“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

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

11

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

20

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.”

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 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

Obrigado! Gracias! Thank you!

rmaxavier@hcpa.edu.br