Analysis of clinical trials of biosimilar infliximab (CT-P13) and comparison against historical clinical studies with the infliximab reference medicinal product

Figures & data

Table 1. Comparison of design and baseline characteristics of clinical studies using RMP or CT-P13 for RA (for efficacy comparison).

References/study		PLANETRA [19]		ATTRACT [21,22]	START [23]	Zhang et al. [24]	Abe et al. [25]	ATTEST [26]
Inclusion criteria		≥6 swollen and ≥6 tender joints and plus two of: morning stiffness ≥45 min, CRP >2 mg/dl, ESR >28 mm/h despite MTX therapy for 3 months			6 swollen and 6 tender joints despite MTX therapy for 3 months	≥3 swollen and ≥8 tender joints and plus two of: morning stiffness ≥45 min, CRP >1.5x upper limit of normal, ESR >28 mm/h despite MTX therapy for 3 months	≥6 swollen and ≥6 tender joints and plus two of: morning stiffness ≥45 min, CRP >2 mg/dl, ESR >28 mm/h despite MTX therapy for 3 months	>10 swollen joints, >12 tender joints, and CRP levels >1 mg/dl (upper limit of the normal range, 0.5), inadequate response to MTX
Number of patients		302	304	86	360	87	49	165
Arms		3 mg/kg CT-P13	3 mg/kg RMP
MTX, mean ± SD or med (IQR)		15.6 ± 3.1 mg/week	15.6 ± 3.2 mg/week	16 ± 4 mg/week	15.0 (10, 18) mg/week	N/A	7.1 ± 1.9 mg/week	16.3 ± 3.6 mg/week
Dosing		At week 0, 2, 6 and q8w (up to week 30)		At week 0, 2, 6 and q8w (up to week 30)	At week 0, 2, 6, 14, 22	At week 0, 2, 6, 14	At week 0, 2, 6	On days 1, 15, 43, 85 and every 56 days thereafter
Primary end point		ACR20 (week 30)		ACR20 (week 30)	A serious infection (week 22)	N/A	ACR20 (week 14)	DAS28 (ESR) at 6 months
Baseline characteristics, mean ± SD or med (IQR)	Tender joints	25.6 ± 13.9 22.0 (N/A)	24.0 ± 12.9 21.0 (N/A)	32 (16, 46)	22 (15, 31)	N/A	19.0 ± 11.8	31.7 ± 14.5
	Swollen joints	16.2 ± 8.7 15.0 (N/A)	15.2 ± 8.3 13.0 (N/A)	19 (13, 30)	15 (11, 21)	N/A	15.1 ± 9.0	20.3 ± 8.0
	CRP (mg/dl)	1.9 ± 2.5 1.1 (N/A)	1.9 ± 2.2 1.1 (N/A)	3.1 (1.3, 5.3)	1.6 (1, 3)	N/A	4.2 ± 3.1	3.3 ± 3.2
	ESR (mm/h)	46.6 ± 22.4	48.5 ± 22.6	49 ± 23	N/A	N/A	N/A	47.8 ± 30.4
	Rheumatoid factor positive (%)	74.5	72.7	84	82.8	N/A	N/A	84.8

ACR: American College of Rheumatology; CRP: C-reactive protein; DAS28: Disease activity score in the 28 joints examined; ESR: Erythrocyte sedimentation rate; IQR: Interquartile range; MTX: Methotrexate; N/A: Not available; q8w: Every 8 weeks; RA: Rheumatoid arthritis; RMP: Reference medicinal product; SD: Standard deviation.

Table 2. ACR response rate in RA patients: comparison of PLANETRA^† and published randomized controlled studies of RMP.

Study	Week	CT-P13	RMP	Analysis population	Ref.
ACR20 (%)
PLANETRA	54	57	52	ITT
ATTRACT	54		42	N/A	[22]
ATTEST	52		55.8	ITT	[26]
PLANETRA	30	60.9	58.9	ITT
ATTRACT	30		∼50	ITT	[21]
ATTEST	28		59.4	ITT	[26]
START	22		58	ITT	[23]
ATTRACT	22		∼53	ITT	[21]
Zhang et al.	18		75.9	N/A	[24]
ATTRACT	18		∼45	ITT	[21]
PLANETRA	14	63.6	58.2	ITT
ATTRACT	14		∼42	ITT	[21]
Abe et al.	14		61.2	N/A	[25]
ACR50 (%)
PLANETRA	54	33.1	31.6	ITT
ATTRACT	54		21	N/A	[22]
ATTEST	52		36.4	ITT	[26]
PLANETRA	30	35.4	33.9	ITT
ATTRACT	30		27	ITT	[21]
ATTEST	28		37	ITT	[26]
START	22		32.1	ITT	[23]
Zhang et al.	18		43.7	N/A	[24]
PLANETRA	14	33.1	29.9	ITT
Abe et al.	14		30.6	N/A	[25]
ACR70 (%)
PLANETRA	54	16.2	15.2	ITT
ATTRACT	54		10	N/A	[22]
ATTEST	52		20.6	ITT	[26]
PLANETRA	30	16.6	15.5	ITT
ATTRACT	30		8	ITT	[21]
ATTEST	28		24.2	ITT	[26]
START	22		14	ITT	[23]
Zhang et al.	18		22.99	N/A	[24]
PLANETRA	14	13.9	12.2	ITT
Abe et al.	14		10.2	N/A	[25]

^†PLANETRA values for week 54 are unpublished data.

ACR: American College of Rheumatology; ITT: Intention to treat; N/A: Not available; RA: Rheumatoid arthritis; RMP: Reference medicinal product.

Table 3. Comparison of design and baseline characteristics of clinical studies using RMP or CT-P13 for AS (for efficacy comparison).

References/study		PLANETAS [20]		Braun et al. [29]	ASSERT [30]	Giardina et al. [31]	Breban et al. [32]
Inclusion criteria		BASDAI score of ≥4 and a visual analog scale score (VAS) for spinal pain of ≥4					BASDAI ≥3 axial pain (second item on the BASDAI) ≥3
Number of patients		125	125	35	201	25	124
Arms		5 mg/kg CT-P13	5 mg/kg RMP
Dosing		At week 0, 2, 6 and q8w (up to week 30)		At week 0, 2, 6	At week 0, 2, 6 and q6w (up to week 18)	At week 0, 2, 6 and q6w (up to week 102)	At weeks 4, 6, 10 and q6w (up to week 52)
Primary end point		AUC, Cmax,ss		BASDAI at week 12	ASAS20 at week 24	ASAS20 at week 12, 24, 36, 48, 96, 104	ASAS20 at 58 weeks
Baseline characteristics (mean ± SD) or (median [IQR])	BASDAI	6.7 ± 1.4	6.6 ± 1.6	6.5	6.6 (5.3–7.6)	6.5 ± 1.2	6.2 ± 1.5
	BASFI	6.2 ± 1.9	6.2 ± 2.2	5.5	5.7 (4.5–7.1)	6.1 ± 0.9	5.4 ± 2

AS: Ankylosing spondylitis; ASAS: Assessment of SpondyloArthritis International Society; AUC: Area under the plasma concentration–time curve; BASDAI: Bath ankylosing spondylitis disease activity index; BASFI: Bath ankylosing spondylitis functional index; C_max,ss: Maximum steady state plasma drug concentration during dosage interval; IQR: Interquartile range; q6w: Every 6 weeks; q8w: Every 8 weeks; RMP: Reference medicinal product; SD: Standard deviation.

Table 4. Clinical response in AS patients: comparison of PLANETAS^† and published randomized controlled studies of RMP.

Study	Week	CT-P13	RMP	Analysis population	Ref.
ASAS20 (%)
Breban et al.	58		75	ITT	[32]
PLANETAS	54	67	69.4	ITT
Giardina et al.	48		∼74	N/A	[31]
Giardina et al.	36		∼72	N/A	[31]
PLANETAS	30	70.5	72.4	ITT
ASSERT	24		74.5	ITT	[30]
Giardina et al.	24		∼73	N/A	[31]
PLANETAS	14	62.8	64.8	ITT
Braun et al.	12		∼68	ITT	[29]
Giardina et al.	12		75	N/A	[31]
BASDAI
Breban et al.	58		3.3	ITT	[32]
PLANETAS	54	3.8	3.7	ITT
PLANETAS	30	3.7	3.8	ITT
ASSERT	24		3.7 (median)	ITT	[30]
PLANETAS	14	3.9	3.8	ITT
Braun et al.	12		3.3	ITT	[29]
Giardina et al.	12		4.8	N/A	[31]
BASFI
Breban et al.	58		3.0	ITT	[32]
PLANETAS	54	3.4	3.5	ITT
PLANETAS	30	3.7	3.6	ITT
ASSERT	24		4.0 (median)	ITT	[30]
PLANETAS	14	3.8	3.7	ITT
Braun et al.	12		3.4	ITT	[29]
Giardina et al.	12		3.5	N/A	[31]

Values for BASDAI and BASFI are mean unless otherwise indicated.

^†PLANETAS values for 54 week data are unpublished data.

AS: Ankylosing spondylitis; ASAS: Assessment of SpondyloArthritis International Society; BASDAI: Bath ankylosing spondylitis disease activity index; BASFI: Bath ankylosing spondylitis functional index; ITT: Intention to treat; N/A: Not available; RMP: Reference medicinal product.

Table 5. Incidence rate of treatment-emergent adverse events of special interest with CT-P13 and RMP.

		PLANETRA/PLANETAS
		Incidence rate, n/N (%)		Incidence rate, 100 PY		Historical data of RMP
		CT-P13	RMP	CT-P13	RMP	Incidence		Incidence rate, 100 PY
						%	Range	100 PY	Range
All infections	RA	127/302 (42.05%)	137/300 (45.67%)	39.97	43.62	61.92	(52.81, 68.48)	76.39	(68.48, 91.79)
	AS	55/128 (42.97%)	49/122 (40.16%)	38.76	36.04	48.15	(35.29, 64.17)	74.70	(57.69, 153.36)
All serious infections	RA	13/302 (4.3%)	7/300 (2.33%)	4.09	2.23	4.14	(1.67, 8.48)	5.42	(2.19, 8.48)
	AS	2/128 (1.56%)	3/122 (2.46%)	1.41	2.21	1.88	(0.99, 2.94)	2.56	(2.15, 12.78)
Malignancy and lymphoma	RA	1/302 (0.33%)	4/300 (1.33%)	0.31	1.27	0.66	(0.00, 1,21)	0.53	(0.00, 1.32)
	AS	1/128 (0.78%)	0/122	0.70	0.00	0.76	(0.00, 0.83)	0.36	(0.00, 0.75)
Infusion-related reaction	RA	30/302 (9.93%)	43/300 (14.33%)	9.44	13.69	27.34	(10.00, 67.35)	26.02	(9.66, 97.55)
	AS	11/128 (8.59%)	15/122 (12.3%)	7.75	11.03	10.84	(0.00, 15.00)	16.37	(0.00, 23.66)

AS: Ankylosing spondylitis; PY: Patient year; RA: Rheumatoid arthritis; RMP: Reference medicinal product.

Table 6. Comparison of populations in studies analyzed for pharmacokinetic data [19,21].

	PLANETRA [19]		ATTRACT [21]
	CT-P13	RMP	RMP
MTX Mean (SD)	15.6 (3.1) mg/week	15.6 (3.2) mg/week	16 (4) mg/week
Age Median (range)	50 (18–75)	50 (21–74)	56 (25–74)
White (%)	72.8	73	93
Female (%)	81.1	84.2	81

MTX: Methotrexate; RMP: Reference medicinal product; SD: Standard deviation.

Figure 1. Mean serum concentration of infliximab. Indicated amount of CT-P13 or RMP were infused at week 0, 2, 6, 14, 22 and the concentration of infliximab was measured before infusion at week 30 [19,21].

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