La terapia con farmaci biotecnologici

I biosimilari nella pratica clinica

gastroenterologica

Luca PastorelliDipartimento di Scienze Biomediche per la Salute

Università di MilanoUnità di Gastroenterologia ed Endoscopia Digestiva

IRCCS Policlinico San Donato(Direttore: Prof. Maurizio Vecchi)

A differenza dei farmaci tradizionali ottenuti mediante sintesi chimica ecaratterizzati chiaramente da una formula chimica ben definita, i farmacibio(tecno)logici sono ottenuti a partire da substrati cellulari viventi mediantetecniche di ingegneria genetica e presentano quindi una maggiore complessitàdi struttura ed un certo grado di variabilità.

I farmaci bio(tecno)logici

I biosimilari - Definizioni

EMA• : similar biological or 'biosimilar' medicines are drugs, which arehighly similar to other biological medicines already licensed, and thatdo not have any clinically meaningful difference to the originator drugin structure, pharmacokinetics, quality, safety or efficacy.

AIFA• : … un medicinale simile a un prodotto biologico di riferimento giaautorizzato nell’Unione Europea e per il quale sia scaduta la coperturabrevettuale…. di fatto la stessa sostanza biologica, potendovi tuttaviaessere presenti differenze minori dovute alla loro natura complessa ealle tecniche di produzione.

Come facciamo a dire che il prodotto è simile a quello di riferimento?

La comparabilità deve essere dimostrata a

tutti i livelli

ESERCIZIO DI COMPARABILITA’Insieme di prove sperimentali (di laboratorio, farmacologiche ecliniche) che assicura la conservazione del profilo di struttura, da cuidiscendono qualità, sicurezza ed efficacia di un prodotto.

Test di comparabilità biosimilare/originatore

• AA analysis (reverse phase HPLC)• Peptide mapping (LC-MS)• N and C-terminal sequencing (MS/MS)• Mass (LC-ES-MS)• Post-translational modifications (LC-MS, HPAEC-PAD)

Identità della sequenza aminoacidica primaria:

Disulphide• bond mappingSulfhydryl reactivity•FTIR, circular • dichroismDSC•

Similarità della struttura secondaria e terziaria:

• Aggregate content and monomeric purity (SEC-HPLC)• Electrophoretic purity (CE-SDS [purity], non-reducing [IgG])• Fragmentation (SDS-PAGE and LC-MS)

Purezza:

EMA/CHMP/589422/2013; CTP-13 Assessment Report; Vos AC, et al, IBD.2012;18:3; Data on file. MRC 14-04-F

Test di comparabilità biosimilare/originatore

sTNF (human, mouse, rat, etc)•tmTNF•hTNF• β

• C1qFc• γ receptors (RI, RIIa, RIIb, RIIIa V/V, V/F, F/F, RIIIb, FcRn)

Legame in vitro a:

• Apoptosis• Reverse signaling• Cytokine production• Complement-dependent cytotoxicity• Antibody-dependent cell-mediated cytotoxicity

Test funzionali cellulari Ex vivo:

EMA/CHMP/589422/2013; CTP-13 Assessment Report, Data on file MRC 14-04–F

N-TERMINAL HETEROGENEITY

AMINOACID CHANGES

ANTIGEN BINDING

FRAGMENTATION

C- TERMINAL HETEROGENEITY

DISULFIDE BONDS

Differences in Fucosylation

CT-P13 has a lower binding affinity for FcgRIIIa

lower levels of antibody-dependent cellular cytotoxicity

(ADCC) in one in vitromodel using natural killer (NK)

cells as effector cells and tmTNF

This has been not confirmed in other models and is not likely to

be clinically relevant

Caratteristiche fisico-chimiche e biologiche di CT-P13

CT-P13 in Reumatologia Farmacocinetica e Sicurezza

Park W et al, ARD 2013;72:1605 Yoo DY et al, ARD 2013;16130 20 40

LiverInf.reactions

Upper tract inf.Blood changes

Urinary infHeadache

HypertensionNausea

RashFever

Bone painZoster

IFX CT-P13

(n=423) (n=439)

CT-P13 in Reumatologia - efficacia

Park W et al, ARD 2013;72:1605 Yoo DY et al, ARD 2013;1613

PLANETAS

(5mg/kg 0,2,6/8..)RA

(3mg/kg 0,2,6,8..+ Mtx 12.5-25/w)

CT-P13(n=125)

IFX(n=125)

IFX(n=304)

CTP-13(n=302)

AUC 32765 31359ASAS 20 70.5% 72.4%ASAS 40 51.8% 43.4%ATI 27.4% 22.5%

ACR 20 60.9% 58.6%

ACR 50 42.3% 40.6%

ACR 70 20.2% 17.9%

ATI 48.4% 48.2%

EMA Conclusions on the use of CT-P13 in IBDThe Applicant has provided convincing evidence that thedifference detected in the amount of afucosylated species hasno clinically relevant impact on the efficacy and safety of CT-P13, in particular in IBD.

EMA/CHMP/589422/ June 2013

CT-P13 (Remsima/inflectra) is produced in the same cell line (Sp2/0Ag14)and approved by the EMA for all indications held by the originator“infliximab RMP” (Remicade):- rheumatoid arthritis [Yoo DY et al, ARD 2013]- ankylosing spondylitis [Park W et al, ARD 2013]- psoriatic arthritis and psoriasis- adult/pediatric Crohn’s disease and UC

By extrapolation: no direct proof of efficacy/safety

CT-P13 in IBD patients

To date, no published randomized controlled trial ofCT-P13 in Crohn’s disease or ulcerative colitis.

Once licensed however, the drug has been used inclinical practice leading to several real lifeobservational surdies.

32 • Naive and 27 switch CD, 42 naive and 9 switch UC

Efficacy and safety of CT-P13, a biosimilar of infliximab, in patients with inflammatory bowel disease: A retrospective multicenter study

Yoon Suk Jung, et al JGH 2015;30:1705-1712

CD UC

• Efficacy maintained in 92,6 % of switched CD (25/27) and 66.7 % of switched UC (6/9)• Safety was good

South Korea

Post-marketing study of biosimilar infliximab (CT- P13) to evaluate its safety and efficacy in KoreaSang Hyoung Park et al., Expert Rev. Gastroenterol. Hepatol. 9(S1), (2015)

173 • pts (83 CD, 12 FCD, 78 UC), different indications, up to 30 wks f-up

South Korea

Response

Remission

Post-marketing study of biosimilar infliximab (CT- P13) to evaluate its safety and efficacy in KoreaSang Hyoung Park et al., Expert Rev. Gastroenterol. Hepatol. 9(S1), (2015)

• 173 pts (83 CD, 12 FCD, 78 UC), different indications, up to 30 wks f-up

South Korea

Adverseevents

Post-marketing study of biosimilar infliximab (CT- P13) to evaluate its safety and efficacy in KoreaSang Hyoung Park et al., Expert Rev. Gastroenterol. Hepatol. 9(S1), (2015)

173 • pts (83 CD, 12 FCD, 78 UC), different indications, up to 30 wks f-up

South Korea

Adverseevents

Gecse KB et al, JCC 2016:133-140

• 210 consecutive IBD (126 CD and 84 UC)

6 w

eeks

14 w

eeks

Hungary

Biosimilar infliximab (CT-P13) in the treatment of inflammatorybowel disease: A Norwegian observational study

Jahnsen J, Expert Rev Gastroenterol Hepatol 2015

• 46 CD and 32 UC patients received CT-P13 at weeks 0, 2 and 6• Efficacy (HBI and pMS) and safety evaluated at 14 weeks

Norway

• 32 pediatric CD patients 7 UC patients• Median n. of originator infusions 8 (4-29) in CD and 5 (1-12) in UC

Poland

Sieczkowska J. Et al., JCC 2016

Infliximab• biosimilar seems to be as effective and safe as its originator even after the switch

83 • adult patients (57 CD, 24 UC, 2 IBD-U)Stable• clinical disease activity, CRP, and fecal calprotectin levelsTL • increased from 3.5 µg/ml to 4.2 µg/ml (p=0.010)

• New detectable ADA response in 2 ptsCT• -P13 discontinuation in 5 pts. No serious adverse events.

The Netherlands

Clinical outcomes following a switch from Remicade®to the biosimilar CT-P13 in inflammatory bowel diseasepatients: a prospective observational cohort study

AIMS evaluate the short-term (16wks) efficacy, safety, pharmacokinetic profile and immunogenicity following a switch to CT-P13 in Remicade® treated IBD patients

Smits LJ, et al. J Crohns Colitis. 2016 Apr 19

C/ switching from Remicade® to CT-P13 is feasible with no significant impact on short-term clinical outcomes

14 observational studies (1OC, 7DOP, 6P) involving more than 1800 pts from Hungary, Czech Republic, Netherlands, Italy, Croatia, Slovakia, Spain, Poland.

Overall: no change in expected safety and efficacy rate.

Low rate of infusion reaction, but more likely in patients with exposure to anti-TNFs and ADA positivity during the induction therapy.

Switching from Originator to Biosimilar can yield substantial cost savings (2,171 GBP per patient in the first 4 months) with apparently minimal risk.

Mucosal healing is achieved in 59% and 71% of UC patients at week 14 and after one year of CT-P13.

CT-P13 has comparable efficacy and safety in severe UC.

Incoming larger, multicenter studies on CT-P13 in IBD from ECCO 2016

Bálint A, et al. DOP010; Lovasz B, et al. DOP033

Bettey M, et al. DOP029

Farkas K, et al. DOP031

Kaniewska M, et al. P645

Prospective observational study on inflammatory bowel disease patients treated with infliximab biosimilars:

preliminary results of the PROSIT-BIO cohort of the IG-IBD

Fiorino G, et al. ECCO 2016

Ongoing studies

Celltrion • international “Head to Head”: phase III, non-inferiorty randomized trial CT-P13 vs Remicade (1:1) plus switch at w30 (1:1) in 207 patients with moderate to severe CD (AntiTNF naïve): enrollment closed

Connect• -IBD: international registry, up to 3.000 pts planned

Nor• -switch: all switched patients in Norway

BSG Guidance on the Use of Biosimilar InfliximabCT-P13 in Inflammatory Bowel Disease

February 2016

There is sufficient data from observational studies to show that safety andclinical efficacy of CT-P13 are comparable to the originator drug, with similarimmunogenicity, and that switching from Remicade to CT-P13 is also safe andeffective.

Infliximab1. must be prescribed by brand name (i.e., Remicade, Remsima orInflectra).For2. patients starting infliximab: Remicade, Remsima or Inflectra can beprescribed, taking into account the evidence showing similar clinicaleffectiveness. The choice of preparation should take into account the cost of thedrug and its administration.There3. is sufficient evidence to recommend that patients who are in a stableclinical response or remission on Remicade therapy can be switched to Remsimaor Inflectra at the same dose and dose interval. This should be done afterdiscussion with individual patients, with explanation of the reason for switching.Automatic4. substitution is not appropriate.Pharmacovigilance5. is essential for any new biological medicine, and patientsprescribed Remsima or Inflectra should be followed for safety in a registry.

BSG Guidance on the Use of Biosimilar InfliximabCT-P13 in Inflammatory Bowel Disease

February 2016

There is sufficient data from observational studies to show that safety andclinical efficacy of CT-P13 are comparable to the originator drug, with similarimmunogenicity, and that switching from Remicade to CT-P13 is also safe andeffective.

1. Infliximab must be prescribed by brand name (i.e., Remicade, Remsima orInflectra).

2. For patients starting infliximab: Remicade, Remsima or Inflectra can beprescribed, taking into account the evidence showing similar clinicaleffectiveness. The choice of preparation should take into account the cost of thedrug and its administration.

3. There is sufficient evidence to recommend that patients who are in a stableclinical response or remission on Remicade therapy can be switched to Remsimaor Inflectra at the same dose and dose interval. This should be done afterdiscussion with individual patients, with explanation of the reason for switching.

4. Automatic substitution is not appropriate.5. Pharmacovigilance is essential for any new biological medicine, and patients

prescribed Remsima or Inflectra should be followed for safety in a registry.

AIFA Position Paper: I farmaci biosimilarimaggio 2013

• La scelta di trattamento con un farmaco biologico diriferimento o con un biosimilare rimane una decisioneclinica affidata al medico specialista prescrittore.

• L’AIFA considera, tuttavia, che i biosimilari non solocostituiscono un’opzione terapeutica a disposizione deicuranti, ma sono da preferire, qualora costituiscano unvantaggio economico, in particolare per il trattamentodei soggetti “naive” (che non abbiano avuto precedentiesposizioni terapeutiche o per i quali le precedentiesposizioni in base al giudizio del clinico sianosufficientemente distanti nel tempo).

How is the current (2015) market in Italy?

How is the market in Italy?

Remicade: 63,7%; Biosimialri: 36,3%

Emilia Romagna

Remicade: 96,2%; Biosimialri: 3,8%

Campania

Lombardia

Remicade: 67,7%; Biosimialri: 32,3%

Toscana

Remicade: 49,8%; Biosimialri: 50,2%

….grazie per la vostra attenzione