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biotech products
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Performance of biotech products (biopharmaceuticals):
Other sources of variability?
Daan J.A. Crommelin
EUFEPS meeting, Verona
– Dept Pharmaceutics, Utrecht University, NL– Scientific Director Dutch Top Institute Pharma,
Leiden, NL
Based on presentation at the EAHP Annual Meeting Bordeaux, MarchBased on presentation at the EAHP Annual Meeting Bordeaux, March 20072007
DefinitionsDefinitions
“A biological medicinal product referring to an existing one and submitted to regulatory authorities for marketing authorization by an independent applicant after the time the original product expired”1
Biosimilar, or similar biological medicinal product
“A medicinal product developed by means of one or more of the following biotechnology practices: rDNA, controlled gene expression, antibody methods”1
Biopharmaceutical
Chemical and therapeutic equivalent of low-molecular-weight drug with expired patent
Generic drug
Classical medicinal pharmaceutical product
Low-molecular-weight drug
1. EMEA definition.EMEA = European Medicines Agency.
BiopharmaceuticalsBiopharmaceuticals
Introduced in the beginning of the 1980sMore than 150 products marketed around the worldOver 370 products in development for a wide range of serious conditions
Biotechnology Industry Organization. 2004. www.bio.org.
Biopharmaceuticals represent a fast-growing and important group of drugs mainly for the treatment of severe diseases
With the highest growth rates within the entire With the highest growth rates within the entire pharmapharma market, market, biopharmaceuticals will reach > US$ 92 billion revenues in 2011biopharmaceuticals will reach > US$ 92 billion revenues in 2011
Biopharmaceuticals will outperform the total pharmaceutical market
– With over 1/3 of ALL pipeline products the market forecast is US$ 92 billion in 2011
Most biopharmaceutical proteins have small
markets, but high value < 10 kg/yr, > US$10,000/g
Knaeplein, 2007Knaeplein, 2007
Emerging
Mar
ket &
Tec
hnol
ogy
Mat
urity
Gene Therapy
Vaccinal Vaccinal recombinant recombinant
proteinsproteins
Extraction-based biological compounds
Immature
• Non validated technologies
• First products entering development phases
• No products in market
Growing Mature Decreasing
• Validated technologies
• More products in development
• Few products in the market
• Mastering technologies
• Ongoing optimization
• Many products in development and in the market
• Fully mastered and opmized technologies
• Many products in development and in the market
• Common technologies
• Manufacturing alternatives required
• Decreasing number of products in development and, eventually, in the market
Cell therapy
Vaccine cell
therapy
Therapeutic Therapeutic recombinant recombinant
proteinsproteins
Chemistry-based
compounds
Technology Evolution in Technology Evolution in Pharma IndustryPharma Industry
Source: Paulo Barbanti
Why biopharmaceuticals are differentWhy biopharmaceuticals are different
High molecular weightComplex three-dimensional structureComplex manufacturing process *Produced by living organisms; therefore often heterogeneous *Difficult to characterize completely by physico-chemical analytical methods or bioassays *Dependence of biological activity on reproducibility of the production process, in-house standards, and maintenance of cold-chain integrityInherent risk of immunogenicity
Crommelin DJA, et al. Int J Pharm. 2003;266:3-16.
Five expression technologies for protein productionFive expression technologies for protein production
Sheep, goat, cow
Transgenic Animals
Yeast
Saccharomyces
Transgenic Plants
Tobacco, moss
Bacteria
Escherichia coli
Mammalian Cells
CHOCHO
knaeplein
Complex production and downstream purification processComplex production and downstream purification process
International Journal International Journal of Pharmaceuticsof Pharmaceutics
2003, November, 2003, November, 266, 3266, 3--1616
Bottom line: complete characterization: mission impossibleBottom line: complete characterization: mission impossible
The quality is
The quality is
in the process
in the process
Two main IFN alpha-2 preparations
Generic Commercial Aa position Naturalname name 23 alelle
Hu IFN Roferon Lys Noalpha-2a
Hu IFN Intron Arg Yesalpha-2b
PEGylatedPEGylated proteinsproteins
PEG-Interferon alfaPEG-G-CSF ……………………….
Strategies for improved protein deliveryStrategies for improved protein delivery
PEGylation: coupling of PEG molecules to protein
http://www.roche.com/pages/facets/10/pegasyse.htm
Different Different epoepo products on the market products on the market outside EU/USoutside EU/US ((epoetin alfa)epoetin alfa)
2 studies: qualitative and quantitative analyses on 11/12 non-FDA/EMEA approved epoetin alfa samples
ConclusionsSignificant deviations from standard specificationsIn vivo bioactivity 71–226% of the EPREX®/ERYPO®
standardIsoform patterns variable, even between samples from the same manufacturerLevel of bacterial endotoxins was unacceptablein 3 samples
Schmidt CA, et al. Arq Bras Endocrinol Metab. 2003;47:183-9; Schellekens H. Eur J Hosp Pharm. 2004;3:43-7.
Isoform distribution
Isoform patterns: deviations displayed by 9 of the 11 samples (including additional basic and acidic isoforms, and increased
bar intensity) compared with the EPREX® standard (E)
E IA IB IIA IIB IIIA IIIB IV V VII VIII E
BA
Cathode
AnodeE VI
Sample
EpoEpo: : isoformisoform distribution (IEF) of distribution (IEF) of epoepo productsproducts
SchellekensSchellekens
Brief Brief historyhistory of the of the proteinprotein immunogenicity immunogenicity problemproblem
Proteins of animal origin (> 1920s)(e.g. equine antisera, porcine/bovine insulin)
Human derived proteins (> 1950s)(e.g. growth hormone, factor VIII)
Recombinant human proteins (> 1980s)(e.g. insulin, interferons, GM-CSF, epo)
Selected papers (2004) on the immunogenicity of Selected papers (2004) on the immunogenicity of recombinant human interferon betarecombinant human interferon beta
In the EU ca. 100 million euro/year is spent on useless IFNIn the EU ca. 100 million euro/year is spent on useless IFN--ββ therapytherapy
Immunogenic biopharmaceuticals and clinical Immunogenic biopharmaceuticals and clinical consequencesconsequences
Loss of efficacyLoss of efficacyInsulinInsulinStreptokinaseStreptokinaseStaphylokinaseStaphylokinaseADAADACalcitoninCalcitoninFactor VIIIFactor VIIIInterferon alpha 2Interferon alpha 2Interferon betaInterferon betaInterleukinInterleukin--22GnRHGnRHTNFR55/IgG1TNFR55/IgG1DenileukinDenileukin diftitoxdiftitoxHCGHCGGMGM--CSF/IL3CSF/IL3
Enhancement of efficacyEnhancement of efficacyGrowth hormoneGrowth hormone
Neutralization of Neutralization of endogenous proteinendogenous proteinMegakaryocyteMegakaryocyte--derived growth derived growth factor (MDGF)factor (MDGF)EpoetinEpoetin
GeneralGeneral immune immune effectseffectsAllergyAllergyAnaphylaxisAnaphylaxisSerum Serum sicknesssickness, etc, etc
Immuno-genicity
AL
CNA
TF K
KTK
AL
SNA
IF K
KFK
Sequence variation Glycosylation
human non-human
Contaminants & impurities Formulation
Application route Dose
Length of treatment Assay technology Patient features Unknown
factorsFebruary
Schellekens, Nature Reviews Drug Discovery, 2002
0
2
4
6
8
10
12
400 200 100 50 25 12,5 6,25 3,1
Neutralizing antibodies standard serum in different laboratories
Neu
tral
izin
gA
ctiv
ity
RomeHanoverUppsala
BaselRijswijkCopenhagen
Serum DilutionInterferon alfa
1996
Assay validation!Assay validation!
TherapeuticTherapeutic effect versus antibody effect versus antibody levellevel in in interferoninterferon--αα treatedtreated patientspatients
Resp
on
seR
esp
on
se
0
2
4
6
8
10
12
14
16
Negative < 2000 > 2000
Two main IFN alpha-2 preparations
Generic Commercial Aa position Naturalname name 23 alelle
Hu IFN Roferon Lys Noalpha-2a
Hu IFN Intron Arg Yesalpha-2b
Antibodies and type of interferon
Type of interferon
% Antibodies
r-IFN alpha 2a r- IFN alpha 2b
20 7
Immunogenicity Immunogenicity differencesdifferences betweenbetween IFNIFN--ααformulationsformulations
DurationDuration of of treatmenttreatment ((monthsmonths))
0200400600800
100012001400160018002000
0 1 2 3 4 5 6 7 8
IFN
neu
tral
izin
gun
its
A (n = 190)A (n = 190)
B (n = 86)B (n = 86)
C (n = 110)C (n = 110)
D (n = 81)D (n = 81)E (n = 74)E (n = 74)
Ryff, J Interferon Cytokine Res, 1997
RPRP--HPLC profile of a highly immunogenic batchHPLC profile of a highly immunogenic batchof interferon (IFN)of interferon (IFN)--alfa2Aalfa2AMo is an oxidized form, which enhances immunogenicity and contriMo is an oxidized form, which enhances immunogenicity and contributes to aggregate formation, butes to aggregate formation, From Schellekens, Nature Reviews, 1, 2002, 457From Schellekens, Nature Reviews, 1, 2002, 457
AntiAnti--epoetin antibodyepoetin antibody--related pure red cell related pure red cell aplasiaaplasia casescases
0
10
20
30
40
50
60
70
80
Num
ber o
f Epo
etin
Alfa
PR
CA
Cas
es
<1997 1998 1999 2000 2001 2002 2003Year
EPO alfa (Epogen /Procrit ) in USAEPO alfa (Eprex ) outside USA
Removal of human serum albumin stabilizer from epoetin alfa (outside USA)
2626
Main Stabilizers Used in Epoetin Main Stabilizers Used in Epoetin FormulationsFormulations
Eprex®
(post 1998)
Polysorbate 80
Glycine
NeoRecormon®
(1990 launch)
Polysorbate 20
Glycine
Complex of5 other amino acids
Calcium chloride
Urea
Epogen®/Procrit®
(US)
HSA
Eprex®
(pre 1998)
HSA
2727
Factors Potentially Contributing to Factors Potentially Contributing to the Immunogenicity of the Immunogenicity of EprexEprex®®
•• Formation of micelles associated with Formation of micelles associated with Epoetin (Hermeling et al, 2003)Epoetin (Hermeling et al, 2003)
•• Silicon droplets in the preSilicon droplets in the pre--filled syringesfilled syringes•• Leachates from rubber stoppersLeachates from rubber stoppers•• MisMis--handlinghandling
0
5
10
15
20
25
30
6 12 18 24
Treatment (months)
NA
b (%
of p
atie
nts)
Avonex
BG9015
Neutralizing antibodies in patients receiving Neutralizing antibodies in patients receiving interferoninterferon––ββ
(same production process, different site)(same production process, different site)
Antigenicity of identical Hu IFN beta producedat different sites
monthsmonths
%%patientspatients
Most Most therapeutictherapeutic proteinsproteins induceinduce antibodiesantibodies
Two mechanisms:
Reaction to neo-antigens(classical immune response)
Breakdown of immune tolerance
Breaking of self-toleranceClassical immune response
The presence of foreignantigens
Fast, often after a single injection
Long duration
Foreign proteins (microbial oranimal origin)
Impurities, aggregates, ...???Cause
Slow, after long treatment
Disappear after treatment
Immune response (antibody production)
Human homologues(recombinant human proteins)
Type of product
Types of immune reaction against therapeutic proteinsTypes of immune reaction against therapeutic proteins
Dogma: protein aggregates are immunogenic
Monomeric proteinsMonomeric proteinsnon-immunogenic
Aggregated proteinsAggregated proteinsimmunogenic
Repetitive epitopes (T cell independent)– Optimum spacing ~ 5-10 nm– Minimum valency ~ 10 epitopes
– Shown for small haptens (Dintzis et al, 1976)
Not Not immunogenicimmunogenic
Not Not immunogenicimmunogenic ImmunogenicImmunogenic
55--10 nm10 nm ~60 nm~60 nm
MechanismsMechanisms forfor breakingbreaking B B cellcell tolerancetolerance
Immuno-genicity
AL
CNA
TF K
KTK
AL
SNA
IF K
KFK
Sequence variation Glycosylation
human non-human
Contaminants & impurities Formulation
Application route Dose
Length of treatment Assay technology Patient features Unknown
factorsFebruary
Schellekens, Nature Reviews Drug Discovery, 2002
Patent expiration of BiopharmaceuticalsPatent expiration of Biopharmaceuticals
AstraZeneca
Genzyme
Roche
Eli Lilly
Serono
Genentech
AmgenChironGenentech
InterMuneGenentech
AmgenEli Lilly
Biogen/ Roche
Abbott
Pioneer company
Expired
Expired
NA
Expired
Expired
Expired
20152006/2012
Expired/2010
2006/2012Expired
2013Expired
Expired
Expired
US patent/market exclusivity expires
Ischaemic events
Gaucher disease
Anaemia
Diabetes
AIDS wasting
Growth disorders
Anaemia, leukaemia, neutropeniaHIVAcute myocardial infarction
Chronic granulomatous disease, malignant osteopetrosis
Acute myocardial infarction
AnaemiaGrowth disorders
Hepatitis B and C
Ischaemic events
Indication(s)
Expired
Expired
Expired
Expired
NA
Expired
2006Expired
ExpiredNA
Expired
Expired (France)2007 (Italy)
Expired
Expired
Expired
EU patent/market exclusivity expires
Streptase® (streptokinase)
Ceredase® (alglucerase); Cerezyme® (imiglucerase)
NeoRecormon® (epoetin)
Humulin® (recombinant insulin)
Serostim® (somatotropin)
Nutropin® (somatropin)
Neupogen® (filgrastim G-CSF)Proleukin® (interleukin-2)
Epogen®, Procrit®, EPREX®
(epoetin)
Humatrope® (somatropin)
TNKase® (tenecteplase TNK-tPA)
Intron A® (interferon-alpha-2b)
Activase®, Alteplase® (tPA)
Actimmune®
(interferon-gamma-Ib)
Abbokinase® (euduraseurokinase)
Product
Adapted from Schellekens H. Trends Biotechnol. 2004;22:406-10. G-CSF = granulocyte colony-stimulating factor; tPA = tissue plasminogen activator.
Biosimilars available on the marketBiosimilars available on the marketoutsideoutside the USA and the EUthe USA and the EU
Limited amount of pre-clinical data publishedIn general, clinical studies involve small patient populations1
1. Combe C, et al. Pharmacotherapy. 2005;25:954-62.
Regulatory framework developmentRegulatory framework development
Regulatory authorities in the EU (EMEA) and the USA (FDA), and the scientific community have recognized that biosimilars differ from generic low-molecular-weight drugs in several ways Not possible at present for 2 different manufacturers to produce 2 identical biopharmaceuticals (similar at best)
The legal and regulatory principles of “essential similarity” (EU) or “bioequivalence” (USA) cannot be applied to biosimilars
FDA = Food and Drug Administration.
Regulatory status of biosimilars in the EURegulatory status of biosimilars in the EU
Since 2001 review of pharmaceutical legislation in EU
Part of the new medicines legislation – came into effect in EU member states in
October 2005
There is a clearly defined legal/regulatory framework in the EU
European Commission: DG Enterprise and Industry. http://pharmacos.eudra.org/F2/review/index.htm.
Key aspects of the new EU legislation Key aspects of the new EU legislation on biosimilars on biosimilars
The centralized procedure is obligatory for biopharmaceuticals and biosimilarsHigh-standard data package on quality, safety, and efficacy to assess application of biosimilarsReference product must be authorized in the EU Strong emphasis on safety Framework for general and product-specific, case-by-case approach
Biosimilars guidelinesBiosimilars guidelines(EMEA concept papers)(EMEA concept papers)
Biosimilars
Product-class-specific annexes (concept papers)
Somato-tropins Epoetins Insulins G-CSF Others?
EMEA guidelines. www.emea.eu.int/pdfs/human/biosimilar/4283205en.pdf.
BiosimilarsBiosimilars with marketing approval in EU:with marketing approval in EU:hGHhGH
OmnitropeOmnitrope®®, , SandozSandoz (ref. (ref. GenotropinGenotropin, Pfizer), Pfizer)ValtropinValtropin®®, , BiopartnersBiopartners (ref. (ref. HumatropinHumatropin, Lilly), Lilly)
EpoEpoBinocritBinocrit®®, , SandozSandozEpoietinEpoietin alfaalfa HexalHexal®®, , HexalHexal Biotech Biotech ForschungForschungAbseamedAbseamed®®, , MediceMedice ArzneimittelArzneimittel PutterPutter
Not approved Not approved InterpheronInterpheron alpha 2aalpha 2a
AlpheonAlpheon®®, , BiopartnerBiopartner (ref. (ref. RoferonRoferon A Roche)A Roche)
InnovatorsInnovators……....
EprexEprex®®, , ProcritProcrit®®, Janssen, Janssen--CilagCilagEpogenEpogen®®, Amgen, AmgenNeoRecormonNeoRecormon®®, Roche, Roche
InterchangeabilityInterchangeability……....
United States (U.S. FDA Considerations on Possible INN Policies for Biosimilars)“U.S. FDA believes that the only way to establish pharmacologic interchangeabilityis through scientific data”
Europe (Thomas Lonngren media interview)“It is not possible we would guarantee a biosimilar is interchangeable (with its originator) … the decision is based on clinical experience that you could switch …”
Identification of Identification of relevantrelevant differences between productsdifferences between products
Wim JiskootWim Jiskoot