L ESPERIENZA ITALIANA

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1 L ESPERIENZA ITALIANA Alessandro Armuzzi IBD Unit Presidio Columbus Fondazione Policlinico Gemelli Università Cattolica - Roma

2 Disclosures Consultant: AbbVie, Biogen, Celltrion, Ferring, Hospira, Janssen, Lilly, MSD, Mundipharma, Pfizer, Samsung, Sofar, Takeda Lecture fees: AbbVie, AstraZeneca, Chiesi, Ferring, Hospira, Janssen, MSD, Mitsubishi Tanabe, Mundipharma, Nikkiso, Pfizer, Otsuka, Takeda, Tigenix, Zambon Research grants: MSD

3 Evaluation of a Biosimilar A stepwise «comparability exercise» 1. Physicochemical characteristics 2. Biological activity (comparison to the RMP) 3. Pre-clinical toxicology studies 4. Pharmacodynamics and pharmacokinetics studies 5. Clinical trials in the target population - Pharmacodynamics and pharmacokinetics - Safety and efficacy studies Guideline on Similar Biological Medicinal Products. CHMP/437/04 Rev 1. Guideline on similar biological medicinal products containing monoclonal antibodies non-clinical and clinical issues. EMA/CHMP/BMWP/403543/2010.

4 Response rate (%) CT-P13 Clinical studies: PK equivalence and clinical efficacy Clinical Pharmacokinetics AS study: PK similar to RMP Clinical efficacy Primary Endpoint: ACR20 at Week 30 RA study: clinical efficacy similarto RMP Concentration µg/ml Treatment difference 2% (95% CI: -6%, 10%) 60,9 58,6 Treatment difference 4% (95% CI: -4%, 12%) 73,4 69, Hour 0 184/ / / /251 ITT population CT-P13 PP population INX Park W, et al. Ann Rheum Dis 2013; 72: Yoo DH, et al. Ann Rheum Dis 2013;72:

5 European Medicines Agency on extrapolation The primary rationale for extrapolation is to avoid unnecessary studies in the target population for ethical reasons, for efficiency, and to allocate resources to areas where studies are the most needed EMA Concept paper on extrapolation of efficacy and safety in medicine development (Final). EMA/129698/2012, 2013 EMA Conclusions on extrapolation to IBD The Applicant has provided convincing evidence that the difference detected in the amount of afucosylated species has no clinically relevant impact on the efficacy and safety of CT-P13, in particular in IBD EMA/CHMP/589422/2013; Inflectra Assessment Report

6 Key Topics related To Infliximab Biosimilar Uptake Countries determine whether to allow switching between biosimilar & originator Different Countries set different guidelines for pricing & reimbursement Inter-changeability & Substitution (automatic, primary, secondary) Pricing & Reimbursement GU Serie Generale n.265 del GU Serie Generale n.302 del EMA decided that infliximab biosimilar should share same INN* as originator INN Naming & Prescribing Guidelines Tender Purchasing Extrapolation Across Indications EMA approved infliximab biosimilar for all indications of originator (June 27, 2013) Biosimilar Uptake IBD Physician Perception? * INN: International Nonproprietary Name

7 Medical society position statements for biosimilars in IBD Learned Society, Country Date Limitations/ additional comments Efficacy Safety Extrapolation Switching and substitution BIRD, Belgium 1 Jan, 2015 Paediatric trials needed Trials needed in IBD patients Trials needed in IBD patients Should not extrapolate Physician s decision BSG, UK 2 Aug, 2015 Prescribe by brand name only Efficacy may differ Registry for safety data No comment No switching, data in IBD needed ANSM, France 3 Sept, 2013 Not specific for IBD Trials for specific indications Pharmacovigilance and traceability needed Full justification needed No switching but substitution on initiation allowed DCCV, Germany 4 Feb, 2015 Prescribe by brand name only Long-term comparability data needed Adverse events recorded in IBD registry No comment No switching, long-term data in IBD needed IG-IBD, Italy 5 Aug, 2014 Expected cost reduction Trials needed in IBD patients Trials needed in IBD patients Should not extrapolate No switching, data in IBD needed SEPD, Spanish 6 March, 2013 Product labelled as biosimilar Trials needed in all phases Trials needed in IBD patients Should not extrapolate Substitution not accepted practice ESPGHAN, Europe 7 Oct, 2015 Concerns regarding paediatric population Post-marketing surveillance mandatory & IBD trials Post-marketing surveillance mandatory & IBD trials With caution and scientific evidence No switching, data in IBD needed FBG & GEDIIB, Brazil 8 April, 2015 Distinct nomenclature needed Manufacturers to provide proof against reference Pharmacovigilance (PV) should be mandatory With scientific proof of efficacy and safety No automatic substitution IBDnet Switzerland 1 Feb, 2014 Paediatric trials needed Trials needed in IBD patients Trials needed in IBD patients Should not extrapolate Physician s decision 8 1. Vermeire et al. Acta Gastro-Enterol Belgica. 2015;78: British Society of Gastroenterology biosimilar statement; 3. ANSM Les medicaments biosimilaires. Etat des lieux. 2013; 4. Positionspapier Biosimilars der DCCV e.v. 2015; 5. Annese & Vecchi Digestive and Liver Disease;46: Argüelles-Arias et al. Rev Esp Enferm Dig. 2013;105(1): de Riddler et al. JPGN. 2015;61: Azevedo et al. Autoimmunity Reviews. 2015;14:

8 Biosimilar Infliximab Clinical Therapy & Observational Data Author Reference Country Year CD UC Switch CD/UC Fail % LOR F-up (wks) Stop % SAEs % ADA % Kang HW 28 Korea 8 9 3/ ng 2014 Jung YS 29 Korea / ng 2015 Gecse KB Hungary na ng death Park SH Korea / ng Sieczkowska J Poland / ng Farkas K Hungary na 30 ng 8 ng ng ng Jahansen J Norway na 21 ng ng Farkas K Czech Rep na 17.5 ng 14 ng ng 11.8 Hungary 2016 Heil R Czech R na 4.5 ng 14 ng 7.7 ng Gecse K Hungary na 49 ng 30 ng Bettey M UK ng Smits L Netherlands / Kolar M Czech R / Fiorino G Italy IBD ng 14 ng

9 A Prolonged Follow-up on The Efficacy And Safety of Infliximab Biosimilar CT-P13 In IBD across Italy: The PROSIT Cohort Methods Study design Multicenter real-life study across referral centers in Italy All consecutive IBD patients undergoing therapy with CT-P13 were prospectively included since March 2015 Study population 1. Naïve to anti-tnfs (never exposed) 2. Previously exposed to anti-tnfs 3. Switched from originator Armuzzi A, et al. DDW 2017; OP 543

10 Results Study population 801 IBD (446 CD, 355 UC) patients enrolled in 33 referral Centers 462 patients were naïve to anti-tnfα 193 patients had a previous exposure to one o more biologics (43 exposed to IFX originator) 146 patients switched from IFX originator to CT-P13 70% 60% 50% 40% 30% 20% 10% 0% CD 66% 56% 57% 51% 49% 44% 43% 34% Overall cohort Naive Previously exposed Switch UC Armuzzi A, et al. DDW 2017; OP 543

11 Results Baseline characteristics Total Cohort (n=801) Naïve (n=462) Previously exposed (n=193) Switch (n=146) P value Sex (females, %) 357 (45%) 212 (46%) 89 (46%) 56 (38%) p=0.25 Age at diagnosis (yrs) 31.8 ± 13.8; 29 (22 41) 32.5 ± 13.6; 30.5 (22 41) 31.6 ± 14.2; 28 (21 43) 29.6 ± 13.8; 27.5 (19 38) p=0.06 Duration of disease (yrs) 8.6 ± 8.5; 6 (2 13) 7.7 ± 7.8; 5 (2 11) 9.9 ± 10.6; 8 (4 16) 9.6 ± 6.9; 7 (5 13) p<0.001 Active smokers 17% 18% 18% 12% p=0.13 Combination with AZA/6-MP Follow-up time (months) 21% 16% 24% 32% p=< ± ± ± ± 7.2 p<0.002 Data are presented as means ± SD, median (range) or percentages when appropriate. The Chi-squared test, and the Kruskal-Wallis (equality-of-populations) rank test, were used for the statistical evaluations. Armuzzi A, et al. DDW 2017; OP 543

12 Results Safety (any adverse event) Incidence Rate Ratios Naïve vs. Switched 1.26 ( ), p = NS Naïve vs. Previously exposed 0.51 ( ), p < Previously exposed vs. Switched 2.48 ( ), p < % 25% * 27,5% 20% 15% 10% 5% 14,3% 13,7% 0% Any adverse event Naïve Previously exposed Switched Armuzzi A, et al. DDW 2017; OP 543

13 Armuzzi A, et al. DDW 2017; OP 543 Results Adverse events (n=139) Other 16% Infections Arthralgia 9% 6% 48% Infusion reactions Skin lesions 21%

14 12% 10% 8% Any AE P value Infusion reactions P value Naive vs. previously exposed IRR: 0.45 ( ) IRR: 0.58 ( ) NS Naive vs. switched IRR: 1.34 ( ) NS IRR: 1.83 ( ) NS Previously exposed vs. switched Results Adverse events leading to discontinuation IRR: 2.98 ( ) IRR: 3.17 ( ) * Previous exposure to infliximab vs. exposed to other anti-tnfs * 6% 4% 2% 0% Infusion reaction rates: 18% vs. 6% Incidence Rate Ratio: 2.81 ( ) p=0.04 5% 4% 10% 5% 3% 9% Any adverse event Naïve Switch Previously exposed Infusion reactions Armuzzi A, et al. DDW 2017; OP 543

15 Results Treatment persistency (n=633*) 100% 94% 92% 98% 75% 80% 82% 83% 65% 67% 50% 55% 25% 0% Week 8 CR Week 26 CR Week 52 CR Naive Previously exposed Switch * Patients with treatment/follow up time > 8 weeks Armuzzi A, et al. DDW 2017; OP 543

16 A randomised, double-blind, parallel group, phase III study to demonstrate non-inferiority in efficacy and to assess safety of biosimilar infliximab (CT-P13) compared with innovator infliximab (INX) in patients with active Crohn s disease: early results Randomization 1:1 INX (5 mg/kg) CT-P13 (5 mg/kg) Primary endpoint Non-responder withdraw Week 6 Week 14 Week 6 Week 14 Switching INX Week 30 CT-P13 Week 30 INX Week 30 CT-P13 Week 30 INX Up to week 54 CT-P13 Up to week 54 INX Up to week 54 CT-P13 Up to week 54 Primary objective: To demonstrate that CT-P13 is non-inferior to INX at week 6, in terms of efficacy, as determined by the CDAI-70 response rate Secondary objectives: To evaluate efficacy of CT-P13 in comparison with INX up to week 54 To evaluate overall safety of CT-P13 in comparison with INX up to week 54 Kim YH, et al. DDW 2017; OP 248

17 (%) A randomised, double-blind, parallel group, phase III study to demonstrate non-inferiority in efficacy and to assess safety of biosimilar infliximab (CT-P13) compared with innovator infliximab (INX) in patients with active Crohn s disease: early results ,2 71,4 64,4 61, ,9 44,6 35,8 30, / /251 5,4 5,5 1,8 1,8 CDAI 70 CDAI 100 CDAI < 150 TEAE TESAE Infusion reactions 2,7 1,8 Infections CT-P13 (N=105) INX (N=101) Kim YH, et al. DDW 2017; OP 248

18 ECCO Position s change (2013 vs 2016) Danese S, et al. J Crohns Colitis 2013; Danese S, et al. J Crohns Colitis 2017

19 Percent (%) ECCO Physician Surveys 1, Advantages and issues with biosimilars 2013 (N=307) 2015 (N=118) 89,5 92,4 67, , , ,9 They can work differently from the originator They can have a different immunogenicity pattern than the originator They will be less expensive than the originator 6,6 3,4 There will be more indications than for the originator Comparison of responses in the 2013 and 2015 ECCO surveys to the multiple choice question What could be issues or advantages of a mab biosimilar?. More than one was answer possible. 1. Danese S, et al. J Crohns Colitis 2014;8: Danese S, et al. J Crohns Colitis. April Manuscript Doi: /ecco-jcc/jjw090.

20 Percent (%) ECCO Physician Surveys 1, Biosimilars should have different INN Interchangeability and automatic substitution 84,8 89,8 Disagreement with automatic substitution 5, (N=307) 2015 (N=118) 44,4 They would switch a patient on sustained remission 22 27,4 72,3 39,9 They would They would not switch, but they switch because would inform the of insufficient patient data to support it 1. Danese S, et al. J Crohns Colitis 2014;8: Danese S, et al. J Crohns Colitis. April Manuscript Doi: /ecco-jcc/jjw090.

21 Percent (%) ECCO Physician Surveys 1,2 40 Confidence in biosimilars 2013 (N=307) 2015 (N=118) 33,9 28,8 26,4 28,7 32, ,8 5 7,6 10,2 9,3 0 Totally confident Very confident Enough confident A little confident Not confident at all 1. Danese S, et al. J Crohns Colitis 2014;8: Danese S, et al. J Crohns Colitis. April Manuscript Doi: /ecco-jcc/jjw090.

22 Conclusions 1. Biosimilars approval to the market follows a comprehensive comparability exercise, which is considered more sensitive to detect BS-to-RMP differences than equivalence clinical trials 2. Biosimilars are a valuable contribution to improve efficiency in providing health care to the population: they are an integral part of physicians prescriptions 3. IBD specialists are generally well informed and educated about biosimilars. Compared with in 2013, there are now fewer concerns and more confidence about their use in clinical practice 4. General disagreement with automatic substitution: clear interchangeability rules are essential to this process, to secure the traceability of each prescription and of each product 5. Worldwide pharmacovigilance is needed to detect early any safety or loss of efficacy signal 6. Patients knowledge and information is essential