The European Biosimilar Quality Experience

Transcription

1 The Eurpean Bisimilar Quality Experience Prfessr Paul Declerck Labratry fr Therapeutic and Diagnstic Antibdies Disclsures speakers fee fr lectures fr varius pharmaceutical cmpanies hnraria fr (nn-prduct specific) advisry bard meetings fr varius pharmaceutical cmpanies 1

2 Learning Objectives Gain detailed insight in the cncept f bisimilarity Gain insight in the challenges f the evaluatin and apprval prcess f a bisimilar Acquire knwledge n the current Eurpean experience with respect t the quality evaluatin f bisimilars Bilgical medicinal prduct A well-defined bilgical prduct prepared by the use f living systems, such as rganisms, tissue cultures r cells. 2

3 Mlecular basis f hetergeneity Glycsylatin Phsphrylatin Sulfatin Methylatin N-acylatin S-Nitrsylatin. Cell type and culture cnditins Deamidatin (e.g. Asn t Asp) Racemizatin (L t D) Oxidatin ( Met, Tyr, His, Trp) Disulfide exchange.. External cnditins (ph, additives, temperature...) > 10 8 variants The prcess determines the prduct Infliximab, InFlixImab cdna infliximab InFlIxImab, infliximab cdna infliximab cdna infliximab infliximab, Infliximab 3

4 Guidelines Bisimilars (EMA, 2006) Similar bitherapeutic prducts (WHO, 2010) Bisimilars (Australia, Canada, Japan, Krea, ; FDA 2015) Quality, safety and efficacy Extensive cmparisn with authrised reference prduct Cncept f bisimilar develpment Cnfirm Bisimilarity Develp a highly similar prduct McCamish. MAbs. 2011;3(2):

5 Study #1 Study #2 14/04/2017 Registratin requirements (Bisimilar) Quality Nnclinical Clinical Drug substance Manufacture Characterisatin Cntrl Reference standard Cntainer Stability Drug prduct Descriptin Develpment Manufacture Cntrl Reference standard Cntainer Stability Cmparability data Analytical cmparisn with 9 reference prduct Pharmaclgy Primary pharm. Secndary pharm. Safety pharm. Interactins Pharmackinetics ADME Interactins Txiclgy Single dse Repeat dse Gentxicity Carcingenicity Reprductin Lcal tlerance Pharmaclgy Pharmackinetics Single dse Repeat dse Special ppulatins Efficacy and safety Dse finding Schedule finding Pivtal Indicatin 1 Indicatin 2 Indicatin 3 Indicatin 4 Pst-marketing studies Safety in larger ppulatin Efficacy in ther indicatins Immungenicity Registratin f bisimilars (Eurpe) 2 refused by the EU cmmissin: Interfern alpha-2a (2006) Insulin human (2015) 9 withdrawn during evaluatin prcedure: Insulin (2008) Insulin Rapid Insulin Lng Insulin 30/70 Mix Insulin (2012) Slumarv Ismarv medium Cmbimarv 2 Pegfilgrastim (2016) Pegfilgrastim (2017) 5

6 Why refused? Slumarv (human insulin) Insufficient details n manufacturing prcess Insufficiently demnstrated whether clinical study batches are representative fr market batches Insufficiently shwn that quality f prpsed bisimilar is cmparable t the reference prduct Frm Eurpean Public Assesment Reprt Slumarv Why refused? Pegfilgrastim (RGB-02) Study results had nt shwn that RGB-02 was handled by the bdy in the same way as the reference medicine (EMA/822769/2016) Pegfilgrastim (LA-EP2006) Study results were nt able t shw that the cncentratins f pegfilgrastim in bld were the same after taking LA- EP2006 and reference medicine (EMA/47326/2017) Lack f a certificate f Gd Manufacturing Practice (GMP) fr the medicine s manufacturing site (EMA/47326/2017) 6

7 Registratin f bisimilars (Eurpe) 31 apprved in Eurpa (02/2017) 2 Human grwth hrmne (2006) 3 Epietin alfa (2007) 2 Epietin zeta (2007) 4 Filgrastim (2008) 2 Filgrastim (2009) 1 Filgrastim (2010) 2 Infliximab (2013) 1 Filgrastim (2013) 1 Fllitrpin alfa (2013) 1 Fllitrpin alfa (2014) 2 Insulin glargine (2014, 2016) 1 Filgrastim (2014) 1 Etanercept (2016) 1 Infliximab (2016) 2 Enxaparin (2016) 2 Teriparatide (2016) 1 Rituximab (2017) 2 Adalimumab (2017) 1 Pegfilgrastim (2015) ( bi-identical ) 1 Etanercept (2017)( bi-identical ) Registratin f bisimilars (Eurpe) 14 under review (02/2017) 1 Etanercept 2 Rituximab 2 Pegfilgrastim 2 Adalimumab 1 Insulin glargine 3 Trastuzumab 1 Insulin Lispr 2 Bevacizumab 7

8 Physicchemical Cmparability Tests: Analytics Set the Fundatin (AS, DP, RMP) Test Methd Cmpares... Test Methd Cmpares Amin acid analysis Peptide mapping (LC-MS) in cmbinatin with MS/MS Peptide mapping (HPLC) Amin acid cmpsitin Peptide cverage and chemical mdificatins Tryptic peptide map by visual inspectin SEC-HPLC CE-SDS (reduced/nnreduced) IEF Purity/Impurity Aggregate cntent and mnmeric purity Electrphretic mbility and purity under nnreducing and reducing cnditins Charged Isfrms Iselectric pint(s) N-terminal sequencing N-terminal sequences IEC-HPLC Charge variant distributin C-terminal sequencing Reduced mass Disulfide bnds Free thil analysis FTIR CD C-terminal sequences Mlecular weights by mass spectrmetry Disulfide bnds lcatin Amunt f free sulfhydryl grups Secndary structures Secndary structure Sialic acid analysis Mnsaccharide analysis Oligsaccharide prfiling N-linked glycan analysis UV 280 Glycsylatin Sialic acid cntent Neutral and amin sugar cmpsitin Glycsylatin pattern (eg,g0f, G1F, G2F) Oligsaccharide structures, attachment sites, and distributin Cntent Prtein cncentratin DSC Thermal stability; als determines thermal transitin temperatures ELISA API cntent Hw similar are bisimilars? Bisimilar ESA (*) Differences were bserved at the glycsylatin level Phsphrylated high mannse type structures were detected at higher levels than in Reference ESA Lwer values n N- glyclyl-neuramic acid and diacetylated neuramic acids as cmpared t Reference ESA Peptide map shwed differences in O-linked glycan due t a higher sialylatin and lwer cntent f the xidized variant Bisimilar hgh (*) The results f this study demnstrate that Bisimilar rhgh prduced at full scale is cmparable t Reference Prduct The impurity prfile f Bisimilar hgh shares sme similarity with Reference hgh; hwever the prfiles are nt identical impurities,, are present in the Bisimilar hgh batches and are nt in any Reference hgh batches Additinally, there appears t be a higher level f deamidated variants in the Bisimilar hgh samples Bisimilars are Similar, nt identical Bisimilar IFX (*).. all majr physicchemical characteristics and bilgical activities f bisimilar IFX were cmparable t thse f the reference prduct.difference in the amunt f afucsylated infliximab, translating int a lwer binding affinity twards FcγRIIIa receptrs and a lwer ex viv antibdy-dependent cellular cyttxicity (ADCC) activity. less intact IgG., mainly due t a higher prprtin f nn-assembled frm.. unlikely t impact its bilgical activity a higher level f C-terminal lysine variability slightly higher level f aggregates (*) Based upn Eurpean Public Assessment Reprt n respective bisimilars. 8

9 Hw similar are bisimilars? Immunlgical events SB2 versus Infliximab reference Higher incidence f ADA frmatin in patients (47 % vs. 38 % at day 71) Impact f ADA n efficacy is nt clear (CHMP: Divergent pinin 14/36 negative) Data frm studies in presence f MTX extraplatin f immungenicity t ther indicatins? Frm Eurpean Public Assesment Reprt Flixabi Hw similar are bisimilars? Immunlgical events SB4 versus Etanercept reference Significantly lwer incidence f ADA frmatin in patients (verall 1 % vs. 13 %) Impact f assay methdlgy lw drug tlerance: data affected by trugh levels, the latter were different at wk 4/8, thus reanalysis after excluding ADA data at wk 4/8 Reanalysis excluding wk 4 and 8: 0.3 vs. 0.7%. it is premature t cnclude that SB4 is less immungenic than reference. Frm Eurpean Public Assesment Reprt Benepali 9

10 Hw similar are bisimilars? Physicchemical / Immunlgical events XM17 versus FSH reference Quality evaluatin: mre nn-human sialic acid (Neu5Gc) in XM17 The abslute quantity f Neu5Gc in Ovaleap is negligible cmpared t the dietary intake f this nn-human sialic acid Frm Eurpean Public Assesment Reprt Ovaleap Chemical drugs generic A and B Bilgical drugs Bisimilar A and B Ref Ref A = B A?? B Bisimilarity des nt autmatically imply Interchangeability 10

11 Cnclusins The cncept fr bisimilar develpment is well-defined The prcess fr apprval is rigrus Pharmaceutical quality f apprved bisimilar is guaranteed Differences in quality attributes are always present Majr challenges include the identificatin f the ptential clinical relevance f differences in quality attributes and nnclinical prperties Cnclusins Residual uncertainties (scientifically r statistically) have s far always been deemed t have n impact n safety and efficacy EPARs cntain sme but limited infrmatin t judge the final utcme f the apprval prcess EPARs cntain hetergenus infrmatin nt cnsistent between different bisimilars fr the same reference prduct 11