The Evolution of Pharmaceutical Biotechnology –Biotechnology –Science, Strategies, Products, and RegulationsRegulationsDr....
2Table of contentDisease Challenges, Strategies and DevelopmentsBiotech History, Process and ProductsBiotech RegulationsBi...
Pre-1950s 1950/60’s 1970/80’s 1990/00’sCells/OrganismsUnderstanding Disease MechanismsWhere did we come from, where are we...
Understanding the disease is one thing -Fitting treatments to patients anotherEffectiveness of treatment can be improved ....
Personalised Healthcare is becoming arealityMolecular insights allow better treatment decisionsIdentifying thosepatients o...
Trastuzumab Changed the Natural History ofHER2+mBCHER2-positive status has become a favorable prognostic factorProbability...
7Table of contentDisease Challenges, Strategies and DevelopmentsBiotech History, Process and ProductsBiotech RegulationsBi...
Serum Therapy 1893E. Bäumler, Auf derSuche nach derZauberkugel,Econ-Verlag 1971•first Nobel prizefor medicalresearch in hi...
1978The first biotech drug using recombinant technology was developed. Herbert Boyerand others succeeded at genetically ma...
Biotech products manufacturingDNA VectorATGStopWorkingCell BankAmplificationMaster Cell Bank
Biological product complexity:Examples of modifications: inherent or due to themanufacturing process11Adapted from: Steven...
Protein MicroheterogeneitySmall MoleculeDrugProteinDrug
Carter, P.J. (2006) Nature Revs. Immunol. 6, 343-357Glycosylation: important modification onMAbs
Enhancing antibody performanceBi-specific antibodybinds to two different targetand enhances specificityAntibody inhibitsor...
Trastuzumab emtansine ADC14 CT performed/ongoingEmtansinereleaseInhibition ofmicrotubulepolymerization15InternalizationHER...
• Increased direct cell-deathinduction• Enhanced antibody-dependentcell-mediated cytotoxicity(ADCC)• Lower complement-depe...
More than 500 clinical trials in over 50 cancersinvestigating the use of Bevacizumab*Bevazizumab has the largest clinical ...
Valuable and Vulnerable Industry• Developing a new medicine is lengthy, risky, and costly.• New drug development takes an ...
Biotech Pharmaceuticals –Where do we stand today?• Biotechnology has produced medical treatment forhitherto serious incura...
20Table of contentDisease Challenges, Strategies and DevelopmentsBiotech History, Process and ProductsBiotech RegulationsB...
How regulatory systems should evolveglobally ?• Greater regulatory convergence of pharmaceutical regulationsis necessary f...
23Table of contentDisease Challenges, Strategies and DevelopmentsBiotech History, Process and ProductsBiotech RegulationsB...
24Biosimilars Global Regulations
25Thomas Palmberger, Pharmaceutical Development, Sandoz Bioharmaceuticals,7-8 June 2011, Basel, Switzerland, 4th PDA Europ...
26
27Biosimilar pathways – EMA biosimilarantibody guideline• The guideline is setting the stage for the overall stepwisedevel...
Biosimilar vs. innovator clinical studies (oncology)Differences in requirements and study designs28Aspects ofDevelopmentBi...
Demonstration of Clinical Similarity and Extrapolationof Indications - A Challenge for Biosimilar Antibodies• Comparative ...
EMA: In support of the EU biosimilar framework“Considering the complexity ofbiomolecules, the limitations atpresent in ana...
Based on science, the Concept ofBiosimilarityis built on five indispensible pillars:The use of existing copies of biothera...
32Thank You !
9. Dr. Thomas Schreitmueller - F. Hoffmann-La Roche
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9. Dr. Thomas Schreitmueller - F. Hoffmann-La Roche

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“The Evolution of Pharmaceutical Biotechnology – Science, Strategies, Products, and Regulations”

Shows the latest developments in pharmaceutical biotechnology and provides a broad overview of biotherapeutic & biosimilar regulations globally and in the EU

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9. Dr. Thomas Schreitmueller - F. Hoffmann-La Roche

  1. 1. The Evolution of Pharmaceutical Biotechnology –Biotechnology –Science, Strategies, Products, and RegulationsRegulationsDr. Thomas Schreitmueller, Regulatory Policy, BiologicsF. Hoffmann – La Roche Ltd., Basel, Switzerland
  2. 2. 2Table of contentDisease Challenges, Strategies and DevelopmentsBiotech History, Process and ProductsBiotech RegulationsBiosimilars
  3. 3. Pre-1950s 1950/60’s 1970/80’s 1990/00’sCells/OrganismsUnderstanding Disease MechanismsWhere did we come from, where are we going?TodayDNA Structure Genetic Code Human GenomeDisease Mechanisms#PlausibleTargets1000’s10’s100PathwaysBasic Biological MechanismsObservational Biology
  4. 4. Understanding the disease is one thing -Fitting treatments to patients anotherEffectiveness of treatment can be improved . . .• 20-75% of patients do not receive effective treatment1• Thousands of deaths/yr from adverse drug reactions (e.g. US2). . . by tailoring treatments to selected patient groups defined bybiomarkers1 Spears et al., Trends Mol Med, 20012 Lazarou et al., JAMA, 1998
  5. 5. Personalised Healthcare is becoming arealityMolecular insights allow better treatment decisionsIdentifying thosepatients optimizes careMoleculardiagnosisPatients with breastcancer: only the portionof patients that showover-expression of theHER2 gene and willbenefit from Trastuzumab
  6. 6. Trastuzumab Changed the Natural History ofHER2+mBCHER2-positive status has become a favorable prognostic factorProbabilityofsurvival(%)Timefromdiagnosis(months)1008060402000 12 24 36 48 60HER2-positiveHerceptin n=191HER2-positiveNo Herceptin n=118HER2-positiveHerceptin n=191HER2-positiveNo Herceptin n=118HER2-negativen=1,782
  7. 7. 7Table of contentDisease Challenges, Strategies and DevelopmentsBiotech History, Process and ProductsBiotech RegulationsBiosimilars
  8. 8. Serum Therapy 1893E. Bäumler, Auf derSuche nach derZauberkugel,Econ-Verlag 1971•first Nobel prizefor medicalresearch in historyfor the discovery of“antibodies” 1901Emil von Behringimmunizing a“serum-horse”Biotech Manufacturing HistoricalPerspectives
  9. 9. 1978The first biotech drug using recombinant technology was developed. Herbert Boyerand others succeeded at genetically manipulating plasmids of E. coli bacteria toproduce insulin with the same amino sequence as seen in humans. (Insulin -Genentech)Herbert W Boyer and Robert A Swanson the founders of Genentech talkingabout recombinant DNA.Image: Courtesy of Genentech IncBioTechnology Developments
  10. 10. Biotech products manufacturingDNA VectorATGStopWorkingCell BankAmplificationMaster Cell Bank
  11. 11. Biological product complexity:Examples of modifications: inherent or due to themanufacturing process11Adapted from: Steven Kozlowski; FDAKpyro-EGDODGODpyro-E• Pyroglutamyl peptidesK• C-terminal LysineDDD • DeamidationOO• Methionine oxidationGG• Glycation• High mannose, G0, G1, G1, G2• SialylationModifications may result in approximately 108 potential variants
  12. 12. Protein MicroheterogeneitySmall MoleculeDrugProteinDrug
  13. 13. Carter, P.J. (2006) Nature Revs. Immunol. 6, 343-357Glycosylation: important modification onMAbs
  14. 14. Enhancing antibody performanceBi-specific antibodybinds to two different targetand enhances specificityAntibody inhibitsor activates signalingNaked Antibodiesbi-specific AntibodiesBi-specific antibodybinds to two differenttargets in different cellsbi-specific AntibodiesdrugdrugAntibody recruits immune effectorcell and induces cytotoxicityADCC enhanced AntibodyAntibody specifiesdelivery of drugArmed Antibodies
  15. 15. Trastuzumab emtansine ADC14 CT performed/ongoingEmtansinereleaseInhibition ofmicrotubulepolymerization15InternalizationHER2Adapted from LoRusso PM, et al. Clin Cancer Res 2011.T-DM1LysosomeNucleusPPP
  16. 16. • Increased direct cell-deathinduction• Enhanced antibody-dependentcell-mediated cytotoxicity(ADCC)• Lower complement-dependentcytotoxicity (CDC) activityIn collaboration with Biogen IdecUmaña et al, Blood 2006; 108, abstract 229, Umaña et al, Ann Oncology 2008, 19 (suppl 4), abstract 098CD20peptideType IIrecognition& elbow-hingeresiduesCarbohydrate glycoengineered (GlycoMabTMtechnology):Overexpression of GnTIII and ManII glycosylation genesin Ab production cell lines leads to Ab glycoforms bearingbisected, complex afucosylated oligosaccharides in FcregionObinutuzumab: glycoengineered, anti-CD20 mAb10 CT performed/ongoing
  17. 17. More than 500 clinical trials in over 50 cancersinvestigating the use of Bevacizumab*Bevazizumab has the largest clinical trial programever initiated in oncology*www.clinicaltrials.gov April 2010
  18. 18. Valuable and Vulnerable Industry• Developing a new medicine is lengthy, risky, and costly.• New drug development takes an average of 10–15 years,and costs approx. € 1.2 billion18INDEFINITEDrug Discovery Preclinical Clinical Trials FDA/EMAReviewScale-Up to Mfg.Post-MarketingSurveillanceONEFDA/EMA-APPROVEDDRUG0.5 – 2YEARS6 – 7 YEARS3 – 6 YEARSNUMBER OF VOLUNTEERSPHASE1PHASE2PHASE35250~ 5,000 – 10,000COMPOUNDSPRE-DISCOVERY20–100 100–500 1,000–5,000INDSUBMITTEDNDASUBMITTEDSources: Drug Discovery and Development: Understanding the R&D Process, www.innovation.org
  19. 19. Biotech Pharmaceuticals –Where do we stand today?• Biotechnology has produced medical treatment forhitherto serious incurable diseases.• Hundreds of biologics drugs approved.• Biotech drugs accounting approx. 17% of the worldpharma market.• Approx. 50% new drugs are biotech drugs.19Source: IMS 2010
  20. 20. 20Table of contentDisease Challenges, Strategies and DevelopmentsBiotech History, Process and ProductsBiotech RegulationsBiosimilars
  21. 21. How regulatory systems should evolveglobally ?• Greater regulatory convergence of pharmaceutical regulationsis necessary facilitating R&D investment and to increase andexpedite patient access to new and innovative medicines– Remove duplicative/different requirements between agencies,which hinder global drug development and supply– Develop a more innovative evaluation framework• adaptive licensing• inter agency reviews– Mutually recognize GMP inspections
  22. 22. 23Table of contentDisease Challenges, Strategies and DevelopmentsBiotech History, Process and ProductsBiotech RegulationsBiosimilars
  23. 23. 24Biosimilars Global Regulations
  24. 24. 25Thomas Palmberger, Pharmaceutical Development, Sandoz Bioharmaceuticals,7-8 June 2011, Basel, Switzerland, 4th PDA Europe Workshop on Monoclonal Antibodies
  25. 25. 26
  26. 26. 27Biosimilar pathways – EMA biosimilarantibody guideline• The guideline is setting the stage for the overall stepwisedevelopment approach having the goal “…ensuring that thepreviously proven safety and efficacy of the drug isconserved.”.• The stepwise approach at the clinical side is outlined more clearlyfocusing on the main principles to be considered when establishingclinical similarity: “The guiding principle is to demonstratesimilar clinical efficacy and safety compared to the referencemedicinal product, not patient benefit per se, which has alreadybeen shown for the reference medicinal product.”.• This has to be achieved by planning all studies “…with theintention to detect any potential differences between biosimilarand reference medicinal product and to determine the relevanceof such differences, should they occur.”
  27. 27. Biosimilar vs. innovator clinical studies (oncology)Differences in requirements and study designs28Aspects ofDevelopmentBiosimilar InnovatorPatient Population Sensitive andhomogeneous (patientsare models)AnyClinical Design Comparative versusinnovator, normallyequivalenceSuperiority vs standard ofcare (SoC*)Study Endpoints SensitiveClinically validated PDmarkersClinical outcomes data oraccepted/establishedsurrogates (e.g. OS andPFS)Safety Similar safety profile toinnovator; no newfindingsAcceptable benefit/riskprofile versus SoC*Immunogenicity Similar immunogenicityprofile to innovatorAcceptable risk/benefitprofile versus SoC** In some cases SoC may not exist
  28. 28. Demonstration of Clinical Similarity and Extrapolationof Indications - A Challenge for Biosimilar Antibodies• Comparative safety and efficacy trials in sensitivepopulations are required to demonstrate clinicalequivalence to the reference product within pre-defined margins.• The sensitive patient population/indication forthe required similarity assessments with respectto PK, PK/PD, Efficacy, Safety or Immunogenicitymay be a different one for each assessment.• Extrapolation across indication will require extensivescientific justification, additional efficacy, safety andimmunogenicity data may be needed as well asspecific risk mitigation strategies.
  29. 29. EMA: In support of the EU biosimilar framework“Considering the complexity ofbiomolecules, the limitations atpresent in analyticalcharacterization and in clinicaltrials (like defining sensitive andfeasible endpoints to detectdifferences), it is necessary thatthe biosimilar concept relies ondemonstrating comparability at allthree levels (that is, quality,preclinical and clinical to ensureas complete a picture as possibleon the features of such complexmolecules). A relaxation of theserequirements is not justified.”Christian K Schneider1,2, John J Borg3, FalkEhmann4, Niklas Ekman5, Esa Heinonen5,6,Kowid Ho7, Marcel H Hoefnagel8, RoelandMartijn van der Plas8, Sol Ruiz9, AntoniusJ van der Stappen8, Robin Thorpe10, KlaraTiitso4, Asterios S Tsiftsoglou11, CamilleVleminckx4, Guenter Waxenecker12, MatsWelin13, Martina Weise14 & Jean-HuguesTrouvin7,15on behalf of the Working Partyon Similar Biological (Biosimilar) MedicinalProducts (BMWP) and the Biologicals WorkingParty (BWP) of the Committee for MedicinalProducts for Human Use (CHMP)
  30. 30. Based on science, the Concept ofBiosimilarityis built on five indispensible pillars:The use of existing copies of biotherapeutic products thathave not gone through an adequate development programis not recommended due to potential safety implications.S c i e n c eAnalyticalSimilarityPre-clinicalSimilarityClinicalSimilarityPharmacovigilanceB i o s i m i l a r i t yProperQualitySystem
  31. 31. 32Thank You !

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