“are we prepared?” · 2017-10-28 · biosimilares aprobados por ema 18 ... bastante...
TRANSCRIPT
“Are we prepared?”
Ricardo M. Xavier Professor Titular Reumatologia
Universidade Federal do Rio Grande do Sul
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
Produtos Biológicos
•Produto uniforme •Pode ser reproduzida por uma variedade de metodologias
• 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
Moléculas Idênticas
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
Estrutura e função
Farmacocinética
Modo de ação
Resultado clínico
Antigenicidade
The uncertainty sequence
Development Program
Caracterização
Físico-química
Caracterização
biológica
Fase Clínica I /
PK/PD
Fase Clínica II
Fase Clínica III
Biológico Inovador
Caracterização
Físico-química
Caracterização
Biológica/PD
Antigenicidade
PK
Fase Clínica III
Biossimilar
Bui LA et al Drug Disc Today 2015 Exercício de Comparabilidade
Jung SK et al., 2014; mAbs, 6:5, 1163-1177
REMSIMA: Chemical characterization
Primary and secondary structures
Peptídeos
Sequência de aminoácidos
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 • PLANETAS1 e PLANETRA2
• Switching within a RCT3
• Real life data4
• Randomising patients on stable long-term treatment5
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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 74th Meeting 2016 4. Glintborg B et al ARD 2017 (ahead of print) 5.
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
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%
* Not Powered for non-inferiority within each diagnostic group
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 5011 (adalimumabe)
Sujeitos sadios Artrite reumatoide Artrite psoriásica
Todas as indicações
CT-P132 (infliximabe)
Espondilite anquilosante
Artrite reumatoide Todas as indicações
SB23 (infliximabe)
Sujeitos sadios Artrite reumatoide Todas as indicações
SB44 (etanercepte)
Sujeitos sadios Artrite reumatoide Todas as indicações
CT-P105 (rituximabe)
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
18
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
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/Novartis
Etanercept-szzs August 2016
Amjevita ABP-510 Humira Amgen Adalimumab-atto
Sept 2016
Renflexis SB2 Remicade Samsung-Bioepis
Infliximab-adba April 2017
Biosimilares aprobados por FDA
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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
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
• 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.
“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
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.”
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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.”
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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 recommendations1
• In patients with stable treatment with a originator drug, switching to a less expensive biosimilar
– More controversial (efficacy,safety,immunogenicity)
1Smolen JS et al ARD 2017;76:960
Algorithm based on 2016 EULAR recommendations on RA management: Phase II
aTNFi (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 bCurrent practice is to start with a bDMARD (+ MTX or another csDMARD) cThe treatment target is clinical remission, according to ACR–EULAR definition, or at least LDA; the target should be reached after 6 months, treatment should be altered if inadequate improvement after 3 months dThe most frequently used combination is MTX, SSZ, and hydroxychloroquine eDose 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
Dose reduction/interval increase in sustained
remissione
Phase II Prognostically unfavorable
factors present Prognostically unfavorable
factors absent
Change to or add a second csDMARD:
LEF, SSZ, MTX alone, or in combinationd
(ideally with addition of GCs as in Phase I)
No
Achieve improvement at 3 months and target at
6 monthsc
such as RF/ACPA, especially at high levels; high disease activity, early
joint damage; failure of ~2 sDMARDs
Achieve improvement at 3 months
and target at 6 monthsc
Failure Phase II: go to Phase III
No Continue Yes
Failure for lack of efficacy and/or toxicity in Phase I
Add a bDMARDa (current practice)
or a JAKib
bDMARD may include an originator or its biosimilar
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 better-communication
• 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
• 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
Nocebo effect requires better-communication
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
Gulacsi L Exp Rev Clin Immunol 2015;11(suppl 1):43
Anticipated cost savings with biosimilars for treatment of rheumatic diseases
Costs of biological DMARDs for RA in Brazilian Health Ministry - 2016
1 billion reais (~300 million USD)
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
Conclusão
Grey areas
• Multiple biosimilars
– Unlikely taht potential differences between them will be formally evaluated
• Effective pharmacovigilance
– Ambiguity of nomenclature
– Formal regulation of interchangibility
