Minireview Submitted: 24.9.2014 Accepted: 20.12.2014 Conflict of interest AN: PD Nast has received honoraria for CME certified educational talks that received direct or indirect sponsoring from Abbott (now AbbVie). SR, KS: Have no conflict of interests.
Alexander Nast, Stefanie Rosumeck, Karin Seidenschnur Division of Evidence Based Medicine (dEBM), Department of Dermatology, Charité – Universitätsmedizin Berlin, Germany
DOI: 10.1111/ddg.12621
Biosimilars: a systematic review of published and ongoing clinical trials of antipsoriatics in chronic inflammatory diseases
Summary Biosimilars for psoriasis treatment are currently being developed. Comparison of their efficacy and safety is a challenge. For approval, the European Medicines Agency (EMA) considers indirect evidence from other indications (for example, rheumatoid arthritis) as sufficient. Systematic review of biosimilars for psoriasis and other indications, review of ongoing trials in trial registers. Systematic search for randomized controlled trials (RCT) on biosimilars to adalimumab, etanercept, infliximab, and ustekinumab compared to their reference medication: (1) Publications in Medline, Medline In-Process, Embase, Cochrane Library (efficacy, safety, immunogenicity) and (2) ongoing studies in clinical trial registers. No trials on biosimilars in psoriasis patients were identified. As to the infliximab biosimilar, there is data on patients with ankylosing spondylitis and rheumatoid arthritis, indicating no clinically relevant differences regarding efficacy and safety. Currently, there are two registered studies of an adalimumab biosimilar and one study of an etanercept biosimilar in psoriasis patients. Further ongoing studies on biosimilars to adalimumab, etanercept, and infliximab – all in rheumatoid arthritis patients – were identified. There is currently only limited data regarding RCTs with biosimilars. Provision of further clinical data and inclusion of patients in patient registers will be crucial.
Introduction The introduction of biologics has dramatically changed the treatment of psoriasis (Pso), providing treatment options to many patients previously unresponsive to conventional treatment approaches. However, the high costs of biologics imposes a heavy burden on the healthcare system. One potential method of reducing costs is the introduction of ’biosimilars’. These are defined as “biological medicine that is similar to another biological medicine that has already been authorised for use. Biological medicines are medicines that are made by or derived from a biological source, such as a bacterium or
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yeast. They can consist of relatively small molecules such as human insulin or erythropoietin, or complex molecules such as monoclonal antibodies“ [1]. Biosimilars are developed to be similar to an existing biologic (’reference medicine’). They are not 100 % identical, but “essentially the same biological substance, though there may be minor differences due to their complex nature and production methods” [2]. The group of anti-TNF-α antibodies has been approved for several indications such as psoriasis, psoriatic arthritis (PA), Crohn’s disease (CD), ulcerative colitis (UC), ankylosing spondylitis (AS), and rheumatoid arthritis (rA). With respect to market introduction and approval for each indication, studies had to
© 2015 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2015/1304
Minireview Biosimilars in chronic inflammatory diseases
be conducted to meet the standards set by EMA (European Medicines Agency) and FDA (U. S. Food and Drug Administration). For biosimilars, the EMA allows extrapolation of clinical efficacy and safety from trials of the reference biologic in other indications. An “overall evidence of comparability […] with a comprehensive discussion of available literature including the involved antigen receptor(s) and mechanism(s) of action” [3] must be provided. The EMA does not state if biosimilars should be used interchangeably with their respective ’reference medicine’. The objective of this review is to help dermatologists to get a clear understanding of published and ongoing studies on biosimilars.
Methods
Published trials Study and participant characteristics were extracted. The Cochrane Collaboration’s tool for assessing risk of bias was used [4]. Efficacy outcomes, data on immunogenicity, and safety outcomes were extracted. Results were presented as risk ratios (RR) with 95 % confidence interval (CI).
Ongoing trials Available study characteristics (for example identification number, sponsor, phase, disease, intervention) and the definition of primary and secondary outcomes were extracted.
We systematically reviewed (1) published trials on efficacy and safety of biosimilars and (2) registers for planned and ongoing trials with biosimilars.
Results
Eligibility criteria
Eighty-one publications were identified; two studies were included (Figure 1). There was no trial providing data on the treatment of psoriasis patients with biosimilars. One RCT on CT-P13 as biosimilar to infliximab in combination with methotrexate (MTX) in 606 patients with rA (PLANETRA study [5, 6]) was identified, as was another trial with 250 AS patients (PLANETAS study [7–9]). Using a 20 % improvement from baseline in the American College of Rheumatology score (ACR 20) at week 30 as primary endpoint, the PLANETRA study showed no differences between both groups (risk ratio [RR]: 1.04, 95 % confidence interval [CI]: 0.91, 1.19). The primary outcome of the PLANETAS study was pharmacokinetic equivalence, with additional secondary outcomes such as a 20 % improvement from baseline in the Ankylosing Spondylitis Assessment Study (ASAS) group criteria. There were no differences for ASAS 20 at week 30 (RR: 0.97, 95 % CI: 0.83, 1.15). The risk of bias was rated as low for both studies (online only).
Randomized controlled trials (RCTs) investigating biosimilars compared to their ’reference medicine’ (adalimumab, etanercept, infliximab, ustekinumab) in chronic inflammatory diseases (Pso, PA, CD, UC, AS, rA) were included. Non-original data and studies with healthy patients were excluded. No language restrictions applied.
Literature search (1) Published RCTs were systematically searched in Medline, Medline In-Process, Embase, and the Cochrane Library on April 30th, 2014 (sample search strategy is available online, Online Resource 1). (2) The following trial registers were searched: www.controlled-trials.com www.clinicaltrials.gov www.anzctr.org.au http://apps.who.int/trialsearch www.clinicaltrialsregister.eu Search items included various terms used for the relevant diseases – ankylosing spondylitis, Crohn’s disease, ulcerative colitis, rheumatoid arthritis, psoriatic arthritis, and psoriasis vulgaris – in combination with biosimilars.
Study selection and data extraction Two reviewers (AN, SR) independently screened abstracts/ titles for relevance and extracted data from the full texts or from records of the registers. Results were compared and differences resolved by checking the data source and in discussion.
Published RCTs (Table 1)
Planned / ongoing RCTs (Table 2) Three hundred and thirty-four publications were identified; nine studies were included. Adalimumab: There are two registered ongoing RCTs of an adalimumab biosimilar versus adalimumab in 798 psoriasis patients [10, 11]. Completion is scheduled for June and August 2015. One ongoing RCT of the adalimumab biosimilar ABP 501 in 530 patients with rA has been registered [12]. Completion is scheduled for April 2015. Etanercept: There are three ongoing RCTs. One RCT on the etanercept biosimilar GP2015 with 546 psoriasis patients has been registered [13]. Completion is scheduled for April
© 2015 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2015/1304
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First author / study name
Drug
Year
Infliximab 3 mg/kg BW at w0, 2, 6, and then every 8w + MTX 12.5-25mg/ week + folic acid
Biosimilar infliximab (CTP13) 3 mg/kg BW at w0, 2, 6, and then every 8w + MTX 12.525mg/week + folic acid
Infliximab 5 mg/kg BW at w0, 2, 6, and then every 8w
Biosimilar infliximab (CTP13) 5 mg/kg BW at w0, 2, 6, and then every 8w
Pts. with active AS according to the 1984 modified New York classification criteria for ≥3m prior to screening
PGA of disease activity: 64.7 (SD: 14.3)
Disease
ASDAS: 3.9 (SD: 1.1)
ASDAS: 3.8 (SD: 0.8)
PGA of disease activity: 65.0 (SD: 13.5)
Severity
Pts. with active rA according to ACR criteria, prior unsuccessful treatment with MTX over at least 3m
1) result w30: 72.4 % (84/116)
w30: 70.5 % (79/112)
w54: 52.0 % (158/304)
w30: 58.6 % (178/304)
w54: 57.0 % (172/302)
w30: 60.9 % (184/302)
2) result w54: 49.1 %
w30: 47.4 % (55/116)
w54: 54.7 %
w30: 51.8 % (58/112)
w54: 31.6 % (96/304)
w30: 34.2 % (104/304)
w54: 33.1 % (100/302)
w30: 35.1 % (106/302)
AEs
3) result w54: 26.7 % (28/105)
w30: 22.5 % (25/111)
w54: 22.9 % (25/109)
w30: 27.4 % (32/117)
w30: TEAEs: 63.9 %
Serious adverse events
9.3 % (28/302)
Withdrawal due to AE
w30: drug-related infusion reaction: 4.9 %
6.4 % (8/125) 4.0 % (5 related: 2 infu(5/125) sion related reaction, pulmonary tuberculosis, cellulitis and wound infection, Appendix G)
4.8 % (6/125) 6.4 % (4 related: tubercu- (8/125) losis, disseminated tuberculosis, esophageal perforation and dyspnea; Appendix G)
w30: 8.3 % TEAEs: 9.2 % (25/301) w30: 7.0 % (21/301) (28/304) (10 related; Apw54: pendix F) 10.3 % (31/300) w54: 10.3 % (31/300)
w54: 13.9 % (42/302)
w30: 6.6 % TEAEs: (20/301) w30: 10.0 % (30/301) w54: 7.6 % (19 related; (23/302) Appendix F)
Infusion- related reactions
w30: w30: TEAEs: 64.8 % drug-related infusion reaction: 3.9 %
w30: w30: 48.2 % TEAEs: 60.8 % (122/253) (183/301); drug-related TEAEs: 35.9 % (108/301) w54: drug-related TEAEs: 44.7 % (134/300)
w30: w30: 48.4 % TEAEs: 60.1 % (122/252) (181/301); drug-related TEAEs: 35.2 % (106/301) w54: drug-related TEAEs: 43.4 % (131/302)
All pts. were premedicated with an antihistamine (chlorpheniramine 2–4 mg or dose of equivalent antihistamine such as cetirizine 10 mg) 30–60 min prior to the start of infusion at the investigator’s discretion; test for equivalence based on pharmacokinetics
All pts. were premedicated with an antihistamine (chlorpheniramine 2–4 mg or dose of equivalent antihistamine) 30–60 min prior to the start of infusion at the investigator’s discretion; ACR20 at w30 - equivalence: if the 95 % CI is within ± 15 %
Comments
BW, body weight; m, month/s; MTX, methotrexate; pts., patients; PGA, Physician Global Assessment; SD, standard deviation; TEAE, treatment-emergent AEs; w, week/s
Abbr.: ACR20/50, American College of Rheumatology (20 % and 50 %); ADA, anti-drug antibodies; ASAS20/40, ASAS responses (20 % and 40 %); ASDAS, Ankylosing Spondylitis Disease Activity Score;
Park [7] PLANETAS Study Park 2012 [8] Park 2012 [9]
2013
Ankylosing spondylitis (AS)
Yoo [5] PLANETRA Study Yoo 2013 [6]
2013
Rheumatoid Arthritis (rA)
Infliximab
Study ID
NCT01217086
NCT01220518
Number (n) randomized 302 304 125
© 2015 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2015/1304
125
Study duration [w] 54 54
1) endpoint ACR20 ASAS20
2) endpoint ACR50 ASAS40
3) endpoint Pts. with ADAs Pts. with ADAs
Sponsor CELLTRION Inc.
296 CELLTRION Inc.
Table 1 Included RCTs investigating biologics and their biosimilars (date: April 30th, 2014).
Minireview Biosimilars in chronic inflammatory diseases
NCT number
Adalimumab 80 mg at w0, followed by 40 mg every other week for 33w
GP2017 80 mg at w0, followed by 40 mg every other week for 33w
Adalimumab 40 mg every other week for 50w
ABP 501 40 mg every other week for 50w
Intervention
© 2015 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2015/1304
Adalimumab 40 mg every other week for 22w
ABP 501 40 mg every other week for 22w
Sponsor Amgen
Sandoz / Hexal
Amgen
Phase 3
3
3
Ongoing, not recruiting
Recruiting
Ongoing, not recruiting
Trial status
NCT01891864 [13]
Psoriasis
Etanercept
Etanercept 50 mg BIW for 12w, thereafter 50 mg QW
GP2015 50 mg BIW for 12w, thereafter 50 mg QW
no registered trials identified
Sandoz / Hexal
3
Ongoing, not recruiting
Ankylosing spondylitis, ulcerative colitis, Crohn’s disease, psoriatic arthritis
NCT01970475 [12]
Rheumatoid arthritis
NCT02016105 [11]
NCT01970488 [10]
Psoriasis
Adalimumab
Estimated enrollment 546
530
448
350
Study start June 2013
October 2013
December 2013
October 2013
April 2015
April 2015
June 2015
August 2015
Estimated primary completion date
Table 2 Included ongoing or planned studies investigating biologics and their biosimilars (date: 30th April, 2014). Secondary outcome measures
Primary outcome measures PASI 75
ACR 20
PASI 75
PASI 50, PASI 90, PASI score, injection site reactions, immunogenicity
DAS 28, ACR 50, ACR 70, ADA, AE, SAE, laboratory values, vital signs
PASI 50, PASI 90, PASI 100, IGA, HRQoL
PASI percentage PASI 75, sPGA, BSA, improvement AE, SAE, laboratory values, vital signs, ADA
Comment -
Continued
Pts. with MTX treatment for at least 12w, stable dose of MTX 7.5–25 mg QW for at least 8w; pts. with an inadequate response to MTX
-
-
Minireview Biosimilars in chronic inflammatory diseases
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298
Intervention
Etanercept 50 mg QW
SB4 50 mg QW
Etanercept 25 mg BIW for 48w
HD203 25 mg BIW for 48w
Etanercept 50 mg QW for 24w
CHS-0214 50 mg QW for 24w
Sponsor Samsung Bioepis Co., Ltd.
Hanwha Chemical
Coherus Biosciences, Inc.
Phase 3
3
3
© 2015 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2015/1304
Ongoing, not recruiting
Unknown
Infliximab 3 mg/kg BW at w0, 2, 6 then every 8 w
SB2 3 mg/kg BW at w0, 2, 6 then every 8w
Infliximab 100 mg/vial for 54w
NI-071 100 mg/vial for 54w
Samsung Bioepis Co., Ltd.
3
Nichi-Iko 3 Pharmaceutical Co., Ltd. Ongoing, not recruiting
Recruiting
584
230
498
300
Study start August 2013
July 2013
June 2013
January 2011
May 2014
August 2014
ACR 20
Secondary outcome measures ACR 50, DAS 28
ACR 20, ACR 50, ACR 70, ACR core-set changes, long term safety, immunogenicity
ACR 50, DAS 28
ACR 50, ACR 70, safety, immunogenicity
not stated
Pts. with MTX treatment for at least 6m, stable dose of MTX 10–25 mg QW for at least 4w
Pts. who received MTX treatment (6- 16 mg QW) for 2w for at least 12w prior to the screening visit
Pts. with MTX treatment for at least 6m, stable dose of MTX 10–25 mg QW for at least 4w
Pts. with concomitant MTX treatment (not exactly specified)
Pts. with a stable dose of MTX of 8-25 mg QW
Comment
alth-related Quality of Life; IGA, Investigator’s Global Assessment; m, month/s; MTX, methotrexate; PASI, Psoriasis Area and Severity Score; pts., patients; QW, once weekly; SAE, serious adverse events; sPGA, static Physicians Global Assessment; w, week/s
Abbr.: AE, adverse event; ACR, American College of Rheumatology; ADA, anti-drug antibodies; BSA, body surface area; BW, body weight; DAS 28, disease activity score 28; HRQoL, He-
no registered trials identified
ACR 20
ACR 20
ACR 20
Primary outcome measures
March 2015 DAS 28
June 2014
June 2012
September 2015
Estimated primary completion date
Psoriasis, rheumatoid arthritis, ankylosing spondylitis, ulcerative colitis, Crohn’s disease, psoriatic arthritis
Ustekinumab
No registered trials identified
Psoriasis, ankylosing spondylitis, ulcerative colitis, Crohn’s disease, psoriatic arthritis
NCT01936181 [17]
NCT01927263 [18]
Rheumatoid arthritis
Infliximab
No registered trials identified
Estimated enrollment
Not yet open 486 for participant recruitment
Trial status
Ankylosing spondylitis, ulcerative colitis, Crohn’s disease, psoriatic arthritis
NCT01895309 [14]
NCT01270997 [15]
NCT02115750 [16]
Rheumatoid arthritis
NCT number
Table 2 Continued.
Minireview Biosimilars in chronic inflammatory diseases
Minireview Biosimilars in chronic inflammatory diseases
Figure 1 Flow chart of literature search and study selection.
2015. A trial on the etanercept biosimilar SB4, including 498 rA patients, was registered in June 2013 [14]. Completion was scheduled for June 2014. There is a registered trial on HD203 with 300 rA patients [15] as well as another on CHS0214 with 486 rA patients [16]. Completion was/is expected in June 2012 and September 2015, respectively. Infliximab: Two ongoing RCTs were identified. A trial on the infliximab biosimilar SB2 with 584 rA patients was registered in August 2013 [17], with a scheduled completion date set for August 2014. Another trial, using NI-071 in 230 rA patients, was registered in July 2013; completion was scheduled for March 2015 [18]. Ustekinumab: No published or ongoing RCTs in patients with psoriasis or other indications were identified.
Discussion At present, there is rather limited evidence from clinical trials that helps clinicians make informed decisions on the use of biosimilars. For most clinicians, the drug approval process remains poorly understood and only few have the time to peruse the complex documents issued by EMA or FDA. The biosimilar to infliximab has obtained market authorization following just one clinical trial (in rA) with clinical outcome as primary endpoint and a second trial (in AS) with pharmacokinetics as primary endpoint. In the latter, data on clinical outcome was only provided as secondary outcomes.
In dermatology, direct data on psoriasis patients is missing. For clinicians, additional confusion arises from the fact that there are two different names (Inflectra® and Remsima®) for the same product. The question has been raised whether such diverse patient populations (Pso, PA, rA, AS, CD, and UC) treated with the same biologic may be compared at all. In general, psoriasis patients have been exposed to previous treatment protocols (for example, UV therapy). They also tend to exhibit different patient characteristics that may make them more susceptible to adverse drug reactions than other patient groups (for example, alcohol abuse, liver toxicity). The fact that, for instance, inflammatory bowel diseases respond to infliximab and adalimumab but not to etanercept, whereas etanercept, on the other hand, is effective in psoriasis and rA also clearly underlines the differences between the various disorders. It currently remains unclear whether the EMA approval process succeeds in ensuring complete comparability between biosimilars and their reference products. At the same time, even reference products seem to have undergone manufacturing changes and may now even be considered “biosimilars“ to themselves marked by differences in protein structure [19]. Considering that only 427 patients were exposed to CTP13 during published clinical trials, physicians have to be aware that statistically rare or very rare adverse reactions are unlikely to have been identified, unless pre-approval analysis picked up on relevant events. When looking at the biosimilar pipeline, the situation does not seem to significantly improve with respect to available RCT data. As to psoriasis, evidence is currently being sought for the adalimumab biosimilars ABP 501 and GP2017 in approximately 400 patients, and for the etanercept biosimilar GP2015 in approximately 270 patients. Regarding the already approved infliximab biosimilar CT-P13, no trial on psoriasis patients has been registered. Although not all ongoing biosimilar trials may have been registered, the present situation in terms of registered trials is unsatisfactory and will leave clinicians with a high degree of uncertainty with respect to their treatment decisions. Within the context of the healthcare system, physicians should be aware that the introduction of biosimilars allows for cost reduction and allocation of valuable resources to other areas. In Germany, biosimilars – used for other indications – that are already on the market have yielded price differences between 8 % and 32 % [20]. However, exchanging reference drugs with biosimilars should only be done after careful consideration. Since EMA has set its rules and begun to approve biosimilars, it is now up to the clinical community to start collecting data on efficacy and particularly safety with independent trials and patient registers [21].
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Minireview Biosimilars in chronic inflammatory diseases Correspondence to PD Dr. med. Alexander Nast Division of Evidence Based Medicine (dEBM) Department of Dermatology Charité – Universitätsmedizin Berlin, Charitéplatz 1 10117 Berlin Germany E-mail: [email protected]
References 1
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Plaque Psoriasis. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [cited 2014 May 26]. Available from http://ClinicalTrials.gov/show/ NCT01970488. NLM Identifier: NCT01970488. 11 Sandoz. Study to Demonstrate Equivalent Efficacy and to Compare Safety of Biosimilar Adalimumab (GP2017) and Humira (ADACCESS). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [cited 2014 May 26]. Available from http://ClinicalTrials.gov/show/ NCT02016105. NLM Identifier: NCT02016105. 12 Amgen. Efficacy and Safety Study of ABP 501 Compared to Adalimumab in Subjects With Moderate to Severe Rheumatoid Arthritis (RA). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [cited 2014 May 26]. Available from http://ClinicalTrials.gov/show/NCT01970475. NLM Identifier: NCT01970475. 13 Sandoz. Study to Demonstrate Equivalent Efficacy and to Compare Safety of Biosimilar Etanercept (GP2015) and Enbrel (EGALITY). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [cited 2014 May 26]. Available from http://ClinicalTrials.gov/show/NCT01891864. NLM Identifier: NCT01891864. 14 Samsung Bioepis Co. Ltd. A Study Comparing SB4 to Enbrel® in Subjects With Moderate to Severe Rheumatoid Arthritis Despite Methotrexate Therapy. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000[cited 2014 May 26]. Available from http://ClinicalTrials.gov/ show/NCT01895309. NLM Identifier: NCT01895309. 15 Hanwha Chemical. Randomized Double-blind Parallel Trial to Evaluate Equivalence in Efficacy and Safety of HD203 and Enbrel in RA Patients. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [cited 2014 May 26]. Available from http://ClinicalTrials.gov/show/ NCT01270997. NLM Identifier: NCT01270997. 16 Coherus Biosciences Inc. Comparison of CHS-0214 to Enbrel (Etanercept) in Patients With Rheumatoid Arthritis (RA) (CHS0214-02). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [cited 2014 May 26]. Available from http://ClinicalTrials.gov/show/NCT02115750. NLM Identifier: NCT02115750. 17 Samsung Bioepis Co. Ltd. A Study Comparing SB2 to Remicade® in Subjects With Moderate to Severe Rheumatoid Arthritis Despite Methotrexate Therapy. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [cited 2014 May 26]. Available from http://ClinicalTrials. gov/show/NCT01936181. NLM Identifier: NCT01936181. 18 Nichi-Iko Pharmaceutical Co. Ltd. A Phase 3 Study of NI-071 in Patients With Rheumatoid Arthritis. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [cited 2014 May 26]. Available from http://ClinicalTrials. gov/show/NCT01927263. NLM Identifier: NCT01927263. 19 Schiestl M, Stangler T, Torella C et al. Acceptable changes in quality attributes of glycosylated biopharmaceuticals. Nat Biotechnol 2011; 29: 310–2. 20 Zylka-Menhorn V, Korzilius H. Biosimilars: Das Wettrennen ist in vollem Gange. Dtsch Arztebl International 2014; 111: 452-5. 21 Radtke MA, Augustin M. Biosimilars in psoriasis: what can we expect? J Dtsch Dermatol Ges 2014; 12: 306–12.
© 2015 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2015/1304
Alexander Nast, Stefanie Rosumeck, Karin Seidenschnur Division of Evidence Based Medicine (dEBM), Department of Dermatology, Charité – Universitätsmedizin Berlin, Germany
DOI: 10.1111/ddg.12621
Biosimilars: a systematic review of published and ongoing clinical trials of antipsoriatics in chronic inflammatory diseases
Summary Biosimilars for psoriasis treatment are currently being developed. Comparison of their efficacy and safety is a challenge. For approval, the European Medicines Agency (EMA) considers indirect evidence from other indications (for example, rheumatoid arthritis) as sufficient. Systematic review of biosimilars for psoriasis and other indications, review of ongoing trials in trial registers. Systematic search for randomized controlled trials (RCT) on biosimilars to adalimumab, etanercept, infliximab, and ustekinumab compared to their reference medication: (1) Publications in Medline, Medline In-Process, Embase, Cochrane Library (efficacy, safety, immunogenicity) and (2) ongoing studies in clinical trial registers. No trials on biosimilars in psoriasis patients were identified. As to the infliximab biosimilar, there is data on patients with ankylosing spondylitis and rheumatoid arthritis, indicating no clinically relevant differences regarding efficacy and safety. Currently, there are two registered studies of an adalimumab biosimilar and one study of an etanercept biosimilar in psoriasis patients. Further ongoing studies on biosimilars to adalimumab, etanercept, and infliximab – all in rheumatoid arthritis patients – were identified. There is currently only limited data regarding RCTs with biosimilars. Provision of further clinical data and inclusion of patients in patient registers will be crucial.
Introduction The introduction of biologics has dramatically changed the treatment of psoriasis (Pso), providing treatment options to many patients previously unresponsive to conventional treatment approaches. However, the high costs of biologics imposes a heavy burden on the healthcare system. One potential method of reducing costs is the introduction of ’biosimilars’. These are defined as “biological medicine that is similar to another biological medicine that has already been authorised for use. Biological medicines are medicines that are made by or derived from a biological source, such as a bacterium or
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yeast. They can consist of relatively small molecules such as human insulin or erythropoietin, or complex molecules such as monoclonal antibodies“ [1]. Biosimilars are developed to be similar to an existing biologic (’reference medicine’). They are not 100 % identical, but “essentially the same biological substance, though there may be minor differences due to their complex nature and production methods” [2]. The group of anti-TNF-α antibodies has been approved for several indications such as psoriasis, psoriatic arthritis (PA), Crohn’s disease (CD), ulcerative colitis (UC), ankylosing spondylitis (AS), and rheumatoid arthritis (rA). With respect to market introduction and approval for each indication, studies had to
© 2015 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2015/1304
Minireview Biosimilars in chronic inflammatory diseases
be conducted to meet the standards set by EMA (European Medicines Agency) and FDA (U. S. Food and Drug Administration). For biosimilars, the EMA allows extrapolation of clinical efficacy and safety from trials of the reference biologic in other indications. An “overall evidence of comparability […] with a comprehensive discussion of available literature including the involved antigen receptor(s) and mechanism(s) of action” [3] must be provided. The EMA does not state if biosimilars should be used interchangeably with their respective ’reference medicine’. The objective of this review is to help dermatologists to get a clear understanding of published and ongoing studies on biosimilars.
Methods
Published trials Study and participant characteristics were extracted. The Cochrane Collaboration’s tool for assessing risk of bias was used [4]. Efficacy outcomes, data on immunogenicity, and safety outcomes were extracted. Results were presented as risk ratios (RR) with 95 % confidence interval (CI).
Ongoing trials Available study characteristics (for example identification number, sponsor, phase, disease, intervention) and the definition of primary and secondary outcomes were extracted.
We systematically reviewed (1) published trials on efficacy and safety of biosimilars and (2) registers for planned and ongoing trials with biosimilars.
Results
Eligibility criteria
Eighty-one publications were identified; two studies were included (Figure 1). There was no trial providing data on the treatment of psoriasis patients with biosimilars. One RCT on CT-P13 as biosimilar to infliximab in combination with methotrexate (MTX) in 606 patients with rA (PLANETRA study [5, 6]) was identified, as was another trial with 250 AS patients (PLANETAS study [7–9]). Using a 20 % improvement from baseline in the American College of Rheumatology score (ACR 20) at week 30 as primary endpoint, the PLANETRA study showed no differences between both groups (risk ratio [RR]: 1.04, 95 % confidence interval [CI]: 0.91, 1.19). The primary outcome of the PLANETAS study was pharmacokinetic equivalence, with additional secondary outcomes such as a 20 % improvement from baseline in the Ankylosing Spondylitis Assessment Study (ASAS) group criteria. There were no differences for ASAS 20 at week 30 (RR: 0.97, 95 % CI: 0.83, 1.15). The risk of bias was rated as low for both studies (online only).
Randomized controlled trials (RCTs) investigating biosimilars compared to their ’reference medicine’ (adalimumab, etanercept, infliximab, ustekinumab) in chronic inflammatory diseases (Pso, PA, CD, UC, AS, rA) were included. Non-original data and studies with healthy patients were excluded. No language restrictions applied.
Literature search (1) Published RCTs were systematically searched in Medline, Medline In-Process, Embase, and the Cochrane Library on April 30th, 2014 (sample search strategy is available online, Online Resource 1). (2) The following trial registers were searched: www.controlled-trials.com www.clinicaltrials.gov www.anzctr.org.au http://apps.who.int/trialsearch www.clinicaltrialsregister.eu Search items included various terms used for the relevant diseases – ankylosing spondylitis, Crohn’s disease, ulcerative colitis, rheumatoid arthritis, psoriatic arthritis, and psoriasis vulgaris – in combination with biosimilars.
Study selection and data extraction Two reviewers (AN, SR) independently screened abstracts/ titles for relevance and extracted data from the full texts or from records of the registers. Results were compared and differences resolved by checking the data source and in discussion.
Published RCTs (Table 1)
Planned / ongoing RCTs (Table 2) Three hundred and thirty-four publications were identified; nine studies were included. Adalimumab: There are two registered ongoing RCTs of an adalimumab biosimilar versus adalimumab in 798 psoriasis patients [10, 11]. Completion is scheduled for June and August 2015. One ongoing RCT of the adalimumab biosimilar ABP 501 in 530 patients with rA has been registered [12]. Completion is scheduled for April 2015. Etanercept: There are three ongoing RCTs. One RCT on the etanercept biosimilar GP2015 with 546 psoriasis patients has been registered [13]. Completion is scheduled for April
© 2015 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2015/1304
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First author / study name
Drug
Year
Infliximab 3 mg/kg BW at w0, 2, 6, and then every 8w + MTX 12.5-25mg/ week + folic acid
Biosimilar infliximab (CTP13) 3 mg/kg BW at w0, 2, 6, and then every 8w + MTX 12.525mg/week + folic acid
Infliximab 5 mg/kg BW at w0, 2, 6, and then every 8w
Biosimilar infliximab (CTP13) 5 mg/kg BW at w0, 2, 6, and then every 8w
Pts. with active AS according to the 1984 modified New York classification criteria for ≥3m prior to screening
PGA of disease activity: 64.7 (SD: 14.3)
Disease
ASDAS: 3.9 (SD: 1.1)
ASDAS: 3.8 (SD: 0.8)
PGA of disease activity: 65.0 (SD: 13.5)
Severity
Pts. with active rA according to ACR criteria, prior unsuccessful treatment with MTX over at least 3m
1) result w30: 72.4 % (84/116)
w30: 70.5 % (79/112)
w54: 52.0 % (158/304)
w30: 58.6 % (178/304)
w54: 57.0 % (172/302)
w30: 60.9 % (184/302)
2) result w54: 49.1 %
w30: 47.4 % (55/116)
w54: 54.7 %
w30: 51.8 % (58/112)
w54: 31.6 % (96/304)
w30: 34.2 % (104/304)
w54: 33.1 % (100/302)
w30: 35.1 % (106/302)
AEs
3) result w54: 26.7 % (28/105)
w30: 22.5 % (25/111)
w54: 22.9 % (25/109)
w30: 27.4 % (32/117)
w30: TEAEs: 63.9 %
Serious adverse events
9.3 % (28/302)
Withdrawal due to AE
w30: drug-related infusion reaction: 4.9 %
6.4 % (8/125) 4.0 % (5 related: 2 infu(5/125) sion related reaction, pulmonary tuberculosis, cellulitis and wound infection, Appendix G)
4.8 % (6/125) 6.4 % (4 related: tubercu- (8/125) losis, disseminated tuberculosis, esophageal perforation and dyspnea; Appendix G)
w30: 8.3 % TEAEs: 9.2 % (25/301) w30: 7.0 % (21/301) (28/304) (10 related; Apw54: pendix F) 10.3 % (31/300) w54: 10.3 % (31/300)
w54: 13.9 % (42/302)
w30: 6.6 % TEAEs: (20/301) w30: 10.0 % (30/301) w54: 7.6 % (19 related; (23/302) Appendix F)
Infusion- related reactions
w30: w30: TEAEs: 64.8 % drug-related infusion reaction: 3.9 %
w30: w30: 48.2 % TEAEs: 60.8 % (122/253) (183/301); drug-related TEAEs: 35.9 % (108/301) w54: drug-related TEAEs: 44.7 % (134/300)
w30: w30: 48.4 % TEAEs: 60.1 % (122/252) (181/301); drug-related TEAEs: 35.2 % (106/301) w54: drug-related TEAEs: 43.4 % (131/302)
All pts. were premedicated with an antihistamine (chlorpheniramine 2–4 mg or dose of equivalent antihistamine such as cetirizine 10 mg) 30–60 min prior to the start of infusion at the investigator’s discretion; test for equivalence based on pharmacokinetics
All pts. were premedicated with an antihistamine (chlorpheniramine 2–4 mg or dose of equivalent antihistamine) 30–60 min prior to the start of infusion at the investigator’s discretion; ACR20 at w30 - equivalence: if the 95 % CI is within ± 15 %
Comments
BW, body weight; m, month/s; MTX, methotrexate; pts., patients; PGA, Physician Global Assessment; SD, standard deviation; TEAE, treatment-emergent AEs; w, week/s
Abbr.: ACR20/50, American College of Rheumatology (20 % and 50 %); ADA, anti-drug antibodies; ASAS20/40, ASAS responses (20 % and 40 %); ASDAS, Ankylosing Spondylitis Disease Activity Score;
Park [7] PLANETAS Study Park 2012 [8] Park 2012 [9]
2013
Ankylosing spondylitis (AS)
Yoo [5] PLANETRA Study Yoo 2013 [6]
2013
Rheumatoid Arthritis (rA)
Infliximab
Study ID
NCT01217086
NCT01220518
Number (n) randomized 302 304 125
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125
Study duration [w] 54 54
1) endpoint ACR20 ASAS20
2) endpoint ACR50 ASAS40
3) endpoint Pts. with ADAs Pts. with ADAs
Sponsor CELLTRION Inc.
296 CELLTRION Inc.
Table 1 Included RCTs investigating biologics and their biosimilars (date: April 30th, 2014).
Minireview Biosimilars in chronic inflammatory diseases
NCT number
Adalimumab 80 mg at w0, followed by 40 mg every other week for 33w
GP2017 80 mg at w0, followed by 40 mg every other week for 33w
Adalimumab 40 mg every other week for 50w
ABP 501 40 mg every other week for 50w
Intervention
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Adalimumab 40 mg every other week for 22w
ABP 501 40 mg every other week for 22w
Sponsor Amgen
Sandoz / Hexal
Amgen
Phase 3
3
3
Ongoing, not recruiting
Recruiting
Ongoing, not recruiting
Trial status
NCT01891864 [13]
Psoriasis
Etanercept
Etanercept 50 mg BIW for 12w, thereafter 50 mg QW
GP2015 50 mg BIW for 12w, thereafter 50 mg QW
no registered trials identified
Sandoz / Hexal
3
Ongoing, not recruiting
Ankylosing spondylitis, ulcerative colitis, Crohn’s disease, psoriatic arthritis
NCT01970475 [12]
Rheumatoid arthritis
NCT02016105 [11]
NCT01970488 [10]
Psoriasis
Adalimumab
Estimated enrollment 546
530
448
350
Study start June 2013
October 2013
December 2013
October 2013
April 2015
April 2015
June 2015
August 2015
Estimated primary completion date
Table 2 Included ongoing or planned studies investigating biologics and their biosimilars (date: 30th April, 2014). Secondary outcome measures
Primary outcome measures PASI 75
ACR 20
PASI 75
PASI 50, PASI 90, PASI score, injection site reactions, immunogenicity
DAS 28, ACR 50, ACR 70, ADA, AE, SAE, laboratory values, vital signs
PASI 50, PASI 90, PASI 100, IGA, HRQoL
PASI percentage PASI 75, sPGA, BSA, improvement AE, SAE, laboratory values, vital signs, ADA
Comment -
Continued
Pts. with MTX treatment for at least 12w, stable dose of MTX 7.5–25 mg QW for at least 8w; pts. with an inadequate response to MTX
-
-
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298
Intervention
Etanercept 50 mg QW
SB4 50 mg QW
Etanercept 25 mg BIW for 48w
HD203 25 mg BIW for 48w
Etanercept 50 mg QW for 24w
CHS-0214 50 mg QW for 24w
Sponsor Samsung Bioepis Co., Ltd.
Hanwha Chemical
Coherus Biosciences, Inc.
Phase 3
3
3
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Ongoing, not recruiting
Unknown
Infliximab 3 mg/kg BW at w0, 2, 6 then every 8 w
SB2 3 mg/kg BW at w0, 2, 6 then every 8w
Infliximab 100 mg/vial for 54w
NI-071 100 mg/vial for 54w
Samsung Bioepis Co., Ltd.
3
Nichi-Iko 3 Pharmaceutical Co., Ltd. Ongoing, not recruiting
Recruiting
584
230
498
300
Study start August 2013
July 2013
June 2013
January 2011
May 2014
August 2014
ACR 20
Secondary outcome measures ACR 50, DAS 28
ACR 20, ACR 50, ACR 70, ACR core-set changes, long term safety, immunogenicity
ACR 50, DAS 28
ACR 50, ACR 70, safety, immunogenicity
not stated
Pts. with MTX treatment for at least 6m, stable dose of MTX 10–25 mg QW for at least 4w
Pts. who received MTX treatment (6- 16 mg QW) for 2w for at least 12w prior to the screening visit
Pts. with MTX treatment for at least 6m, stable dose of MTX 10–25 mg QW for at least 4w
Pts. with concomitant MTX treatment (not exactly specified)
Pts. with a stable dose of MTX of 8-25 mg QW
Comment
alth-related Quality of Life; IGA, Investigator’s Global Assessment; m, month/s; MTX, methotrexate; PASI, Psoriasis Area and Severity Score; pts., patients; QW, once weekly; SAE, serious adverse events; sPGA, static Physicians Global Assessment; w, week/s
Abbr.: AE, adverse event; ACR, American College of Rheumatology; ADA, anti-drug antibodies; BSA, body surface area; BW, body weight; DAS 28, disease activity score 28; HRQoL, He-
no registered trials identified
ACR 20
ACR 20
ACR 20
Primary outcome measures
March 2015 DAS 28
June 2014
June 2012
September 2015
Estimated primary completion date
Psoriasis, rheumatoid arthritis, ankylosing spondylitis, ulcerative colitis, Crohn’s disease, psoriatic arthritis
Ustekinumab
No registered trials identified
Psoriasis, ankylosing spondylitis, ulcerative colitis, Crohn’s disease, psoriatic arthritis
NCT01936181 [17]
NCT01927263 [18]
Rheumatoid arthritis
Infliximab
No registered trials identified
Estimated enrollment
Not yet open 486 for participant recruitment
Trial status
Ankylosing spondylitis, ulcerative colitis, Crohn’s disease, psoriatic arthritis
NCT01895309 [14]
NCT01270997 [15]
NCT02115750 [16]
Rheumatoid arthritis
NCT number
Table 2 Continued.
Minireview Biosimilars in chronic inflammatory diseases
Minireview Biosimilars in chronic inflammatory diseases
Figure 1 Flow chart of literature search and study selection.
2015. A trial on the etanercept biosimilar SB4, including 498 rA patients, was registered in June 2013 [14]. Completion was scheduled for June 2014. There is a registered trial on HD203 with 300 rA patients [15] as well as another on CHS0214 with 486 rA patients [16]. Completion was/is expected in June 2012 and September 2015, respectively. Infliximab: Two ongoing RCTs were identified. A trial on the infliximab biosimilar SB2 with 584 rA patients was registered in August 2013 [17], with a scheduled completion date set for August 2014. Another trial, using NI-071 in 230 rA patients, was registered in July 2013; completion was scheduled for March 2015 [18]. Ustekinumab: No published or ongoing RCTs in patients with psoriasis or other indications were identified.
Discussion At present, there is rather limited evidence from clinical trials that helps clinicians make informed decisions on the use of biosimilars. For most clinicians, the drug approval process remains poorly understood and only few have the time to peruse the complex documents issued by EMA or FDA. The biosimilar to infliximab has obtained market authorization following just one clinical trial (in rA) with clinical outcome as primary endpoint and a second trial (in AS) with pharmacokinetics as primary endpoint. In the latter, data on clinical outcome was only provided as secondary outcomes.
In dermatology, direct data on psoriasis patients is missing. For clinicians, additional confusion arises from the fact that there are two different names (Inflectra® and Remsima®) for the same product. The question has been raised whether such diverse patient populations (Pso, PA, rA, AS, CD, and UC) treated with the same biologic may be compared at all. In general, psoriasis patients have been exposed to previous treatment protocols (for example, UV therapy). They also tend to exhibit different patient characteristics that may make them more susceptible to adverse drug reactions than other patient groups (for example, alcohol abuse, liver toxicity). The fact that, for instance, inflammatory bowel diseases respond to infliximab and adalimumab but not to etanercept, whereas etanercept, on the other hand, is effective in psoriasis and rA also clearly underlines the differences between the various disorders. It currently remains unclear whether the EMA approval process succeeds in ensuring complete comparability between biosimilars and their reference products. At the same time, even reference products seem to have undergone manufacturing changes and may now even be considered “biosimilars“ to themselves marked by differences in protein structure [19]. Considering that only 427 patients were exposed to CTP13 during published clinical trials, physicians have to be aware that statistically rare or very rare adverse reactions are unlikely to have been identified, unless pre-approval analysis picked up on relevant events. When looking at the biosimilar pipeline, the situation does not seem to significantly improve with respect to available RCT data. As to psoriasis, evidence is currently being sought for the adalimumab biosimilars ABP 501 and GP2017 in approximately 400 patients, and for the etanercept biosimilar GP2015 in approximately 270 patients. Regarding the already approved infliximab biosimilar CT-P13, no trial on psoriasis patients has been registered. Although not all ongoing biosimilar trials may have been registered, the present situation in terms of registered trials is unsatisfactory and will leave clinicians with a high degree of uncertainty with respect to their treatment decisions. Within the context of the healthcare system, physicians should be aware that the introduction of biosimilars allows for cost reduction and allocation of valuable resources to other areas. In Germany, biosimilars – used for other indications – that are already on the market have yielded price differences between 8 % and 32 % [20]. However, exchanging reference drugs with biosimilars should only be done after careful consideration. Since EMA has set its rules and begun to approve biosimilars, it is now up to the clinical community to start collecting data on efficacy and particularly safety with independent trials and patient registers [21].
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Minireview Biosimilars in chronic inflammatory diseases Correspondence to PD Dr. med. Alexander Nast Division of Evidence Based Medicine (dEBM) Department of Dermatology Charité – Universitätsmedizin Berlin, Charitéplatz 1 10117 Berlin Germany E-mail: [email protected]
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