Are we prepared? Ricardo M. Xavier Professor Titular Reumatologia Universidade Federal do Rio Grande do Sul rmaxavier@hcpa.edu.br
Disclosures Consulting Janssen Pfizer Eli-Lilly Roche Abbvie Speaker UCB Abbvie Roche Janssen Pfizer BMS Eli-Lilly Clinical trials Abbvie UCB Pfizer Roche GSK Eli-Lilly
Different Aspects of Are we prepared? Science of Biosimilars Efficacy and safety data Regulation Approval Interchangeability Pharmacovigilance Physician Education Adoption Patient Education Acceptance Society/Health system Public Private
Biologic product depends on the production process Pequenas Moléculas Produto uniforme Pode ser reproduzida por uma variedade de metodologias Moléculas Idênticas Produtos Biológicos Produto específico do processo de manufatura (não pode ser duplicado exceto com a mesma linhagem celular e mesma metodologia) Grupo heterogêneo de proteínas Produzido em uma única linhagem celular Microheterogeneidade 1. Kresse GB. Eur J Pharm Biopharm 2009;72:479-486. 2. Strober BE, et al. J Am Acad Dermatol 2012;66:317-322. 4
The uncertainty sequence Antigenicidade Modo de ação Resultado clínico Estrutura e função Farmacocinética
Development Program Biológico Inovador Biossimilar Fase Clínica III PK Fase Clínica III Fase Clínica II Antigenicidade Fase Clínica I / PK/PD Caracterização biológica Caracterização Biológica/PD Caracterização Físico-química Caracterização Físico-química Bui LA et al Drug Disc Today 2015 Exercício de Comparabilidade
REMSIMA: Chemical characterization Primary and secondary structures Peptídeos Sequência de aminoácidos Jung SK et al., 2014; mabs, 6:5, 1163-1177
CREMSIMA: Chemical characterization Tertiary and quaternary structures Jung SK et al., 2014; mabs, 6:5, 1163-1177
RENSIMA: PK in AS Park W et al ARD 2013;72:1605
RENSIMA: PLANETRA study in RA Yo DH et al ARD 2013;72:1613
Evidence of switch Open label extension of RCT PLANETAS 1 e PLANETRA 2 Switching within a RCT 3 Real life data 4 Randomising patients on stable long-term treatment 5 1. Park W et al ARD 2017;76:346 2. Yoo DH et al ARD 2017;76:355 3. Strober B et al American Academy of Dermatology 74 th Meeting 2016 4. Glintborg B et al ARD 2017 (ahead of print) 5. 11
EGALITY Study: Includes 3 treatment switches GP2015 (ETN biosimilar) vs ETN originator in plaque psoriasis Griffiths CEM et al Br J Dermatol 2017;176 928
- 802 pacientes com tratamento estável com IFX (m=6,8 anos) CT=P13 - Atividade de doença similar após 3 meses - Retenção ajustada: 83,4% (levemente menor do que controles históricos com IFX)
NOR-SWITCH: Disease flare * Not Powered for non-inferiority within each diagnostic group Número de pacientes Análise Per Protocol (PPS*) INX n=202 CT-P13 n=206 Pacientes com piora da doença 95% IC Todos (desfecho primário) 53 (26.2%) 61 (29.6%) -12.7-3.9% Doença de Crohn* 14 (21.2%) 23 (36.5%) -29.3 0.7% Colite ulcerativa* 3 (9.1%) 5 (11.9%) -15.2-10.0% Espondiloartrites* 17 (39.5%) 14 (33.3%) -14.5-27.2% Artrite psoriásica* 7 (53.8%) 8 (61.5%) -45.4-28.1% Artrite Reumatoide* 11 (36.7%) 9 (30%) -20.3-29.3% Psoríase* 1 (5.9%) 2 (12.5%) -26.9-13.2% 1. Adapted from: Jorgensen K, et.al. Abstr LB15 UEGW Vienna Austria, Oct 17, 2016 2.UEGW LB15 Biosimilar Infliximab (CT-P13) is not inferior to originator infliximab: Results from the 52-Week randomized NOR-SWITCH Trial * PPS= Per-Protocol Set 1. Jorgensen KK et al Lancet 2017, online first
Different Aspects of Are we prepared? Science of Biosimilars Efficacy and safety data Regulation Approval Interchangeability Pharmacovigilance Physician Education Adoption Patient Education Acceptance Society/Health system Public Private
Regulation of Biosimilar Approvals
Biosimilars available in Rheumatology are safe and effective Approved in UE Biossimiar Fase 1 Fase 3 Extrapolação ABP 501 1 (adalimumabe) CT-P13 2 (infliximabe) SB2 3 (infliximabe) SB4 4 (etanercepte) CT-P10 5 (rituximabe) Sujeitos sadios Espondilite anquilosante Artrite reumatoide Artrite psoriásica Artrite reumatoide Todas as indicações Todas as indicações Sujeitos sadios Artrite reumatoide Todas as indicações Sujeitos sadios Artrite reumatoide Todas as indicações Linfoma folicular Artrite reumatoide Todas as indicações 1. EMA Amgevita EPAR 2017 2. EMA Remsima EPAR 2013 3. EMA Flixabi EPAR 2016 4. EMA Benepali EPAR 2015 5. EMA Truxima EPAR 2016
Biosimilares aprobados por EMA inflectra infliximab Hospira 10 / 09/ 2013 remsima infliximab Celltrion 10 / 09/ 2013 benepali etanercept Samsung Bioepis 14 / 01/ 2016 flixabi infliximab Samsung Bioepis 26 / 05/ 2016 truxima rituximab Celltrion 17 / 02/ 2017 amjevita adalimumab Amgen 22/ /03/ 2017 solymbic adalimumab Amgen 22/03/2017 rixaton rituximab Sandoz 19/06/2017 erelzi etanercept Sandoz 27/06/2017 tuxella rituximab Celltrion/Tevas 29/06/2017 imraldi adalimumab Samsung Bioepis 25/08/2017 18
Anti-TNF Biosimilars approved by FDA (April 2016- April 2017) Biosimilar AKA Originator Pharma Generic (+suffix) Approved Inflectra CPT-10 Remicade Celltrion Infliximab-dyyb April 2016 Erelzi GP-2015 Enbrel Sandoz/No vartis Amjevita ABP-510 Humira Amgen Adalimumabatto Renflexis SB2 Remicade Samsung- Bioepis Etanercept-szzs August 2016 Sept 2016 Infliximab-adba April 2017
Biosimilares aprobados por FDA benepali etanercept Samsung 14/01/2016 inflextra infliximab Pfizer Hospira 05 / 04/ 2016 erelzi etanercept Sandoz 30/ 08/ 2016 amjevita adalimumab Amgen 26/ 09 /2016 renflexis / flixabi Infliximab -abda Samsung 21/04/2017 cyltezo adalimumab Boehringer Ingelheim 25/08/2017 20
Biosimilars: EU Experience Over the last 10 years, the EU monitoring system for safety concerns has not identifed any relevant difference in the nature, severity or frequency of adverse effects between biosimilars and their reference medicines. European Medicines Agency: Biosimilars in the EU information guide for healthcare professionals http://www.ema.europa.eu - accessed Aug 2017
Non-medical Switch: Medical Associations A BSR desaconselha a mudança sumária de todos os pacientes que atualmente recebem um produto de referência que é eficaz e bem tolerado para um biossimilar. A decisão de mudar deve ser feita caso a caso e até que dados adicionais sejam disponibilizados para corroborar a mudança segura; fortes salvaguardas são necessárias para assegurar que os pacientes que responderam bem a um medicamento existente não sejam mudados por motivos não clínicos 1 O ACR acredita que existe muito desconhecimento sobre biossimilares para presumir que a mudança repetida será uma prática segura 2 As 4 instituições fortemente apoiam a introdução de biossimilares no mercado brasileiro(...) Os especialistas não permitem a substituição automática, porque ela acontece sem consentimento médico 3 1. British Society for Rheumatology Position Statement on Biosimilar Medicines, Feb 2015, http://www.rheumatology.org.uk/about_bsr/press_releases/bsr_supports_the_use_of_biolsimilars_but_recommends_measures_to_monitor_safety.aspx. Last accessed May 19, 2016; 2. ACR Position Statement on Biosimilars, Mar 2015, http://www.rheumatology.org/about-us/newsroom/press-releases/id/33/acr-releases-new-position-statement-on-biosimilars- Encourages-Strict-Oversight-Scientific-Study-Physician-Involvement. Last accessed May 19, 2016; 3. Azevedo VF, Meirelles Ede S, Kochen Jde A, et al. Recommendations on the use of biosimilars by the Brazilian Society of Rheumatology, Brazilian Society of Dermatology, Brazilian Federation of Gastroenterology and Brazilian Study Group on Inflammatory Bowel Disease-- Focus on clinical evaluation of monoclonal antibodies and fusion proteins used in the treatment of autoimmune diseases. Autoimmun Rev. 2015;14(9):769-73.
ANVISA (GAPB): Nota de Esclarecimento 003/2017 OBJETO: Intercambialidade entre produtos registrados pela via de desenvolvimento por comparabilidade ( biossimilares ) e o produto biológico comparador. a GPBIO entende que a intercambialidade está mais diretamente relacionada à prática clínica do que a um status regulatório.... a política e diretrizes sobre substituição e intercambialidade entre produtos biossimilares e o produto biológico inovador deverá ser definidas pelo médico prescritor e pelo Ministério da Saúde. 23
ANVISA (GAPB): Nota de Esclarecimento 003/2017 Importante ressaltar que a avaliação médica é imprescindível no caso de substituição e intercambialidade de produtos biossimilares e seus comparadores, tanto para fins de prescrição do produto adequado ao paciente quanto para fins de farmacovigilância e acompanhamento pós-mercado desses produtos. A GPBIO também entende não serem adequadas múltiplas trocas entre produtos biossimilares e o produto biológico comparador, ficando a rastreabilidade e monitoramento do uso bastante dificultados nestes casos. 24
Different Aspects of Are we prepared? Science of Biosimilars Efficacy and safety data Regulation Approval Interchangeability Pharmacovigilance Physician Education Adoption Patient Education Acceptance Society/Health system Public Private
Prescription of a Biosimilar for RA When starting new therapy and when changing for medical reasons Not controversial in most EU countries Supported by 2016 EULAR recommendations 1 In patients with stable treatment with a originator drug, switching to a less expensive biosimilar More controversial (efficacy,safety,immunogenicity) 1 Smolen JS et al ARD 2017;76:960
Algorithm based on 2016 EULAR recommendations on RA management: Phase II Phase II Prognostically unfavorable factors present such as RF/ACPA, especially at high levels; high disease activity, early joint damage; failure of ~2 sdmards Failure for lack of efficacy and/or toxicity in Phase I Prognostically unfavorable factors absent Add a bdmard a (current practice) or a JAKi b No Achieve improvement at 3 months and target at 6 months c Change to or add a second csdmard: LEF, SSZ, MTX alone, or in combination d (ideally with addition of GCs as in Phase I) Failure Phase II: go to Phase III No Achieve improvement at 3 months and target at 6 months c Yes Continue bdmard may include an originator or its biosimilar a TNFi (ADA, CZP, ETN, GOL, IFX), ABA, IL-6 inhibitors, or RTX; IL-6 inhibitors and tsdmards may have advantages in patients who cannot use csdmards as comedication Dose reduction/interval b Current practice is to start with a bdmard (+ MTX or another csdmard) increase in sustained c The treatment target is clinical remission, according to ACR EULAR definition, or at least LDA; the target remission e should be reached after 6 months, treatment should be altered if inadequate improvement after 3 months d The most frequently used combination is MTX, SSZ, and hydroxychloroquine e Dose reduction or interval increase can safely be done with all bdmards with little risk of flares Smolen JS, et al. Ann Rheum Dis 2017;0:1 18
Adoption in Real World Adoption has varied considerably between countries, hospitals, medical specialties Reason is probably behavioral Starting new patients on a biosimilar is no issue Transition of current users in dependent on several variables
Real world adoption Interplay of economics, ethics and balance of powers and interest between society, patients, hospitals, health insurance and Big Pharma Transition Mandatory transition Consensual
Physicians: Transition Reluctant: efficacy and safety Transition could be cumbersome Physician organizations: different guidelines on switch Solutions: Leave it to the field slow uptake of biosimilars Mandatory transition fast uptake, but less freedom
Uptake of biosimilars for inflammatory conditions varies across Europe IMS The Impact of Biosimilar Competition in Europe May 2017
Patients Fear lack of efficacy or safety issues Want to use their rights to be informed and say no Nocebo and attibution effects to biosimilars
Nocebo effect requires bettercommunication Estudo Bio-Switch 4 hospitais (n=222 patients RA, PsoA, SpA) Stable Remicade 196 (88%) patients agreed to switch to Remsima In 6 months: 24% had stopped Remsima; 20% returned to Remicade No differences in drug levels No differences in anti-drug antibodies No higher objective differences in disease activity Alfons den Broeder, EULAR presentation 2017
Nocebo effect requires bettercommunication Bio-Span Study Same hospitals, 642 patients on Enbrel Educational program before switching to Benepali Letters to patients Training employees in communication skills Logistic pharmacy including injection instruction After 6 months: 8% stopped Disease activity unchanged Alfons den Broeder, EULAR presentation 2017
Different Aspects of Are we prepared? Science of Biosimilars Efficacy and safety data Regulation Approval Interchangeability Pharmacovigilance Physician Education Adoption Patient Education Acceptance Society/Health system Public Private
Anticipated cost savings with biosimilars for treatment of rheumatic diseases Gulacsi L Exp Rev Clin Immunol 2015;11(suppl 1):43
Costs of biological DMARDs for RA in Brazilian Health Ministry - 2016 1 billion reais (~300 million USD)
Conclusão Being prepared is a dynamic process, and we are doing well! Science of Biosimilars Efficacy and safety data Regulation Approval Interchangeability Pharmacovigilance Physician Education Adoption Patient Education Acceptance Society/Health system Public Private
Grey areas Multiple biosimilars Unlikely taht potential differences between them will be formally evaluated Effective pharmacovigilance Ambiguity of nomenclature Formal regulation of interchangibility
Obrigado! Gracias! Thank you! rmaxavier@hcpa.edu.br