14. Dr. Thomas Kirchlechner - Sandoz Biopharmaceuticals Development

2,379 views

Published on

“Challenges of biosimilar product development and experience gained”


Shows the development process for biosimilars, focusing specifically on the company’s experience

Published in: Health & Medicine, Business
0 Comments
1 Like
Statistics
Notes
  • Be the first to comment

No Downloads
Views
Total views
2,379
On SlideShare
0
From Embeds
0
Number of Embeds
5
Actions
Shares
0
Downloads
101
Comments
0
Likes
1
Embeds 0
No embeds

No notes for slide
  • The presentation is structured in line with the global BU key messages, as outlined on the final slide of the Sandoz Biopharmaceuticals section: Biologic drugs have revolutionized modern medicine and will continue to do so, but patient access is increasingly limited by high costs and growing demand. Access is also an unmet medical need. High-quality, clinically-proven biosimilars, pioneered by Sandoz, are making biologics more affordable. Sandoz is collaborating with governments, payors and health care professionals to maximize access and benefits for patients. Sandoz – a Novartis company – is the world leader in developing, manufacturing and commercializing biosimilars. We are committed to driving the next biologics revolution to transform patient care. The fourth section provides optional back-up material about Sandoz as a company.
  • This slide outlines the origins and impact of biologic medicines, showing how we got to where we are today: 1950s: Watson and Crick decipher the structure of the DNA molecule. Apart from a small piece in one newspaper, the double helix did not make the news. Today, most scientists consider it to be the most momentous discovery of the 20th century, if not the millennium. 1960s: Genetic code was "cracked.” Watson and Crick discovered that genetic information is contained in our DNA and that it’s organized in a certain way (i.e., this is the instruction manual for life and we now know the letters of its alphabet). The next step was to figure out how those alphabet letters form words. In 1961, scientists had the first success in finding a “word” in the language of the genetic code (the word for phenylalanine). Five years later they showed that a sequence of three nucleotide bases, called a codon, determines each of 20 amino acids. This new knowledge of the genetic code opened the door to genetic engineering: if you know code, you can program. 1970s: Birth of recombinant DNA and genetic engineering techniques to cut and paste DNA and reproduce new DNA in bacteria -- the technology that would make the biotech industry possible. 1980s: First commercial biotech companies formed and first biotech products commercialized In the 1990’s and through to today: Made tremendous progress and a number of successful biomedicines have revolutionized the treatment of several diseases. You see here some of the more successful products – you may be familiar with some of them. Tomorrow: New technologies hold even more promise: Human Genome Project, completed in 2003, sequenced the 2.85 billion nucleotides of the human genome and made that information freely available – anyone can get it on the Internet. Though the sequencing of the human chromosomes is essentially "finished," the exact number of genes encoded by the genome is still unknown (estimated to be 20-25,000). Still don’t know what all these genes do. That’s what you have to know before you can use the gene in any beneficial way. Stem cell research, no real therapeutic leads have yet emerged Gene therapy research underway, but so far clinical results have been disappointing.
  • Total global revenue of top 10 drugs in 2016: USD 70.6 bn Total global revenue of top 20 drugs: USD 105.9 bn 10 of the top 20 pharmaceuticals will be biologics
  • This slide introduces the comparability approach – a central Sandoz message for all audiences. The point to make re the graphs on the right is that they are difficult to read for a reason : the lines for biosimilars and originator virtually overlap.
  • This slide (self-explanatory) explains why biologics are so complex. There are two main types of biologic production process: mammalian (e.g., using yeast or bacteria) and cell culture (using animal cells).
  • The presentation is structured in line with the global BU key messages, as outlined on the final slide of the Sandoz Biopharmaceuticals section: Biologic drugs have revolutionized modern medicine and will continue to do so, but patient access is increasingly limited by high costs and growing demand. Access is also an unmet medical need. High-quality, clinically-proven biosimilars, pioneered by Sandoz, are making biologics more affordable. Sandoz is collaborating with governments, payors and health care professionals to maximize access and benefits for patients. Sandoz – a Novartis company – is the world leader in developing, manufacturing and commercializing biosimilars. We are committed to driving the next biologics revolution to transform patient care. The fourth section provides optional back-up material about Sandoz as a company.
  • 1. Assess quality of the reference product, define target for development 2. Independent design & development effort; continuous feedback loop to target profile 3. Characterization and proof of comparability at all required levels
  • The presentation is structured in line with the global BU key messages, as outlined on the final slide of the Sandoz Biopharmaceuticals section: Biologic drugs have revolutionized modern medicine and will continue to do so, but patient access is increasingly limited by high costs and growing demand. Access is also an unmet medical need. High-quality, clinically-proven biosimilars, pioneered by Sandoz, are making biologics more affordable. Sandoz is collaborating with governments, payors and health care professionals to maximize access and benefits for patients. Sandoz – a Novartis company – is the world leader in developing, manufacturing and commercializing biosimilars. We are committed to driving the next biologics revolution to transform patient care. The fourth section provides optional back-up material about Sandoz as a company.
  • Total global revenue of top 10 drugs in 2016: USD 70.6 bn Total global revenue of top 20 drugs: USD 105.9 bn 10 of the top 20 pharmaceuticals will be biologics
  • Total global revenue of top 10 drugs in 2016: USD 70.6 bn Total global revenue of top 20 drugs: USD 105.9 bn 10 of the top 20 pharmaceuticals will be biologics
  • Total global revenue of top 10 drugs in 2016: USD 70.6 bn Total global revenue of top 20 drugs: USD 105.9 bn 10 of the top 20 pharmaceuticals will be biologics
  • The presentation is structured in line with the global BU key messages, as outlined on the final slide of the Sandoz Biopharmaceuticals section: Biologic drugs have revolutionized modern medicine and will continue to do so, but patient access is increasingly limited by high costs and growing demand. Access is also an unmet medical need. High-quality, clinically-proven biosimilars, pioneered by Sandoz, are making biologics more affordable. Sandoz is collaborating with governments, payors and health care professionals to maximize access and benefits for patients. Sandoz – a Novartis company – is the world leader in developing, manufacturing and commercializing biosimilars. We are committed to driving the next biologics revolution to transform patient care. The fourth section provides optional back-up material about Sandoz as a company.
  • This slide summarizes the presentation and the three key messages. The focus throughout should be on broadening access (comes back to the BU Vision). The reference to meeting unmet medical needs brings Sandoz firmly into line with Novartis Group messaging. The reference to quality and clinical proof helps to differentiate Sandoz from competitors. The “next biologics revolution“ refers to both revolutionizing access to medicines (primarily through lower prices) and to improving overall service and quality levels (e.g., by differentiating devices)
  • 14. Dr. Thomas Kirchlechner - Sandoz Biopharmaceuticals Development

    1. 1. 1 Moscow / Thomas Kirchlechner, May 2013Challenges of biosimilar product developmentand experience gainedIFPMA/AIPM Biotherapeutic Medicines Regulatory WorkshopMoscow, 15-16 May 2013Dr. Thomas KirchlechnerSandoz Biopharmaceuticals Development, Austria
    2. 2. 2 Moscow / Thomas Kirchlechner, May 2013AgendaIntroduction to biosimilarsFuture of biosimilarsHow are biosimilars developed?Sandoz experience
    3. 3. 3 Moscow / Thomas Kirchlechner, May 2013Biologics have revolutionized modern medicine –and will continue to do soToday / futureHumangenomeStem-cellresearchGene therapy1990s to todayLeadingbiotech brandsemerge1950sDNA moleculedecodedGenetic codecracked1960sBasicbiotechnologyenabled1970s Offer real hope for many unmet needs, particularly complexdiseases Bind to specific targets within the body – simply not possiblewith other medicines Contribute significantly to improved survival rates, enhancedlongevity, and better quality of lifeSource: Company websites and annual reportsNote: All trademarks, logos and pictures are the property of the respective ownerCommercialbiotech firmsfounded1980s®®®
    4. 4. 4 Moscow / Thomas Kirchlechner, May 2013By 2016, 7 of the top 10 pharmaceuticalsworldwide will be biologics1Product Type2016 Rev.(USD bn)2011 Rev.(USD bn)1. HUMIRA® Biologic 11.2 8.32. ENBREL® Biologic 7.5 7.93. RITUXAN® Biologic 7.4 7.14. AVASTIN® Biologic 7.2 6.05. REMICADE® Biologic 7.0 7.26. SERETIDE®/ADVAIR® Respiratory / device 6.8 8.17. HERCEPTIN® Biologic 6.3 5.98. REVLIMID® Small molecule 5.9 3.29. CRESTOR® Small molecule 5.8 7.110. LANTUS® Biologic 5.5 5.51Source: Evaluate Pharma March 20 2012, vaccines excludedNote: All trademarks are the property of their respective owners.
    5. 5. 5 Moscow / Thomas Kirchlechner, May 2013What is a biosimilar (or follow-on biologic)?• A biologic approved via a stringentregulatory pathway demonstratingcomparabilityOverview• Successor to a biologic medicine thathas lost exclusivity• Not a simple generic due to complexity:size, structure and manufacturingRegulatorydefinitionComparabilityapproach• Highly analogous structure(via robust analytical characterization)• Comparable quality, safety andefficacy (via clinical trials)Description140120100806040200MinmAUZarzio®Neupogen®GCSF Peptide MappingDetermination of Receptor Binding:Surface plasmon resonance spectroscopyRigorous analyticalcharacterizationAssociation rate Dissociation rate0 200 400 600 800 1000 1200 1400rel.response(RU)time (s)806040200-20Association rate0 200 400 600 800 1000 1200 1400rel.response(RU)time (s)806040200-20Batch 1Batch 2Batch 3Batch 4Batch 5Batch 6Batch 7
    6. 6. 6 Moscow / Thomas Kirchlechner, May 2013protein proteinProtein(no sugars)Monoclonal antibody~150 kDaGlycoprotein(with sugars)MammalianBacteria, Yeastcalcitonin~3.5 kDaepoetin~30 kDasomatropin~22 kDaPeptidefilgrastim~19 kDaAspirin0.18kDa1x 19x 105x 122x 170x 833xBiologics are more complex than smallmolecules…
    7. 7. 7 Moscow / Thomas Kirchlechner, May 2013…and are produced from living organismsModify host cells(e.g., bacteria,mammalian yeast) toproduce recombinantproteinsExtract, refold,purify(downstream) –generate drugsubstanceFormulate tostable finisheddrug product(vial, syringe,cartridge)Grow cellsunder controlledconditions(fermentation).
    8. 8. 8 Moscow / Thomas Kirchlechner, May 2013Access to biologics is a growing issue aroundthe worldAlmost one-quarter of 46 European countries do notprovide access to biologics for arthritis1Canadian children with juvenile idiopathic arthritis maynot receive "standard" care because pediatric coveragefor biologic drugs is limited and inconsistent3Cancer patients twice as likely as general populationto go bankrupt a year after their diagnosis2Only 50% of severe RA patients receive biologicsacross EU5, US and Japan41EULAR 2012: Annual Congress of the European League Against Rheumatism2Cancer diagnosis as a risk factor for personal bankruptcy, ASCO 20113Access to biologic therapies in Canada for children with juvenile idiopathic arthritis. J.Rheum, September 20124Stakeholder Insight: Rheumatoid Arthritis DMHC2592/ Published 09/2010
    9. 9. 9 Moscow / Thomas Kirchlechner, May 2013Biosimilar guidelines and regulations are beingdeveloped worldwideEU Biosimilars legalframework establishedUS Health Care Reform enactedMarch 2010, includes BiosimilarsJapan final guidelinereleased on March 4,2009Australia has adopted EU guidelines,no separate pathway will beestablishedCanada final guideline onSEBs released in March2010WHO released finalguidance in April 2010TaiwanMalaysiaArgentiniaColumbiaTurkeyVenezuelaMexicoBrazilSaudi-ArabiaSouth KoreaSingapore
    10. 10. 10 Moscow / Thomas Kirchlechner, May 2013AgendaIntroduction to biosimilarsFuture of biosimilarsHow are biosimilars developed?Sandoz experience
    11. 11. 11 Moscow / Thomas Kirchlechner, May 2013Significant time, resources and expertiserequired for developing biosimilarsTime &InvestmentClinical Trials• Significant expense (USD 75 - 250m)• Long time to develop (7-8 years)• Confirm comparable efficacy and safety• Support extrapolation across indications & commercial success• Speed of patient recruitment / trial executionKey challengesTechnicalDevelopment• Achieving molecule profile highly comparable tooriginator• Developing high yielding manufacturing process
    12. 12. 12 Moscow / Thomas Kirchlechner, May 2013Purification processdevelopmentBioprocess developmentRecombinant cell line developmentDrug productdevelopmentPK/PDPreclinicalBiologicalcharacterizationPhysicochemicalcharacterizationClinicalReferenceproduct variabilityProcessdevelopmentAnalytics3. Confirmationof biosimilarityBiological variability2. Target directeddevelopmentTarget range1. Target definitionBiosimilar mAbs must be systematicallyengineered to match the reference product
    13. 13. 13 Moscow / Thomas Kirchlechner, May 2013Pre-clinical and clinical development ofbiosimilarsPre-clinicalPhase III(confirmatory)CharacteristicsPhase I(PK/PD)Avg TimeAbbreviated pre-clinical programDemonstration of PK/PD equivalence in a sensitivepopulation - can be healthy volunteersNo phase II dose finding studies are neededDemonstration of similar efficacy & safety, usuallyin one indicationPost approvaltrialsContinue to follow the product, generateadditional data6 – 12months9 – 12months2 – 4 yrsVariable1423
    14. 14. 14 Moscow / Thomas Kirchlechner, May 2013AgendaIntroduction to biosimilarsFuture of biosimilarsHow are biosimilars developed?Sandoz experience
    15. 15. 15 Moscow / Thomas Kirchlechner, May 2013Structure: High resolution, orthogonality andredundancy in analytical characterization provide fullunderstandingProteins can be well characterized at least upto the complexity of monoclonal antibodies Primary structure determined from recombinant DNAsequence and fully accessible to analytical verification Set of orthogonal analytical methods available tocharacterize the identity and amount of relatedvariants with high sensitivity Glycosylation profile can be comprehensivelydetermined with regard to identity and content ofindividual glycans with high sensitivity Accurate and relevant bioassays for pivotal biologicalfunctions availableAttributes: Primary structure Mass Disulfide bridging Free cysteines Thioether bridging Higher orderstructure N- and C-terminalheterogeneity Glycosylation(isoforms, sialicacids, NGNA,fucosylation, alphagal, site specific) Glycation Fragmentation Oxidation Deamidation AggregationMethods e.g.: MS (ESI, MALDI-TOF/TOF, MS/MS) Peptide mapping Ellman‘s CGE SDS-PAGE CD H-D exchange FT-IR HPLC HPAEC IEF 2AB NP-HPLC SE-HPLC FFF AUC DLS MALLS
    16. 16. 16 Moscow / Thomas Kirchlechner, May 2013Originators have changed their biologicsmanufacturing processes multiple times after approvalSource: C Schneider, Ann Rheum Dis March 2013 Vol 72 No 3Number of changes in the manufacturing process after approval for monoclonal antibodies (mAbs)/cepts authorised in rheumatologicalindications (A). Products in order of date of approval in Europe (from MabThera, authorised on 2 June 1998 for the initial authorisation in oncology,to Benlysta, licensed on 13 July 2011)Changes include e.g.• Change in the supplier ofa cell culture media• New purification methods• New manufacturing sites
    17. 17. 17 Moscow / Thomas Kirchlechner, May 20130,00,40,81,21,62,008.2007 12.2008 05.2010 09.2011Expiry DateUnfucosylated G0[% of glycans]608010012014008.2007 12.2008 05.2010 09.2011Expiry DateADCC Potency[% of reference]Post-ShiftPre-ShiftPre-ShiftPost-Shift Monitoring batches of an approved mAb revealed a shift inquality Shift in glycosylation (structure) pattern results in differentpotency in cell-based assays (function) Indication of a change in the manufacturing process Sandoz observed such shifts in several original productsOriginator variability is the basis for thebiosimilarity goal posts...Schiestl, M. et al., Nature Biotechnology 29,310-312, 2011)
    18. 18. 18 Moscow / Thomas Kirchlechner, May 20130 2 4 6 80100200300400500600700ADCC(%ofReference)bG0-F [rel. %]Variability ofreference productVariability observed duringcell line developmentVery narrowgoalposts forbiosimilarBiologically possible variability...and these goal posts are verynarrow
    19. 19. 19 Moscow / Thomas Kirchlechner, May 2013Originator manufacturing changes over time are thebasis for biosimilarity goal postsA biosimilar product can be as similar to its reference product,.....as that reference product is to itself over its lifetime due to processchangesOriginatorProcess OLDBiosimilarGoal postsfor a givenparameterOriginatorProcess NEWOriginator product changesare basis for biosimilars andjustify:– extrapolation acrossindications– interchangeability• Manufacturing process changes are tightly regulated (see ICH Q5E)• Change of quality attributes only acceptable if they do not alter safety/efficacy• To demonstrate biosimilarity, it is therefore acceptable to use upper and lowerlimit of pre- and post-shift material• However, biosimilar release specification should be as tight as currentreference product specification
    20. 20. 20 Moscow / Thomas Kirchlechner, May 2013Quality attributes can be influenced at all stagesof cell line and process development...QualityCell line■ Host cell line.■ Transfection/amplification pool■ Genetic “set up” of production cell line (clone).Process■ Growth medium composition.■ Culture conditions (pH, T, aeration,...)■ USP type (batch, fed batch, perfusion,...)■ USP regime (duration, fed type, perfusion rate..)■ Culture history (genetic stability, process stability..)■ Individual DSP steps■ Hold times■ Storage (buffer, container, conditions..)12
    21. 21. 21 Moscow / Thomas Kirchlechner, May 2013Example for Quality by Design:Attention to detail is essential...High resolution identification andquantification of major (G0,G1,G2)and minor glycan structures(down to a level of 0.1 rel.%)Characterization of mAb glycosylation heterogeneityTargeting ADCC activity and fucosylation by clone selection2xOriginators ParentalCellsPool 18 Pool 16 Clone 190246810bG0(-F)[%]0 2 4 6 80100200300400500600700ADCC(%ofReference)bG0-F [rel. %]
    22. 22. 22 Moscow / Thomas Kirchlechner, May 2013Source: Mike Doherty, Global Head Regulatory Affairs, Roche Pharmaceuticals, at Roche Investor Day 2010, March 18, 2010, seehttp://www.roche.com/investors/ir_agenda/rid_2010.htm?track=8 and www.roche.com/irp100318_md.pdf...and follow-on biologics not fulfilling these highstandards are not biosimilars and will not be approvedin EU Higher host cell protein content Content of aggregates not comparable Charge distribution not comparable Glycosylation not comparable ADCC effector function not comparable Clinical data: Only PK/PD study in 17patients
    23. 23. 23 Moscow / Thomas Kirchlechner, May 2013Isoelectric focusing gels“Non-Comparable biologics” – not approved inhighly regulated markets – are NOT biosimilarsSample E IA IB IIA IIB IIIA IIIB IV V VII VIII EBrockmeyer C & Seidl A et al. Eur J Hosp Pharm Pract 2009;15:34–40Schellekens H et al. Eur J Hosp Pharm Pract 2004;3:43–7Approved biosimilar in EUSample 1 2 3 4NO difference to originatorAlternative biologics ≠biosimilarNOT similar to Reference ENovartis/Sandoz does not represent all these approaches
    24. 24. 24 Moscow / Thomas Kirchlechner, May 2013Biosimilars must match originators acrossmultiple quality attributesPost translat. modif. e.g.:•NP-HPLC-(MS) N-glycans•AEX N-glycans•MALDI-TOF N-glycans•HPAEC-PAD N-glycans•MALDI-TOF O-glycans•HPAEC-PAD sialic acids•RP-HPLC sialic acidsPrimary structure e.g.:•LC-MS intact mass•LC-MS subunits•Peptide mappingHigher order structure e.g.:•NMR•CD spectroscopy•FT-IRImpurities e.g.:•CEX, cIEF acidic/basic variants•LC glycation•Peptide mapping deamidation,•oxidation, mutation, glycation•SEC/FFF/AUC aggregationCombination of attributes e.g.:•MVDA, mathematical algorithmsBiological activity e.g.:•Binding assay•ADCC assay•CDC assayFor monoclonal antibodies typically > 40 different methodologies are applied,analyzing more than 100 different quality attributes
    25. 25. 25 Moscow / Thomas Kirchlechner, May 2013Examples of clinical experience withbiosimilars Clinical studies started more than 12 years ago Product evaluated for 84 months in clinical phase III study ~ 35.000.000 patient days of safe use (2005-today) ~ 3.500.000 patient days of safe use (2009-today) Evaluated in multiple studies with >5000 patients overall ~ 67.000.000 patient days of safe use (2007-today)Somatropin (Human Growth Hormone):Filgrastim (Granulocyte-Colony Stimulating Factor/G-CSF):Epoetin alfa (Erythropoietin/Epo):
    26. 26. 26 Moscow / Thomas Kirchlechner, May 2013AgendaIntroduction to biosimilarsFuture of biosimilarsHow are biosimilars developed?Sandoz experience
    27. 27. 27 Moscow / Thomas Kirchlechner, May 2013Source: IMS, NHSUK G-CSF volume growthPercent change vs. previous yearSept. 2008biosimilarsapproved byEMA G-CSF prevents hospital re-admissiondue to infection More physicians start G-CSF treatmentearlier (primary prophylaxis) due tomore affordable cost2010200920082007 2011Biosimilar expand patient access already today
    28. 28. 28 Moscow / Thomas Kirchlechner, May 2013• Today, biologics can be thoroughly understood both structurally andfunctionally• Biosimilars can be created with product attributes that fall within thevariability of the original products – “highly similar”• Clinical trials confirm similarity - de novo proof of efficacy notnecessary• Many years experience have shown that EMA approved biosimilarsare as safe and effective as the original products• Biosimilars are broadening patient access and improving affordabilityalready todayConclusions2013 © All rights reserved. All trademarks are the property of their respective owners.
    29. 29. 29 Moscow / Thomas Kirchlechner, May 2013Thank you!

    ×