Switching to biosimilars: current perspectives in immune-mediated inflammatory diseases

Figures & data

Table 1. Currently approved biosimilars with an IMID indication.

Product name(s)	Manufacturer(s)	Initial marketing authorization date
Infliximab biosimilars
BOW015: Infimab	Reliance Life Sciences	India: 09/2014
CT-P13: Inflectra, Remsima	Celltrion	EMA: 09/2013 (Remsima/Inflectra) FDA: 04/2016 (Inflectra) Korea: 07/2012 (Remsima/Inflectra) Australia: 08/2015 (Remsima/Inflectra) Canada: 01/2014 (Remsima/Inflectra)
SB2: Flixabi, Renflexis	Samsung Bioepis	EMA: 05/2016 (Flixabi) FDA: 05/2017 (Renflexis) Korea: 12/2015 (Renflexis) Australia: 11/2016 (Renflexis) Canada: 02/2018 (Renflexis)
Etanercept biosimilars
SB4: Benepali, Brenzys	Samsung Bioepis	EMA: 01/2016 (Benepali) Korea: 09/2015 (Brenzys) Australia: 07/2016 (Brenzys) Canada: 08/2016 (Benepali/Brenzys)
GP2015: Erelzi	Sandoz	EMA: 06/2017 FDA: 08/2016 Australia: 11/2017 Canada: 08/2017
Adalimumab biosimilars
ABP501: Amgevita, Amjevita	Amgen	EMA: 03/2017 (Amgevita) FDA: 09/2016 (Amjevita) Australia: 09/2017 (Amgevita)
BI 695501: Cyltezo	Boehringer Ingelheim	EMA: 11/2017 (subsequently withdrawn by manufacturer) FDA: 08/2017
FKB327: Hulio	Mylan S.A.S.	EMA: 09/2018
GP2017: Hyrimoz	Sandoz	EMA: 07/2018 FDA: 10/2018 Australia: 03/2019
MSB11022: Idacio	Fresenius Kabi	EMA: 01/2019
SB5: Imraldi, Hadlima	Samsung Bioepis	EMA: 08/2017 (Imraldi) Korea: 09/207 (Hadlima) Australia: 01/2018 (Hadlima) Canada: 05/2018 (Hadlima)
Rituximab biosimilars
CT-P10: Truxima	Celltrion	EMA: 02/2017 FDA: 11/2018 Korea: 11/2016 Australia: 04/2018
GP2013: Riximyo, Rixathon	Sandoz	EMA: 06/2018 (Riximyo, Rixathon) Australia: 11/2017 (Riximyo)

Marketing authorization information taken from publicly available sources (correct as of March 2019)

Table 2. Summary of randomized controlled trial switching studies (including open-label extensions).

Study	Indications	N*	Study/switch design^†	Duration after switch (weeks)	Efficacy outcomes	Safety/immunogenicity/PK/other outcomes	Limitations
CT-P13 (infliximab)
PLANETRA-OLE Yoo 2017 [79]	RA	302	OLE study Single switch after a 62w DB study CT-P13 maintenance pts vs RP/CT-P13 switch pts	40	ACR20/50/70 similar between groups	Proportion of pts with ADAs and AEs similar for maintenance vs switch groups 16% of maintenance and 11% of switch groups discontinued treatment	OL study No continuous RP control arm Not powered to evaluate switching
Tanaka 2017 [80]	RA	71	OLE study Single switch after a 54w DB study CT-P13 maintenance pts vs RP/CT-P13 switch pts	105	Mean DAS28-ESR similar between groups	Proportion of pts with AEs similar for maintenance vs switch groups 16% of maintenance and 33% of switch groups discontinued treatment	OL study No continuous RP control arm Not powered to evaluate switching Small number of pts in each group
PLANETAS-OLE Park 2017 [81]	AS	174	OLE study Single switch after a 54w DB trial: CT-P13 maintenance pts vs RP/CT-P13 switch pts	40	ASAS20/40 and ASAS partial remission were similar between groups	Proportion of pts with ADAs and AEs similar between groups 8% of maintenance and 10% of switch groups discontinued treatment	OL study No continuous RP control arm Not powered to evaluate switching
NOR-SWITCH Jorgensen 2017 [60]	IBD, SpA, RA, PsA, PsO	481	DB RCT Single switch after ≥6 months of treatment with RP RP maintenance vs RP/CT-P13 switch	52	RP/CT-P13 switch was not inferior to RP maintenance (measured by disease worsening)	Frequency of AEs was similar between groups 10% of maintenance and 8% of switch groups discontinued treatment	Not powered to show non-inferiority in individual diseases
NOR-SWITCH OLE Goll 2019 [82]	IBD, SpA, RA, PsA, PsO	380	OLE study Single switch after a 52w DB trial CT-P13 maintenance pts vs RP/CT-P13 switch pts	78	Disease worsening occurred in 16.8% maintenance pts vs 11.6% switch pts	Frequency of AEs and ADAs was similar between groups	OL study No continuous RP control arm Not powered to show non-inferiority in individual diseases
NCT02096861 Kim 2017 [83] Ye 2018 [84]	IBD	220	DB RCT Single switch at w30 RP maintenance vs CT-P13 maintenance vs RP/CT-P13 switch vs CT-P13/RP switch	24	Clinical worsening and CDAI-70 responses were similar between the 4 groups	Frequency of AEs, SAEs and infections was similar between groups No clinically meaningful differences in immunogenicity between groups	No statistical analyses present Short follow up after switch
SIMILAR Volkers 2017 [85]	IBD	47	DB RCT Single switch in patients receiving RP prior to randomization RP maintenance vs RP/CT-P13 switch	30	To date 1 pt experienced a relapse (switch group)	2 pts experienced an SAE	Preliminary results only Only 21 pts have completed the 30w follow up to date
NI-071 (infliximab)
NCT01927263 Matsuno 2018 [71]	RA	242	OLE study Single switch after a DB 30w trial Continued NI-071 vs RP/NI-071 switch	24	No significant differences in DAS28-ESR, DAS28-CRP, or ACR20/50/70 responses between treatment groups	Incidence of related TEAEs was comparable between groups	OL study No continuous RP control arm Not powered to show differences after switching
SB2 (infliximab)
NCT01936181 Smolen 2018 [70]	RA	584	DB RCT Single switch at w54 RP maintenance vs SB2 maintenance vs RP/SB2 switch	24	ACR20 was sustained and comparable across treatment groups	TEAEs occurred in 35.6%, 40.3%, and 36.2% of RP, SB2 and RP/SB2 groups ADAs occurred in 14.6%, 14.9%, and 14.1% of RP, SB2 and RP/SB2 groups 5.0%, 7.5%, and 6.4% of RP, SB2, and RP/SB2 pts discontinued before w78	Not powered to show differences in efficacy after switching Short follow up after switching
BOW015 (infliximab)
UNIFORM OLE Kay 2015 [72]	RA	157	OLE study Single switch after a 16w DB study BOW015 maintenance pts vs RP/BOW015 switch pts	38	Disease activity was similar between the 2 groups throughout the OLE	NR	OL study Not powered to show differences after switching No continuous RP control arm
GP2015 (etanercept)
EGALITY Gerdes et al 2018 [73]	PsO	531	DB RCT Multiple switches: 3 alternating 6-week periods between w12 to 30 Pooled RP and GP2015 maintenance groups vs pooled switch groups	40	PASI 50/75/90 response rates and all other efficacy parameters were similar between the pooled switched and pooled continued treatment groups	Incidence of TEAEs was similar between the switched and continued groups Discontinuations due to TEAEs occurred in 3.1% of switched pts and 1.0% of continued pts	Not powered to show differences after switching Groups were pooled rather than analyzed separately
EQUIRA Matucci-Cerinic et al 2018 [74]	RA	376	DB RCT Single switch after a 24w DB study GP2015 maintenance pts vs RP/GP2015 switch pts	24	Mean change in DAS28-CRP and EULAR and ARC 20/50/70 response rates were comparable between the two groups	Frequency of AEs and SAEs was similar between the 2 groups Non-neutralizing, low titer ADAs were detected in 4 GP2015 maintenance pts	No statistical analyses described or presented Short follow up after switching No continuous RP control arm
SB4 (etanercept)
NCT01895309 Emery et al 2017 [75]	RA	245	OLE study Single switch after 52w DB study SB4 maintenance pts vs RP/SB4 switch pts	48	ACR20 response rates were comparable between the two groups	Rates of TEAEs were comparable between the groups 1 pt in each group developed ADAs Approx. 5% of both groups discontinued before the end of the trial	OL study Not powered to show differences after switching No continuous RP control arm
LBEC0101 (etanercept)
Song et al. 2018 [76]	RA	148	OLE study Single switch after a 52w DB study Continued LBEC0101 pts vs RP/LBEC0101 switch pts	48	DAS28-ESR scores were maintained in both groups to end of study	Incidence of AEs and new ADAs was comparable between groups	Not powered to show difference after switching No continuous RP control arm
ABP501 (adalimumab)
NCT01970488 Papp et al 2017 [61]	PsO	326	DB RCT Single switch at w16 Continued ABP501 pts vs continued RP pts vs RP/ABP501 switch pts	36	PASI % improvements were similar across all 3 groups No significant differences in % of PASI 50, 75, 90, 100 responders	AEs were balanced between groups % of pts with ADAs and NABs were similar between groups	Not powered to show differences after switching
NCT02114931 Cohen et al. 2016 [62]	RA	467	OLE study Single switch after a 26w DB study Continued ABP501 pts vs RP/ABP501 switch pts	72	Efficacy results were similar between ABP501 maintenance and RP/ABP501 switch groups	Rates of TEAEs and ADAs were similar between groups	OL study Not powered to show differences after switching No continuous RP control arm Only interim analysis results available (at this time only 1 pt had completed the study)
BI 695501 (adalimumab)
VOLTAIRE-RA Cohen et al 2018 [63]	RA	593	DB RCT Single switch at w24 Continued BI 695501 pts vs continued RP pts vs RP/BI 695501 switch pts	34	Mean change in DAS28-ESR and ACR20/50/70 response rates were similar across all 3 groups	Immunogenicity and safety and tolerability profiles were similar between all three groups	Not powered to show differences after switching
CHS-1420 (adalimumab)
NCT02489227 Hodge et al 2017 [64]	PsO, PsA	545	DB RCT Single switch at w16 Continued CHS-1420 pts vs RP/CHS-1420 switch pts	8	No statistically significant differences in PASI75 response rates, HAQ-DI, or hsCRP between groups at w24	Similar incidences of TEAEs and ADAs between groups	Not powered to show differences after switching Short follow up after switching No continuous RP control arm
FKB327 (adalimumab)
ARABESC-OLE Genovese et al 2017 [65]	RA	645	OLE study Multiple switches: 1/3 switched to alternate treatment at week 24 of parent trial, all switched to FKB327 at week 52	76	ACR20 was comparable after continuous or switched treatment	Safety profiles were comparable for all treatment sequences	Not powered to show differences after switching Group sizes were reduced after switching Only interim OLE results published to date
GP2017 (adalimumab)
ADACCESS Blauvelt et al 2018 [66]	PsO	379	DB RCT Multiple switches: 3 alternating 6w periods between w17 and w35 Pooled continuous treatment pts vs pooled switched pts	34	PASI improved over time and was similar between treatment groups	No relevant safety or immunogenicity differences between treatment groups	Not powered to show differences after switching
NCT02744755 ADMYRA [69]	RA	284	OL RCT Single switch at w24 Continued GP2017 pts vs RP/GP2017 switch pts	22	No impact of switch on efficacy	No impact of switch on immunogenicity and safety	OL after switching Not powered to show differences after switching No continued RP control arm Results not yet published (EU-CTR data only)
MSB11022 (adalimumab)
NCT02660580 AURIEL-PsO [68]	PsO	443	Double blind RCT Single switch at w16 Continued MSB11022 pts vs continued RP pts vs RP/MSB11022 switch pts	36	Switching from RP to MSB11022 did not impact efficacy	Switching from RP to MSB11022 did not impact safety or immunogenicity	Not powered to show differences after switching Results not yet published (EU-CTR data only)
SB5 (adalimumab)
NCT02167139 Weinblatt et al. 2018 [67]	RA	542	DB RCT Single switch at w24 Continued SB5 pts vs continued RP pts vs RP/SB5 switch pts	28	ACR20/50/70 rates were comparable across treatment groups	Safety profile and incidence of ADAs were comparable across treatments 2.4%, 3.9%, and 6.4% of continued SB5, continued RP, and RP/SB5 pts discontinued treatment before end of study	Not powered to show differences after switching
CT-P10 (rituximab)
NCT01873443 Park et al. 2017 [77]	RA	87	OLE study Single switch after completion of a 48w or 72w DB study Continued CT-P10 pts vs RP/CT-P10 switch pts	56	Mean change in DAS28-ESR and proportion of pts with good/moderate EULAR responses was comparable between groups	ADAs were detected in 13.2% and 15.0% of pts in the continued and switch groups, respectively CT-P10 treatment was well-tolerated 8% and 15% continued CT-P10 and switch pts discontinued before end of study	Not powered to show differences after switching Small group sizes No continued RP control arm
GP2013 (rituximab)
ASSIST-RT Tony et al. 2019 [78]	RA	107	DB RCT Single switch in patients receiving the RP prior to randomization Continued RP pts vs RP/GP2013 switch pts	24	NR	Incidence of hypersensitivity and infusion-related reactions was similarly low in both treatment groups No NABs were reported No clinically meaningful differences in AEs between treatment groups	Unpowered study Small group sizes

*Number of patients randomized to a whole study with a switch design; for OLEs, patients randomized to the OLE. †Switching could occur in a single arm or both arms. Studies included in this table were identified from three systematic reviews of the literature [28–30] combined with a PubMed search performed in March 2019. ACR: American College of Rheumatology; ADA: antidrug antibody; AE: adverse event; AS: ankylosing spondylitis; ASAS: Assessment of Spondyloarthritis international society; CRP: C-reactive protein; DAS28-ESR: Disease Activity Score in 28 joints using erythrocyte sedimentation rate; DB: double-blind; HAQ-DI: Health Assessment Questionnaire Disability Index; hsCRP: high sensitivity C-reactive protein; IBD: inflammatory bowel disease; OL: open-label; OLE: open-label extension; NAb: neutralizing antibody; PASI: Psoriasis Area and Severity Index; PK: pharmacokinetics; PsA: psoriatic arthritis; PsO: psoriasis; pts: patients; RA: rheumatoid arthritis; RCT: randomised controlled trial; RP: reference product; SAE: serious adverse event; SpA: spondyloarthritis; TEAE: treatment-emergent adverse event; w: weeks.

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