.5 mg/kg i.v. loading dose and 0.03 mg/kg/h maintenance dose i.v. over 7 hours and 45 min	1 mg/kg (Loading Dose) and 0.1 mg/kg/h (Maintenance Dose) Nangibotide n=3 Participants Part B, Cohort 4: 1 mg/kg i.v. loading dose and 0.1 mg/kg/h maintenance dose i.v. over 7 hours and 45 min	2 mg/kg (Loading Dose) and 0.3 mg/kg/h (Maintenance Dose) Nangibotide n=3 Participants Part B, Cohort 5: 2 mg/kg i.v. loading dose and 0.3 mg/kg/h maintenance dose i.v. over 7 hours and 45 min	5 mg/kg (Loading Dose) and 1 mg/kg/h (Maintenance Dose) Nangibotide Part B, Cohort 6: 5 mg/kg i.v. loading dose and 1 mg/kg/h maintenance dose i.v. over 7 hours and 45 min	5 mg/kg (Loading Dose) and 3 mg/kg/h (Maintenance Dose) Nangibotide Part B, Cohort 7: 5 mg/kg i.v. loading dose and 3 mg/kg/h maintenance dose i.v. over 7 hours and 45 min	5 mg/kg (Loading Dose) and 6 mg/kg/h (Maintenance Dose) Part B, Cohort 8: 5 mg/kg i.v. loading dose and 6 mg/kg/h maintenance dose i.v. over 7 hours and 45 min
Statistical Analysis of LR12 PK Parameters: CL	NA L/kg/h Geometric Coefficient of Variation NA CL values for cohort 3 were non-calculable due to very low LR12 concentration at 7h45min post maintenance dose (below the level of detection)	9.47 L/kg/h Geometric Coefficient of Variation 9	6.79 L/kg/h Geometric Coefficient of Variation 17	6.73 L/kg/h Geometric Coefficient of Variation 25	5.66 L/kg/h Geometric Coefficient of Variation 22	7.50 L/kg/h Geometric Coefficient of Variation 20	—	—	—

SECONDARY outcome

Timeframe: V was assessed only for Groups 3-8 who received loading dose over 15 min and maintenance dose over 7 h and 45 min. V is derived from both CL and ke which are calculated from the LR12 concentration time curve from predose to 10h after loading dose start.

Population: There was 1 subject per cohort In cohort 1 and cohort 2 and the subjects received only a loading dose. LR12 plasma concentrations were quantifiable only at 15 min post-start of the infusion. No PK analysis was planned for these two cohorts. Also, V values for cohort 3, 4 and 5 were non-calculable. For this reason, no results were presented for cohorts 1-6.

The volume of distribution was estimated according to the following equation: V= CL x MRT (mean residence time). However, regarding administration procedures, MRT could not be calculated precisely. Furthermore, in some cases MRT could not be estimated. Thus, the following formula was used V = CL / ke. The terminal rate constant (ke) was estimated by log-linear regression analysis on data points visually assessed to be on the terminal log-linear phase. Of note, it can be said that this apparent increase in V is also explained by the detection of a slow elimination phase, which was below limit of quantification for the lower doses.

Outcome measures

Outcome measures
Measure	Placebo n=3 Participants Placebo: Placebo	1 mg (Loading Dose) Nangibotide n=3 Participants Part A, Cohort 1: 1 mg (loading dose) over 15 minutes i.v.	10 mg (Loading Dose) Nangibotide n=3 Participants Part A, Cohort 2: 10 mg (loading dose) over 15 minutes i.v.	0.5 mg/kg (Loading Dose) and 0.03 mg/kg/h (Maintenance Dose) Nangibotide n=3 Participants Part B, Cohort 3: 0.5 mg/kg i.v. loading dose and 0.03 mg/kg/h maintenance dose i.v. over 7 hours and 45 min	1 mg/kg (Loading Dose) and 0.1 mg/kg/h (Maintenance Dose) Nangibotide n=3 Participants Part B, Cohort 4: 1 mg/kg i.v. loading dose and 0.1 mg/kg/h maintenance dose i.v. over 7 hours and 45 min	2 mg/kg (Loading Dose) and 0.3 mg/kg/h (Maintenance Dose) Nangibotide n=3 Participants Part B, Cohort 5: 2 mg/kg i.v. loading dose and 0.3 mg/kg/h maintenance dose i.v. over 7 hours and 45 min	5 mg/kg (Loading Dose) and 1 mg/kg/h (Maintenance Dose) Nangibotide Part B, Cohort 6: 5 mg/kg i.v. loading dose and 1 mg/kg/h maintenance dose i.v. over 7 hours and 45 min	5 mg/kg (Loading Dose) and 3 mg/kg/h (Maintenance Dose) Nangibotide Part B, Cohort 7: 5 mg/kg i.v. loading dose and 3 mg/kg/h maintenance dose i.v. over 7 hours and 45 min	5 mg/kg (Loading Dose) and 6 mg/kg/h (Maintenance Dose) Part B, Cohort 8: 5 mg/kg i.v. loading dose and 6 mg/kg/h maintenance dose i.v. over 7 hours and 45 min
Statistical Analysis of LR12 PK Parameters: Volume of Distribution (V)	NA L/kg Geometric Coefficient of Variation NA V values for cohort 3, 4 and 5 were non-calculable (below the level of detection).	NA L/kg Geometric Coefficient of Variation NA V values for cohort 3, 4 and 5 were non-calculable (below the level of detection).	NA L/kg Geometric Coefficient of Variation NA V values for cohort 3, 4 and 5 were non-calculable (below the level of detection).	0.26 L/kg Geometric Coefficient of Variation 46	2.43 L/kg Geometric Coefficient of Variation 30	7.34 L/kg Geometric Coefficient of Variation 62	—	—	—

SECONDARY outcome

Timeframe: tmax was assessed only for Groups 3-8 who received loading dose over 15 min and maintenance dose over 7 h and 45 min. tmax is determined over a period of time starting from predose to 10h after start of the loading dose.

Population: There was 1 subject per cohort in cohort 1 and 2 and the subjects received only a loading dose. LR12 plasma concentrations were quantifiable only at 15 min post-start of the infusion. No PK analysis was planned for these two cohorts. For this reason, results for cohort 1 and 2 were not presented.

Plasma concentrations of LR12 were measured by a validated LC-MS/MS assay and analysed using noncompartmental methods to obtain estimates of the PK parameter of the time at which Cmax is apparent, identified by inspection of the plasma drug concentration vs.time data by WinNonlin (tmax).

Outcome measures

Outcome measures
Measure	Placebo n=3 Participants Placebo: Placebo	1 mg (Loading Dose) Nangibotide n=3 Participants Part A, Cohort 1: 1 mg (loading dose) over 15 minutes i.v.	10 mg (Loading Dose) Nangibotide n=3 Participants Part A, Cohort 2: 10 mg (loading dose) over 15 minutes i.v.	0.5 mg/kg (Loading Dose) and 0.03 mg/kg/h (Maintenance Dose) Nangibotide n=3 Participants Part B, Cohort 3: 0.5 mg/kg i.v. loading dose and 0.03 mg/kg/h maintenance dose i.v. over 7 hours and 45 min	1 mg/kg (Loading Dose) and 0.1 mg/kg/h (Maintenance Dose) Nangibotide n=3 Participants Part B, Cohort 4: 1 mg/kg i.v. loading dose and 0.1 mg/kg/h maintenance dose i.v. over 7 hours and 45 min	2 mg/kg (Loading Dose) and 0.3 mg/kg/h (Maintenance Dose) Nangibotide n=3 Participants Part B, Cohort 5: 2 mg/kg i.v. loading dose and 0.3 mg/kg/h maintenance dose i.v. over 7 hours and 45 min	5 mg/kg (Loading Dose) and 1 mg/kg/h (Maintenance Dose) Nangibotide Part B, Cohort 6: 5 mg/kg i.v. loading dose and 1 mg/kg/h maintenance dose i.v. over 7 hours and 45 min	5 mg/kg (Loading Dose) and 3 mg/kg/h (Maintenance Dose) Nangibotide Part B, Cohort 7: 5 mg/kg i.v. loading dose and 3 mg/kg/h maintenance dose i.v. over 7 hours and 45 min	5 mg/kg (Loading Dose) and 6 mg/kg/h (Maintenance Dose) Part B, Cohort 8: 5 mg/kg i.v. loading dose and 6 mg/kg/h maintenance dose i.v. over 7 hours and 45 min
Statistical Analysis of LR12 PK Parameters: Tmax	15 minute Interval 15.0 to 15.0	15 minute Interval 15.0 to 15.0	15 minute Interval 15.0 to 15.0	15 minute Interval 15.0 to 15.0	5 minute Interval 5.0 to 15.0	5 minute Interval 5.0 to 15.0	—	—	—

SECONDARY outcome

Timeframe: t last was assessed only for Groups 3-8 who received loading dose over 15 min and maintenance dose over 7 h and 45 min. t last is determined as the time of last observed concentration which can go up to 10h after loading dose start.

This PK parameter was calculated from measured plasma concentrations of LR12 and it represents the time of last observed concentration.