Biosimilars

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Biosimilars

• Prof. Dr. János Borvendég
• CHMP member
• Hungary

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Do we have a market for biosimilar?

• The market is driven by two factors
• by unmet clinical needs (diseases unmanageable
  with conventional therapeutics)
• by a premium price

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The biopharmaceutical market is very attractive

• 10 - 15 of the world pharmaceutical market
• growth between 2004-20103,4 year for total
  market11 year for biopharmaceuticals
• biosimilar market in EU US 16,4 billion by
  2011

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The most important patent expirations

• imiglucerase
• human insulin
• somatropin
• interferon alfa
• interferon beta
• erythropoietin
• filgrastim
• tPA
• IL-2
• sterptokinase

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Sales in 2006 and predicted sales in 2010 for six
leading biosimilars in US
global sales growth proportion in US market predicted sales 2010
Erythropoietin 13 billion 7 69 701 million
Human growth hormone 1,9 billion 2 33 442 million
Recombinant human insulin 8,0 billion 138 million
Interferon alfa 2,3 billion 6 35 188 million
Interferon beta 3,7 billion 55 131 million
G-CSF 5,6 billion 15 63 605 million
EU markets only US major EU markets EU markets only US major EU markets EU markets only US major EU markets EU markets only US major EU markets EU markets only US major EU markets
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Recent regulatory issues in biosimilarity
assessment and acceptance by the Regulatory
Agencies

• USA
• Promoting Innovation and Access to Life-Saving
  Medicine Act HR. 1427(11.03. 2009)Mr. Waxmans
  bill
• Pathways for Biosimilars Act (draft)Mrs. Eshoo
  bill (competing approach)

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Extracts from the Act H.R. 1427

• definition (biological, reference product)
• regulations of Biosimilars and Interchangeable
  biological products
• submission of abbreviated biological product
  application
• approval of biosimilar or Interchangeable
  biological products
• determinations on interchangeability
• market exclusivity for the original and
  biosimilar/interchangeable products
• --
• standard requirements for biosimilarity and for
  interchangeability have to be established by the
  FDA (within 2 years of passage of the bill).

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Recent regulatory issues in biosimilarity
assessment and acceptance by the Regulatory
Agencies

• EU/EMEA
• Several guidelines on
• Comparability exercises (non-clinical/clinical)EM
  EA/CHMP 49348/2005EMA/CHMP 42832/2005
• PK of therapeutic proteinsEMEA/CHMP 89249/2004
• Immunogenicity assessmentEMEA/CHMP/BWP/24511/2005
  
• Quality issuesEMEA/CHMP/BWP/3204-EMEA/CHMP/BWP/4
  9348/2005
• Validation of bioanalytical methodeEMEA/CHMP/EWP/
  531305/2008 (concept paper)
• Development, production, characterisation and
  specification for mAB and related
  productsEMEA/CHMP/BWP/157653/2007

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Basic principles of the EMEA regulation on
biosimilar products (BP)

• BP have different levels of complexity
• The regulatory requirements are guided (on case
  by case basis) by the- extent of the
  physicochemical/biological characterisation of
  the product,- nature of possible changes in the
  quality/structure of the biological product
  due to the changes in the manufacturing
  process (and their expected outcomes)-
  clinical/regulatory experiences with the
  particular class of the product in question
• The traditional bioequivalence (PK/PD) studies
  can not be applied with the same relevance

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What is a Biosimilar Product?

• Biosimilar, or similar biological medicinal
  product is a new biological medicinal product,
  similar to licensed reference medicinal product
  in - quality - efficacy - safety
• Biological medicinal productscontain
  biotechnology derived products asactive
  substance
• Biosimilar and reference biological medicines are
  similar but not identical

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Biopharmaceuticals are different from traditional
medicines

• Complex manufacturing process
• High molecular weight
• Complex 3-D structure
• Difficult to characterize
• Stability problems
• Immunogenicity

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Factors which may change the structure of the
proteins during the manufacturing process (even
under strictly controlled condition).

• Chemicallyoxidation, deamidation, disulfide
  shufflingracemisation
• Physicallyunfoldingmisfoldingaggregationpreci
  pitationfragmentation

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Quality considerations

• full Quality dossier is required
• State of Art analytical methods(physicochemical
  plus bioanalytical)
• Additional elements- comparability exercise-
  focusing on possible differences in
  manufacturing process minor structural
  diff. impurities

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Non-clinical considerations

• Comparative studies (similarity and differences
  at several doses level)in vitro receptor
  binding cell based assays in vivo PK/PD
• Toxicity spec. tox. rutin tox.?

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How to design clinical studies?
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Clinical studies with biosimilar products

• Requirements depend on- type/properties of the
  biological product- extent of the
  physicochemical/biological characterisation-
  non-clinical analysis- therapeutic indication-
  clinical experiences of the reference product
• Stepwise procedure- PK- PD- Therapeutic
  equivalence studies

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Pharmacokinetic (PK) considerations

• The requirements for PK studies are the same as
  for conventional product (single dose/steady
  state studies)
• Specific problems of bio-analysis- validation of
  the analytical assay (specificity, accuracy,
  precision, limit of detection)- methodological
  problems drug assay (interference with endogen
  substances) antibody assay (presence of the
  active substance in the plasma)
• Specific problems in PK clinical studies- great
  variability (inter/intra subject)-
  immunogenicity (antibody formation) ? change in
  PK parameters

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Pharmacodynamic (PD) considerations

• Availability of PD markers/surrogate biomarkers
• Sensitivity to changes in activity?
• Do they signal clinical endpoints?
• Is there quantitative relationship between the
  surrogate and clinical endpoint?
• Is there correlation between the PK an PD values?
• Are they validated?

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Equivalence efficacy/safety clinical trials

• General recommendations
• Are these clinical trials really needed?
• It depends on
• mechanism of action of the biological product
  (disease specific?)
• indication (target organ)
• PK properties
• availability of surrogate markers
• safety profile and
• immonogenicity of the product
• sensitivity of the clinical study
• clinical experiences with the reference product

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Individualized regulatory requirements for
clinical comparative studies

• Recombinant human insulin (rh Insulin)PK single
  dose, cross-over (in patients with type II
  diabetes) AUC, Cmax, tmax, t/2PD double
  blind, cross-over (euglycaemic clamp)Efficacy
  waived if the biosimilarity is justified by PK/PD
  dataSafety 6 months (Pre-approval)
  study 12 months (Post-marketing) study
  commitmentPhV.P - allergic reactions -
  compare the daily dose of previous and of
  the new insulin, needed by the patients

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Individualized regulatory requirements for
clinical comparative studies
(cont.)

• Human Somatropin (rSTH)PK single dose,
  cross-over comparative s.c. in healthy
  volunteers (AUC, Cmax, tmax, t/2)PD biomarkers
  IGF-1 IGF BP-3Efficacy - comparative,
  double blind, parallel groups in hypophyser
  dwarfs- endpoints growth in cm/year, SD score-
  duration 6-12 monthsSafety immunotoxicity
  (12 months) IGF-1, IGF BP-3, insulin,
  plasma glucosePhV.P - diabetogen effect -
  incidency of malignancy - anti rh GH antibodies

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Individualized regulatory requirements for
clinical comparative studies
(cont.)

• rG-CSFPK single dose, cross-over comparative
  (s.c./i.v.) (AUC, Cmax, tmax, t/2)PD
  absolute neutrophil count. (CD34)Efficacy
  (indications)- mitigation of neutropenia(at
  chemo th./myeloablative th)- mobilisation of
  progenitor cells- congenit./idiopathic
  neutropeniaSafety - 6 months comparative
  trial - immunogenicityPhV.P/Risk
  Management Program

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Individualized regulatory requirements for
clinical comparative studies
(cont.)

• Interferon alfaPK single dose, cross-over
  s.c./i.v. healthy volunteersPD - ?-2
  microglobulin - neopterin - se 2, 5
  oligoadenylate synthetase activityEfficacy
  - randomised, parallel group, comparative -
  treatment naive patients with HCV ? 48
  weeksEndpoints - undetectable levels of HCV
  RNA (by quantitative PCR) - co-primary
  endpoint 2-10 log decrease in viral loadSafety
  - flu-like illness, alopecia, myalgia,
  leucopenia, anaemia,
  thrombocytopenia Ref. Prep. -
  immunogenicity/neutralising capacityExtrapolation
  if the mechanism of actions known to
  be the same condition

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Individualized regulatory requirements for
clinical comparative studies
(cont.)

• Low Molecular Weight-HeparinsPK not
  applicablePD single dose, randomized,
  cross-over healthy volunteers
  surrogate markers anti F Xa anti F
  11a activity
  TFPI Efficacy - randomised, double
  blind, parallel group th. equivalence
  study - prevention of venous/arterial
  thrombolism treatment /VTE, DVT,
  PE) - patients with major orthopedic
  surgery ultra sonography renography death
  Safety - major bleeding - heparin
  induced thrombocytopeniaPhV.P/Risk Management
  Program

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Individualized regulatory requirements for
clinical comparative studies
(cont.)

• Recombinant ErythropoietinsPK single dose,
  cross-over, comparative (s.c./i.v.)PD
  comparative, multiple dose (4 weeks)
  dose ascending endpoint change in
  HgbEfficacy - comparative, randomized,
  parallel groups, double blind
  ? correction phase (s.c.) ?
  maintenance phase (i.v.) - target population
  (anaemia due to chronic renal faliure)
  - 6 month - endpoints Hgb level in
  correction/maintenance phase
  the reacting patients in
  epoetin dosage transfusion
  requirementsSafety immunotoxicity (12 months,
  comparative) Ph.V.P. Risk
  Management ProgramExtension to other indication
  allowed

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Is it simple to make a biosimilar?
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Leading biosimilar players

• Teva Pharmaceuticals Lonza (Basel)
• Biopartners (Barr, Switzerland) Bioton rGH,
  Alpheon (interferon alfa)
• Sandoz (generic arm of Novartis (Basel) Merck
  Co. Merck Bio Ventures
• Omnitrope (rGH) Binocrit (Epoetin alfa
  Hexal) filgrastim
• Insmed (Richmond VA) rG-CSF pegylated rG-CSF

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Smaller biosimilar focused companies

• Cangene (Winnipeg)
• Hospira (Lake Forest)
• Phage (Biotechnology, San-Diego)
• Gene Medix (Offaly, Ireland)
• Emerging biosimilar developers
• Dragon Pharmaceutical (Vancouver)
• Shanta Biotech (New Delhi)
• Bharat Biotech (Hyderabad, India)

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Hurdles in the faster growth of biosimilar market

• Biosimilars are specific products
• Regulations for marketing approval are much
  stricter than those for conventional generics
• The required capital investment and cost of
  manufacturing are much higher for biosimilars and
  the probability of successful lauch is lower than
  those for chemical-based generics

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Hurdles in the faster growth of biosimilar market
(cont.)

• Post-approval safety monitoring is compulsory
• Manufacturers of innovator/branded products are
  likely use sophisticated defensive tactics
  (improved delivery devices, improving the PK
  properties of the original products etc.)
• Physicians are reluctant to switch to biosimilar
  products
• Relatively small price differentce (20-25
  discount optimum) reduces the incentive to switch.

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The significance of biosimilar products (BP) can
not be ignored

• the majority of BP-s is of very important
  medicine (including th. for cancers, genetic
  diseases)
• the price of the innovator BP-s is extremely high
• to curb the healthcare spending and to promote
  the access to life-saving medicines are in the
  interest of the whole society

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Opportunities in the Biosimilar Market in the
future

• Key factors
• Capital investment- financial strength-
  combination of generic and branded business-
  licensing, collaborations, and mergers
• Developmentexpertise in - manufacturing
  proteins - sophisticate analytical methods
  - clinical studies (comparative PK/PD/Th
  studies)
• Marketing expertise in sales, promotion, safety
  monitoring
• --
• Rational and flexible regulation of marketing
  authorisation. Simplified guidelines.
• Suitable price policy / price competition
• The financial policy / capability of the Social
  Security system

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• Outlook
• I am optimistic.
• and you?