L ESPERIENZA DEL REUMATOLOGO. Prof. Roberto Giacomelli Direttore Cattedra e scuola di specializzazione Reumatologia L Aquila

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1 L ESPERIENZA DEL REUMATOLOGO Prof. Roberto Giacomelli Direttore Cattedra e scuola di specializzazione Reumatologia L Aquila

2 INTRODUCTION Biosimilars, biopharmaceuticals that have been assessed by regulatory agencies to have efficacy and safety similar to their reference products, are approved by these agencies according to specific evaluation pathways. For approval, a comprehensive dossier of analytical, preclinical, pharmacokinetic, pharmacodynamic and clinical data that demonstrates comparable efficacy and safety of the biosimilar and its offpatent reference biopharmaceutical is required. Several biosimilars are now available for the treatment of rheumatic diseases. Dörner, T. & Kay, J. Nat. Rev. Rheumatol. 2015

3 Biosimilars and biomimics (biocopies) The European Medicines Agency (EMA) defines biosimilars as biological medicinal products that contain a version of the active substance of an already authorized, original biological medicinal product. A biosimilar agent is similar to the reference medicinal product in terms of quality characteristics, biological activity, safety and efficacy based on a comprehensive comparability exercise. The distinction between biosimilars and biomimics versions of monoclonal antibodies or fusion proteins available in countries where regulation is less strict is of great importance. Biomimics are known as biocopies, intended copies, or nonregulated biologics. Dörner T; Ann. Rheum. Dis. 72, (2013) Scheinberg MA Nat. Rev. Rheum. 8, (2012) Schneider C Ann. Rheum. Dis. 72, (2013) Castañeda-Hernandez, GJ oint Bone Spine 81, (2014)

4 Some biomimics, including Etanar and Infinitam, both etanercept Biomimics, and Kikuzubam, a rituximab biomimic, have distinct safety profiles with higher rates of adverse events when compared with their reference products. In a cohort of 647 patients with a spectrum of rheumatic diseases, 198 (30.6%) experienced at least one adverse event with these drugs. These events emphasize the importance of rigorous regulatory pathways for biosimilar approval in ensuring patient safety. Castañeda-Hernández, G., RMD Open 2015, e (2015)

5 Rationale for the development of biosimilars In 2012, worldwide sales of the top three selling TNFi reached US$20 billion,13 with total annual sales for rheumatic disorders approaching US$30 billion per year. This amounts to a US$ per patient per year financial burden to patients or third-party payers of healthcare. In addition, there is a humanistic burden due to restricted access caused by budget constraints in many countries around the world. Thus, there is significant interest in efficacious, lower-cost biosimilars. Dorner T Ann Rheum Dis 2013;72: The Biologics Price Competition and Innovation Act (BPCI Act), which is part of the Patient Protection and Affordable Care Act, created an abbreviated pathway for licensure of biologic products that are demonstrated to be biosimilar to or interchangeable with a previously approved FDA-licensed biological product (termed reference product), which are expected to improve access to biologic drugs for rheumatologic and other diseases.

6 Overview of biosimilar product development NP Nikolov, Nat Rev Rheumatol. 2017

7 NP Nikolov, Nat Rev Rheumatol. 2017

8 EMA guidance on biosimilar mabs: a stepwise approach Dörner, T. & Kay, J. Nat. Rev. Rheumatol. 2015

9 Essential characteristics and clinical study requirements for the approval of biosimilar products in the EU and USA Dorner T Ann Rheum Dis 2013;72:

10 A. Rischin, Inflammopharmacology Apr;25(2):

11 Approved etanercept biosimilars HD203 is an etanercept biosimilar with an amino acid sequence identical to that of its reference product (Enbrel, Amgen Inc., USA). This biosimilar is produced by recombinant DNA technology in Chinese hamster ovary cells, as is the reference product. In November 2014, the South Korean Ministry of Food & Drug Safety (MOFDS) granted Hanwha Chemical Co., Ltd of South Korea approval to market HD203 as Davictrel to treat RA. In January 2015, Samsung Bioepis (South Korea) submitted an application for market authorization within the EU to the EMA for SB4, another etanercept biosimilar.

12 The efficacy and safety of HD203 and reference etanercept, each administered in combination with MTX, were compared in the HERA study in 294 Korean patients with RA who were randomly allocated in a 1:1 ratio to receive either drug for 48 weeks. The proportion of patients who achieved a clinical response according to the ACR20 at week 12 did not differ significantly between the HD203 group (83.48%) and reference etanercept group (81.36%). No significant differences were observed between the two treatment groups in any of the secondary endpoints (ACR50, ACR70, DAS28). The rate of treatment-emergent adverse events was also similar between the two groups: 76.87% for HD203 and 78.08% for reference etanercept. Furthermore, no significant differences between the HD203 and reference etanercept groups were observed in the number or severity of adverse events, treatment discontinuation owing to adverse events, infections or rare adverse events. Yi, S, BioDrugs 26, (2012). Bae, S. C. Arthritis Rheumatol. 66, S1234 (2014).

13 Burness CB, BioDrugs Aug;30(4):371-8.

14 Approved infliximab biosimilars CT-P13 was the first infliximab biosimilar for which marketing approval was granted by regulatory agencies. This approval was based on two landmark clinical trials in which CT-P13 was compared to reference infliximab (Remicade, Janssen Biotech, Inc.). A phase I study (PLANETAS) of 250 patients with AS, and a phase III study (PLANETRA) of 606 patients with RA who were also receiving MTX.

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16 Mean serum concentrations of infliximab (INX) and CT-P13 versus time by treatment. Efficacy was highly similar between the two groups, as measured by all efficacy endpoints. Mean serum drug concentration of CTP13 and INX following administration of Doses 1 6 ASAS20 response was achieved in 62.6% and 70.5% for CT-P13 and 64.8% and 72.4% for INX at weeks 14 and 30. ASAS40 response was achieved in 41.7% and 51.8% for CT-P13 and 45.9% and 47.4% for INX at weeks 14 and 30 respectively. The mean change from baseline in the ASDAS-CRP score was highly similar for both treatment groups at weeks 14 ( 1.8; SD=1.1 vs 1.8; SD=1.1) and 30 ( 1.8; SD=1.2 vs 1.7; SD=1.2) for CT-P13 and INX, respectively.

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19 Approved adalimumab biosimilars ZRC-3197 was approved as a similar biologic of adalimumab by the DCGI on December 9, 2014 and, as such, was the first adalimumab biosimilar approved by a regulatory agency. ZRC-3197, developed and marketed by Zydus Cadila (India) in India as Exemptia to treat RA, juvenile inflammatory arthritis, PsA and AS, is described as a fingerprint match of the reference adalimumab (Humira, Abbvie Inc., USA) in terms of safety, purity and potency. Functional properties, including affinity for TNF and FcγRIIIa receptors and in vitro TNF-neutralizing activity, were also highly similar. A comparative toxicology study conducted in animals showed no significant differences between ZRC-3197 and reference adalimumab in vivo.

20 The Cadila Healthcare Laboratory (India) conducted a clinical trial in India that compared ZRC-3197 and reference adalimumab in 120 patients with RA. The results of this trial have not been published in a peer-reviewed journal nor have they been presented at a major meeting in abstract form. Instead, the trial results were posted on the Exemptia website. ZRC-3197 and reference adalimumab were each administered subcutaneously, presumably at a dose of 40 mg every other week, to 120 patients with active RA who were randomly allocated in a 1:1 ratio to receive either drug for 12 weeks. In the per protocol population at week 12, 82% of ZRC-3197-treated patients achieved an ACR20 response, compared with 79.2% of those treated with reference adalimumab. No statistically significant difference was observed between treatment groups in ACR20, ACR50 or ACR70 responses. Similar numbers of adverse events and serious adverse events were reported by patients in each treatment group. Exemptia. Clinical Data [online], (2015). Exemptia. Adalimumab. Exemptia [online], (2014).

21 Immunogenicity of biosimilars One of the interesting lessons provided by biosimilar research relates to aspects of immunogenicity, both for biosimilars and for reference products. Monoclonal antibodies generated in vitro to be administered to patients are foreign antigens that undergo a set of defined processes from transcription to various posttranslational modifications. These processes can generate heterogeneity of the expressed monoclonal protein, which contributes to its immunogenicity. Although biosimilar agents are produced by cell lines and undergo various purification steps in vitro, studies reported to date have not found substantial differences between biosimilars and their reference products in the three domains rigorously studied during biosimilar development pharmacokinetics, pharmacodynamics and immunogenicity. Interestingly, the different proprietary methods used to produce reference products and biosimilars have not resulted in differences in efficacy or safety, including immunogenicity. Dörner, T. & Kay, J. Nat. Rev. Rheumatol. 2015

22 ADA induction after treatment with infliximab or CT-P13. The frequency of ADAs was higher among patients with RA, who received 3 mg/kg infliximab (biosimilar or reference) in combination with MTX, than among patients with AS, who received 5 mg/kg infliximab (biosimilar or reference) as monotherapy. This observation might reflect the different immunological processes underlying these two diseases, but the higher levels of therapeutic monoclonal antibodies in patients with AS (who were treated with a higher dose of infliximab) could have induced immunological tolerance.

23 A phase I trial of another infliximab biosimilar, PF , compared infliximab produced in the EU (infliximab-eu), infliximab produced in the USA (infliximab-us) and PF (randomized 1:1:1) in 146 healthy volunteers over 85 days. However, fewer individuals treated with the biosimilar agent (6/37; 16.2%) developed ADAs compared with those treated either with infliximab-eu (14/43; 32.6%) or with infliximab-us (11/39; 28.2%). Most of the ADA-positive individuals in the study developed neutralizing antibodies. In a phase III study of the infliximab biosimilar BOW015, conducted in patients with RA, ADAs were detected (using a bridging ELISA) at week 14 in 22.1% of individuals who received BOW015 and 35.5% of those who received reference infliximab. In the subsequent open-label phase, during which all individuals received BOW015, ADA development was similar in patients who received initial treatment with either the biosimilar or the reference drug (42% versus 47% at week 30, and 65% versus 66% at week 58, respectively). Kay, J Ann. Rheum. Dis. 74 (Suppl. 2), 706 (2015) Lambert, J Ann. Rheum. Dis. 74 (Suppl. 2), 462 (2015).

24 Effects of ADA on drug efficacy Data from comparative studies between biosimilars and their reference products indicate clearly that ADAs have the potential to influence the efficacy of biologic therapy, at least in RA and AS. ADAs should be considered as an important biomarker of the response to both biosimilar and reference drugs. Data on reference TNF inhibitors, such as adalimumab and infliximab, have already documented that ADAs and resulting drug levels are associated with better clinical responses in patients with RA. This effect is generally accepted for inflammatory bowel diseases, in which patients are dosed according to the trough level of the drug, but this approach is not widely used in rheumatology practice. Mazilu, D. Biomed. Res. Int. 2014, (2014). D Haens, G. RJ. Crohns Colitis 8, (2014).

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29 Monitoring biosimilars, Switching, substitution and interchangeability Drug switching takes place when a patient is transitioned from one biopharmaceutical to another or from a reference biopharmaceutical to its biosimilar. A switch study demonstrating no loss of efficacy nor increase in risk would support the transition under consideration. Drug substitution, on the other hand, refers to the replacement of one biopharmaceutical with another by someone other than the licensed healthcare professional who prescribed the medication. In the USA, according to the Biologics Price Competition and Innovation Act of 2009 if a biosimilar agent is determined to be interchangeable with its reference product, a pharmacist would be allowed to substitute a prescribed biological therapy for a biosimilar agent without involving the prescribing physician. Dörner, T. & Kay, J. Nat. Rev. Rheumatol. 2015

30 EMA. Study design to compare the efficacy of reference drugs and biosimilars. Switching, as has been carried out in clinical trials of some biosimilars, is compared with substitution involving single or multiple switches, as potential study designs to support the FDA designation of interchangeability. Switch studies are not required for approval by the

31 In the EU, the EMA does not designate biosimilars as interchangeable; rather, this decision is left with the national agency that regulates health-care drugs in each member country. Norway has initiated the NOR-SWITCH study for CT-P13, in which the transition from reference infliximab to CT-P13 is being evaluated in 500 patients with diseases for which infliximab is approved (AS, Crohn disease, PsA, psoriasis, RA and ulcerative colitis). Health Canada does not address the issue of interchangeability; instead, regulation of drug substitution remains with the pharmacy board in each Canadian province. EULAR. Biosimilars: what do patients need to consider? The European League Against Rheumatism [online], pdf (2015). US National Library of Medicine. ClinicalTrials.gov [online], (2015).

32 DAN-BIO registry Disease activity, median (IQR) Delta-values, median (IQR) P* 3 months Switch 3 months Pre-switch Post-switch pre-switch post-switch RA/PSA DAS ( ) 2.3 ( ) 2.3 ( ) 0.0 ( ) 0.1 ( ) 0.07 HAQ 0.6 ( ) 0.6 ( ) 0.5 ( ) 0.0 ( ) 0.0 ( ) 0.5 CRP, mg/l 4 (2 7) 4 (2 8) 6 (3 9) 0 ( 2 1) 0 ( 1 3) 0.03 VAS pt's global, mm 26 (11 52) 27 (11 56) 26 (11 55) 0 ( 7 8) 0 ( 7 9) 0.04 SpA BASDAI, mm 26 (12 47) 23 (7 41) 23 (7 41) 0 ( 4 5) 0 ( 3 3) 0.5 CRP, mg/l 4 (1 8) 2 (1 5) 5 (1 9) 0 ( 2 2) 0 ( 2 2) 0.5 VAS pt's global, mm 28 (15 57) 31 (15 56) 24 (10 52) 1 ( 4 8) 2 ( 9 2) 0.3 ASDAS 2.0 ( ) 1.9 ( ) 1.8 ( ) 0.0 ( ) 0.0 ( ) 0.8 In 647 patients with inflammatory rheumatic diseases treated with Remicade for >4 years, disease activity was largely unaffected in the majority of patients 3 months after non-medical switch to biosimilar Remsima and comparable to the fluctuations observed in the 3 months prior to the switch. However, several patients ( 6%) stopped treatment due to LOE or AE. This warrants further investigation before such a non-medical switch can be recommended.

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34 Monitoring biosimilars, Pharmacovigilance, Naming Pharmacovigilance, embedded in postmarketing surveillance, is of critical importance for biosimilars. As the abbreviated clinical development programme of biosimilar agents is less able to identify small safety risks (compared with the development of reference products), appropriate pharmacovigilance measures need to be implemented after approval is granted. To avoid confusion between biosimilar agents and their reference products during pharmacovigilance, specific nomenclature is necessary to distinguish each biosimilar from its reference drug and from each other. It has been suggested that a Greek letter or a combination of several letters could be appended to the end of the International Nonproprietary Name (INN) of each biopharmaceutical. Alternatively, a biologic qualifier (BQ) (a four-digit code proposed by the WHO) could be used to distinguish reference products and biosimilars from one another. World Health Organization. 55 th Consultation on International Nonproprietary Names for Pharmaceutical Substances, Geneva, October 2012 [online], European Commission. Commission implementing directive 2012/52/EU of 20 December 2012 laying down measures to facilitate the recognition of medical prescriptions issued in another Member State [online],.

35 Extrapolation of indications Once licensed, a biosimilar agent is no longer granted special consideration when seeking additional indications, being considered as a licensed biopharmaceutical like all others. As such, to obtain any additional indication, the licensed biosimilar must follow the traditional regulatory pathway for biopharmaceuticals. In the USA, the 351(a) pathway for biopharmaceutical approval requires two randomized, placebo-controlled clinical trials (conducted in patients with the disease for which the indication is being sought) that demonstrate both efficacy and safety of the biological agent in that disease state. Thus, even if regulatory agencies grant approval to a biosimilar for indications for which the reference product is licensed, but in which the biosimilar agent has not been studied, clinicians might be reluctant to follow this approval. Danese, S. J. Crohns Colitis 7, (2013). Danese, J. Crohns Colitis 8, (2014). Fiorino, Best Pract. Res. Clin. Gastroenterol. 28, (2014). Fiorino, G. Autoimmun. Rev. 13, (2014). Gecse, K. BGut 62, (2013). Hlavaty, T. Eur. J. Gastroenterol. Hepatol. 26, (2014).

36 T. A. Kanters, Front. Pharmacol., 31 May 2017

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38 CONCLUSIONS As with the introduction of targeted biologic therapies at the end of the past millennium, the availability of biosimilars in clinical practice is a paradigm shift in the treatment of patients with rheumatological and other inflammatory diseases. However, unanswered questions remain, particularly regarding extrapolation of indications, switching and interchangeability, naming and traceability, and long-term safety of biosimilars. Further studies, including postmarketing surveillance using data acquired from registries, are needed to give health-care providers confidence in these lower-cost therapeutics. Information gained from the comparative study of biosimilars and their reference products will also provide important additional information about the reference biopharmaceuticals. Importantly, health-care providers must retain full authority regarding the decision of which biopharmaceutical to use to treat their patients.