Pharmacokinetics and pharmacodynamics of a proposed tocilizumab biosimilar MSB11456 versus both the US-licensed and EU-approved products: a randomized, double-blind trial

Figures & data

Figure 1. Subject disposition.

Table 1. Subject demographics and characteristics at baseline, by treatment group and overall (safety analysis set^a).

	MSB11456 (N = 231)	US-licensed tocilizumab(N = 229)	EU-approved tocilizumab(N = 225)	Overall (N = 685)
Age (years), mean ± SD	27 ± 7.7	27 ± 7.4	28 ± 7.6	27 ± 7.6
Male, n (%)	121 (52.4)	120 (52.4)	115 (51.1)	356 (52.0)
Race, n (%)
White	165 (71.4)	177 (77.3)	165 (73.3)	507 (74.0)
Black/African American	0 (0.0)	2 (0.9)	1 (0.4)	3 (0.4)
Asian	18 (7.8)	19 (8.3)	19 (8.4)	56 (8.2)
Native Hawaiian/other Pacific Islander	12 (5.2)	6 (2.6)	6 (2.7)	24 (3.5)
American Indian/Alaska Native	1 (0.4)	0 (0.0)	1 (0.4)	2 (0.3)
Other^b	34 (14.7)	25 (10.9)	33 (14.7)	92 (13.4)
Ethnicity, n (%)
Hispanic/Latino	10 (4.3)	14 (6.1)	14 (6.2)	38 (5.5)
Weight (kg)^c, mean ± SD	73.7 ± 9.4	73.3 ± 9.3	73.7 ± 9.6	73.5 ± 9.4
Weight ≥60 and ≤80 kg, n (%)	175 (75.8)	173 (75.5)	170 (75.6)	518 (75.6)
Weight >80 and ≤100 kg, n (%)	56 (24.2)	56 (24.5)	55 (24.4)	167 (24.4)
BMI (kg/m^2), mean ± SD	24.5 ± 2.7	24.3 ± 2.5	24.6 ± 2.6	24.5 ± 2.6
BMI ≤20 kg/m^2, n (%)	10 (4.3)	3 (1.3)	5 (2.2)	18 (2.6)
BMI >20 and ≤28 kg/m^2, n (%)	191 (82.7)	209 (91.3)	192 (85.3)	592 (86.4)
BMI >28 kg/m^2, n (%)	30 (13.0)	17 (7.4)	28 (12.4)	75 (10.9)
sIL-6 R (ng/mL), mean ± SD	44.7 ± 15.6	44.8 ± 27.8	43.7 ± 12.9	NR
CRP (µg/mL), mean ± SD	1.28 ± 3.56	1.18 ± 1.70	1.64 ± 5.71	NR
Site
Site 1	123 (53.2)	121 (52.8)	119 (52.9)	363 (53.0)
Site 2	108 (46.8)	108 (47.2)	106 (47.1)	322 (47.0)

^aAll subjects who received study drug; subjects were analyzed according to the actual treatment they received.

^bThe majority were Māori, White/Māori, Latin American, White/Native Hawaiian, or other Pacific Islander.

^cAt day −1

BMI, body mass index; CRP, C-reactive protein; NR, not reported; SD, standard deviation; sIL-6 R, soluble interleukin-6 receptor.

Figure 2. Arithmetic mean (SD) tocilizumab serum concentration–time profiles following a single dose of MSB11456, US-licensed tocilizumab or EU-approved tocilizumab in healthy subjects on a linear scale (pharmacokinetic analysis set^a).

Table 2. Pharmacokinetic results after a single dose of MSB11456, US-licensed tocilizumab or EU-approved tocilizumab in healthy subjects (pharmacokinetic analysis set^a).

	MSB11456		US-licensed tocilizumab		EU-approved tocilizumab
Parameter	n	Estimate	n	Estimate	n	Estimate
	Geometric mean (GCV%)
AUC0-∞ (µg·h/mL)	194	1890 (72.9)	190	1790 (55.3)	200	1790 (58.3)
AUC0-t (µg·h/mL)	230	1490 (104.8)	226	1460 (78.6)	224	1560 (75.9)
AUC0-72 (µg·h/mL)	229	298 (121.3)	225	279 (98.7)	224	297 (90.8)
Cmax (µg/mL)	230	7.89 (84.2)	226	7.68 (67.1)	224	8.26 (63.6)
tmax (h)^b	230	96.0 (36.0; 240.0)	226	96.0 (36.0; 240.2)	224	96.0 (36.0; 196.9)
tlast (h)^b	230	406.5 (167.5; 505.1)	226	405.9 (236.6; 504.1)	224	406.5 (168.0; 505.0)
CL/F (L/h)	194	0.0859 (72.9)	190	0.0903 (55.3)	200	0.0904 (58.3)
t1/2 (h)	194	43.0 (30.7)	190	43.3 (27.0)	200	42.8 (27.1)

^aAll subjects who received study drug and had at least one of the primary pharmacokinetic parameters calculated without clinically important protocol deviations or events that may have significantly affected the pharmacokinetic assessments.

^bMedian (minimum; maximum).

AUC, area under the concentration–time curve; AUC_0-∞, AUC from time zero (pre-dose) extrapolated to infinity; AUC_0-t, AUC from time zero (pre-dose) to the last sampling time at which a quantifiable concentration was obtained; AUC_0-72, AUC from time zero (pre-dose) to 72 hours; CL/F, apparent total body clearance; C_max, maximum observed concentration; GCV%, geometric coefficient of variation; t_1/2, apparent terminal half-life; t_last, time to last observed serum concentration; t_max, time to C_max

Table 3. Geometric LS mean ratios for primary pharmacokinetic parameters after a single dose of MSB11455, US-licensed tocilizumab, or EU-approved tocilizumab in healthy subjects^a (pharmacokinetic analysis set^b).

Comparison	Parameter	Treatment	n	Geometric LS Mean	Ratio^c (%)	90% CI of Ratio
MSB11456 versus US-licensed tocilizumab	AUC0-∞ (µg·h/mL)	MSB11456	194	1880	106.16	(96.80, 116.43)
		US-licensed tocilizumab	190	1770
	AUC0-t (µg·h/mL)	MSB11456	230	1470	104.15	(93.58, 115.90)
		US-licensed tocilizumab	226	1410
	Cmax (µg/mL)	MSB11456	230	7.91	104.45	(95.05, 114.77)
		US-licensed tocilizumab	226	7.57
MSB11456 versus EU-approved tocilizumab	AUC0-∞ (µg·h/mL)	MSB11456	194	1880	104.03	(94.96, 113.96)
		EU-approved tocilizumab	200	1810
	AUC0-t (µg·h/mL)	MSB11456	230	1470	94.78	(85.15, 105.50)
		EU-approved tocilizumab	224	1550
	Cmax (µg/mL)	MSB11456	230	7.91	94.83	(86.28, 104.22)
		EU-approved tocilizumab	224	8.34
US-licensed tocilizumab versus EU-approved tocilizumab	AUC0-∞ (µg·h/mL)	US-licensed tocilizumab	190	1770	97.99	(89.40, 107.41)
		EU-approved tocilizumab	200	1810
	AUC0-t (µg·h/mL)	US-licensed tocilizumab	226	1410	91.01	(81.71, 101.36)
		EU-approved tocilizumab	224	1550
	Cmax (µg/mL)	US-licensed tocilizumab	226	7.57	90.79	(82.57, 99.84)
		EU-approved tocilizumab	224	8.34

Predefined equivalence range for the 90% CI of the ratio (80.00%–125.00%).

^aBased on an analysis of covariance model including treatment (MSB11456, US-licensed tocilizumab, and EU-approved tocilizumab) as a fixed effect, baseline weight category, baseline BMI (continuous), and study site as covariates. Pharmacokinetic parameters were natural log-transformed prior to analysis, then results were transformed back to the original scale.

^bAll subjects who received study drug and had at least one of the primary pharmacokinetic parameters calculated without clinically important protocol deviations or events that may have significantly affected the pharmacokinetic assessments.

^cRatio of geometric LS mean value for upper to lower tocilizumab formulation.

AUC, area under the concentration–time curve; AUC_0-∞, AUC from time zero (pre-dose) extrapolated to infinity; AUC_0-t, AUC from time zero (pre-dose) to the last sampling time at which a quantifiable concentration was obtained; BMI, body mass index; CI, confidence interval; C_max, maximum observed concentration; LS, least squares.

Figure 3. Arithmetic mean (SD) sIL-6 R baseline-adjusted serum concentration–time profiles following a single dose of MSB11456, US-licensed tocilizumab or EU-approved tocilizumab in healthy subjects on a linear scale (pharmacodynamic analysis set^a).

Table 4. Geometric LS mean ratios for pharmacodynamic parameters after a single dose of MSB11455, US-licensed tocilizumab, or EU-approved tocilizumab in healthy subjects^a (pharmacodynamic analysis set^b).

Comparison	Baseline-adjusted parameter	Treatment	n	Geometric LS Mean	Ratio^c (%)	90% CI of Ratio
sIL-6 R parameters
MSB11456 versus US-licensed tocilizumab	Emax (ng/mL)	MSB11456	230	301	102.66	(97.72, 107.86)
		US-licensed tocilizumab	228	293
	AUE (ng·h/mL)	MSB11456	230	92,500	106.16	(99.18, 113.63)
		US-licensed tocilizumab	228	87,100
MSB11456 versus EU-approved tocilizumab	Emax (ng/mL)	MSB11456	230	301	98.28	(93.53, 103.27)
		EU-approved tocilizumab	224	306
	AUE (ng·h/mL)	MSB11456	230	92,500	97.85	(91.39, 104.76)
		EU-approved tocilizumab	224	94,500
US-licensed tocilizumab versus EU-approved tocilizumab	Emax (ng/mL)	US-licensed tocilizumab	228	293	95.73	(91.09, 100.61)
		EU-approved tocilizumab	224	306
	AUE (ng·h/mL)	US-licensed tocilizumab	228	87,100	92.17	(86.07, 98.71)
		EU-approved tocilizumab	224	94,500
CRP parameters^d
MSB11456 versus US-licensed tocilizumab	Emin (µg/mL)^e	MSB11456	230	0.168	93.04	(84.93, 101.92)
		US-licensed tocilizumab	228	0.181
MSB11456 versus EU-approved tocilizumab	Emin (µg/mL)^e	MSB11456	230	0.168	99.17	(90.50, 108.68)
		EU-approved tocilizumab	224	0.170
US-licensed tocilizumab versus EU-approved tocilizumab	Emin (µg/mL)^e	US-licensed tocilizumab	228	0.181	106.60	(97.24, 116.85)
		EU-approved tocilizumab	224	0.170

Pre-defined equivalence range for the 90% CI of the ratio (80.00%–125.00%).

^aBased on an analysis of covariance model including treatment (MSB11456, US-licensed tocilizumab, and EU-approved tocilizumab) as a fixed effect, baseline weight category, baseline BMI (continuous), and site as covariates. Pharmacodynamic parameters were natural log-transformed prior to analysis, then results were transformed back to the original scale.

^bAll subjects who received study drug and had at least one of the primary pharmacodynamic parameters calculated without clinically important protocol deviations or events that may have significantly affected the pharmacodynamic assessments.

^cRatio of geometric LS mean value for upper to lower tocilizumab formulation.

^dAdditional CRP parameters that could have negative values (E_max and AUE) are summarized in Supplementary Table 3. These analyses were performed on the original scale without log-transformation, and the LS mean treatment difference and associated 90% CI were calculated and presented in lieu of the geometric LS mean treatment ratio and associated 90% CI.

^eObserved parameter.

AUE, area under the effect–time curve; BMI, body mass index; CI, confidence interval; CRP, C-reactive protein; E_max, maximum observed effect; E_min, minimum observed effect; LS, least squares; sIL-6 R, soluble interleukin-6 receptor.

Table 5. Safety and tolerability of tocilizumab, by treatment group and overall (safety analysis set^a).

	MSB11456 (N = 231)	US-licensed tocilizumab(N = 229)	EU-approved tocilizumab(N = 225)	Overall (N = 685)
Any TEAE	177 (76.6)	158 (69.0)	168 (74.7)	503 (73.4)
Any treatment-related TEAE	59 (25.5)	46 (20.1)	50 (22.2)	155 (22.6)
Any Grade ≥3 TEAE	2 (0.9)	1 (0.4)	1 (0.4)	4 (0.6)
Any treatment-related Grade ≥3 TEAE	1 (0.4)	1 (0.4)	1 (0.4)	3 (0.4)
Any serious TEAE	3 (1.3)^b	1 (0.4)^c	1 (0.4)^d	5 (0.7)
Any treatment-related serious TEAE	2 (0.9)	1 (0.4)	1 (0.4)	4 (0.6)
Any AESI	19 (8.2)	3 (1.3)	13 (5.8)	35 (5.1)
Any TEAE leading to death	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)
Most common adverse events^e
Upper respiratory tract infection	52 (22.5)	40 (17.5)	44 (19.6)	136 (19.9)
Headache	41 (17.7)	46 (20.1)	43 (19.1)	130 (19.0)
Oropharyngeal pain	15 (6.5)	12 (5.2)	15 (6.7)	42 (6.1)
Vessel puncture site bruise	13 (5.6)	14 (6.1)	9 (4.0)	36 (5.3)
Nausea	9 (3.9)	16 (7.0)	10 (4.4)	35 (5.1)
Injection site erythema	15 (6.5)	3 (1.3)	12 (5.3)	30 (4.4)
Dizziness	7 (3.0)	11 (4.8)	9 (4.0)	27 (3.9)
Injection site bruising	16 (6.9)	3 (1.3)	6 (2.7)	25 (3.6)
Abdominal pain	7 (3.0)	10 (4.4)	6 (2.7)	23 (3.4)
Back pain	7 (3.0)	6 (2.6)	10 (4.4)	23 (3.4)
Mouth ulceration	7 (3.0)	13 (5.7)	3 (1.3)	23 (3.4)
Contusion	7 (3.0)	6 (2.6)	8 (3.6)	21 (3.1)

Reported values are number (%) of subjects with at least one event.

^aAll subjects who received study drug; subjects were analyzed according to the actual treatment they received.

^bPerforated appendicitis (n = 1; Grade 3), spontaneous abortion (n = 1; Grade 1), spontaneous pneumothorax (n = 1; Grade 3; not considered treatment-related).

^cAbdominal pain (n = 1; Grade 3).

^dPerforated appendicitis (n = 1; Grade 3).

^eEvents occurring in at least 3% of subjects overall.

AESI, adverse events of special interest; MedDRA, Medical Dictionary for Regulatory Activities; TEAE, treatment-emergent adverse event, based on MedDRA, version 22.1 terms.