Efficacy & Safety
Efficacy and Safety of Biosimilars
The costs of anti-TNF products are often high, placing a financial burden on the healthcare system and at times limiting the access to these products.1 As an alternative, anti-TNF biosimilars enable earlier and wider access to appropriate therapy without the financial burden associated with the reference product.2 But does the efficacy and safety data for anti-TNF biosimilar treatments support their use in the treatment of key gastroenterology, rheumatology, and dermatology conditions?
There has been a lack of confidence amongst HCPs to prescribe biosimilars largely stemming from concerns regarding extrapolation and the lack of clinical data for biosimilars in their relevant indication. Additionally, patients have been reluctant to accept biosimilars in the past - highlighting the need for patient education and effective communication from informed medical professionals, confident in the reasoning behind their choice of biosimilar.3
Fortunately, there appears to be a shift in attitudes since recent real-world data has provided a wealth of data supporting the effectiveness and safety of biosimilars in many indications, for example, inflammatory bowel diseases (IBD) such as Crohn’s disease (CD) and ulcerative colitis (UC).4 HCPs are increasingly recognising that biosimilars expand access to therapy, greatly impacting the care they can provide their patients. For example, a key role in changing attitudes around biosimilars in IBD was the potential to significantly decrease complications like strictures or perforations in early CD.5
With additional data confirming the safety and efficacy of biosimilars (over and above the data required for approval), confidence and comfort in using biosimilars should increase in both HCPs and patients alike.6 In general, the evidence acquired over ten years of clinical experience shows that biosimilars approved through the EMA can be used as safely and effectively in all their approved indications as other biological medicines. Furthermore, of more than 50 biosimilars approved in the EU to date, none have been withdrawn or suspended for reasons of safety or efficacy.7
In IBD specifically, the first biosimilar to be FDA-approved for CD and UC (and for all the indications of the reference product infliximab) was CT-P13. While the only controlled clinical studies of this biosimilar were carried out in ankylosing spondylitis (AS) (phase 1) and rheumatoid arthritis (RA) (phase 3), the approval to extrapolate to IBD was supported by the non-clinical data supporting similarity across different potential mechanisms of action, pharmacokinetics, immunogenicity, and toxicity data.8 As data has emerged from a number of studies examining the use of biosimilars in IBD confidence has increased in the safety and effectiveness of biosimilars in this group of patients.
The NOR-SWITCH trial was a double-blind, non-inferiority study of patients (with various IMIDs) receiving the reference drug infliximab who were randomly assigned to either continue this treatment or switch to CT-P13. The study showed non-inferiority between the biosimilar and the reference biologic, and that there were no significant differences in serum drug concentrations or the occurrence of anti-drug antibodies.9 Further investigation in CD patients naïve to biological therapy also reported non-inferiority of CT-P13 to infliximab with no notable differences between groups for faecal calprotectin, C-reactive protein, anti-drug antibodies, pharmacokinetics, safety, or the number of patients in clinical remission at one year.1
A recent observational study demonstrating real-world data indicated the effectiveness of CT-P13 is equivalent to that of the reference product infliximab (for infliximab-naïve patients with CD) and that no differences in safety outcomes were observed.10 Interim analyses from an observational study of patients with IBD treated with SB2 reported that the efficacy and safety of SB2 appears to be overall similar to those reported for the reference product (infliximab) and the biosimilar CT-P13.11 Additionally, a prospective, observational cohort study of CD and UC patients that switched from infliximab originator to biosimilar SB2 in 2017 were followed-up for 18-months. Median disease activity, CRP levels, trough levels, anti-drug antibodies, and adverse events were reported, and the study concluded that switching from infliximab to SB2 was not associated with an increase in disease activity and no clinically meaningful changes in trough levels or immunogenicity were identified. SB2 was well tolerated in a real-life setting.12
Table 18, Further selected studies and guidelines pertinent to the use of biosimilars in IBD are listed below.
Biosimilars used to treat rheumatology diseases also show excellent efficacy and safety in comparison to their reference products with CT-P13 investigated as a treatment for multiple rheumatology conditions including RA and AS. The two main studies from these investigations were the PLANETRA study (RA)13 and the PLANETAS study (AS)14. Both studies reported comparable safety, efficacy, and immunogenicity of CT-P13 to infliximab and both extension studies reported that clinical efficacy was similar in patients in the maintenance (continued CT-P13) and switch groups (switched from reference biologic to CT-P13).13,15,16
Comparable efficacy and safety of SB2 compared with infliximab has also been reported in patients with RA, with no clinically relevant immunogenicity or treatment-emergent issues after switching from the reference product.17 SB5 has also been shown to have equivalent efficacy and comparable safety results to that of the reference adalimumab in patients with moderate-to-severe RA,18 with evidence that SB5 was well tolerated over 1 year and that switching from the reference product to SB5 had no treatment-emergent issues.19
*Patients having at least one positive ADA result during the last transition-extension period among all patients regardless of prior ADA results up to week 54. † Patients having at least one positive ADA result during the transition period among patients with overall negative ADA results up to week 54.
In dermatological indications, a 2018 study examined the safety, efficacy and time to discontinuation of a number of biologics (adalimumab, etanercept, infliximab, secukinumab, and ustekinumab) in patients with moderate-to-severe psoriasis. The authors also compared originators etanercept with biosimilar, and infliximab with biosimilar, reporting that switching from originator to biosimilar had no significant impact on the time to discontinuation; in addition, the safety profiles were comparable. 20 The EGALITY study – a randomised, double-blind study comparing GP2015, an etanercept biosimilar, to the originator, demonstrated equivalent efficacy, comparable safety and immunogenicity in patients with moderate-to-severe chronic plaque-type psoriasis.21 Additionally, Gerdes et al evaluated the effects of repeated switching between GP2015 and the originator and reported no effects in the short term on clinical data of doing so. 22
The evidence of the safety and efficacy of biosimilars compared with their reference products in gastroenterology, rheumatology, and dermatology should instil ever more confidence in HCPs to prescribe them and, armed with such knowledge, HCPs can help put their patients at ease with using them. This can have a significant impact on adherence and reduce the risk of nocebo effects.4
The adoption of biosimilars early in the course of treatment can improve the health outcomes of the patient population overall. Importantly, the use of biosimilars reduces the need to reply on expensive branded biologics, and compounds traditionally used in the onset of IMIDs. They also increase market competition bringing the cost of the reference biologics down, resulting in the overall reduction in cost of treatment, expanding not only the number of patients who can access early biologic treatment, but increasing the number of treatment options available for HCPs to offer their patients. Biosimilars increase access and options to timely, life-changing treatment.
The burden of disease in IBD patients can be wide-ranging and variable due to the chronic and unpredictable nature of the disease. The symptoms of IBD are often painful and embarrassing leading individuals to develop many daily concerns, such as bowel control, bowel urgency, pain management, and fatigue.
Longer-term concerns such as treatment options, the prospect of surgery, the development of cancer, and the personal financial burden due to reduced working hours (absenteeism), all contribute to the significant psychosocial burden of the disease, and the well-documented decrease in the quality of life (QoL) when compared to healthy individuals.23
The underuse of biologics is an issue in gastroenterology, rheumatology, and dermatology despite the evidence that biologics offer effective treatment in all indications. For example, patterns of biologic prescribing for CD in Europe vary from 8–33%, similar variations were seen for RA, and only 20% of patients with moderate-to-severe PsO were prescribed biologics in Europe and North America.
The reasons for underuse are complex and country specific, however, in countries where biologics are less affordable, eligibility criteria tend to be more restrictive and the most common reason for dermatologists to not initiate or maintain a biologic is cost.4
- Ye BD, Pesegova M, Alexeeva O, et al. Efficacy and safety of biosimilar CT-P13 compared with originator infliximab in patients with active Crohn’s disease: an international, randomised, double-blind, phase 3 non-inferiority study. The Lancet. 2019;393(10182):1699-1707. doi:10.1016/S0140-6736(18)32196-2
- Edwards CJ, Hercogová J, Albrand H, Amiot A. Switching to biosimilars: current perspectives in immune-mediated inflammatory diseases. Expert Opinion on Biological Therapy. 2019;19(10):1001-1014. doi:10.1080/14712598.2019.1610381
- Waller J, Sullivan E, Piercy J, Black CM, Kachroo S. Assessing physician and patient acceptance of infliximab biosimilars in rheumatoid arthritis, ankylosing spondyloarthritis and psoriatic arthritis across Germany. Patient Preference and Adherence. 2017;11:519-530. doi:10.2147/PPA.S129333
- Baumgart DC, Misery L, Naeyaert S, Taylor PC. Biological therapies in immune-mediated inflammatory diseases: Can biosimilars reduce access inequities? Frontiers in Pharmacology. 2019;10(MAR):1-13. doi:10.3389/fphar.2019.00279
- Biosimilars Benefit Patients With Expanded Access, but Physicians Still Need Education. https://www.centerforbiosimilars.com/conferences/medicines-for-europe-2019-biosimilars/biosimilars-benefit-patients-with-expanded-access-but-physicians-still-need-education. Published 2019. Accessed January 13, 2020.
- Kaida-Yip F, Deshpande K, Saran T, Vyas D. Biosimilars: Review of current applications, obstacles, and their future in medicine. World Journal of Clinical Cases. 2018;6(8):161-166. doi:10.12998/wjcc.v6.i8.161
- Ruiz S. Biosimilars in the EU. Biosimilar Drug Product Development. 2017:395-411. doi:10.1201/9781315119878-15
- Rudrapatna VA, Velayos F. Biosimilars for the Treatment of Inflammatory Bowel Disease. Pract Gastroenterol. 2019;43(4):84-91.
- Jørgensen KK, Olsen IC, Goll GL, et al. Switching from originator infliximab to biosimilar CT-P13 compared with maintained treatment with originator infliximab (NOR-SWITCH): a 52-week, randomised, double-blind, non-inferiority trial. The Lancet. 2017;389(10086):2304-2316. doi:10.1016/S0140-6736(17)30068-5
- Meyer A, Rudant J, Drouin J, Weill A, Carbonnel F, Coste J. Effectiveness and safety of reference infliximab and biosimilar in Crohn disease: A French equivalence study. Annals of Internal Medicine. 2019;170(2):99-107. doi:10.7326/M18-1512
- Macaluso FS, Cappello M, Giuffrida E, et al. Oc.12.3 Sposib Sb2 – a Sicilian Prospective Observational Study of Patients With Inflammatory Bowel Disease Treated With Infliximab Biosimilar Sb2 (Flixabi®): Interim Analysis. Digestive and Liver Disease. 2019;51(2019):e110. doi:10.1016/s1590-8658(19)30203-8
- Fischer S, Mesfin S, Klenske E, et al. Efficacy , safety , and pharmacokinetics after switching from infliximab originator to biosimilar SB2 in inflammatory bowel disease patients : A long-term observational, prospective cohort study. journal of Crohn's and Colitis, Volume 14, Issue Supplement_1, January 2020, Pages S466–S467.
- Yoo DH, Racewicz A, Brzezicki J, et al. A phase III randomized study to evaluate the efficacy and safety of CT-P13 compared with reference infliximab in patients with active rheumatoid arthritis: 54-week results from the PLANETRA study. Arthritis Research and Therapy. 2016;18(1):94-95. doi:10.1186/s13075-016-0981-6
- Park W, Hrycaj P, Jeka S, et al. A randomised, double-blind, multicentre, parallel-group, prospective study comparing the pharmacokinetics, safety, and efficacy of CT-P13 and innovator infliximab in patients with ankylosing spondylitis: The PLANETAS study. Annals of the Rheumatic Diseases. 2013;72(10):1605-1612. doi:10.1136/annrheumdis-2012-203091
- Park W, Yoo DH, Miranda P, et al. Efficacy and safety of switching from reference infliximab to CT-P13 compared with maintenance of CT-P13 in ankylosing spondylitis: 102-week data from the PLANETAS extension study. Annals of the Rheumatic Diseases. 2017;76(2):346-354. doi:10.1136/annrheumdis-2015-208783
- Yoo DH, Prodanovic N, Jaworski J, et al. Efficacy and safety of CT-P13 (biosimilar infliximab) in patients with rheumatoid arthritis: Comparison between switching from reference infliximab to CT-P13 and continuing CT-P13 in the PLANETRA extension study. Annals of the Rheumatic Diseases. 2017;76(2):355-363. doi:10.1136/annrheumdis-2015-208786
- Smolen JS, Choe JY, Prodanovic N, et al. Safety, immunogenicity and efficacy after switching from reference infliximab to biosimilar SB2 compared with continuing reference infliximab and SB2 in patients with rheumatoid arthritis: Results of a randomised, double-blind, phase III transition study. Annals of the Rheumatic Diseases. 2018;77(2):234-240. doi:10.1136/annrheumdis-2017-211741
- Weinblatt ME, Baranauskaite A, Niebrzydowski J, et al. Phase III Randomized Study of SB5, an Adalimumab Biosimilar, Versus Reference Adalimumab in Patients With Moderate-to-Severe Rheumatoid Arthritis. Arthritis and Rheumatology. 2018;70(1):40-48. doi:10.1002/art.40336
- Weinblatt ME, Baranauskaite A, Dokoupilova E, et al. Switching From Reference Adalimumab to SB5 (Adalimumab Biosimilar) in Patients With Rheumatoid Arthritis: Fifty-Two–Week Phase III Randomized Study Results. Arthritis and Rheumatology. 2018;70(6):832-840. doi:10.1002/art.40444
- Egeberg A, Ottosen MB, Gniadecki R, et al. Safety, efficacy and drug survival of biologics and biosimilars for moderate-to-severe plaque psoriasis. British Journal of Dermatology. 2018;178(2):509-519. doi:10.1111/bjd.16102
- Griffiths CEM, Thaçi D, Gerdes S, et al. The EGALITY study: a confirmatory, randomized, double-blind study comparing the efficacy, safety and immunogenicity of GP2015, a proposed etanercept biosimilar, vs. the originator product in patients with moderate-to-severe chronic plaque-type psoriasis. British Journal of Dermatology. 2017;176(4):928-938. doi:10.1111/bjd.15152
- Gerdes S, Thaçi D, Griffiths CEM, et al. Multiple switches between GP2015, an etanercept biosimilar, with originator product do not impact efficacy, safety and immunogenicity in patients with chronic plaque-type psoriasis: 30-week results from the phase 3, confirmatory EGALITY study. Journal of the European Academy of Dermatology and Venereology. 2018;32(3):420-427. doi:10.1111/jdv.14605
- Knowles SR, Graff LA, Wilding H, Hewitt C, Keefer L, Mikocka-Walus A. Quality of Life in Inflammatory Bowel Disease: A Systematic Review and Meta-analyses - Part i. Inflammatory Bowel Diseases. 2018;24(4):742-751. doi:10.1093/ibd/izx100
- Rosen M, A D, SA S. Inflammatory Bowel Disease in Children and Adolescents. Physiology & behavior. 2015;169(11):1053-1060. doi:10.1001/jamapediatrics.2015.1982.
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- Boonen A, Severens JL. The burden of illness of rheumatoid arthritis. Clinical Rheumatology. 2011;30(SUPPL. 1):3-8. doi:10.1007/s10067-010-1634-9
- Kotsis K, Voulgari P v., Drosos AA, Carvalho AF, Hyphantis T. Health-related quality of life in patients with ankylosing spondylitis: A comprehensive review. Expert Review of Pharmacoeconomics and Outcomes Research. 2014;14(6):857-872. doi:10.1586/14737167.2014.957679
- Scriffignano S, Perrotta FM, de Socio A, Lubrano E. Role of comorbidities in spondyloarthritis including psoriatic arthritis. Clinical Rheumatology. 2019;38(1):3-10. doi:10.1007/s10067-018-4332-7
- van Onna M, Boonen A. The challenging interplay between rheumatoid arthritis, ageing and comorbidities. BMC Musculoskeletal Disorders. 2016;17(1):1-9. doi:10.1186/s12891-016-1038-3
- Nurmohamed MT, Heslinga M, Kitas GD. Cardiovascular comorbidity in rheumatic diseases. Nature Reviews Rheumatology. 2015;11(12):693-704. doi:10.1038/nrrheum.2015.112
- van Breukelen-van der Stoep DF, van Zeben D, Klop B, et al. Marked underdiagnosis and undertreatment of hypertension and hypercholesterolaemia in rheumatoid arthritis. Rheumatology (United Kingdom). 2016;55(7):1210-1216. doi:10.1093/rheumatology/kew039
- Gorelick J, Shrom D, Sikand K, et al. Understanding Treatment Preferences in Patients with Moderate to Severe Plaque Psoriasis in the USA: Results from a Cross-Sectional Patient Survey. Dermatology and Therapy. 2019;9(4):785-797. doi:10.1007/s13555-019-00334-1
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