Infliximab biosimilar GP1111: a review of 5 years’ post-approval experience

ABSTRACT

Introduction

Infliximab is a chimeric monoclonal antibody against tumor necrosis factor alpha, and GP1111 (Zessly®, Sandoz) is the most recently approved infliximab biosimilar in Europe. We reviewed the approval process and key evidence for GP1111, focusing primarily on the indications of rheumatoid arthritis (RA) and inflammatory bowel disease (IBD).

Areas covered

This narrative review discusses preclinical, clinical, and real-world data for GP1111.

Expert opinion

Results from the Phase III REFLECTIONS trial in patients with moderate-to-severe active RA despite methotrexate therapy confirmed the similarity in efficacy and safety between GP1111 and reference infliximab. Switching from reference infliximab to GP1111 in REFLECTIONS had no impact on efficacy or safety. Since the European approval of GP1111 in March 2018, real-world data have also confirmed the efficacy and safety of switching from another infliximab biosimilar to GP1111 in patients with RA and IBD. In addition, budget impact analysis of various sequential targeted treatments in patients with RA found that GP1111 was cost-effective when used early after failure of conventional synthetic disease-modifying antirheumatic drugs. Therefore, 5 years’ post-approval experience with GP1111 in RA and IBD, and key clinical and real-world evidence, support the safety and efficacy of continued use of GP1111 in all infliximab-approved indications.

KEYWORDS:

• Crohn’s disease
• GP1111
• infliximab
• infliximab biosimilar
• rheumatoid arthritis
• ulcerative colitis

1. Introduction

Infliximab is a chimeric monoclonal antibody with high affinity for membrane-bound and soluble tumor necrosis factor alpha (TNF-α) [1,2]. Since its introduction in 1998, this biologic medicine has been widely used in the treatment of immune-related inflammatory diseases [3,4], and is approved for use in the following indications: rheumatoid arthritis (RA), Crohn’s disease (CD), ulcerative colitis (UC), ankylosing spondylitis, psoriatic arthritis, and plaque psoriasis [1,2]. Wide-ranging evidence from randomized controlled trials, registries, and post-marketing surveillance studies in these populations has shown that infliximab is effective and offers an acceptable safety profile [5–7].

Guideline recommendations in the EU and the US regarding the use of infliximab across all approved indications are shown in Table 1. For example, the European Alliance of Associations for Rheumatology (EULAR) recommends biologic disease-modifying antirheumatic drugs (bDMARDs, including infliximab) for patients with RA who are not reaching treatment targets with methotrexate (MTX) and have poor prognostic factors such as high swollen joint count, presence of early erosions, or failure of two or more conventional synthetic DMARDs [8]. The European Crohn’s and Colitis Organisation (ECCO) recommends that adults with moderate-to-severe CD and inadequate induction responses to conventional therapy can receive infliximab combined with a thiopurine, and also recommends infliximab for the induction and maintenance of remission in adults with difficult-to-treat complex perianal fistulizing CD [10]. In adults with moderate-to-severe UC, ECCO also recommends anti-TNF therapy (e.g. infliximab) for inducing remission in those who have an inadequate response or intolerance to conventional therapy, as well as maintaining remission in those who respond to induction therapy with the same medicine [15].

Table 1. Guideline recommendations for the use of infliximab across the approved indications.

Disease	EU recommendation	US recommendation	References
RA	The addition of bDMARDs such as infliximab is recommended if the treatment target is not achieved with 1 L MTX and poor prognostic factors are present (SoR: A) bDMARDs can also be combined with a conventional synthetic DMARD (SoR: A)	In patients with inadequate response to 1 L MTX, the addition of bDMARDs such as infliximab is recommended over triple therapy (CoE: very low)	EU: [8] US: [9]
Adult CD	In adults with moderate-to-severe CD: Induction: combination therapy with a thiopurine is recommended when starting infliximab to induce remission in those having had an inadequate response to conventional therapy (SoR: strong) Remission: TNFis (e.g. infliximab) are recommended in those who have not responded to conventional therapy (SoR: strong) Maintenance: infliximab monotherapy can be used in those achieving long-term remission using infliximab plus immunosuppressants (SoR: weak) Complex perianal fistulizing disease: infliximab is recommended for the induction and maintenance of remission (SoR: strong)	In severe/fulminant disease: TNFis (e.g. infliximab) can be considered to treat severely active CD (SoR: strong) Infliximab may be administered to treat fulminant CD (SoR: conditional) In moderate-to-severe luminal and perianal fistulizing CD: Induction and maintenance of remission: the use of TNFi is recommended over no treatment (SoR: strong) Induction of remission in biologic-naïve outpatients: infliximab, adalimumab, and ustekinumab are recommended over certolizumab pegol (SoR: strong, conditional) Induction and maintenance of remission in biologics and immunomodulator-naïve outpatients: infliximab combined with thiopurines is recommended over infliximab monotherapy (SoR: conditional) Induction and maintenance of fistula remission in outpatients with CD and active perianal fistula: infliximab is recommended over no treatment (SoR: strong)	EU: [10] US: [11,12]
Pediatric CD	TNFi is recommended for: Inducing and maintaining remission in children with chronically active luminal CD despite prior optimized immunomodulator therapy (100% agreement) Inducing remission in children with active steroid-refractory disease (100% agreement) Primary induction and maintenance therapy for children with active perianal fistulizing disease in combination with appropriate surgical intervention (84% agreement) Maintaining remission using regularly scheduled treatment in children responding to induction therapy with TNFi (100% agreement)	In children with perianal CD: Simple perianal fistula without inflammation, and complex perianal fistula with/without inflammation: antibiotics, immunomodulators, and TNFi (no grading of recommendation given) Deep perianal abscesses: surgical drainage followed by treatment of intestinal disease with TNFi (no grading of recommendation given)	EU: [13] US: [14]
Adult UC	TNFi (e.g. infliximab) is recommended for: Inducing remission in patients with moderate-to-severe Maintaining remission in patients with UC who responded to induction therapy with the same medicine (SoR: strong)	In adults with moderate-to-severe UC: In adult outpatients: infliximab, adalimumab, golimumab, vedolizumab, tofacitinib, or ustekinumab are recommended over no treatment (SoR: strong) Induction of remission in biologic-naïve outpatients with UC: use infliximab or vedolizumab rather than adalimumab (SoR: conditional) In hospitalized adult patients with acute severe UC refractory to IV CS: use infliximab or cyclosporine (SoR: conditional) In hospitalized adult patients with acute severe UC being treated with infliximab: no recommendation on routine use of intensive versus standard infliximab dosing	EU: [15] US: [16]
Pediatric UC	In TNFi-naïve children for whom IV CS treatment fails: 2 L infliximab is recommended (100% agreement) In children responding to infliximab commenced during acute severe UC: continue infliximab as maintenance treatment following discharge (100% agreement)	No US pediatric guidelines identified However, NASPGHAN training documents refer to ECCO/ESPGHAN 2018 guidance	EU: [17] US: [18]
AS	In patients with persistently high disease axial activity despite conventional treatments: consider TNFi, anti-IL-17, or JAK inhibitors (SoR: A) Following first failure with b/tsDMARD: consider switching to another bDMARD or JAK inhibitor (e.g. TNFi after TNFi; SoR: B) During sustained remission: consider tapering bDMARD (e.g. TNFi) (SoR: B)	In adults with active AS despite treatment with NSAIDs: Strongly recommend TNFi over no treatment with TNFi (PICO 6); do not recommend any particular TNFi (PICO 5) Conditionally recommend TNFi over treatment with secukinumab or ixekizumab (PICO 59), or tofacitinib (PICO 60) In adults with active AS despite treatment with the first TNFi used: For secondary non-response to TNFi: conditionally recommend treatment with a different TNFi versus a non-TNFi biologic (PICO 10) Strongly recommend against switching to a biosimilar of the first TNFi (PICO 62) In adults with stable AS receiving treatment with a biologic (e.g. TNFi): Conditionally recommend against discontinuation of the biologic (PICO 66) Conditionally recommend against tapering of the biologic dose as a standard approach (PICO 65) In adults with stable AS receiving treatment with TNFi and NSAIDs or a conventional synthetic DMARD: Conditionally recommend continuing treatment with TNFi alone over TNFi plus NSAIDs (PICO 11) or conventional synthetic DMARD (PICO 12) In adults with stable AS on reference TNFi: Strongly recommend continuing treatment with the reference TNFi over mandated switching to its biosimilar (PICO 63) In adults with AS and recurrent uveitis or IBD: Conditionally recommend treatment with TNFi monoclonal antibodies over treatment with other biologics (recurrent uveitis, PICO 29; IBD, PICO 32)	EU: [19] US: [20]
PsA	In patients with active predominantly axial disease and insufficient response to NSAIDs: Therapy with a bDMARD should be considered, which according to current practice is a TNFi (SoR: B) In patients who do not adequately respond to, or are intolerant of, a bDMARD: Switching to another bDMARD should be considered, including one switch within a class (SoR: C) In patients in sustained remission, cautious tapering of DMARDs may be considered (SoR: C)	In oral small molecule* and other treatment-naïve patients with active PsA: Conditionally recommend treating with TNFi versus oral small molecules* (PICO 10a – e), anti-IL-17 (PICO 14), or anti-IL-12/23 (PICO 13) In adult patients with active PsA despite treatment with an oral small molecule* [22]: Conditionally recommend switching to a TNFi over a different oral small molecule (PICO 23), anti-IL-17 (PICO 17), anti-IL-12/23 (PICO 16), abatacept (PICO 67), tofacitinib (PICO 76), or MTX and TNFi combination therapy (PICO 19) In adult patients with active PsA despite TNFi monotherapy: Conditionally recommend a different TNFi over switching to anti-IL-17 (PICO 28), anti-IL-12/23 (PICO 27), abatacept (PICO 70), tofacitinib (PICO 73), or MTX and TNFi combination therapy (PICO 30) Conditionally recommend a different TNFi (with or without MTX) over adding MTX to the same TNFi (PICO 26 and 26A) In adult patients with active PsA despite treatment with MTX and TNFi combination: Conditionally recommend switching to a different TNFi plus MTX over switching to a different TNFi monotherapy (PICO 33) In adult patients with active PsA despite treatment with anti-IL-17 monotherapy: Conditionally recommend switching to TNFi over an anti-IL-12/23 (PICO 39), a different anti-IL-17 (PICO 42), or over adding MTX to anti-IL-17 (PICO 41) In adult patients with active PsA despite treatment with anti-IL-12/23 monotherapy: Conditionally recommend switching to TNFi over anti-IL-17 (PICO 38), or over adding MTX to anti-IL-12/23 (PICO 36) In patients with active PsA with psoriatic spondylitis/axial disease despite treatment with NSAIDs: Conditionally recommend switching to TNFi over anti-IL-17 (PICO 46), or anti-IL-12/23 (PICO 45) In adult patients with active PsA and predominant enthesitis who are both oral small molecule*- and biologic treatment-naïve: Conditionally recommend starting TNFi over an oral small molecule (specifically apremilast) (PICO 48A) In adult patients with active PsA and predominant enthesitis despite treatment with an oral small molecule*: Conditionally recommend switching to TNFi over anti-IL-17 (PICO 53), anti-IL-12/23 (PICO 52), or another oral small molecule (PICO 49) In adult patients with active PsA and concomitant active IBD who have not received an oral small molecule* or biologic treatment: Conditionally recommend starting monoclonal antibody TNFi over an oral small molecule (PICO 62) In adult patients with active PsA and concomitant active IBD despite treatment with an oral small molecule*: Strong recommendation for switching to a monoclonal antibody TNFi over biologic TNF-soluble receptors (i.e. etanercept) (PICO 58) or anti-IL-17 (PICO 59) Conditionally recommend switching to TNFi monoclonal antibody over anti-IL-12/23 (PICO 61)	EU: [21] US: [22]
PsO, plaque PsO	In patients with moderate-to-severe PsO with an inadequate response, contraindication, or intolerance to 1 L conventional therapy, consider TNFi (e.g. infliximab), anti-IL-12/23, or PDE-4 small molecule inhibitors	Infliximab monotherapy is recommended in adult patients with: Moderate-to-severe plaque PsO (SoR: A) Plaque PsO of any severity when associated with significant PsA (infliximab also inhibits radiographically detected damage of joints in patients with PsA) (SoR: A) Moderate-to-severe plaque PsO affecting the palms and soles (plaque-type palmoplantar PsO), nails, or scalp (all SoR: B) Other subtypes (pustular or erythrodermic) of moderate-to-severe plaque PsO (SoR: C) In adult patients with moderate-to-severe plaque PsO, infliximab may be combined with the following: MTX (SoR: B), topicals (e.g. high-potency CS with or without a vitamin D analog) (SoR: B), acitretin (SoR: C), or apremilast (when clinically indicated; SoR: C)	EU: [23] US: [24]

*MTX, sulfasalazine, leflunomide, cyclosporine, or apremilast.

1 L: first-line; 2 L: second-line; AS: ankylosing spondylitis; bDMARD: biologic disease-modifying antirheumatic drug; CD: Crohn’s disease; CoE: certainty of evidence; CS: corticosteroid; DMARD: disease-modifying antirheumatic drug; ECCO: European Crohn’s and Colitis Organisation; ESPGHAN: European Society for Paediatric Gastroenterology, Hepatology and Nutrition; IBD: inflammatory bowel disease; IL: interleukin; IV: intravenous; JAK: Janus kinase; MTX: methotrexate; NASPGHAN: North American Society for Pediatric Gastroenterology, Hepatology and Nutrition; NSAID: nonsteroidal anti-inflammatory drug; PDE-4: phosphodiesterase-4; PICO: Patient-Intervention-Comparator-Outcome; PsA: psoriatic arthritis; PsO: psoriasis; RA: rheumatoid arthritis; SoR: strength of recommendation; TNF: tumor necrosis factor; TNFi: tumor necrosis factor inhibitor; tsDMARD: targeted synthetic disease-modifying antirheumatic drug; UC: ulcerative colitis

Biosimilars are biologic medicines that correspond to a reference medicine in terms of physicochemical, biological, immunological, efficacy, and safety properties. Although biosimilars are not identical copies of the reference medicine, biosimilars must have an identical amino acid sequence and show indistinguishable post-translational modifications and higher-order protein structure. Regulatory evaluation of biosimilars is therefore based on demonstrating structural and functional similarity to a reference biologic. The absence of clinically significant differences between the biosimilar and reference biologic is then confirmed by clinical pharmacokinetics (PK), effectiveness, and safety investigations. The use of biosimilars can reduce costs, contribute to budget sustainability in healthcare, and expand patient access to treatment [25]. Four biosimilars of reference infliximab (Remicade®) have been approved in the EU: Inflectra® and Remsima® in 2013, Flixabi® in 2016, and Zessly® (GP1111) in 2018 [26].

Here, we review the approval process and key clinical evidence for the infliximab biosimilar GP1111. We also summarize the available real-world evidence for GP1111, focusing primarily on data in the indications of RA and inflammatory bowel disease (IBD), given the paucity of data in the other approved indications. With the increasing relevance of switching between biosimilars in daily practice, we review the evidence for switching from other infliximab biosimilars to GP1111. In addition, we provide an overview of recent administration and cost-effectiveness data for GP1111.

2. Development and approval of GP1111 (biosimilar infliximab)

GP1111 was approved by the European Medicines Agency in May 2018 (Table 2) [27,29]. Regulatory approval of biosimilars is granted by the European Medicines Agency and US Food and Drug Administration based on an extensive comparison that establishes similarity in quality characteristics, structure, biological activity, clinical safety, efficacy, and immunogenicity to those of the licensed reference biologic medicine. A robust, consistent manufacturing process is also required [30].

Table 2. Approved indications for infliximab medicines, including biosimilars, in Europe and the USA.

Disease	EU indication [1,27]	US indication [2,28]
RA	In combination with MTX to reduce signs and symptoms and improve physical function in adults with active disease who have had an inadequate response to DMARDs (including MTX), or with severe, active, and progressive disease not previously treated with MTX or other DMARDs	In combination with MTX to reduce signs and symptoms, inhibit the progression of structural damage, and improve physical function in patients with moderate-to-severe active disease
CD	Moderate-to-severe active disease: adults who have failed to respond despite full and appropriate therapy with a CS and/or an immunosuppressive agent, or who are intolerant to, or have a contraindication to, such therapies Fistulizing, active disease: adults who have not responded despite a full and adequate course of therapy with first-line therapy (including antibiotics, drainage, and immunosuppressive therapy)	Reduce signs and symptoms, and induce and maintain clinical remission in adult patients with moderate-to-severe active disease who have had an inadequate response to conventional therapy Reduce the number of draining enterocutaneous and rectovaginal fistulas and maintain fistula closure in adult patients with fistulizing disease
Pediatric CD	Children and adolescents aged 6–17 years with severe, active disease for whom conventional therapy has failed (including a CS, an immunomodulator, and primary nutritional therapy), or who are intolerant to, or have medical contraindications for, such therapies	Reduce signs and symptoms, and induce and maintain clinical remission in patients with moderate-to-severe active disease who have had an inadequate response to conventional therapy
UC	Adults with moderate-to-severe active disease who have had an inadequate response to conventional therapy (including CS, mercaptopurine, or azathioprine), or who are intolerant to, or contraindicated for, such therapies	Reduce signs and symptoms, induce and maintain clinical remission and mucosal healing, and eliminate CS use in adults with moderate-to-severe active disease who have had an inadequate response to conventional therapy
Pediatric UC	Children and adolescents aged 6–17 years with severe active disease who have responded inadequately to conventional therapy (including CS, mercaptopurine, or azathioprine), or who are intolerant to, or contraindicated for, such therapies	Reduce signs and symptoms, and induce and maintain clinical remission in patients with moderate-to-severe active disease who have had an inadequate response to conventional therapy
AS	Adults with severe, active disease who have had an inadequate response to conventional therapy	Reduce signs and symptoms in patients with active disease
PsA	In combination with MTX in adults with active and progressive disease with an inadequate response to previous DMARD therapy, or as monotherapy in patients who are intolerant to, or contraindicated for, MTX	Reduce signs and symptoms of active arthritis, inhibit the progression of structural damage, and improve physical function
PsO (EU), plaque PsO (USA)	Adults with moderate-to-severe plaque PsO who are intolerant to, or have a contraindication for, other systemic therapy (including ciclosporin, MTX, or PUVA), or for whom those therapies have failed	In combination with MTX to reduce signs and symptoms, inhibit the progression of structural damage, and improve physical function in patients with moderate-to-severe active disease

AS: ankylosing spondylitis; CD: Crohn’s disease; CS: corticosteroid; DMARD: disease-modifying antirheumatic drug; MTX: methotrexate; PsA: psoriatic arthritis; PsO: psoriasis; PUVA: psoralen plus ultraviolet; RA: rheumatoid arthritis; UC: ulcerative colitis.

Approval of GP1111 considered the totality of evidence, that is, the whole body of analytical, preclinical, and clinical evidence, which demonstrated that GP1111 matched reference infliximab in terms quality characteristics, structure, biological activity, PK, pharmacodynamics, clinical safety, efficacy, and immunogenicity, supporting its use in all relevant indications [3,31]. GP1111 has similar physicochemical characteristics to reference infliximab with regard to primary, secondary, and tertiary structures, with tertiary structures being assessed through the use of crystallography and analytical ultracentrifugation studies [32,33]. PK similarity of GP1111 to reference infliximab has been demonstrated in healthy volunteers and in patients with moderate-to-severe RA despite MTX therapy [34,35]. The key studies for GP1111, including clinical and post-approval studies, are summarized in Figure 1. Pharmacodynamic similarity of GP1111 to reference infliximab has been shown with respect to Fab-related and Fc-related properties (e.g. binding to soluble TNF-α and response inhibition, TNF-α binding kinetics, antibody-dependent cellular cytotoxicity, and complement-dependent cytotoxicity activity) [33,36]. A pivotal Phase III, multinational, randomized, double-blind, double-arm, parallel-group study in patients with moderate-to-severe RA despite MTX therapy (REFLECTIONS B537-02) established the similarity of GP1111 to reference infliximab in terms of safety, efficacy, and immunogenicity [37]. Based on the totality of evidence establishing the biosimilarity of GP1111 to reference infliximab, GP1111 was approved for all indications in which the reference medicine was approved (Table 2).

Figure 1. Timeline highlighting key studies for GP1111. ACR20: American College of Rheumatology 20% improvement criteria; AxSpA: axial spondyloarthritis; CD: Crohn’s disease; EMA: European Medicines Agency; FDA: US Food and Drug Administration; HBI: Harvey–Bradshaw Index; IV: intravenous; OLE: open-label extension; PsA: psoriatic arthritis; PMS: Partial Mayo Score; RA: rheumatoid arthritis; ref-IFX: reference infliximab; UC, ulcerative colitis.

3. GP1111 in immune-mediated inflammatory diseases

3.1. Clinical trial data for GP1111 in RA

REFLECTIONS was a Phase III, double-blind, parallel-group, confirmatory study that assessed intravenous (IV) GP1111 or reference infliximab administered in combination with MTX in 650 patients with moderate-to-severe active RA despite MTX therapy [37]. At the start of the 78-week study, patients were randomized 1:1 to either GP1111 or reference infliximab. At Week 30, patients receiving reference infliximab were re-randomized to GP1111 or reference infliximab, then at Week 54, the remaining patients receiving reference infliximab were switched to GP1111 until the end of the study. The study design is summarized in Figure 2. In REFLECTIONS, American College of Rheumatology 20% improvement criteria (ACR20) response rates after 14 weeks of treatment, the primary endpoint, were 62.7% for GP1111 and 64.1% for reference infliximab; both results were within the range reported in historical registration trials for reference infliximab (50–76%) [37]. In addition, ACR20, ACR50, and ACR70 response rates were similar between the two groups at all time points through Week 30 [37]. Subgroup analyses at Week 14 showed that ACR20 response rates and changes in high-sensitivity C-reactive protein (hs-CRP) and Disease Activity Score in 28 joints, with four components based on hs-CRP (DAS28-CRP), were similar between GP1111 and reference infliximab in patient cohorts stratified by age, sex, race, region, treatment history, and immunogenicity status [38]. Results to Week 30 continued to show similar efficacy of GP1111 and reference infliximab across all subgroups [38]. The safety profiles of GP1111 and reference infliximab were comparable, with no clinically meaningful differences observed between treatment arms [37,39,40]. In REFLECTIONS, the incidence of treatment-related adverse events (AEs) over 30 weeks of treatment was 25.1% versus 23.0% for GP1111 versus reference infliximab [37]. There were no notable differences in the incidence and characteristics of treatment-emergent AEs of special interest (infusion-related reactions, hypersensitivity, infections [including tuberculosis and pneumonia], and malignancy [including lymphoma]) between the GP1111 and reference infliximab groups [37]. Over the initial 30-week treatment period, the incidence of antidrug antibody (ADA) development was 48.6% versus 51.2% for GP1111 versus reference infliximab [37]; of the ADA-positive patients, 79.0% and 85.6% tested positive for neutralizing antibodies against GP1111 and reference infliximab, respectively.

Figure 2. Timeline highlighting key studies for GP1111. Adapted from Cohen SB, et al. Arthritis Res Ther. 2018;20:155 [37]. Image adapted under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.Org/licenses/by/4.0/).

^aIntravenous infliximab 3 mg/kg was given as an induction regimen at Weeks 0, 2, and 6, followed by maintenance treatment with a 3 mg/kg dose starting at Week 14 and continuing every 8 weeks thereafter. Dose escalation to 5 mg/kg infliximab was permitted at or after Week 14 for patients with inadequate response. EOT, end of treatment.

In REFLECTIONS, there was no significant impact on efficacy or tolerability when switching from reference infliximab to GP1111 [39]. During the 24-week period following the first switch to GP1111 (Weeks 30–54), efficacy was sustained regardless of whether patients continued to receive GP1111, switched from reference infliximab to GP1111, or continued to receive reference infliximab. Switching had no impact on efficacy, with ACR20, ACR50, and ACR70 response rates and DAS28-CRP scores at Week 54 similar across the three treatment groups [39]. Results from Weeks 54‒78, when all patients received open-label treatment with GP1111, demonstrated that ACR20 response rates and DAS28-CRP scores were sustained, with no clinically meaningful differences in efficacy between patients who maintained GP1111 throughout the 78 weeks of the study and those who switched from reference infliximab to GP1111 [40]. During Weeks 30‒54 and 54‒78, there were no clinically meaningful differences in immunogenicity between the treatment groups [39,40].

In a meta-analysis, seven randomized controlled clinical trials, including REFLECTIONS, were assessed [41]. This analysis covered six infliximab biologic agents (ABP 710, BCD-055, CT-P13, GP1111, NI-071, SB2) and 3,168 patients with active RA and an inadequate response to MTX. The meta-analysis indicated no significant difference in ACR20 response rates and serious AEs between infliximab biosimilars and reference infliximab [41].

3.2. Real-world evidence for switching from another infliximab biosimilar to GP1111

In the years following the approval of infliximab biosimilars, only limited data on switching from one biosimilar to another became available. An evaluation based on data of the Danish DANBIO registry provided new insights in RA and other inflammatory rheumatic diseases. In this observational cohort study of 1,605 patients with RA, psoriatic arthritis, or axial spondyloarthritis, outcomes were investigated after a nationwide infliximab biosimilar-to-biosimilar switch from CT-P13 to GP1111 [42]. The switch was based on Danish guidelines recommending the use of the cheapest infliximab medicine available in the absence of individual patient considerations [43]. Treatment retention at 1 year following switches between biosimilars was high (80–87% in patients with all conditions who switched with no prior reference infliximab treatment exposure, and 90–96% in patients who switched with prior reference infliximab experience) [42]. Withdrawal rates were lower in reference infliximab-experienced patients than in reference infliximab-naïve patients across all indications (statistically significant in patients with RA: hazard ratio 0.36; 95% confidence interval 0.19, 0.68; and in patients with psoriatic arthritis: hazard ratio 0.23; 95% confidence interval 0.07, 0.75). Disease activity in individual patients 4 months pre and post-switch was stable, with no clinically relevant differences [42]. These real-world data support the effectiveness and safety of switching to GP1111 from another infliximab biosimilar in patients with RA and related disorders.

In patients with IBD, multiple switching between GP1111 and SB2 or CT-P13 has been investigated in two real-world studies. A multicenter, observational, retrospective study of 87 pediatric patients with CD or UC in the Sicilian Network for IBD found that over a median follow-up of 15 months, 20 (23%) were multiply switched from biosimilar CT-P13 to GP1111 or SB2, or vice versa [44]. At 12 months, 66% of patients had achieved clinical remission, 91% persisted with treatment, and there was a low incidence of nonserious AEs [44]. In addition, an observational, retrospective study of switching in patients with IBD at a single center in Italy reported the results for 10 patients who switched between reference infliximab and/or three biosimilars (GP1111, SB2, and CT-P13). After two to four switches, disease activity, as determined by the Harvey–Bradshaw Index or the Partial Mayo Score, either remained stable (n = 6) or decreased (n = 4) for all patients [45]. These data suggest that in real-world clinical practice, multiple successive switches between GP1111 and other infliximab biosimilars appear to be effective with an acceptable safety profile in patients with IBD.

4. Administration of GP1111

Physicochemical and biological analyses have demonstrated that GP1111 is not negatively affected by reconstitution, dilution, or extended storage of diluted preparations required for IV infusion in clinical practice [46]. Following reconstitution (10 mg/mL), the physicochemical and biological stability of GP1111 was maintained for 30 days in refrigerated storage (5°C [±3°C]) and for 14 days at room temperature (25°C [±2°C] and 60% [±5%] relative humidity). After dilution (0.4 mg/mL or 4.0 mg/mL) for IV infusion, GP1111 stability was maintained for up to 30 days in refrigerated storage or at room temperature [46].

5. Cost-effectiveness of GP1111

Due to price competition introduced by biosimilars, increasing acceptance of biosimilars could result in many more patients benefiting from biologic therapies [26]. The budget impact of various treatment sequences in patients in Thailand with RA for whom three or more conventional synthetic DMARDs had failed was analyzed [47]. The treatments analyzed included targeted therapies for RA approved and marketed in Thailand by 2019, including two infliximab biosimilars (CT-P13 and GP1111). Direct medical costs relevant to healthcare payers were also included in the model. The results for the base case scenario and various sensitivity analyses showed that the treatment sequence of rituximab as first-line therapy, followed by GP1111, tofacitinib, and tocilizumab, had the smallest impact on the budget for the treatment of moderate-to-severe RA over 5 years. The second lowest budget impact was the treatment order of GP1111 as first-line therapy and rituximab as second-line therapy, followed by tofacitinib and tocilizumab. These results suggest that GP1111 was cost-effective when used after the failure of conventional synthetic DMARDs [47].

In an Italian survey of respondents from 26 pediatric IBD departments in Italy, most centers (n = 20) reported switching from the reference medicine to a biosimilar in everyday clinical practice, and most centers (n = 20) did not register any acute side effects. All centers used infliximab biosimilars, including two centers that used GP1111, and all centers considered cost savings as the main benefit of biosimilars [48].

6. Discussion and conclusion

The totality of evidence for GP1111 compared to reference infliximab led to its approval in 2018 for use in RA, CD, UC, ankylosing spondylitis, psoriatic arthritis, and plaque psoriasis. Evidence gathered in the 5 years following the approval of GP1111 underscores the safety and efficacy profile of GP1111. Clinical and real-world data in the RA and IBD settings demonstrate that switching from reference infliximab or another infliximab biosimilar to GP1111 does not appear to have an impact on efficacy, safety, or immunogenicity [37,39,40,42,44,45]. In real-life settings, patients are likely to switch multiple times between GP1111 and other infliximab biosimilars, and it is reassuring that in doing so, efficacy and safety appear to be maintained. These additional post-approval data for GP1111 are particularly important to guide treatment decisions and provide reassurance to healthcare professionals and patients who may have concerns, particularly when considering switching between infliximab biosimilars.

In patients with immune-mediated inflammatory diseases, there remains a need for access to biologics and appropriate timing for initiation of treatment with these agents [49,50]. After considering effectiveness, safety, and treatment recommendations, cost may also determine which biologic is used and when. Although limited, available data suggest that GP1111 is a cost-effective treatment option that may help improve access to or enable earlier use of biologic therapy in this patient population [47,48].

In conclusion, experience for GP1111 five years after approval in patients with RA and IBD, based on clinical trials and real-world evidence, supports its continued safe and effective use.

7. Expert opinion

In the 5 years since the approval of GP1111 in Europe, real-world evidence has supported the safety and efficacy of GP1111 in patients with RA and IBD, including scenarios where patients switched to GP1111 from another infliximab biosimilar or the reference medicine. In the next 5 years, it is reasonable to expect that further real-world data will emerge supporting the safety and efficacy of the routine use of GP1111 across all reference infliximab-approved indications. Since the approval of CT-P13 (Remsima®), the first infliximab biosimilar, increased understanding of biosimilar development and regulatory approval have contributed to a change in the perception of IBD experts, demonstrating an increase in confidence to prescribe biosimilars [51,52].

With infliximab biosimilars in use across healthcare systems globally, the volume of evidence for the positive economic impact of infliximab biosimilars should also increase over the next 5 years. The impact on real-world outcomes in clinical settings has been significant, particularly regarding the savings incurred in switching from reference biologic therapy to biosimilars [26]. As savings are realized in the treatment of patients receiving infliximab across various healthcare systems, these savings may be reinvested in the care of patients eligible for infliximab therapy, leading to wider patient access to infliximab. In many healthcare systems, there is a strong preference to prescribe biosimilars, while the option to prescribe infliximab has been limited. In comparison with healthcare systems with a free choice, we do not observe worse patient outcomes. This may also lead to changes in attitude toward the use of infliximab by payors who are balancing the contradicting forces of optimizing patient care while managing limited healthcare resources. In addition, in countries where governments, and thereby taxes, pay for healthcare, the savings incurred by prescribing infliximab biosimilars over the reference medicine may also contribute to increased availability of resources for new, innovative treatments, highlighting an advantage not just for patients who require infliximab therapy for their disease but also for other patients living with other health conditions that are currently not satisfactorily managed [53].

As prescription of infliximab biosimilars becomes more commonplace, it would also be prudent to continually update the literature for differences in adherence between reference infliximab and biosimilars, including GP1111, to better understand how treatment patterns are evolving with the advancement of biosimilars. An adherence study published in 2022 has shown that adherence for reference infliximab was greater (64%) than infliximab biosimilars (36%) in patients who were prevalent infliximab users; however, larger sample sizes are needed to accurately assess adherence in patients using infliximab biosimilars [54].

Five years from now, we expect there to be more research into how different factors may influence the likelihood of both a physician prescribing biosimilar treatment and a patient’s willingness to receive biosimilar treatment, given patients’ high level of trust in specialists’ recommendations and their widespread use of external sources of information [55]. It will also be interesting to see how factors including age, level of education, the presence of comorbidities, and disease-related complications may influence adherence to biosimilars.

Article highlights

• Clinical studies have demonstrated the biosimilarity of GP1111, an infliximab biosimilar, to reference infliximab

• In the Phase III, randomized, double-blind, REFLECTIONS trial, there was no significant impact on efficacy or tolerability when switching from reference infliximab to GP1111 in patients with moderate-to-severe rheumatoid arthritis (RA) despite methotrexate therapy

• GP1111 was approved by the European Medicines Agency in May 2018

• Since approval, real-world studies have further demonstrated the effectiveness and safety of GP1111 in patients with RA and inflammatory bowel disease, including in cases where patients have switched to GP1111

• Limited cost-effectiveness data have also indicated that GP1111 is a cost-saving medicine

Abbreviations

ACR20: American College of Rheumatology 20% improvement criteria; ACR50: American College of Rheumatology 50% improvement criteria; ACR70: American College of Rheumatology 70% improvement criteria; ADA: antidrug antibody; AE: adverse event; bDMARD: biologic disease-modifying antirheumatic drug; CD: Crohn’s disease; DAS28-CRP: Disease Activity Score in 28 joints, with four components based on high-sensitivity C-reactive protein; DMARD: disease-modifying antirheumatic drug; ECCO: European Crohn’s and Colitis Organisation; EULAR: European Alliance of Associations for Rheumatology; hs-CRP: high-sensitivity C-reactive protein; IBD: inflammatory bowel disease; IV: intravenous; MTX: methotrexate; PK: pharmacokinetics; RA: rheumatoid arthritis; TNF: tumor necrosis factor; TNF-α: tumor necrosis factor alpha; UC: ulcerative colitis.

Declaration of interest

TWJ Huizinga reports receiving research support/lecture fees/consultancy fees from Abbott, Ablynx, Biotest, Boehringer Ingelheim, Bristol Myers Squibb, Galapagos, Janssen, Eli Lilly and Company, Merck, Novartis, Pfizer, Roche, Sanofi-Aventis, and UCB. J Heyn and M Zabransky report employment with Sandoz/HEXAL AG. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

A reviewer on this manuscript has received research, speaking and/or consulting support from Eli Lilly and Company, GlaxoSmithKline/Stiefel, AbbVie, Janssen, Alovtech, vTv Therapeutics, Bristol-Myers Squibb, Samsung, Pfizer, Boehringer Ingelheim, Amgen, Dermavant, Arcutis, Novartis, Novan, UCB, Helsinn, Sun Pharma, Almirall, Galderma, Leo Pharma, Mylan, Celgene, Ortho Dermatology, Menlo, Merck & Co, Qurient, Forte, Arena, Biocon, Accordant, Argenx, Sanofi, Regeneron, the National Biological Corporation, Caremark, Teladoc, Bristol Myers Squibb, Ono, Micreos, Eurofins, Informa, UpToDate, and the National Psoriasis Foundation. They hold stock in Causa Research and Sensal Health. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Acknowledgments

The authors met criteria for authorship as recommended by the International Committee of Medical Journal Editors (ICMJE). The authors did not receive payment related to the development of this manuscript. Medical writing support was provided by Dan Hami, of Rhea, OPEN Health Communications, in accordance with Good Publication Practice (GPP) guidelines (www.ismpp.org/gpp-2022).

Additional information

Funding

Medical writing support was funded by Sandoz/HEXAL AG.