Bioequivalence, safety and immunogenicity of BI 695501, an adalimumab biosimilar candidate, compared with the reference biologic in a randomized, double-blind, active comparator phase I clinical study (VOLTAIRE®-PK) in healthy subjects

Figures & data

Figure 1. Patient flow.

PK: pharmacokinetic. ^aThe safety population consisted of subjects who received a single dose of study drug. ^bThe pharmacokinetic population consisted of all subjects who received a single dose of study drug, had at least one evaluable PK end point and were without protocol deviations or violations likely to impact the PK of the study drugs.

Table 1. Summary of PK parameters in healthy subjects after a single dose of BI 695501, US- or EU-approved adalimumab.

	BI 695501^a		US-approved adalimumab^b		EU-approved adalimumab^c
	Geometric mean (gCV%)	Mean ± SD	Geometric mean (gCV%)	Mean ± SD	Geometric mean (gCV%)	Mean ± SD
AUC0–inf, pred (µg*h/mL)	2630 (52.4)	2920 ± 1270	2470 (51.2)	2760 ± 1290	2650 (38.5)	2830 ± 1040
AUC0–tz(µg*h/mL)	2440 (47.8)	2660 ± 1020	2300 (45.1)	2500 ± 1010	2480 (33.5)	2600 ± 798
Cmax (µg/mL)	3.9 (34.1)	4.1 ± 1.27	3.9 (34.5)	4.11 ± 1.26	4.1 (30.4)	4.31 ± 1.22
λ/z (1/h)	0.003 (95.6)	0.005 ± 0.010	0.003 (83.4)	0.004 ± 0.003	0.003 (82.9)	0.004 ± 0.003
T1/2 (h)	234 (95.7)	309 ± 228	243 (83.4)	313 ± 228	258 (82.9)	328 ± 234
CL/F (mL/h)	15.2 (52.4)	17.8 ± 15.7	16.2 (51.2)	18.2 ± 9.7	15.1 (38.5)	16.2 ± 6.5
Vz/F (mL)	5130 (51.8)	5770 ± 2860	5680 (46.1)	6250 ± 2870	5630 (56.6)	6420 ± 3400
	Median (minimum–maximum)
Tmax (h)	132 (48–649)		109 (59–480)		120 (12–648)

AUC: Area under the concentration–time curve; AUC_{0–inf, pred}: AUC of the analyte in plasma over the time interval from zero extrapolated to infinity; AUC_0–tz: AUC of the analyte in plasma over the time interval from time zero to the last measurable concentration; CL/F: apparent clearance of the analyte in the plasma after extravascular administration; C_max: maximum observed drug concentration in plasma; gCV: geometric coefficient of variation; PK: pharmacokinetic; T_1/2: terminal half-life of the analyte in plasma; T_max: time from administration to maximum observed concentration of the analyte in plasma; V_z/F: apparent volume of distribution during the terminal phase following an extravascular dose; λ/z: terminal rate constant in plasma. ^an = 106 for all parameters except for C_max and T_max which were n = 107; ^bn = 105 for AUC_{0–inf, pred}, λ/z, T_1/2, CL/F, V_z/F, n = 107 for AUC_0–tz, and n = 108 for C_max and T_max; ^cn = 105 for all parameters except AUC_0–tz, which was n = 106 and C_max and T_max which were n = 107.

Figure 2. Arithmetic mean plasma concentration–time profiles in healthy subjects after a single dose of study drug for (a) BI 695501, US- and EU-approved Humira, (b) Forest plot presenting point estimate and 90% confidence intervals for primary PK parameters for BI 695, 501, US- and EU-approved Humira (bioequivalence was declared if the 90% confidence intervals were within prespecified acceptance ranges of 80–125%).

AUC_{0–inf, pred}: AUC of the analyte in plasma over the time interval from zero extrapolated to infinity; AUC_0–tz: AUC of the analyte in plasma over the time interval from time zero to the last measurable concentration; C_max: maximum observed drug concentration in plasma; PK: pharmacokinetic.

Figure 3. Development of ADAs in healthy subjects after a single dose of study drug at Days 28 and 71 for BI 695501, US- and EU-approved Humira. (a) Frequency of ADA-positive responses, (b) median ADA titer and (c) end-of-study titers for healthy subjects with ADA-positive responses. Median values are depicted by a line within the 25% and 75% percentile boxes; arithmetic mean = diamond shape; individual outliers = individual points; minimum and maximum values or 1.5× interquartile range = vertical lines out of the box plot. ADAs: antidrug antibodies.

Figure 4. Neutralizing antibody development in healthy subjects after a single dose of study drug at baseline, Day 28 and Day 71 for BI 695501, US- and EU-approved Humira.

nAb: neutralizing antibody.

Figure 5. Impact of antidrug antibody titer (high [>16] vs. low [≤16]) on the exposure (AUC_{0–inf, pred}) to the study drugs in healthy subjects after a single dose of BI 695501, US- or EU-approved Humira. Median values are depicted by a line within the 25% and 75% percentile boxes; arithmetic mean = diamond shape; individual outliers = individual points; minimum and maximum values or 1.5× interquartile range = vertical lines out of the box plot.

AUC_{0–inf, pred}: AUC of the analyte in plasma over the time interval from zero extrapolated to infinity.

Table 2. Summary of adverse events occurring in healthy subjects with one or more AEs, in any treatment group, after a single dose of BI 695501, US- or EU-approved Humira.

n (%)	BI 695501 (n = 108)	US-approved Humira (n = 108)	EU-approved Humira (n = 108)
Subjects with ≥1 AE	76 (70.4)	79 (73.1)	77 (71.3)
Serious AEs (intensity)	3 (2.8)	3 (2.8)	2 (1.9)
Concussion (severe)	1 (0.9)	0	0
Fracture (moderate/severe)	2 (1.9)	0	0
Abdominal pain (moderate/severe)	1 (0.9)^a^b	0	1 (0.9)^a
Appendicitis (moderate)	0	2 (1.9)^b	0
Laceration (severe)	0	1 (0.9)	0
Nephrolithiasis (moderate)	0	0	1 (0.9)
Drug-related AEs ≥2% in any of the treatment groups	21 (19.4)	29 (26.9)	28 (25.9)
Headache	6 (5.6)	10 (9.3)	11 (10.2)
Upper respiratory tract infection	4 (3.7)	3 (2.8)	5 (4.6)
Rhinorrhea	1 (0.9)	2 (1.9)	4 (3.7)
AE of special interest (severity)	2 (1.9)	2 (1.9)	1 (0.9)
Injection site reactivation/delayed hypersensitivity (mild)	2 (1.9)	0	1 (0.9)
Hypersensitivity reaction (mild)	0	1 (0.9)	0
Urticaria (moderate)	0	1 (0.9)	0
AEs leading to discontinuation of study drug	0	0	0
Death	0	0	0

Only the most severe occurrence of each subject was counted. Drug-related AEs are defined as any that are considered by the investigator to be related to the study drug.

AEs: Adverse events. ^aThe incidence of abdominal pain in the BI 695501 group was severe, and the incidence in the EU-approved Humira group was moderate. ^bOne incidence each of abdominal pain and appendicitis was considered by the investigator to be related to the study drug.