Biosimilars: let op wat mis kan gaan

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Biosimilars: let op wat mis kan gaan
Biosimilars:
beware of either medical or economical
carelessness
@ VAN BODEGRAVEN
ZUYDERLAND MC
HEERLEN-SITTARD-GELEEN
Experiments of nature
Agenda

Concept of biosimilars

All pigs are equal

Clinical efficacy and biosimilars – the
IFX case

Safety and biosimilars – the IFX case

Economical reasoning versus medical
sense

Appropriate use
Biosimilars today
Medicine Name
Active Substance
Marketing Authorisation Holder
Authorisation date
Abseamed
epoetin alfa
Medice Arzneimittel Pütter GmbH &
Co. KG
28/08/2007
Binocrit
epoetin alfa
Sandoz GmbH
28/08/2007
Epoetin Alfa Hexal
epoetin alfa
Hexal AG
28/08/2007
Retacrit
epoetin zeta
Hospira UK Limited
18/12/2007
Silapo
epoetin zeta
Stada Arzneimittel AG
18/12/2007
Accofil
filgrastim
Accord Healthcare Ltd
18/09/2014
Biograstim
filgrastim
AbZ-Pharma GmbH
15/09/2008
Filgrastim Hexal
filgrastim
Hexal AG
06/02/2009
Grastofil
filgrastim
Apotex Europe BV
18/10/2013
Hospira UK Ltd
Nivestim
filgrastim
08/06/2010
Ratiograstim
filgrastim
Ratiopharm GmbH
15/09/2008
Tevagrastim
filgrastim
Teva GmbH
15/09/2008
Zarzio
filgrastim
Sandoz GmbH
06/02/2009
Bemfola
follitropin alfa
Finox Biotech AG
27/03/2014
Ovaleap
follitropin alfa
Teva Pharma B.V.
27/09/2013
Inflectra
infliximab
Hospira UK Limited
10/09/2013
Remsima
infliximab
Celltrion Healthcare Hungary Kft.
10/09/2013
Abasaglar
insulin glargine
Eli Lilly Regional Operations GmbH
09/09/2014
Omnitrope
somatropin
Sandoz GmbH
12/04/2006
Biosimilar = Generics
the Infliximab case
C6428H9912N1694O1987S46 =144190.3 g/mol
Manufacturing:
Gecse et al. 2013, D’Haens et al. 2014
Approval CT-P13 - safety
Non-clinical results
 identical

Amino acid sequences

Same production cell-line (Sp2/0-AG1)

Secondary and tertiary structures

 highly comparable
Deamidation and oxidation profiles  similar (some numerical

Binding affinity Fcγ receptors  extremely similar, except FcγRIIIa

Binding affinity TNF  extremely similar

Extent TNF neutralization in cell lines  equivalent
differences in glycosylation)
Rinaudo-Gaujous et al. 2013, McKeage et al. 2014, Hlavaty et al. 2014, Gomollón et al. 2014
Approval CT-P13 - safety
Non-clinical results
Isaacs et al. 2015
Approval process - efficacy
Registration studies PLANETAS: AS = 250; PLANETRA: RA = 606
CT-P13
IBD
Papamichael et al. 2015
Scientific evidence and daily practice
From Approval CT-P13 to clinical Extrapolation
General observations

Biologics and indications: the anti-TNF file
 IFX,
ADA, CZB, Etanercept, GMAB, and BS-IFX

Safety data concerning high incidence AE, no
data on low incidence AE

Idiosyncratic reactions unknown
Gecse et al. 2013
From Approval CT-P13 to clinical Extrapolation
Inflammatory Bowel Disease

Immunogenicity not the same between various
indications/diseases
 Clinical
experience in CD and UC may reveal
differences unknown from data in other indications

IBD; no trial evidence for combination with
thiopurines/co-meds

Statistical “evidence-based” versus daily practice
Gecse et al. 2013
Patient 1
Male, 28 yrs
Crohn’s fistulas and
refractory disease
First BS-IFX infusion
general malaise,
fever and three
days later skin
eruptions
CAUSE ?
Patient 2
Male 83 yrs, UC
Steroid refractory
pancolitis
BS-IFX rescue
treated NHL and
bladder cancer
2nd infusion BS-IFX,
pneumonitis, death
CAUSE??
So much similarity– so little registration
IFX – a short history
cA2 / IFX – sepsis, TH1/Th2 paradigm
Centocor
Remicade – RA/CD/Psoriasis & more
Schering-Plough
MSD
Janssen / J&J
paradigm shift to treat UC
BS-IFX
Samsung/Hospira/Pfizer/ Mundipharma
Biogene
biosimilar
the opinion of MD:
Federatie Medische Specialisten

Geen bezwaar tegen start BS indien biological-naief.

Monitoring van effectiviteit en veiligheid.

Substitutie van een biologisch geneesmiddel door een
(andere) biosimilar bij goed responderende patiënten wordt
niet aanbevolen.

Alleen onder strikte voorwaarden kan substitutie
plaatsvinden.

De traceerbaarheid van biosimilars dient gewaarborgd te
zijn.

De effectiviteit en veiligheid van biosimilars dient nauwgezet
geregistreerd te worden.
The flipside of the Originator coin:
costs

WORLDWIDE US $250.000 million all biologicals
(expectation for 2020)

US $4.000 million infliximab (2013)

EU $2.200 million infliximab(2013)

NHS $279 million infliximab (2014)

NL €507 million (2014) Remicade®, Embrel®, Humira®
Hawkes et al. 2015, Weise et al. 2012, Rinaudo-Gaujous et al. 2013, Hlavaty et al. 2014, Gomollón et al.
2014
IFX in IBD in NL


van der Valk et al. 2014
Healthcare costs due to anti-TNF:

CD: 64% (only 23% prescribed)

UC: 31.7% (only 4% prescribed)
Healthcare costs due to infliximab:

CD: 30.2% = €490,84 (only 10.4%
prescribed)

UC: 24.4% = €145,= (only 3.0%
prescribed)
Conclusion

Biosimilars are here to stay

Similarity is likely (pharmaceutical)

Clinical efficacy BS is as likely as the originator with current regulation

Effectiveness remains questionable for non-believers

Safety (low incidence) is matter of concern in biologicals

Biosimilars switches based on economical reasons increase likelihood of safety incidents

Biosimilars provide indispensable sales competition

Biosimilar use necessitates:

medical knowledge and responsibility over economical reasoning

additional general registration of individual use, outcome and AE

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