Background: A biosimilar version of infliximab (CT-P13) was recently approved for use in Saudi Arabia. Clinical data support its use in the treatment of rheumatic disease, however, there is a lack of local data regarding the efficacy and tolerability of CT-P13 among patients with rheumatological disorders in Saudi Arabia.
Submitted: 16 September 2020; Revised: 30 January 2021; Accepted: 8 February 2021; Published online first: 22 February 2021
Tumour necrosis factor (TNF) is an inflammatory cytokine involved in the pathogenesis of rheumatoid arthritis (RA) . It is produced by a number of cell types in the human body, including those in the synovial membrane and fluid of RA patients [2, 3]. Blocking TNF has been shown to have anti-inflammatory and protective effects in RA . TNF is also important in the pathogenesis of ankylosing spondylitis (AS)  and previous studies have identified high levels of TNF mRNA expression near the site of new bone formation and increased TNF protein levels in serum in patients with AS [6, 7].
Infliximab was one of the first TNF inhibitors (TNFI) to be used clinically for the treatment of RA, AS and other inflammatory diseases . In 2013, the first infliximab biosimilar, CT-P13, was approved by the European Medicines Agency (EMA) based on randomized controlled trials in RA and AS, demonstrating no statistically significant differences in safety profile compared with the originator [9-11].
CT-P13 was launched on the market in Saudi Arabia at the end of 2016. Clinical data support its use in the treatment of a number of rheumatological diseases, however, there is a lack of local data regarding its safety profile and efficacy among patients in Saudi Arabia. Therefore, the present study was carried out to explore the pharmacological, therapeutic and clinical effects of CT-P13 in patients with RA, AS and BD, encountered during clinical practice in the Department of Rheumatology in Khamis Mushayt General Hospital, Saudi Arabia.
This study included 13 patients seen at the Department of Rheumatology in Khamis Mushayt General Hospital. All patients were being treated with originator infliximab and were required to switch to the biosimilar version due to the originator becoming unavailable. Patients were recruited between January 2018 and June 2019. Biosimilar infliximab was given as a standard (3–7.5 mg/kg) IV infusion every 8 weeks. Patients were followed up once every three months, for 12 months.
The RA disease activity score 28 (DAS28) was used for clinical assessment of RA patients. The DAS28, which is a validated tool to define remission in established cases of RA, includes measurement of the number of swollen and tender joints, levels of inflammatory markers in blood (Erythrocyte Sedimentation Rate (ESR)), and assessment of patient general health.
Assessment of AS patients was dependent on the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score. This clinically validated index takes into account fatigue, neck, back and hip pain, and other joint symptoms, in addition to assessment of overall discomfort, e.g. areas tender to touch.
The assessment of BD patients depended on clinical assessment of the major manifestations of BD, such as orogenital ulceration, and ocular, musculoskeletal and cutaneous manifestations.
Information about infliximab and its possible adverse effects were described in detail and consents were given in all cases. The study proposal was also approved by the Research Ethics Local Committee, College of Medicine, University of Bisha.
The Shapiro-Wilk test revealed that the data were abnormally distributed. As such, a Wilcoxon signed ranks test was used to compare clinical scores before and after starting treatment with the biosimilar (CT-P13). A p-value < 0.05 was considered significant in all cases.
In total, 13 patients (six with RA, five with AS and two with BD) were switched to biosimilar infliximab (CT-P13) between January 2018 and June 2019. Table 1 summarizes the demographic and clinical characteristics of the patients. Patients were aged between 25 and 55 years (mean age = 39.7±11.7) and 61.5% were women. The majority (n = 11/13) maintained treatment with CT-P13 throughout the follow-up period with no reported major adverse events, excluding two patients with RA who had upper respiratory infection.
Table 2 shows significant improvement in RA disease activity, as measured by the DAS28. The mean DAS28 score was 3.61±1.24 prior to infliximab biosimilar therapy, which reduced to 2.63±1.54 at one year of follow-up (p = 0.046).
Several studies have assessed the safety, efficacy and immunogenicity of switching from the infliximab originator to the CT-P13 biosimilar version. However, the majority of these studies have not included control arms and have been observational in nature, in addition to investigating a single switch only. Importantly for Saudi Arabia, none of these studies were carried out in the locality. Therefore, this study was carried out to investigate the therapeutic and clinical effects of CT-P13 in patients with RA, SA and BD, and demonstrates local experience with the biosimilar.
A number of previous studies have investigated the effects of switching between the infliximab originator and the biosimilar, CT-P13. For example, in the second-year extension to the PLANETAS study , adverse events associated with biosimilar treatment were observed in 71.4% of patients who switched compared with 48.9% of those who continued receiving treatment with the originator. In addition, in the DANBIO register , approximately 6% of patients stopped treatment within three months of switching from originator infliximab to CT-P13 due to adverse events or lack of efficacy. In a study carried out on AS patients who switched from originator infliximab to its biosimilar, 11% of patients from the biosimilar group and 7% of the reference group discontinued the study during the 18-month follow-up period. Of those who discontinued biosimilar treatment, 80% did so due to adverse effects and 20% because of loss of efficacy .
The present case study did not identify any statistically significant differences in efficacy or tolerability between CT-P13 and originator infliximab in this small group of subjects in Saudi Arabia. This is in line with previous studies, such as the work of Jørgensen KK et al. , who reported that, according to a prespecified non-inferiority margin of 15%, the frequency of serious adverse events was not statistically different between patients treated with originator infliximab and those treated with CT-P13.
Additional observational studies and data from the extensions of the PLANETRA and PLANETAS studies identified few concerns regarding the efficacy and/or safety of CT-P13 [12, 16-19]. A recent systematic literature review including 70 full articles or abstracts evaluated the safety and efficacy of switching between originator and biosimilar infliximab in patients with inflammatory disorders. This review reported that most studies were observational, not containing a control group, and included only six randomized controlled trials (RCTs). It also concluded that no clinically relevant efficacy or safety concerns were associated with switching .
An additional survey carried out among adult patients in the United States (US) with RA, AS, and psoriatic arthritis who switched from infliximab to infliximab-dyyb biosimilar therapy evaluated the safety and efficacy of the biosimilar treatment, as well as patient awareness of biosimilar therapy. This paper concluded that patients were generally satisfied with their current therapy, whether this was originator infliximab or infliximab-dyyb. However, patients had concerns about switching, in particular, relating to price, safety, and efficacy .
The present study reported improvement in RA disease activity following biosimilar treatment (mean DAS28 of 3.61±1.24 prior to switching, compared to 2.63±1.54 one-year post-switching). However, another RCT identified no significant change in DAS28 between RA patients treated with the originator and those treated with the biosimilar .
In addition, in the present study, the five patients with AS who were switched from the originator to its biosimilar exhibited an improvement in their disease activity index (the BASDAI mean score reduced from 3.3±0.7 before biosimilar therapy to 0.28±0.52 after one year of biosimilar therapy, however, the result was not significant), see Table 3. This can be compared to the results of another study, where the BASDAI score was 3.7±0.4 in a group of AS patients treated with biosimilar infliximab, compared to 3.8±0.2 among those treated with the originator .
In terms of limitations, this study includes data from a limited number of patients (n = 13) and was not randomized nor double-blinded. However, the aim of the study is to report experiences with switching to biosimilar infliximab in Saudi Arabia, which has not previously been examined. The findings from this study suggest that CT-P13 has comparable tolerability and efficacy to originator infliximab and may reduce disease activity in RA patients. However, a larger, double-blind RCT is recommended to ensure the safety and efficacy of the biosimilar. These findings provide important preliminary data and are considered the first evidence (after a literature search in the PubMed and Google Scholar) on switching between originator infliximab to a biosimilar infliximab product in Saudi Arabia.
The findings from this study suggest that CT-P13 has comparable tolerability and efficacy to originator infliximab and may reduce disease activity in RA patients. However, a larger double-blind randomised controlled trial (RCT) is recommended to ensure the safety and efficacy of the biosimilar. These important preliminary data are considered the first evidence (based on a literature search of PubMed and Google Scholar conducted up to November 2020) on switching from originator infliximab to a biosimilar infliximab product in Saudi Arabia.
This study received approval of the ethical clearance from the Research Ethics Local Committee of the College of Medicine, University of Bisha (UBCOM-RELOC) (registration no. H-06-BH-087) based on the recommendation of the committee issued on 15 August 2020.
Competing interests: There was no support of any kinds (including for presentation of data, travel or publication) provided to any of the authors by the manufacturer prior to or after the study was conducted.
Provenance and peer review: Not commissioned; externally peer reviewed.
1Department of Medicine, Rheumatology Division, King Khalid University Medical City, 3294 Al Muruj District, Unit number 300, Building No. 8294, 62527-3989 Abha, Saudi Arabia
2College of Medicine, King Khalid University, Almahala Street, 62562 Aseer-Abha, Saudi Arabia
3Asser Central Hospital, Bani Malik Street, 62526 Abha, Saudi Arabia
4Department of Medicine, Rheumatology Division, Khamis Mushayt General Hospital, Almahala Street, 62562 Aseer-Abha, Saudi Arabia
1. Smolen JS, Steiner G. Therapeutic strategies for rheumatoid arthritis. Nat Rev Drug Discov. 2003;2(6):473-88.
2. Chu CQ, Field M, Feldmann M, Maini RN. Localization of tumor necrosis factor alpha in synovial tissues and at the cartilage-pannus junction in patients with rheumatoid arthritis. Arthritis Rheum. 1991;34(9):1125-32.
3. Saxne T, Palladino MA Jr, Heinegård D,Talal N, Wollheim FA. Detection of tumor necrosis factor alpha but not tumor necrosis factor beta in rheumatoid arthritis synovial fluid and serum. Arthritis Rheum. 1988;31:1041-5.
4. Feldmann M, Maini RN. Anti-TNF alpha therapy of rheumatoid arthritis: what have we learned? Annu Rev Immunol. 2001;19:163-96.
5. Hreggvidsdottir HS, Noordenbos T, Baeten DL. Inflammatory pathways in spondyloarthritis. Mol Immunol. 2014;57(1):28-37.
6. Gratacós J, Collado A, Filella X, Sanmartí R, Cañete J, Llena J, et al. Serum cytokines (IL-6, TNF-alpha, IL-1 beta and IFN-gamma) in ankylosing spondylitis: a close correlation between serum IL-6 and disease activity and severity. Br J Rheumatol. 1994;33(10):927-31.
7. Braun J, Bollow M, Neure L, Seipelt E, Seyrekbasan F, Herbst H, et al. Use of immunohistologic and in situ hybridization techniques in the examination of sacroiliac joint biopsy specimens from patients with ankylosing spondylitis. Arthritis Rheum. 1995;38(4):499-505.
8. Yoo DH, Oh C, Hong SS, Park W. Analysis of clinical trials of biosimilar infliximab (CT-P13) and comparison against historical clinical studies with the infliximab reference medicinal product. Expert Rev Clin Immunol. 2015;11 Supp1:S15-24.
9. European Medicines Agency. Committee for Medicinal Products for Human Use (CHMP). Assessment report: Remsima (infliximab). 27 June 2013. EMA/CHMP/589317/2013 [homepage on the Internet]. [cited 2021 Jan 30]. Available from: www.ema.europa.eu/docs/en_GB/document_library/EPAR_Public_assessmentreport/human/002576/ WC500151486.pdf
10. Yoo DH, Hrycaj P, Miranda P, Ramiterre E, Piotrowski M, Shevchuk, S, et al. A randomised, double-blind, parallel-group study to demonstrate equivalence in efficacy and safety of CT-P13 compared with innovator infliximab when coadministered with methotrexate in patients with active rheumatoid arthritis: the PLANETRA study. Ann Rheum Dis. 2013;72(10):1613-20.
11. Park W, Hrycaj P, Jeka S, Kovalenko V, Lysenko G, Pedro Miranda P, 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. Ann Rheum Dis. 2013;72(10):1605-12.
12. Park W, Yoo DH, Miranda P, Brzosko M, Wiland P, Gutierrez-Ureña S, 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. Ann Rheum Dis. 2017;76(2):346-54.
13. Glintborg B, Juul Sørensen I, Vendelbo Jensen D, Krogh NS, Loft AG, et al. Three months’ clinical outcomes from a nationwide non-medical switch from originator to biosimilar infliximab in patients with inflammatory arthritis, results from the DANBIO registry. Ann Rheum Dis. 2016;75(Suppl 2):142.
14. Kaltsonoudis E, Pelechas E, Voulgari PV, Drosos AA. Maintained clinical remission in ankylosing spondylitis patients switched from reference Infliximab to its biosimilar: an 18-month comparative open-label study. J Clin Med. 2019;8(7):956.
15. Jørgensen KK, Olsen IC, Goll GL, Lorentzen M, Bolstad N, Haavardsholm EA, 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. Lancet. 2017;389(10086):2304-16.
16. Buer LC, Moum BA, Cvancarova M, Warren DJ, Medhus AW, Hoivik ML. Switching from Remicade® to Remsima® is well tolerated and feasible: a prospective, open-label study. J Crohns Colitis. 2017;11(3):297-304.
17. Smits LJT, Derikx LAA, de Jong DJ, Boshuizen RS, van Esch AAJ, Drenth, JPH, et al. Clinical outcomes following a switch from Remicade® to the biosimilar CT-P13 in inflammatory bowel disease patients: a prospective observational cohort study. J Crohns Colitis. 2016;10:1287-93.
18. Yoo DH, Prodanovic N, Jaworski J, Miranda P, Ramiterre E, Lanzon A, 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. Ann Rheum Dis. 2017;76(2):355-63.
19. Vergara-Dangond C, Sáez Bello M, Climente Martí M, Llopis Salvia P, Alegre-Sancho JJ. Effectiveness and safety of switching from innovator infliximab to biosimilar CT-P13 in inflammatory rheumatic diseases: a real‐world case study. Drugs R D. 2017;17(3):481-5.
20. Feagan BG, Lam G, Ma C, Lichtenstein GR. Systematic review: efficacy and safety of switching patients between reference and biosimilar infliximab. Aliment Pharmacol Ther. 2019;49(1):31-40.
21. Chau J, Delate T, Ota T, Bhardwaja B. Patient perspectives on switching from Infliximab to Infliximab-dyyb in patients with rheumatologic diseases in the United States. ACR Open Rheumatol. 2019;1(1):52-7.
22. Genovese MC, Sanchez-Burson J, Oh MS, Balazs E, Neal J, Everding A, et al. Comparative clinical efficacy and safety of the proposed biosimilar ABP 710 with infliximab reference product in patients with rheumatoid arthritis. Arthritis Res Ther. 2020;22(1):60.
23. Kaltsonoudis E, Pelechas E, Voulgari PV, Drosos AA. Maintained clinical remission in ankylosing spondylitis patients switched from reference Infliximab to its biosimilar: an 18-month comparative open-label study. J Clin Med. 2019;8(7):956.
Author for correspondence: Mansour Somaily, MD, Consultant, Department of Medicine, Rheumatology Division, King Khalid University Medical City, 3294 Al Muruj District, Unit number 300, Building No. 8294, 62527-3989 Abha, Saudi Arabia
Disclosure of Conflict of Interest Statement is available upon request.
Copyright © 2021 Pro Pharma Communications International
Permission granted to reproduce for personal and non-commercial use only. All other reproduction, copy or reprinting of all or part of any ‘Content’ found on this website is strictly prohibited without the prior consent of the publisher. Contact the publisher to obtain permission before redistributing.
Source URL: https://gabi-journal.net/biosimilars-in-saudi-arabia-a-single-centre-open-label-case-series-examining-infliximab-switching.html
Copyright ©2022 GaBI Journal unless otherwise noted.