Ιατρική Σχολή Πανεπιστημίου Ιωαννίνων

Παρουσίαση με θέμα: "Ιατρική Σχολή Πανεπιστημίου Ιωαννίνων"— Μεταγράφημα παρουσίασης:

1 Ιατρική Σχολή Πανεπιστημίου Ιωαννίνων
SB4:Η Ετανερσέπτη από τη Biogen. Κλινικά δεδομένα και ιδιαίτερα χαρακτηριστικά Αλέξανδρος Α. Δρόσος Ιατρική Σχολή Πανεπιστημίου Ιωαννίνων

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3 Mahajan TD, et al. Curr Opin Rheumatol 2018;30:231-237

4 Mahajan TD, et al. Curr Opin Rheumatol 2018;30:231-237

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7 Ορισμός βιοομοειδών (I)
World Healthcare Organization (WHO) A biotherapeutic product similar in terms of quality, safety, and efficacy to an already licensed reference biotherapeutic product U.S Food & Drugs Administration (FDA) A biological product that is highly similar to a reference biological product notwithstanding minor differences in clinically inactive components and there are no clinically meaningful differences between the biological product and reference product in terms of the safety, purity, or potency of the product European Medicines Agency (EMA) A biosimilar is biological medicine highly similar to another already approved biological medicine in the European Union (EU), for which marketing exclusivity rights have expired. They are required to demonstrate through comprehensive comparability studies with the “reference” biological medicine that it is highly similar and that there are no clinically meaningful differences between the biosimilar and the reference medicine in terms of safety, quality and efficacy

8 Ορισμός βιοομοειδών (II)
Greek Rheumatology Society (E.R.E) Ως βιοομοειδές ορίζεται ένα βιολογικό φαρμακευτικό προϊόν το οποίο είναι παρόμοιο με το προϊόν αναφοράς, το οποίο είναι ένας ήδη εγκεκριμένος βιολογικός παράγοντας. Δεδομένης της ενδογενούς περιπλοκότητας και μεταβλητότητας των βιολογικών παραγόντων αυτών καθ’ εαυτών, η οποία οφείλεται στη διαδικασία παραγωγής τους εντός σειρών κυτταρικών καλλιεργειών, την τεταρτοταγή πρωτεϊνική τους δομή και τις μετα-μεταφραστικές τροποποιήσεις που αυτοί υφίστανται, το βιοομοειδές εξ ορισμού δεν μπορεί να είναι ταυτόσημο με το πρωτότυπό του, και αυτό το διαχωρίζει από τα «αντίγραφα»

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10 Περίγραμμα ομιλίας: Δημοσιεύσεις (I)

11 Περίγραμμα ομιλίας: Δημοσιεύσεις (II)
Emery P, Vencovský J, Sylwestrzak A et al. A phase III randomised, double-blind, parallel-group study comparing SB4 with etanercept reference product in patients with active rheumatoid arthritis despite methotrexate therapy. Ann Rheum Dis Jan;76(1):51-57 Emery P, Vencovský J, Sylwestrzak A, et al. 52-week results of the phase 3 randomized study comparing SB4 with reference etanercept in patients with active rheumatoid arthritis Rheumatology (Oxford) Dec 1;56(12): Emery P, Vencovský J, Sylwestrzak A et al. Long-term efficacy and safety in patients with rheumatoid arthritis continuing on SB4 or switching from reference etanercept to SB4. Ann Rheum Dis Aug 9. doi: /annrheumdis [Epub ahead of print]

12 Περίγραμμα ομιλίας: Δημοσιεύσεις (III)

13 Lee YJ, et al. Br J Clin Pharmacol. 2016 Jul;82(1):64-73.
Φαρμακοκινητική μελέτη Φάσης Ι που συγκρίνει το SB4 με ΕΤΝ, σε υγιείς άρρενες Lee YJ, et al. Br J Clin Pharmacol Jul;82(1):64-73. This phase I, single-blind, 3-part, 2-treatment sequence, 2-period, cross-over study in healthy volunteers has been designed according to the 2014 EMA (European Medicines Agency) guideline, which declares a single-dose cross-over study with full characterization of the PK profile, including the late elimination phase as preferable. Single-blind means that only the investigating physicians were not aware of which product was injected subcutaneously. Overall it needs to be highlighted that this SB4 Phase I study is very well designed and delivers robust data because Both EU- and US-sourced etanercept (EU-ETN, US-ETN) were used as reference products in order to examine whether three-biologic etanercepts from different manufacturing sources are comparable to each other primarily in pharmacokinetics (PK). The advantage of this 3-part study design is that once you are able to demonstrate comparability of the biosimilar to originator drugs from different sources in Phase I, you can use an originator from only one source for Phase III. This procedure may pre-empt potential concerns of regulatory bodies who may not decide to extrapolate the results evaluated with a single-source reference drug to another reference drug sourced from a different origin. This was for example the case with Celltrion®; the FDA questioned comparability to US-sourced Remicade®, which was not used in their clinical study program, and asked for additional studies. Primary and secondary objectives were assessed in healthy volunteers to reduce the risk of confounding factors that may have been encountered when examining the PK profile of patients who suffer from a disease – e.g.: Phase 1 study of Celltrion® in ankylosing spondylitis

14 Στόχοι μελέτης Πρωτεύον Τελικό Σημείο
Επίδειξη της φαρμακοκινητικής βιοϊσοδυναμίας του: SB4 και του προερχόμενου από την EΕ (EU-ETN) SB4 και του προερχόμενου από τις ΗΠΑ ETN (US-ETN) EU-ETN και US-ETN Δευτερεύοντα Τελικά Σημεία Σύγκριση της ασφάλειας, της ανοχής και της ανοσογονικότητας του SB4 με αυτά της ΕΕ-ΕΤΝ και των ΗΠΑ- ΕΤΝ σε υγιή αρσενικά άτομα Primary and secondary study objectives The primary objective of this study was to demonstrate pharmacokinetic (PK) equivalence of SB4 to EU-sourced etanercept (EU-ETN), of SB4 to US-sourced etanercept (US-ETN) and of EU-ETN to US-ETN. The secondary objective of this study was to compare safety, tolerability, and immunogenicity between SB4 and EU-ETN, SB4 and US-ETN, and EU-ETN and US- ETN in healthy male subjects. The primary PK endpoints were: Area under the concentration–time curve (i.e. the total drug exposure in the body over time) from time zero to infinity (AUCinf) Area under the concentration–time curve from time zero to the last quantifiable concentration (AUClast) Maximum serum concentration (Cmax) Secondary endpoints encompassed: Time needed to achieve the peak serum concentration (Tmax), volume of distribution (Vd), elimination half life (t1/2), safety, and immunogenicity were also measured. Benepali® (etanercept) Εκπαιδευτική ενότητα Lee YJ, et al. Br J Clin Pharmacol Jul;82(1):64-73.

15 Περίοδος 1 Περίοδος 2 SB4 EU-ETN US-ETN Μέρος A(n=46) Δόση Εβδομάδα –3 Ημέρα –21 Εβδομάδα 0 Ημέρα 1 Εβδομάδα 3 Ημέρα 21 Εβδομάδα 4 Ημέρα 29 Εβδομάδα 7 Ημέρα 49 Διαλογή Δειγματοληψία ανοσογονικότητας PK Δειγματοληψία Σχεδιασμός μελέτης 138 υγιείς άρρενες τυχαιοποιήθηκαν για να λάβουν μία εφάπαξ δόση SB4, EU-ETN ή US-ETN 50 mg με υποδόρια ένεση την περίοδο 1, ακολουθούμενη από διασταυρούμενη θεραπεία στην περίοδο 2. Study Design The study consisted of the following three parts: Part A: Comparison between SB4 and EU-sourced etanercept (EU-ETN) Part B: Comparison between SB4 and US-sourced etanercept (US-ETN) Part C: Comparison between EU-ETN and US ETN A total of 138 healthy male subjects aged 18–55 years were enrolled for all three parts combined. In each individual part, 46 healthy male subjects were randomized to receive a single, 50 mg subcutaneous injection of the test drug or originator drug (or the two originator drugs) in period 1 until week 3. After an 8-day washout period, subjects received the crossover treatment in period 2 until week 7 (The cross-over design is favorable as the influence of confounding covariates is reduced because each crossover patient basically serves as his or her own control). Immunogenicity sampling took place on Day 1 (before the first dose) and on Day 29 (before the second dose). Pharmacokinetic sampling took place before treatment and from 6 to 480 hours after each treatment at various time points throughout the study ETN, etanercept; EU-ETN, EU-sourced ETN; PK, pharmacokinetic; US-ETN, US-sourced ETN. Lee YJ, et al. Br J Clin Pharmacol Jul;82(1):64-73.

16 Τα προφίλ PK των SB4 και ΕΕ-ΗΠΑ για το ETN ήταν πολύ παρόμοια
Συγκέντρωση στον ορό – χρονικά προφίλ (mean ± SD) Benepali vs. EU-ETN Benepali vs. US-ETN US-ETN vs EU-ETN 10.0 10.0 10.0 1.0 1.0 1.0 Συγκέντρωση στον ορό (μg/mL) Serum concentration (μg/mL) Serum concentration (μg/mL) 0.1 0.1 0.1 SB4 SB4 EU-ETN Pharmacokinetics 128 subjects were included for pharmacokinetic (PK) analysis: 42 in Part A, 44 in Part B, and 42 in Part C. 4 subjects (3 in Part A and 1 in Part B) were excluded from the PK analysis because of carry-over effects. The mean serum etanercept (ETN) concentration–time profiles of the two treatments in each part were superimposable: In Part A, SB4 was comparable to EU-ETN In Part B, SB4 was comparable to US-ETN In Part C, US-ETN was comparable to EU-ETN EU-ETN US-ETN US-ETN 0.01 0.01 0.01 100 200 300 400 500 100 200 300 400 500 100 200 300 400 500 Χρόνος (h) Χρόνος (h) Χρόνος (h) ETN, etanercept; SD, standard deviation Lee YJ, et al. Br J Clin Pharmacol Jul;82(1):64-73.

17 Γεωμετρικοί μέσοι ελαχίστων τετραγώνων
Τα διαστήματα εμπιστοσύνης (CI 90%) για τις δοκιμασίες ως προς το φάρμακο αναφοράς των παραμέτρων ΡΚ ήταν ικανοποιητικά εντός του προκαθορισμένου περιθωρίου ισοδυναμίας Στατιστική σύγκριση των πρωτογενών παραμέτρων ΡΚ μεταξύ των δοκιμαζόμενων και των αρχικών φαρμάκων (περιθώριο ισοδυναμίας 0,8-1,25) Παράμετροι PK Θεραπεία n Γεωμετρικοί μέσοι ελαχίστων τετραγώνων Αναλογία (90% CI) Μέρος A: SB4 vs EU-ETN AUCinf (µg × h/mL) SB4 42 0.990 (0.947–1.036) EU-ETN Cmax (µg/mL) 3.319 1.037 (0.985–1.092) 3.201 Μέρος B: SB4 vs US-ETN 44 1.011 (0.958–1.067) US-ETN 3.613 1.044 (0.977–1.114) 3.463 Μέρος C: EU-ETN vs US-ETN 1.005 (0.915–1.104) 3.408 1.033 (0.947–1.127) 3.300 Pharmacokinetics Statistical comparisons of primary pharmacokinetic parameters demonstrated equivalence of treatments in each part of the study. The 90% confidence intervals of the pairwise comparisons for the the area under the concentration–time curve from time zero to infinity (AUCinf) and maximum serum concentration (Cmax) were completely contained within the equivalence margin (0.8 to 1.25) in each part of the study: Part A: AUCinf and Cmax were similar between SB4 and EU-sourced etanercept (EU- ETN) Part B: AUCinf and Cmax were similar between SB4 and US-sourced etanercept (US- ETN) Part C: AUCinf and Cmax were similar between EU-ETN and US-ETN According to the new EMA 2014 guideline, the acceptance interval for the 90% confidence interval of the ratio of the test and reference drugs, for both AUC and Cmax, must in general be contained between and %. This was pre- specified for SB4 and agreed with the regulatory agency. AUCinf , area under the concentration–time curve from time zero to infinity; Cmax, maximum serum concentration; ETN, etanercept; LS, least squares; PK, pharmacokinetic. Lee YJ, et al. Br J Clin Pharmacol Jul;82(1):64-73.

18 Ανοσογονικότητα: χαμηλότερη συχνότητα ADAs στο SB4
EU-ETN US-ETN 6 6 5 5 4 4 Αριθμός ασθενών με ADA 3 3 2 1 SB4 EU-ETN SB4 US-ETN EU-ETN US-ETN Immunogenicity The incidence of anti-drug antibodies (ADAs) was lower in subjects treated with SB4 than in subjects treated with EU-sourced Enbrel® (EU-Enbrel®) or US-sourced Enbrel® (US-Enbrel®). Part A: No subjects in the SB4 treatment group had positive ADA results. 3 subjects were confirmed positive for ADA after EU-Enbrel® administration, only 1 of whom had a positive result for neutralizing antibodies (NAbs). Part B: No subjects in the SB4 treatment group were confirmed positive for ADAs. 4 subjects were confirmed positive for ADA after US-Enbrel® administration, none of whom had a positive result for NAbs. Part C: 4 subjects were confirmed positive for ADA after EU-Enbrel® administration 6 subjects were confirmed positive for ADA after US-Enbrel® administration. None of the subjects had a positive result for NAbs. Μέρος A Μέρος B Μέρος C Ένα άτομο στο σκέλος ΕΕ-ΕΤΝ στο Μέρος Α είχε θετικό αποτέλεσμα για τα NAbs ADA, anti-drug antibody; ETN, etanercept; NAbs, neutralising antibodies. Lee YJ, et al. Br J Clin Pharmacol Jul;82(1):64-73.

19 Συμπεράσματα - SB4 Φάση Ι
Αυτή η μελέτη PK φάσης Ι που συγκρίνει το SB4 με τα πρωτότυπα φάρμακα που προέρχονται από την ΕΕ και την Αμερική, το EU-ETN και το US-ETN, σε υγιείς άρρενες εθελοντές έδειξε: Βιοομοιότητα του SB4 σε σχέση με τα φάρμακα που κυκλοφορούν στο εμπόριο από την άποψη των προφίλ PK τους Το SB4 ήταν γενικά καλά ανεκτό, με προφίλ ασφαλείας συγκρίσιμο με εκείνο των φαρμάκων προελεύσεως Μικρότερη επίπτωση ADAs σε άτομα που έλαβαν SB4 από ότι σε άτομα που έλαβαν EU-ETN ή US-ETN Conclusions The primary endpoints were met. SB4 was shown to be similar to its marketed originator drugs in terms of all measured PK parameters: The primary PK parameters, area under the concentration– time curve from time zero to infinity (AUCinf) and in the maximum serum concentration (Cmax) of etanercept The secondary PK parameters, area under the curve from time zero to last measurable concentration (AUClast), time to Cmax (tmax), apparent volume of distribution (Vz/F), half-life (t½), and apparent clearance (CL/F). The safety profile of SB4 was similar to those of its originator drugs, EU-ETN and US-ETN The incidence of ADAs (immunogenicity profile) of SB4 was lower than that of EU- ETN or US-ETN. In conclusion, SB4 was shown to be equivalent to its originator drugs in terms of PK parameters and safety profiles. The immunogenicity of SB4 was lower than that of each of its originator drugs. ADA, anti-drug antibody; ETN, etanercept; PK, pharmacokinetic. Lee YJ, et al. Br J Clin Pharmacol Jul;82(1):64-73.

20 Emery P, et al. Ann Rheum Dis. 2017 Jan;76(1):51-57.
Κλινικό πρόγραμμα SB4 Μια τυχαιοποιημένη, διπλή τυφλή, παράλληλων ομάδων μελέτη φάσης ΙΙΙ που συγκρίνει το SB4 με την ΕTN σε ασθενείς με ενεργό ρευματοειδή αρθρίτιδα με σύγχρονη θεραπεία με μεθοτρεξάτη Introduction After equivalence of the pharmacokinetic (PK) profiles of SB4 and Enbrel® was demonstrated in a phase I study conducted in healthy male subjects, the objective of this Phase III study was to compare the efficacy, safety, PK, and immunogenicity of SB4 and European-sourced ETN (50mg etanercept in pre-filled syringes in each treatment arm) in patients with active rheumatoid arthritis despite methotrexate (MTX) therapy. In addition, each patient also took a stable dose of oral or parenteral MTX (10-25mg weekly) and was required to take folic acid 5-10mg weekly while taking MTX (because MTX is a folate antagonist). This study is a double-blind, 52-week, comparative, parallel-group trial as it has been agreed with the regulatory agencies. Emery P, et al. Ann Rheum Dis Jan;76(1):51-57.

21 Σχεδιασμός μελέτης Τυχαιοποιημένη μελέτη 52 εβδομάδων με ανοικτή επέκταση 48 εβδομάδων 1: 1 τυχαιοποίηση σε 50 mg / εβδομάδα SB4 έναντι ΕΤΝ με υπόβαθρο MTX Ανοιχτή περίοδο επέκτασης ενός βραχίονα έως την εβδομάδα 100 Τυχαίοποιηση, διπλή-τυφλή περίοδος Ανοιχτής επισήμανσης, περίοδος επέκτασης SB4 (n=299) R SB4 (n≈250) Enbrel® (n=297) 259 (86.6%) patients in the SB4 arm and 246 (82.8%) patients in the Enbrel ®arm completed the randomized equivalence study up to week 52. A subset of patients, representing about 40% of the study population (n≈250), was enrolled in an additional open-label single arm extension period that is currently ongoing in 2 countries For this open-label extension period, patients who had been treated with Enbrel® have been switched to SB4 so that efficacy and safety information can be gathered on switching patients who are stable on Enbrel® to SB4. Low number of patients in the extension is due to the fact that this study was conducted only after enrolment in two countries (Czech Republic and Poland) Εβδομάδα 0 Εβδομάδα 24 Πρωτεύον τελικό σημείο Εβδομάδα 52 Εβδομάδα 100 1. Data on file.

22 Επισήμανση Τα αποτελέσματα της κύριας μελέτης του κλινικού προγράμματος φάσης ΙΙΙ «έδωσαν» 3 δημοσιεύσεις. Για τις 24 εβδομάδες, τις 52 εβδομάδες και την ανοιχτή επέκταση των 100 εβδομάδων. Θα περιγραφούν όλα στα παρακάτω slides

23 Πρωτεύον τελικό σημείο
Μελέτη 24 εβδομάδων Διπλή-τυφλή περίοδος SB4 (n=299) R Enbrel® (n=297) Εβδομάδα 0 Εβδομάδα 24 Πρωτεύον τελικό σημείο 259 (86.6%) patients in the SB4 arm and 246 (82.8%) patients in the Enbrel ®arm completed the randomized equivalence study up to week 52. A subset of patients, representing about 40% of the study population (n≈250), was enrolled in an additional open-label single arm extension period that is currently ongoing in 2 countries For this open-label extension period, patients who had been treated with Enbrel® have been switched to SB4 so that efficacy and safety information can be gathered on switching patients who are stable on Enbrel® to SB4. Low number of patients in the extension is due to the fact that this study was conducted only after enrolment in two countries (Czech Republic and Poland) 1. Data on file.

24 Μελέτη 24 εβδομάδων Σκοπός της μελέτης
Σύγκριση αποτελεσματικότητας και ασφάλειας Ετανερσέπτης SB4 και Ετανερσέπτης αναφοράς (ΕΤΝ) σε ασθενείς με μέτρια έως σοβαρή ΡA, με συγχορήγηση MTX Μέθοδος Πολυκεντρική, τυχαιοποιημένη, διπλή τυφλή μελέτη φάσης ΙΙΙ, παράλληλων ομάδων Οι ασθενείς τυχαιοποιήθηκαν σε θεραπεία 50mg υποδορίως ΕΤΝ ή SB4 Πρωτεύων τελικό σημείο Ανταπόκριση κατά ACR20 για ΕΤΝ και SB4 την Εβδομάδα 24 Δευτερεύοντα τελικά σημεία Αξιολόγηση επιπρόσθετων παραμέτρων αποτελεσματικότητας, καθώς και αξιολόγηση ασφάλειας, ανοσογονικότητας και ΡΚ. The primary objective was to demonstrate equivalence of SB4 to European-sourced etanercept (ETN) with regard to the ACR20 response at week 24 (20% improvement of the hybrid measure of the American College of Rheumatology that encompasses 7 outcomes such as tender and swollen joint count, and patient and physician assessments of symptoms such as pain and physical function, which all together feed into this single ACR20 measure that reflects very well the breadth of RA activity). ACR20 was selected as a well-established primary efficacy endpoint in agreement with EMA and FDA – also with regard to the fact that the primary efficacy endpoint in etanercept pivotal trials was the ACR20 response rate. However, it is acknowledged that clinical assessment methods in RA advance over time and this is why other efficacy endpoints such as ACR-N, DAS-28 and EULAR response were included as secondary clinical endpoints. Secondary trial objectives were to evaluate efficacy using other relevant endpoints, PK, safety and immunogenicity. 50 and 70% improvements of the ACR measure Disease activity score in 28 joints (a composite of the tender joint count (TJC), the swollen joint count (SJC), the ESR (erythrocyte sedimentation rate), and the patient’s global assessment of disease activity. ACR-N: While the DAS28 is a measure of the level of disease activity, the ACR-N provides a single number that characterizes the percentage of improvement from baseline that a patient has experienced in analogy to ACR20, ACR50 and ACR70 responses. This measure of improvement includes a greater number of patient-reported outcomes, including the Health Assessment Questionnaire score and pain assessed on a visual analog scale. EULAR response: defines the level of response (from ’no response’ to ‘good response’ based on the current DAS28 and the DAS28 improvement) Pharmacokinetic measures such as the area under the curve of the ACR index of improvement in RA and of the disease activity change in DAS were assessed in order to evaluate drug concentration in relation to time and response. Other PK parameters included trough concentration (Ctrough) at Weeks 0, 2, 4, 8, 12, 16, and 24 (A trough level is the lowest level of a drug present in the body. Trough levels are therefore measured just before the next drug administration) , area under the concentration– time curve (AUCt) during the dosing interval at steady-state at Week 8, and inter-subject variability (CV%). Furthermore safety (adverse events and serious adverse events) and immunogenicity (incidence of ADA and neutralizing antibodies) were assessed. ACR20/ACR50/ACR70, American College of Rheumatology 20/50/70% improvement criteria; MTX, methotrexate; PK, pharmacokinetics; RA, rheumatoid arthritis. Emery P, et al. Ann Rheum Dis Jan;76(1):51-57.

25 73 κέντρα σε 10 χώρες Κολομβία 1% Ουγγαρία 2% Ηνωμένο Βασίλειο 0.2%
Μεξικό 4% Νότιος Κορέα 4% Βουλγαρία 8% Πολωνία 36% Λιθουανία 9% The study was conducted at 73 centres across 10 countries in Europe, Latin America and Asia. Τσεχία 15% Ουκρανία 20% 1. Study protocol. Data on file.

26 Κύρια κριτήρια εισαγωγής
Κύρια κριτήρια αποκλεισμού Άρρενες ή θήλεα ηλικίας ετών Θεραπεία προηγουμένως με οποιοδήποτε βιολογικό παράγοντα Διάγνωση ΡA σύμφωνα με τα αναθεωρημένα κριτήρια ACR του 1987 (≥ 6 μηνών, ≤ 15 ετών) Μη φυσιολογική αιματολογική, νεφρική ή ηπατική λειτουργία Μέτρια έως σοβαρή, ενεργή ΡA με ≥ 6 SJC και ≥ 6 TJC Ιστορικό ή παρουσία λοίμωξης Θετική ορολογική εξέταση για ηπατίτιδα Β ή ηπατίτιδα C Ενεργή φυματίωση Σοβαρή λοίμωξη ή θεραπεία με ενδοφλέβια αντιβιοτικά για λοίμωξη εντός 8 εβδομάδων ή αντιβιοτικά από το στόμα εντός 2 εβδομάδων πριν από την τυχαιοποίηση ESR (Westergren) ≥ 28 mm/h ή CRP ≥ 1.0 mg/dL Ιστορικό ή παρουσία άλλων συννοσηροτήτων Ιστορικό οποιασδήποτε κακοήθειας κατά τα προηγούμενα 5 χρόνια πριν από την εξέταση Ιστορικό λεμφοϋπερπλαστικής νόσου συμπεριλαμβανομένου του λεμφώματος Ιστορικό συμφορητικής καρδιακής ανεπάρκειας (NYHA III / IV) ή ασταθής στηθάγχη Ιστορικό απομυελινωτικών διαταραχών Άλλες φλεγμονώδεις ή ρευματικές παθήσεις Εγκυμοσύνη ή θηλασμός κατά την περίοδο της διαλογής MTX για τουλάχιστον 6 μήνες σε σταθερή δόση mg / εβδομάδα για τουλάχιστον 4 εβδομάδες πριν από τη διαλογή Study method – Patient Main Eligibility Criteria Key inclusion criteria Subjects aged 18–75 years were eligible for the study if they had been diagnosed with rheumatoid arthritis according to the 1987 revised American College of Rheumatology criteria for ≥ 6 months and ≤ 15 years prior to screening. Subjects had to have active disease defined as ≥ 6 swollen and ≥ 6 tender joints and either an ESR ≥ 28 mm/h or serum C-reactive protein (CRP) ≥ 1.0 mg/dL despite MTX treatment for ≥ 6 months (stable dose of 10–25 mg/week for ≥ 4 weeks prior to screening). Non-steroidal anti-inflammatory drugs and oral glucocorticoids (equivalent to ≤ 10 mg prednisolone) were permitted if received at a stable dose for ≥ 4 weeks prior to randomization. Key exclusion criteria Key exclusion criteria were previous treatment with any biological agents, history of lymphoproliferative disease, congestive heart failure (New York Heart Association Class III/IV) or demyelinating disorders, diagnosis of active tuberculosis, and pregnancy or breast feeding at screening. Benepali® (etanercept) Εκπαιδευτική ενότητα ACR, American College of Rheumatology; CRP, C-reactive protein; ESR,  erythrocyte sedimentation rate; MTX, methotrexate; NYHA, New York Heart Association functional classification; RA, rheumatoid arthritis; SJC, swollen joint count ; TJC, tender joint count. Emery P, et al. Ann Rheum Dis Jan;76(1):51-57.

27 Περίοδος θεραπείας μελέτης Enbrel® 50 mg/week + MTX (n = 299)
Σχεδιασμός μελέτης Ασθενείς με μέτρια έως σοβαρή ΡA, παρά τη θεραπεία με MTX, τυχαιοποιημένοι σε αναλογία 1: 1 για να λάβουν είτε υποδόρια SB4 είτε Enbrel® 50 mg κάθε εβδομάδα 1 2 4 8 12 16 24 ACR20 32 40 52 56 Επίσκεψη (Εβδομάδα) ≤ –6 Ανάλυση ανοσογονικότητας Ανάλυση PK Διαλογή Περίοδος θεραπείας μελέτης R SB4 50 mg/week + MTX (n = 299) Enbrel® 50 mg/week + MTX (n = 299) follow-up αποτελεσματικότητας follow-up ασφάλειας Study Design Patients with moderate-severe RA despite MTX therapy were randomized in a 1:1 ratio to receive 50 mg of either an etanercept (ETN) biosimilar (SB4) or Enbrel®. Patients self-administered SB4 or ETN once weekly for up to 52 weeks by subcutaneous injection. While the primary endpoint of the study was at week 24, patients were able to continue up until week 52 when efficacy was evaluated again or even up to week 56 when safety was assessed again. ALT, alanine aminotransaminase; PK, pharmacokinetic. Emery P, et al. Ann Rheum Dis Jan;76(1):51-57.

28 Τελικά σημεία μελέτης Εκπαιδευτική ενότητα
Το πρωτεύον τελικό σημείο ήταν το ποσοστό ανταπόκρισης ACR20 την εβδομάδα 24 στο σύνολο ανά πρωτόκολλο (PPS) Το περιθώριο ισοδυναμίας για το ποσοστό απόκρισης ACR20 καθορίστηκε στο -15% έως +15% την Εβδομάδα 24 Δευτερεύοντα τελικά σημεία αποτελεσματικότητας: ACR50, ACR70, ACR-N, DAS28 βασισμένο στον ESR, AUC του ACR-N, AUC της μεταβολής στο DAS28, EULAR ανταπόκριση Οι αναλύσεις ΡΚ πραγματοποιήθηκαν σε ένα υποσύνολο ασθενών σε προκαθορισμένα κέντρα της μελέτης Τα βασικά τελικά σημεία PK περιελάμβαναν την κατώτατη συγκέντρωση στον ορό (Ctrough), την περιοχή κάτω από την καμπύλη συγκέντρωσης-χρόνου κατά τη διάρκεια του διαστήματος δοσολόγησης (AUCτ) σε σταθερή κατάσταση Τελικά σημεία ασφάλειας Επίπτωση ανεπιθύμητων συμβάντων (AEs) Επίπτωση σοβαρών ανεπιθύμητων συμβάντων (SAEs) Περιλαμβάνονται τα τελικά σημεία ανοσογονικότητας Η συχνότητα εμφάνισης αντισωμάτων κατά του φαρμάκου (ADAs) Η συχνότητα εμφάνισης εξουδετερωτικών αντισωμάτων (NAbs) Study Endpoints Primary endpoint The primary endpoint was the rate of response according to the American College of Rheumatology (ACR) 20% improvement index (ACR20) at Week 24 in the per-protocol set. The biosimilar was considered equivalent to the originator drug if the 95% confidence interval of the adjusted difference was completely contained within the predefined margin of −15% to 15% as set by the regulatory agency EMA . Secondary efficacy endpoints included: 50 and 70% improvements of the ACR measure Disease activity score in 28 joints (a composite of the tender joint count (TJC), the swollen joint count (SJC), the ESR (erythrocyte sedimentation rate), and the patient’s global assessment of disease activity. ACR-N: While the DAS28 is a measure of the level of disease activity, the ACR-N provides a single number that characterizes the percentage of improvement from baseline that a patient has experienced in analogy to ACR20, ACR50 and ACR70 responses. This measure of improvement includes a greater number of patient-reported outcomes, including the Health Assessment Questionnaire score and pain assessed on a visual analog scale. EULAR response: defines the level of response (from ’no response’ to ‘good response’ based on the current DAS28 and the DAS28 improvement Except for the ACR responses, all other secondary endpoints are analyzed descriptively. Pharmacokinetic measures such as the area under the curve of the ACR index of improvement in RA and of the disease activity change in DAS were assessed in order to evaluate drug concentration in relation to time and response. Other PK parameters included trough concentration (Ctrough) at Weeks 0, 2, 4, 8, 12, 16, and 24 (A trough level is the lowest level of a drug present in the body. Trough levels are therefore measured just before the next drug administration) , area under the concentration– time curve (AUCt) during the dosing interval at steady-state at Week 8, and inter-subject variability (CV%). Serum concentrations were determined by using a validated enzyme-linked immunosorbent assay, and PK parameters were calculated by non-compartmental analyses (WinNonlin V.5.2 or higher, Pharsight, Mountain View, California, USA). Safety assessments (adverse events and serious adverse events) Immunogenicity assessments (incidence of ADA and neutralizing antibodies) A single-assay approach with an SB4 tag was used to assess immunogenicity. ADAs were measured by using validated electrochemiluminescence immunoassays, and NAbs were measured by using a competitive ligand binding assay. The incidences of ADA and NAb were summarised by treatment group. Benepali® (etanercept) Εκπαιδευτική ενότητα ACR20, American College of Rheumatology 20% improvement criteria; PK, pharmacokinetics. Emery P, et al. Ann Rheum Dis Jan;76(1):51-57.

29 Κατανομή Ασθενών Εκπαιδευτική ενότητα Benepali® (etanercept)
Ασθενείς επιλέχθηκαν n=181 Αποτυχίες διαλογής Δεν πληρούσαν τα κριτήρια ένταξης (n=40) Πληρούσαν τα κριτήρια μη ένταξης (n=13) Χαμένο follow-up (n=3) Απόσυρση συναίνεσης (n=18) Άλλο (n=16) n=596 Ασθενείς τυχαιοποιηθηκαν n=299 SB4 50 mg n=297 Enbrel® 50 mg n=283 Συμπλήρωσαν την εβδομάδα 24 n=16 Αποσυρθήκαν πριν την εβδ. 24 n=268 Συμπλήρωσαν την εβδ. 24 n=29 Αποσυρθήκαν πριν την εβδ. 24 Patient Disposition Patient screening began in June 2013, and the 24-week evaluation of the last patient occurred in April 2014. Overall, 777 patients were screened. There were 181 screening failures, mainly because the exclusion criteria were not met, and 596 patients were included in the study. Multiple exclusion reasons per patient were possible. All 596 patients randomized were included in the full analysis set (FAS=Intention-to- treat analysis) and the safety set, and a total of 551 patients completed 24 weeks of treatment. Patients who dropped out prematurely prior to week 24 Patient (withdrawal mainly due to adverse events (3.7%) and withdrawal of consent (2.7%) but who had received at least one single dose of either Enbrel® or SB4 were handled as non-responders, which supports the robustness of this study. Of 481 (80.7%) patients included in the per-protocol set (PPS), 75 were excluded because of protocol deviations. Benepali® (etanercept) Εκπαιδευτική ενότητα Ανεπιθύμητο συμβάν (8) Παραβίαση πρωτοκόλλου (1) Διακριτική ευχέρεια του ερευνητή (2) Αποσύρθηκε η συναίνεση (5) Ανεπιθύμητο συμβάν (14) Παραβίαση πρωτοκόλλου (3) Διακριτική ευχέρεια του ερευνητή (1) Αποσύρθηκε η συναίνεση (11) Emery P, et al. Ann Rheum Dis Jan;76(1):51-57.

30 Δημογραφικά χαρακτηριστικά και βασικά χαρακτηριστικά: καλά ισορροπημένα μεταξύ των ομάδων θεραπείας
Χαρακτηριστικά κατά την έναρξη SB4 (n=299) Enbrel® (n=297) Total (n=596) Ηλικία (έτη) 52.1 ± 11.72 51.6 ± 11.63 51.8 ± 11.67 Φύλο (Θήλεα) 83.3% 85.2% 84.2% Φυλή (Λευκή) 93.3% 91.9% 92.6% BMI (kg/m2) 26.8 ± 5.51 26.3 ± 5.30 26.6 ± 5.41 Ρευματοειδής παράγοντας θετικός 79.3% 77.8% 78.5% Διάρκεια νόσου (έτη) 6.0 ± 4.20 6.2 ± 4.41 6.1 ± 4.30 Σύνολο ευαίσθητων αρθρώσεων (68 αρθρώσεις) 23.5 ± 11.90 23.6 ± 12.64 23.5 ± 12.26 Σύνολο οιδηματοδών αρθρώσεων (66 αρθρώσεις) 15.4 ± 7.48 15.0 ± 7.30 15.2 ± 7.39 CRP (mg/dL) 1.5 ± 2.00 1.3 ± 1.60 1.4 ± 1.81 ESR (mm/h) 46.5 ± 22.10 46.4 ± 22.62 46.5 ± 22.34 HAQ-DI 1.5 ± 0.55 1.5 ± 0.56 Πόνος VAS (mm) 61.8 ± 20.22 62.3 ± 19.22 62.1 ± 19.71 Ασθενής GA, VAS (mm) 61.7 ± 18.97 63.0 ± 17.70 62.4 ± 18.35 Θεράπων GA, VAS (mm) 62.2 ± 15.09 63.2 ± 14.76 62.7 ± 14.92 DAS28-ESR 6.5 ± 0.91 6.5 ± 0.88 6.5 ± 0.89 Demographic and Baseline Characteristics The demographic characteristics were well balanced between the treatment groups in all patients randomized, with no significant differences between groups – hence the treatment groups were absolutely comparable. The average age was 51.8 years, and the average disease duration was 6.1 years. Similarly, the baseline disease characteristics for rheumatoid arthritis measures were well balanced between the SB4 and Enbrel® treatment groups. The mean tender-joint count was 23.5 in the SB4 group and 23.6 in the Enbrel® group; the mean swollen-joint count was 15.4 in the SB4 treatment group and 15.0 in the Enbrel® treatment group. BMI, body mass index; CRP, C-reactive protein; DAS28, disease activity score in 28 joints; ESR, erythrocyte sedimentation rate; GA, global assessment; HAQ-DI, Health Assessment Questionnaire-Disability Index; VAS, visual analogue scale. Emery P, et al. Ann Rheum Dis Jan;76(1):51-57.

31 Ποσοστό ανταπόκρισης ACR20 την Εβδομάδα 24: ισοδύναμο για SB4 και Enbrel®
100 Προσαρμοσμένη διαφορά: −2.22 95% CI (−9.41 έως 4.98)* Προσαρμοσμένη διαφορά: 1.92 95% CI (−5.24 έως 9.07)* 80 78.1 (193/247) 80.3 (188/234) 73.8 (220/298**) 71.7 (213/297) 60 Ποσοστό ανταπόκρισης (%) 40 20 Primary Efficacy Endpoint ACR20 response rates The primary endpoint at Week 24 was met: the 95% CI of the adjusted treatment difference between SB4 and Enbrel® in ACR20 response rate in the PPS was within the predefined equivalence margin of −15% to 15%, which is – according to the EMA – needed to declare bioequivalence. The American College of Rheumatology 20% improvement criteria (ACR20) response rate at Week 24 in the per-protocol set (PPS) was 78.1% for SB4 and 80.3% for Enbrel®. The 95% confidence interval (CI) of the adjusted difference (SB4 − Enbrel®) in ACR20 response rate was within the predefined equivalence margin of −15% to 15% in both the PPS (95% CI −9.41% to 4.98%) and full analysis set (FAS; 95% CI −5.24% to 9.07%), thus indicating therapeutic equivalence in efficacy of SB4 and Enbrel®. The 95% CI of the differences of ACR20 response rates was estimated using an adjustment for the baseline CRP. The statistical analysis plan pre-specified the inclusion of the baseline CRP as a covariate because the baseline CRP is one of the components for ACR response evaluation and thus has a strong association to ACR response. However, additional analysis without the covariate adjustment has been performed and confirmed the conclusion of equivalence. The ACR20 responses observed in this study (73.8% with SB4 and 71.7% with Enbrel®) in the FAS were within the range of ACR20 response rates reported in pivotal studies of Enbrel® (49–86%) but slightly higher than assumed (60%). Because active treatment is used in both treatment groups, biosimilar studies tend to show higher ACR20 response rates than are observed in pivotal controlled studies. Benepali® (etanercept) Εκπαιδευτική ενότητα Σύνολο κατά πρωτόκολλο (PPS) Πλήρες σύνολο ανάλυσης (FAS) * Predefined equivalence margin –15% to 15%. **One patient from the SB4 group was excluded from the FAS because of missing efficacy data at baseline. ACR20, American College of Rheumatology 20% improvement criteria Emery P, et al. Ann Rheum Dis Jan;76(1):51-57.

32 Τα ποσοστά ανταπόκρισης ACR50, ACR70 την Εβδομάδα 24: ισοδύναμα για τα SB4 και Enbrel®
60 Προσαρμοσμένη διαφορά: 1.92 95% CI (−5.24 έως 9.07)* Προσαρμοσμένη διαφορά : 4.79 95% CI (−3.92 έως 13.49) Προσαρμοσμένη διαφορά : 4.02 95% CI (−3.74 έως 11.78) 46.6 (115/247) 40 42.3 (99/234) 43.0 (128/298*) 39.1 (116/297) Προσαρμοσμένη διαφορά : 3.02 95% CI (−4.47 έως 10.51) Προσαρμοσμένη διαφορά : 3.35 95% CI (−3.10 έως 9.81) Ποσοστό Ανταπόκρισης (%) 25.5 (63/247) 20 22.6 (53/234) 23.2 (69/298*) 19.9 (59/297) Explain why we use comparable and not equivalent Secondary Efficacy Endpoints ACR50 and ACR70 response rates Secondary efficacy variables at week 24 were comparable between the SB4 and EU Enbrel® treatment groups. The ACR50 response rates in the PPS were 46.6% with SB4 and 42.3% with Enbrel®, and the ACR70 response rates were 25.5% with SB4 and 22.6% with Enbrel®. Benepali® (etanercept) Εκπαιδευτική ενότητα PPS FAS-NRI PPS FAS-NRI ACR50 ACR70 *One patient from the SB4 group was excluded from the FAS because of missing efficacy data at baseline. ACR50/70, American College of Rheumatology 50%/70% improvement criteria; FAS, full analysis set; NRI, non-responder imputation; PPS, per-protocol set. Emery P, et al. Ann Rheum Dis Jan;76(1):51-57.

33 ACR20 ρυθμός ανταπόκρισης (%)
Καμπύλες ανταπόκρισης χρόνου για ACR20: παρόμοιες ανταποκρίσεις για SB4 και Enbrel® Εκτιμώμενες καμπύλες ανταπόκρισης χρόνου που αφορούν το ρυθμού ανταπόκρισης ACR20 στο σύνολο κατά πρωτόκολλο SB4 (n=247) Enbrel® (n=234) 100 80 60 ACR20 ρυθμός ανταπόκρισης (%) 40 20 Secondary Efficacy Endpoints Time–response curve for the ACR20 response Time–response curves of ACR20 response rate up to Week 24 were estimated in the per-protocol set. The ACR20 time–response curves over 24 weeks of treatment were comparable for SB4 and Enbrel®. As the primary efficacy assessment [American College of Rheumatology 20% improvement criteria (ACR20), response at Week 24] was conducted at a time point in the therapeutic plateau, various efficacy endpoints and statistical methods were applied to detect any non-equivalence in efficacy and to support the robustness of the primary efficacy analysis. For this purpose, the ACR20 response rate was measured at several different time points early in the treatment period. Benepali® (etanercept) Εκπαιδευτική ενότητα 2 4 8 12 16 24 Χρόνος (εβδομάδες) Data points are measured ACR20 response rates for SB4 and ETN at each visit (PPS), and the curve was fitted by non-linear mixed models using an exponential time-response model. ACR20, American College of Rheumatology 20% improvement criteria. Emery P, et al. Ann Rheum Dis Jan;76(1):51-57.

34 Συγκρίσιμη βελτίωση στη μέση τιμή DAS μεταξύ του SB4 και του Enbrel®
8 6 Μέσος DAS28 4 2 Secondary Efficacy Endpoints DAS28 The change in DAS28 was comparable in the SB4 and Enbrel® groups in the 24- week treatment period. At Week 24, the mean improvement from baseline in DAS28 was 2.6 with SB4 and 2.5 with Enbrel® [95% confidence interval −0.14 to 0.28]. Because the primary efficacy assessment [American College of Rheumatology 20% improvement criteria (ACR20), response at Week 24] was conducted at a time point in the therapeutic plateau, various efficacy endpoints were also applied here to detect any non-equivalence in efficacy and to support the robustness of the primary efficacy analysis. For this purpose, the disease activity score in 28 joints (DAS28) was measured at several different time points early in the treatment period. Benepali® (etanercept) Εκπαιδευτική ενότητα 2 4 8 12 16 24 Χρόνος (εβδομάδες) DAS28, disease activity score in 28 joints. Emery P, et al. Ann Rheum Dis Jan;76(1):51-57.

35 EULAR ανταπόκριση (% ασθενών)
Δεδομένα αποτελεσματικότητας: συγκρίσιμη ανταπόκριση EULAR, LDAS και ύφεση μεταξύ του SB4 και του Enbrel® Η μέση βελτίωση στην ανταπόκριση EULAR, LDAS ή ύφεση ήταν συγκρίσιμη για τα SB4 και Enbrel® Μη ανταπόκριση Μέση Καλή SB4 Enbrel® 100 100 12.9 11.8 80 80 60 55.1 58.5 60 31.4 EULAR ανταπόκριση (% ασθενών) Patients (%) 27.6 40 40 Secondary Efficacy Endpoints EULAR response, LDAS, and remission SB4 is comparable in efficacy to Enbrel® at Week 24 in terms of the proportion of patients achieving good or moderate European League Against Rheumatism (EULAR) response in the full analysis set, and low disease-activity score (LDAS; defined as DAS28 ≤3.2) and remission (defined as DAS28 ≤2.6) 16.7 16.2 Benepali® (etanercept) Εκπαιδευτική ενότητα 20 20 32.1 29.8 SB4 Enbrel® LDAS* Ύφεση** * DAS28  3.2; ** DAS28  2.6; DAS28, disease activity score in 28 joints; EULAR, European League Against Rheumatism; LDAS, low-disease activity score. Emery P, et al. Ann Rheum Dis Jan;76(1):51-57.

36 Προφίλ ασφάλειας: συγκρίσιμο για SB4 και Enbrel®
SB4 50 mg (n=299), n (%) Enbrel® 50 mg (n=297), n (%) Προτιμώμενος ορισμός TEAE που αναφέρθηκε σε ≥2% patients Λοίμωξη του ανώτερου αναπνευστικού συστήματος 21 (7.0) 15 (5.1) Αύξηση της αμινοτρανσφεράσης της αλανίνης 15 (5.0) 14 (4.7) Ρινοφαρυγγίτιδα Πονοκέφαλος 13 (4.3) 8 (2.7) Υπέρταση 10 (3.3) 10 (3.4) Αύξηση της ασπαρτικής αμινοτρανσφεράσης 7 (2.3) Ιογενής λοίμωξη 5 (1.7) Ερύθημα στο σημείο της ένεσης 6 (2.0) 33 (11.1) Ρευματοειδής αρθρίτιδα 9 (3.0) Βρογχίτιδα Διάρροια 7 (2.4) Φαρυγγίτιδα 4 (1.3) Λοίμωξη του ουροποιητικού συστήματος Μείωση του αριθμού των λεμφοκυττάρων Βήχας 3 (1.0) Ερύθημα 2 (0.7) Ζάλη Εξάνθημα στο σημείο της ένεσης Αντίδραση στη θέση της ένεσης 1 (0.3) Safety The overall safety profile of SB4 was comparable to that of Enbrel®. Overall, 165 (55.2%) patients treated with SB4 and 173 (58.2%) patients treated with Enbrel® reported at least one treatment-emergent adverse event (TEAE). Most TEAEs were mild to moderate in severity, and TEAEs considered related to the study drug were reported in 83 (27.8%) patients in the SB4 group and 106 (35.7%) patients in the Enbrel group. Serious TEAEs were reported in 13 patients in each of the SB4 and Enbrel® groups, and 34 patients discontinued treatment because of TEAEs (15 [5.0%] patients receiving SB4 and 19 [6.4%] patients receiving Enbrel®). Considerable difference in terms of injection site erythema in favour of SB4 (Please note that various terms were used for injection site reactions (ISRs) across study sites) Benepali® (etanercept) Εκπαιδευτική ενότητα TEAE, treatment-emergent adverse events.

37 Αριθμητική ανισορροπία στις αντιδράσεις στο σημείο χορήγησης (ISR’s: injection site reactions)
SB4 n=299 Enbrel® n=297 Συμβάντα Αριθμός Ασθενών % 22 11 3.7 156 51 17.2 Οι ΑΕ που σχετίζονται με το σημείο της ένεσης ήταν γενικά ήπιες και επιλύθηκαν εντός μερικών ημερών Η ανάλυση της υποομάδας αποκάλυψε ότι η επίπτωση των ISR’s δεν επηρεάστηκε από τη θετική ή αρνητική κατάσταση των αντισωμάτων κατά του φαρμάκου Injection site reactions (ISRs), counted under the higher-level term “administration site reactions”, occurred in significantly fewer patients in the SB4 group than in the Enbrel® group. There were 22 ISRs reported in 11 (3.7%) patients treated with SB4 and 156 ISRs reported in 51 (17.2%) patients treated with Enbrel®. Most of the ISRs occurred early (between Weeks 2 and 8), were mild in severity and resolved in within few days The proportion of patients in the Enbrel® group who experienced at least one ISR in this study (17.2%) is in line with findings from recently conducted studies of Enbrel® 50 mg once weekly. In addition, most ISRs occurred in the first month, in accordance with the originator drug label. Although it is not clear why the incidence of ISRs was lower with SB4 than with Enbrel®, contributing factors may be differences in drug-product formulation, (lack of L-arginine in SB4), and the container-closure system: (lack of latex in the needle shield of SB4). Benepali® (etanercept) Εκπαιδευτική ενότητα Emery P, et al. Ann Rheum Dis Jan;76(1):51-57.

38 Συμπεράσματα - SB4 Φάση ΙΙΙ 24 εβδομάδων
Το SB4 θεωρήθηκε ότι είναι ισοδύναμο με Enbrel® όσον αφορά την κλινική αποτελεσματικότητα Ισοδύναμα ποσοστά ανταπόκρισης ACR20 την εβδομάδα 24 Συγκρίσιμα δεδομένα αποτελεσματικότητας όσον αφορά την ACR50, ACR70, DAS28, EULAR απόκριση, LDAS, και ποσοστά ύφεσης Συγκρίσιμο προφίλ ασφαλείας των SB4 και Enbrel® Οι αριθμητικές ανισορροπίες που παρατηρήθηκαν στις αντιδράσεις της θέσης ένεσης, οι ηπατικές διαταραχές και οι κακοήθειες θεωρήθηκαν πολύ μικρές ώστε να καταλήξουν σε διαφορά δυναμικού Συγκρίσιμο φαρμακοκινητικό προφίλ των SB4 και Enbrel® Χαμηλότερη συχνότητα εμφάνισης ADAs στην ομάδα SB4 Δεν υπάρχει συσχέτιση μεταξύ ανάπτυξης ADA και κλινικής αποτελεσματικότητας ή ασφάλειας Benepali® (etanercept) Εκπαιδευτική ενότητα ACR20/ACR50/ACR70, American College of Rheumatology 20/50/70% improvement criteria; ADA, anti-drug antibody; DAS28, disease activity score in 28 joints; EULAR, European League Against Rheumatism; ISR, injection site reaction; LDAS, low-disease activity score. Emery P, et al. Ann Rheum Dis Jan;76(1):51-57.

39 Αποτελέσματα 52 εβδομάδων
Emery P, et al. Ann Rheum Dis Jan;76(1):51-57. Benepali® (etanercept) Εκπαιδευτική ενότητα

40 Ποσοστό ανταπόκρισης (%)
Συγκρίσιμα ποσοστά ανταπόκρισης ACR20, ACR50 και ACR70 των SB4 και Enbrel® την Εβδομάδα 52 SB4 Enbrel® 100 Adjusted difference: 0.74 95% CI (−8.03 to 6.56) 80 80.8 81.5 Adjusted difference: 4.48 95% CI (−2.90 to 11.87) 70.2 Adjusted difference: 4.50 95% CI (−4.67 to 13.67) 60 65.7 58.5 Adjusted difference: 5.48 95% CI (−2.32 to 13.29) Ποσοστό ανταπόκρισης (%) 53.2 47.8 Adjusted difference: 7.02 95% CI (−1.69 to 15.74) 40 42.1 Adjusted difference: 5.90 95% CI (−1.12 to 12.93) 37.5 31.0 30.4 20 24.6 181/224 176/216 210/299 195/297 131/224 115/216 143/299 125/297 84/224 67/216 91/299 73/297 At week 52, the secondary efficacy parameters of ACR20, ACR50 and ACR70 were comparable between SB4 and Enbrel® in the per-protocol (PPS) and the full analysis set (FAS). ‘NRI’ stands for ‘non-responder imputation’, which means that all patients who dropped out prematurely but had at least one injection with an active drug were included in the analysis as non-responders. Benepali® (etanercept) Εκπαιδευτική ενότητα PPS FAS-NRI PPS FAS-NRI PPS FAS-NRI ACR20 ACR50 ACR70 ACR20/50/70, American College of Rheumatology 20/50/70% improvement criteria; FAS-NRI, full analysis set, non-responder imputation; PPS2, per-protocol set 2. 1. Data on file.

41 EULAR ανταπόκριση (% ασθενών)
Συγκρίσιμη βαθμολογία DAS28 έως την εβδομάδα 52 και ανταπόκριση EULAR την εβδομάδα 52 για SB4 και Enbrel® Μέση τιμή DAS28 EULAR ανταπόκριση SB4 (n=299) Enbrel® (n=297) Μη ανταπόκριση Μέση Καλή 8 100 34.6 80 41.7 6 60 Μέση τιμή DAS28 4 EULAR ανταπόκριση (% ασθενών) 40 56.5 51.0 2 The adjusted adjusted DAS28 change in disease activity ratios in the PPS and the FAS were also within the pre-defined equivalence margins of -0.6 to +0.6, indicating bioequivalence also with regard to changes in DAS28. EULAR response rate at Week 52 was comparable between SB4 and Enbrel®. 20 7.3 8.9 2 4 6 8 12 16 24 32 40 52 SB4 Enbrel® Χρόνος (Εβδομάδες) DAS28, disease activity score based on a 28 joint count; ETN, etanercept; EULAR, European league against rheumatism. Vencovsky J, et al. Arthritis Rheumatol Oct;67 Suppl 10:

42 Συγκρίσιμες μεταβολές στην τροποποιημένη συνολική βαθμολογία TSS για SB4 και Enbrel® την εβδομάδα 52
Η μεταβολή από την αρχική τιμή του mTSS ήταν συγκρίσιμη μεταξύ του SB4 (0,45) και του Enbrel® (0,74) Προσαρμοσμένος ρυθμός διαφοράς: -0,27, 95% CI: (0,80, 0,26) Περίληψη των ακτινογραφικών αλλαγών SB4 (n=250) Enbrel® (n=228) mTSS κατά την έναρξη 43.26 (67.083) 38.88 (52.256) mTSS την εβδ. 52 43.70 (67.081) 39.62 (53.414) Μεταβολή του mTSS 0.45 (2.497) 0.74 (3.356) Comparable changes were also assessed with regard to changes in the modified total sharp score at week 52 The Sharp method for scoring radiographs of hands and feet in rheumatoid arthritis was modified by Dr. Désirée van der Heijde (this why the score is also often referred to as ‘van der Heijde score’) and is used in the majority of clinical trials and longitudinal observational studies. When scoring the hands, erosions of the surface areas of involved joints are scored from 0-5 depending on the degree of erosions identified on the X-ray. In each joint, individual erosions are summed up to a maximum of 5. As an example, the maximal erosion score for each hand is thus 80, considering the 16 areas for erosions per hand. Joint space narrowing and joint subluxation or luxation are combined in a single score with a range of 0 to 4, again depending on the degree of joint space narrowing, subluxation/luxation and bony ankylosis. The criteria for scoring the feet are identical to those of the hands – i.e.: according to the radiographic degree of erosions, joint space narrowing and joint (sub-) luxation. This scoring method supports an objective evaluation of joint destruction but should not be used for any judgment on whether the findings are due to RA or to osteoarthritis. Benepali® (etanercept) Εκπαιδευτική ενότητα RA, rheumatoid arthritis; SE, standard error. Vencovsky J, et al. Arthritis Rheumatol Oct;67 Suppl 10:

43 Αλλαγή στην τροποποιημένη TSS την εβδομάδα 52 Ασθενείς (Αθροιστικό %)
Η αναλογία των ασθενών με μεταβολή στο mTSS μεγαλύτερη από την SDC (2,3) ήταν χαμηλότερη στο SB4 σε σύγκριση με το Enbrel® (8,4% έναντι 14,0%, p = 0,050) SB4 Enbrel® 30 20 10 Μεταβολή στο mTSS SDC=2.3 Benepali® (etanercept) Εκπαιδευτική ενότητα –10 10 20 30 40 50 60 70 80 90 100 Ασθενείς (Αθροιστικό %) mTSS, modified total Sharp score; SDC, smallest detectable change Vencovsky J, et al. Arthritis Rheumatol Oct;67 Suppl 10:

44 Συγκρίσιμα τελικά σημεία ασφαλείας για τα SB4 και Enbrel® την Εβδομάδα 52
Τελικό σημείο SB4 (n=299) Enbrel® (n=297) n (%) Τουλάχιστον 1 TEAE 175 (58.5)  179 (60.3)  Τουλάχιστον 1 SAE 18 (6.0)  15 (5.1)  Τουλάχιστον 1 TEAE που οδηγεί στη διακοπή του φαρμάκου της μελέτης 16 (5.4)  20 (6.7)  Σοβαρή λοίμωξη 1 (0.3)  5 (1.7)  Ενεργός φυματίωση (0.0) Αντιδράσεις στη θέση ένεσης* 11 (3.7) 52 (17.5) Κακοήθειες† 4 (1.3) (0.3) Θάνατος§ 2 (0.7) The safety endpoints for SB4 and Enbrel® at week 52 were comparable with regard to the number and severity of treatment-emergent adverse events (TEAEs) as well as to the number of severe adverse events (SAEs) *Defined under the higher level term “administration site reactions”. †SB4: gastric adenocarcinoma, basal cell carcinoma, breast cancer, lung cancer metastatic; Enbrel®: invasive ductal breast carcinoma. §SB4:Two deaths due to adenocarcinoma gastric and cardiopulmonary failure, which were not considered related to study drug. SAE, serious adverse event; TEAE, treatment-emergent adverse event. Vencovsky J, et al. Arthritis Rheumatol Oct;67 Suppl 10:

45 Συγκρίσιμες μείζονες TEAEs
Αριθμός (%) ασθενών με ΤΕΑΕ με προτιμώμενο όρο που εμφανίστηκε σε ≥ 3% των ασθενών σε οποιαδήποτε ομάδα θεραπείας SB4 (n=299) Enbrel® (n=297) Σύνολο (n=596) Προτιμώμενος όρος n (%) Λοίμωξη του ανώτερου αναπνευστικού συστήματος 24 (8.0) 16 (5.4) 40 (6.7) Ερύθημα στο σημείο της ένεσης 6 (2.0) 33 (11.1) 39 (6.5) Αυξημένη αμινοτρανσφεράση της αλανίνης 18 (6.0) 17 (5.7) 35 (5.9) Ρινοφαρυγγίτιδα 15 (5.0) 31 (5.2) Υπέρταση 11 (3.7) 22 Πονοκέφαλος 13 (4.3) 8 (2.7) 21 (3.5) Ρευματοειδής αρθρίτιδα 9 (3.0) 10 (3.4) 19 (3.2) Αυξημένη ασπαρτική αμινοτρανσφεράση (2.9) Βήχας 4 (1.3) 14 (2.3) Ερύθημα 2 (0.7) 12 The overall incidence of major treatment-emergent adverse events was comparable between SB4 and Enbrel®. Upper respiratory tract infection was more frequently reported with SB4 than with Enbrel®. Reports of injection site erythema were significantly lower with SB4 than with Enbrel®. Benepali® (etanercept) Εκπαιδευτική ενότητα Most hepatobiliary disorders were mild to moderate in severity and not related to the study drug No new hepatobiliary adverse events after 24-week CSR cut-off date Malignancy: 4 (1.3%) in SB4 arm and 1 (0.3%) in ETN arm Vencovsky J, et al. Arthritis Rheumatol Oct;67 Suppl 10:

46 Συνολικά συμπεράσματα: Αποτελέσματα την εβδομάδα 241- & 522 (I)
Αποτελεσματικότητα Το SB4 θεωρήθηκε ότι είναι ισοδύναμο με το Enbrel® όσον αφορά το ποσοστό ανταπόκρισης ACR20 την εβδομάδα 24 Το 95% CI ήταν εντός του προκαθορισμένου περιθωρίου ισοδυναμίας Άλλα τελικά σημεία αποτελεσματικότητας μέχρι την Εβδομάδα 52 ήταν συγκρίσιμα μεταξύ του SB4 και του Enbrel® Ασφάλεια Οι περιπτώσεις TEAEs, SAEs, TEAEs που οδήγησαν στη διακοπή της μελέτης του φαρμάκου και οι σοβαρές μολύνσεις ήταν συγκρίσιμες μεταξύ του SB4 και του Enbrel® Οι αριθμητικές ανισορροπίες που παρατηρήθηκαν στις αντιδράσεις της θέσης ένεσης, τα ηπατοχολικά συμβάντα και οι κακοήθειες μεταξύ των δύο βραχιόνων θεωρήθηκαν πολύ μικρές για να καταλήξουν σε μια διαφορά δυναμικού. Emery P, et al. Ann Rheum Dis Jan;76(1):51-57 Vencovsky J,et al. Arthritis Rheumatol 2015; 67 (suppl 10)

47 Συνολικά συμπεράσματα: Αποτελέσματα την εβδομάδα 241- & 522 (συνέχεια)
Συνολικά συμπεράσματα: Αποτελέσματα την εβδομάδα 241- & 522 (συνέχεια) Ανοσογονικοτητα Τα προφίλ ανοσογονικότητας των SB4 και Enbrel® ήταν συγκρίσιμα Φαρμακοκινητικη Οι ελάχιστες συγκεντρώσεις (Trough concentrations) ήταν συγκρίσιμες για το SB4 και το Enbrel® Η φαρμακοκινητική σταθερής κατάστασης κατά την Εβδομάδα 8 ήταν υψηλότερη στο SB4 σε σύγκριση με το Enbrel® λόγω της υψηλής μεταβλητότητας μεταξύ των ασθενών Emery P, et al. Ann Rheum Dis Jan;76(1):51-57 Vencovsky J,et al. Arthritis Rheumatol 2015; 67 (suppl 10)

48 Emery P, et al. Ann Rheum Dis 2017
Long-term efficacy and safety in patients with RA continuing on SB4 or switching from reference ETN to SB4 Emery P, et al. Ann Rheum Dis 2017

49 Patient baseline and demographic characteristics
Demographic and baseline characteristics were well balanced between the two treatment groups SB4/SB4 (N=126) ETN/SB4 (N=119) Age, years 49.9 (12.05) 52.1 (10.91) Female, n (%) 107 (84.9%) 100 (84.0%) BMI, kg/m2 26.7 (5.80) 26.1 (5.05) Disease duration, years 5.7 (3.94) 5.8 (4.18) MTX dose at baseline, mg/week 16.9 (4.92) 16.5 (4.91) Duration of MTX use, months 46.0 (35.63) 43.9 (39.81) Swollen joint count 14.4 (7.25) 14.4 (7.74) Tender joint count 21.0 (9.96) 21.4 (11.08) HAQ-DI 1.38 (0.555) 1.45 (0.597) DAS28 (ESR) 6.22 (0.91) 6.3 (0.88) SDAI 37.01 (12.037) 37.65 (12.052) CDAI 35.85 (11.586) 36.45 (11.672) CRP, mg/L 11.5 (15.71) 12.0 (16.35) ESR, mm/h 41.9 (23.26) 41.7 (19.53) Rheumatoid factor positive, n (%) 99 (78.6%) 89 (74.8%) Unless otherwise indicated, data are presented in mean (SD). Emery P, et al. Ann Rheum Dis 2017;76:1986–91.

50 Patient disease activity at Week 52
Disease activities were comparable between SB4/SB4 and ETN/SB4 at Week 52 SB4/SB4 (N=126) ETN/SB4 (N=119) Swollen joint count 2.9 (4.84) 2.8 (4.30) Tender joint count 5.0 (7.11) 5.6 (7.86) HAQ-DI 0.68 (0.585) 0.74 (0.651) Physician global assessment VAS, mm 16.8 (14.47) 18.8 (15.27) Patient global assessment VAS, mm 24.9 (20.97) 26.8 (19.62) Patient pain assessment VAS, mm 25.8 (21.86) 27.0 (21.32) CRP, mg/L 6.2 (15.84) 3.8 (5.47) ESR, mm/h 24.5 (18.63) 22.2 (16.21) Data are presented in mean (SD). Emery P, et al. Ann Rheum Dis 2017;76:1986–91.

51 ACR response rates after Week 52
ACR response rates were sustained and comparable between SB4/SB4 and ETN/SB4 after Week 52 Values for ACR 20, 50 and 70 for week 52, 76 an 100 can also be referenced to abstract as they are included in a table 95% CI. Emery P, et al. Ann Rheum Dis 2017;0:1–6. doi: /annrheumdis

52 EULAR response rate at Week 100
Good Moderate No response EULAR response* Proportion of patients *Number of patients with available data at each time point. Emery P, et al. Ann Rheum Dis 2017;0:1–6. doi: /annrheumdis

53 Comparable efficacy results at Week 100
SB4/SB4 (n=126) ETN/SB4 (n=119) DAS28 Improvement from baseline, mean (SD) 2.9 (1.5) 3.0 (1.5) Disease activity, n/N* (%) Low (≤3.3) 60/121 (49.2) 63/115 (54.8) Remission (<2.6) 37/122 (30.3) 40/115 (34.8) SDAI Score 27.4 (15.5) 28.7 (14.6) Low (>3.3 and ≤11) 41/123 (33.3) 44/115 (38.3) Remission (≤3.3) 38/123 (30.9) 39/115 (33.9) CDAI Score 26.8 (15.0) 27.9 (14.1) Low (>2.8 and ≤10) 46/115 (40.0) Remission (≤2.8) 40/123 (32.5) 33/115 (28.7) Boolean-based remission, n/N* (%) 31/123 (25.2) 23/115 (20.0) *Number of patients with available data at each time point. Emery P, et al. Ann Rheum Dis 2017;0:1–6.

54 ACR response rates up to Week 100
ACR response rates were sustained and comparable between SB4/SB4 and ETN/SB4 after Week 52 Values for ACR 20, 50 and 70 for week 52, 76 an 100 can also be referenced to abstract as they are included in a table *Retrospective analysis was performed in the extended population. Emery P, et al. Ann Rheum Dis 2017;76:1986–91.

55 Mean DAS28 up to Week 100 Mean DAS28 was comparable between SB4/SB4 and ETN/SB4 Values for ACR 20, 50 and 70 for week 52, 76 an 100 can also be referenced to abstract as they are included in a table Emery P, et al. Ann Rheum Dis 2016;75(Suppl. 2):236.

56 Radiographic progression up to Week 100
Radiographic progression was comparable and negligible between SB4/SB4 and ETN/SB4 Values for ACR 20, 50 and 70 for week 52, 76 an 100 can also be referenced to abstract as they are included in a table Data based on patients with available radiographic assessment results at each visit. Emery P, et al. Ann Rheum Dis 2016;75(Suppl. 2):236.

57 Change in mTSS at Week 100 Radiographic progression was comparable and negligible between SB4/SB4 and ETN/SB4 Radiographic results* SB4/SB4 ETN/SB4 Change from baseline in JSN erosion score, mean (SD) 0.19 (1.98) 0.39 (2.86) Change from baseline in joint erosion score, mean (SD) 0.28 (2.57) 0.61 (3.08) Change from baseline in mTSS, mean (SD) 0.48 (4.05) 1.0 (5.56) Data based on number of patients who completed Week 100 visit with available radiographic assessment results at Weeks 0 and 100 (SB4/SB4, n=108; ETN/SB4, n=104). Emery P, et al. Ann Rheum Dis 2017;0:1–6. doi: /annrheumdis

58 Safety after Week 52 and following transition
Safety profiles were comparable between SB4/SB4 and ETN/SB4 SB4/SB4 (N=126) ETN/SB4 (N=119) Number of patients with n (%) At least one TEAE 60 (47.6) 58 (48.7) Frequently reported TEAEs Upper respiratory tract infection 10 (7.9) 9 (7.6) Pharyngitis 9 (7.1) 5 (4.2) RA 7 (5.6) 3 (2.5) Bronchitis 6 (4.8) 7 (5.9) Nasopharyngitis Viral infection 4 (3.2) 1 (0.8) Laryngitis 0 (0) Hypertension Any serious TEAE 2 (1.7) TEAEs leading to study drug discontinuation Serious infection Active tuberculosis 0 (0.0) Injection site reactions* Malignancy† Death† Only marked values can be referenced with poster or abstract Table results are for the period from week 52 to week 100 *TEAEs with high-level group term of administration site reaction; †Hepatic cancer, which was not considered related to the study drug. Emery P, et al. Ann Rheum Dis 2017;76:1986–91.

59 Immunogenicity One patient each in SB4/SB4 and ETN/SB4 developed ADA (non-neutralizing) after Week 52 Incidence of ADAs SB4/SB4 (N=126) ETN/SB4 (N=119) n/N (%) n/N (%) Week 52 overall* (after Week 0) 3/126 (2.4) 17/119 (14.3) Week 76 0/126 (0.0) 1/117 (0.9) Week 100 1/123 (0.8) 0/115 (0.0) Week 100 overall (after Week 0) 4/126 (3.2) 18/119 (15.1) Week 100 overall* (after Week 52) 1/126 (0.8) Only marked values can be reference with poster or abstract N: number of patients with available overall 52-week ADA assessment results. Percentages were based on N. *Patients with at least one ADA-positive result in the extended population. Emery P, et al. Ann Rheum Dis 2016;75(Suppl. 2):236.

60 Conclusions Switching from ETN to SB4 had no treatment emergent issues such as an increase in AEs, an increase in immunogenicity, or loss of efficacy SB4 was well tolerated and effective over 2 years in patients with RA Emery P, et al. Ann Rheum Dis 2017;76:1986–91.

61 Emery P, et al. Ann Rheum Dis. Jul 6. pii: annrheumdis-2015-207588.
Επισκόπηση μελετών switching από Enbrel από διάφορες χώρες, registries, ιδρύματα Benepali® (etanercept) Εκπαιδευτική ενότητα Emery P, et al. Ann Rheum Dis. Jul 6. pii: annrheumdis

62 RWD Author Institution/registry N Acceptance %
patients maintained on BENEPALI® treatment (follow-up duration) Post-switch efficacy Safety Glintborg B et al.1 DANBIO registry, Denmark 1548 100%* 91% (median 154 days) Disease activity largely unaffected at 3 months post-switch vs. 3 months pre- switch Discontinuations (n=129): 59, lack of efficacy; 42, AEs; 28, other reasons Tweehuysen L et al.2 BIO-SPAN study, Netherlands 643 99% (636 of 643 patients switched to BENEPALI®) 92% (6 months) Not reported Discontinuations (n=36): 53%, lack of effect; 42% AEs; 5% remission Sigurdardottir V et al.3 Falun hospital, Sweden 147 99%* 86% (mean duration since switching at follow-up was 22 weeks for the RA and PsA patients) Low mean disease activity was maintained in evaluated RA/PsA patients Discontinuations (n=21): 5, lack of efficacy; 7, inactive disease; 9 requested to switch back Szlumper C et al.4 Guy’s & St Thomas’ Hospital, United Kingdom 109 94% No loss of efficacy observed No complications observed Holroyd C et al.5 University Hospital Southampton, United Kingdom 92 99% 91% (6 months) At 6 months post- switch: mean last DAS28 –2.67 (1.32) mean last BASDAI –4.58 (2.47) Discontinuations (n=8): 7, lack of efficacy; 1, AEs Rabbitts R et al.6 Musgrove Park Hospital, United Kingdom 70 Of the 44 patients reviewed, 84% have had continued efficacy Discontinuations (n=8): 5, lack of efficacy; 3, AEs or surgery

63 Switching Η απόφαση για αλλαγή σε ένα βιοομοειδές επαφίεται στην κρίση του θεράποντα ιατρού σε συνεννόηση με τον ασθενή. Επίσης, ούτε ο φαρμακοποιός ούτε οι υπηρεσίες του ΕΟΠΠΥ μπορούν να ανταλλάξουν το αρχικό βιολογικό φάρμακο με το βιοομοειδές Τα παραπάνω έχει ενστερνισθεί και η Ελληνική Ρευματολογική Εταιρεία και Επαγγελματική Ένωση Ρευματολόγων Ελλάδος (ΕΡΕ-ΕΠΕΡΕ)

64 Δημοσιεύσεις για την προτίμηση ασθενών και επαγγελματιών υγείας στην πένα του Benepali vs Enbrel pen

65

66 Συμπέρασμα Η αντίληψη και η προτίμηση των ασθενών για τη χρήση της ένεσης και της πένας του SB4 ήταν καλύτερη από εκείνη του Enbrel Παρόμοια αποτελέσματα έδειξαν και οι μελέτες που αφορούν την αντίληψη και την προτίμηση των νοσηλευτών και των επισκεπτών υγείας για τη χρήση της πένας του SB4 σε σύγκριση με το Enbrel

67 Γενικά Συμπεράσματα (Ι)
Το SB4 φαίνεται ότι είναι ισοδύναμο με το Enbrel όσον αφορά την κλινική αποτελεσματικότητα την εβδομάδα 24, 52 και 100 Ισοδύναμα ποσοστά απόκρισης κατά ACR 20, 50, 70, DAS 28, EULAR απόκριση και LDA Συγκρίσιμο προφίλ ασφάλειας Λιγότερο συχνές αντιδράσεις στο σημείο της ένεσης Συγκρίσιμο φαρμακοκινητικό προφίλ

68 Γενικά Συμπεράσματα (ΙΙ)
Χαμηλότερη συχνότητα εμφάνισης ADA στην ομάδα SB4 συγκριτικά από το Enbrel Η αλλαγή του ETN στο SB4 ήταν καλά ανεκτή και αποτελεσματική χωρίς νέες παρενέργειες και απώλεια της αποτελεσματικότητας Η προτίμηση των ιατρών, των νοσηλευτών και των λειτουργών υγείας αναφορικά με τη χρήση της πένας ήταν υπέρ του SB4 συγκριτικά με το Enbrel

69 Medical School, University of Ioannina