Biosimilar-to-Biosimilar Switching: What is the Rationale and Current Experience?

Abstract

Over time, clinicians have become increasingly comfortable embracing the prescription of biosimilars-highly similar versions of innovator or reference biological agents-for their patients with inflammatory diseases. Although a switch from a reference product to a licensed biosimilar version (or vice versa) is a medical decision robustly supported by the stepwise accumulation of clinical trial evidence concerning comparable safety, immunogenicity, and efficacy between these products, a switch from one biosimilar to another biosimilar of the same reference product, or a cross-switch, is not. Similarity among biosimilars of a reference product is not a regulatory agency concern and therefore is unlikely to be investigated in randomized controlled trials in the foreseeable future. Yet in clinical practice, across a diverse range of patients, the option to cross-switch from one biosimilar to another can and does arise for valid reasons such as convenience or tolerability issues, or driven by third parties (e.g., payers). In the absence of clinical trial data, clinicians must attempt to objectively evaluate the emerging real-world cross-switching evidence within the context of what is known about the science underpinning a designation of biosimilar. That knowledge then needs to be integrated with what clinicians know about their patients and their disease on a case-by-case basis. This review aims to consolidate relevant emerging real-world data and other key information about biosimilar-to-biosimilar cross-switching for prescribing clinicians. In the absence of clear clinical guidelines addressing this topic at present, this review may serve to facilitate discretionary and educated treatment decision making.

Fig. 1

Potential switching scenarios. The dot (•) end of the arrow indicates the initial biologic. Switch: •A→A1; reverse-switch: •A1→A; multiple switches: •A→A2→A, •B2→B→B1; cross-switch: •A1→A2, •A2→A1; switch within the same drug class: •A→B; •B→A; intraclass cross-switch: •A1→B1, •B1→A1; intraclass switch: •A→B1; intraclass reverse-switch: •B2→A

Fig. 2

Infliximab reference product and its biosimilars (CT-P13 and SB2) demonstrate high cross-reactivity ex vivo [128]. ADA antidrug antibody, CT-P13 biosimilar infliximab, IBD inflammatory bowel disease, ICC intraclass correlation coefficient, LLOQ lower limit of quantification, R-IFX infliximab reference product, SB2 biosimilar infliximab; TNFα tumor necrosis factor alpha. Bar chart adapted from Magro et al. [128]. ^© The Author(s). Reprinted with permission [https://creativecommons.org/licenses/by/4.0/]

Fig. 3

Antibody cross-reactivity appears equivalent between infliximab reference product and its biosimilars CT-P13 or SB2 [114]. Ab antibody, CD Crohn’s disease, CI confidence interval, CID chronic inflammatory disease, CT-P13 biosimilar infliximab, ELISA enzyme-linked immunosorbent assay, IBD inflammatory bowel disease, IFX infliximab, pts patients, R-IFX infliximab reference product, UC ulcerative colitis, wk week

Fig. 4

Summary of cross-switching study in patients with chronic plaque psoriasis [123]. *6 months after cross-switch (•), SB2 was considered as effective and safe as CT-P13. AE adverse event, CT-P13 biosimilar infliximab, mo months, PASI Psoriasis Area and Severity Index, SB2 biosimilar infliximab, SD standard deviation

Fig. 5

Study flow and key results of real-world biosimilar cross-switching in patients with inflammatory bowel disease [122]. *Mean values. CD Crohn’s disease, CT-P13 biosimilar infliximab, discont’d discontinued, FU follow-up, HBI Harvey Bradshaw Index, IBD inflammatory bowel disease, mo months, pts patients, R-IFX infliximab reference product, SB2 biosimilar infliximab, Tx treatment, UC ulcerative colitis, wk week(s), y year(s)

Fig. 6

Efficacy and safety of cross-switching between infliximab biosimilars for patients with IBD [121]. *Infusion reactions. AE adverse event, CD Crohn’s disease, CI confidence interval, CRP C-reactive protein, CT-P13 biosimilar infliximab, discont’d discontinued, LoR loss of response, mo months, OR odds ratio, pts patients, R-IFX infliximab reference product, SB2 biosimilar infliximab, Tx treatment, UC ulcerative colitis, y years

Fig. 7

Cross-switching immunogenicity study in patients with chronic inflammatory diseases who were on infliximab maintenance (Cohort-1) or who were biologic-naïve (Cohort-2) [1]. a Study flow and results for Cohort-1. *12/30 ADA-positive pts completed the cross-switch; 7/12 gradually became seronegative and 5/12 remained ADA-positive. ^†5/30 ADA-positive pts continued R-IFX therapy despite undetectable trough and exhibited a good clinical response. ^‡20/60 pts (33%) who discontinued treatment were ADA-positive versus 30/205 (15%) pts who reverse-switched (p = 0.002). ^§Pts (n) who reverse-switched did so after [no. of CT-P13 infusions]: 19 pts [1], 14 [2], 17 [3], and 5 [> 3]. b Study flow and results for Cohort-2. *Among the patients who discontinued treatment because of LoR (primary or secondary), 4 were ADA-positive and 2 halted treatment due to an infusion-related reaction (both ADA-positive). ^†Cross-switch groups consisted of AxSpA, n = 11 pts; IBD, n = 8; RA, n = 7; PsA, n = 1; uveitis, 0; and other CID, n = 2. ADA antidrug antibody, AE adverse event, AxSpA axial spondyloarthritis, CD Crohn’s disease, CI confidence interval, CID chronic inflammatory disease, CRP C-reactive protein, CT-P13 biosimilar infliximab, discont’d discontinued, IBD inflammatory bowel disease, LoR loss of response, mo months, MTX methotrexate, PsA psoriatic arthritis, RA rheumatoid arthritis, R-IFX infliximab reference product, SB2 biosimilar infliximab, Tx treatment, UC ulcerative colitis, y year

Fig. 8

Immunogenicity-free survival from 24 to 36 months among Cohort-1 patients who were ADA-free at baseline and remained on a biosimilar, reverse-switched, or cross-switched [1]. *ADA-positivity for CT-P13 was only 6/145 pts (4%) from baseline to 12 months and 2/140 pts (1.5%) from 12 to 24 months. Modified with permission from Lauret et al. [1]. Effects of successive switches to different biosimilars infliximab on immunogenicity in chronic inflammatory diseases in daily clinical practice, Issue 6, Pages 1449–1456, Copyright (2020), with permission from Elsevier [OR APPLICABLE SOCIETY COPYRIGHT OWNER]. ADA antidrug antibody, CT-P13 biosimilar infliximab, pts patients, R-IFX infliximab reference product, SB2 biosimilar infliximab

Fig. 9

SB2 persistence at 12 months among patients in the PERFUSE study by rheumatological disease and prior therapy [133]. ^*Persistence over 12 months (95 % confidence interval). Bio-IFX→SB2 switched from a biosimilar IFX to SB2 (cross-switched), IFX infliximab, IFX-naïve initiated treatment on SB2, R-IFX→SB2 switched from IFX reference product to SB2, SB2 biosimilar infliximab

Fig. 10

Key gaps and next steps related to the adoption of cross-switching