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  2. Retinal conditions – Current scenario Source:
  3. VEGF-A: key mediator of angiogenesis and vascular permeability....... The development of antivascular endothelial growth factor (anti-VEGF) has revolutionised the treatment of a plethora of ocular angiogenic disease processes. Tah et al. Anti- VEGF Therapy and the Retina – An Update; Journal of Ophthalmology 2015
  4. Evolution of Anti-VEGFs Hypothesized - a diffusible, hypoxia- induced, angiogenic “factor X” was responsible for iris and retinal neovascularization associated with ischaemic retinopathies. initiated phase 1 trials for the development of an anti-VEGF molecule (bevacizumab) Discovered a candidate glycoprotein and termed vascular permeability factor Discovered a tumour-derived factor named vascular permeability factor (VPF), which was responsible for inducing vascular permeability Decades later 1948 Michaelson 1989 Leung et al. 1990 Keck et al. The diffusible, hypoxia induced, endothelial cell- specific factor VEGF conceivably represents Michelson’s retinal tissue “factor X” Elevated levels of VEGF in ocular fluids from patients with active neovascular ocular disease were found compared with ocular fluids with no vascularisation. Simultaneous Research showed All the evidence of angiogenesis points to the role of VEGF in ocular neovascularisatio n 1997 Genentech Tah et al. Anti- VEGF Therapy and the Retina – An Update; Journal of Ophthalmology 2015
  5. Evolution of Anti-VEGFs....contd 2003 - 2004 Furthermore, with the knowledge that VEGF played a significant role in neovascular AMD, FDA approved pegaptanib (Macugen) was created, making it the first antiangiogenic therapy for ocular neovascularisation Bevacizumab approved for the treatment of colon cancer in combination with chemotherapy – based on successful results from phases 2 and 3 trials. 2004 - 2005 Believing that bevacizumab would not efficiently diffuse through the retina to reach the choroid, Genetech decided to generate a truncated alternative molecule (Ranibizumab) 2007 Ranibizumab (Lucentis) was approved based on data from two large Phase III clinical trials: • MARINA (minimally classic/occult trial of the anti- VEGF antibody ranibizumab in the treatment of neovascular AMD) • ANCHOR (anti-VEGF antibody for the treatment of predominantly classic choroidal neovascularisation in AMD) trials • 1st Anti-VEGF for intraocular use 2011 Regeneron developed a chimeric fusion protein (Aflibercept) that acted as a decoy receptor to sequester VEGF and thereby block its biological effects Tah et al. Anti- VEGF Therapy and the Retina – An Update; Journal of Ophthalmology 2015 Since its approval in 2006, ranibizumab has revolutionized the treatment of retinal diseases
  6. The evolution of ranibizumab Innovator CNV, choroidal neovascularization; BRVO, branch retinal vein occlusion; CRVO, central retinal vein occlusion; DME, diabetic macular edema; mCNV, myopic CNV; nAMD: neovascular age-related macular degeneration; ROP, retinopathy of prematurity nAMD 2007 2011 DME 2012 2014 Pre-filled syringe Other CNV 2016 2018 2020 2013 mCNV 2017 2019 BRVO CRVO
  7. Rbz Innovator : supported by a large amount of clinical evidence with 17 million injections across indications • Rbz Innovator is the only anti-VEGF agent which has: 1. Novartis Pharma AG. Accentrix Summary of Product Characteristics, September 2014; 2. Rofagha S, et al. Ophthalmology 2013;120:2292-9; 3. Novartis Pharma AG. Press release September 2013.; 4. Bloch SB, et al. Am J Ophthalmol 2012;153:209-13; 5. Brand C, et al. Presented at ARVO, 5 May 2013, Seattle, WA, abstract #3831 Most extensive patient follow-up program Patient-years, from continued post-marketing, real-world data, and pharmacovigilance studies4,5 Years of long-term data available2 ANCHOR SEVEN-UP PIER SAILOR SUSTAIN MONT BLANC MARINA FOCUS EXTEND EXCITE GEFAL HARBOR WAVE LUMIÈRE CATT IVAN VIEW BRAMD COMPASS LUMINOUS SAVE SECURE LAST FUSION HORIZON PrONTO Largest number of clinical trials Patients included in the extensive clinical trials program3 Largest amount of patient data Rbz Innovator has a well-defined efficacy and safety profile supported by clinical trials and real-world data Number of indications approved for treatment1 Largest number of approved indications nAMD Myopic CNV DME CRVO BRVO
  8. Real-world evidence shows over 70,000 patients have been treated with ranibizumab innovator Cumulative number of patients *Except other choroidal neovascularization. †Includes n=401 eyes 1. Cohen SY, et al. Graefes Arch Clin Exp Ophthalmol 2011;249:521–7; 2. Shona O, et al. Clin Exp Ophthalmol 2011;39:5–8; 3. Pushpoth S, et al. Br J Ophthalmol 2012;96:1469–73; 4. Novartis, Data on file Cumulative number of patients included in ranibizumab real-world studies (all indications)*1-4
  9. Anti-VEGFs – Current Status Innovator biologics like 1. Ranibizumab 2. Aflibercept 3. Bevacizumab (Off-label) are well known and successful....... In the world of ophthalmology, Biosimilars 1. Ranibizumab 2. Bevacizumab Now.......companies are developing anti-VEGF biosimiliars in attempts to get a foothold in the anti-VEGF market.... Are biosimilars the same as Innovator biologics?
  10. Biologics Are Large, Protein-Based Therapeutics That Vary in Size and Complexity Small Molecule Biologics Acetylsalicylic acid1 ~ 180 daltons Insulin2 ~ 5,700 daltons Growth hormone3 191 amino acids ~ 22,000 daltons Monoclonal antibody4 ~ 1,300 amino acids ~ 150,000 daltons Increasing Complexity 1. Aspirin (acetylsalicylic acid) prescribing information, Bayer. 2. Insulin product information, Sigma-Aldrich. aldrich/docs/Sigma/Product_Information_Sheet/2/i6634pis.pdf. Accessed February 6, 2017. 3. Online Mendelian Inheritance in Man. Accessed Feburary 6, 2017. 4. Chennamsetty N, et al. mAbs. 2009;1:580-582
  11. What Is a Biosimilar? • Undergone rigorous analytical and clinical assessment, in comparison to its reference product • AND • Been approved by a regulatory agency according to a specific pathway for biosimilar evaluation A biosimilar is a “copy” of a commercially available biopharmaceutical (reference product) that no longer is protected by patent which has: A biosimilar is “highly similar” to its reference product in physicochemical characteristics, efficacy, and safety. Dörner T, et al. Ann Rheum Dis. 2016;75(6):974-982.
  12. Biosimilars Are Not… Woodcock J, et al. Nat Rev Drug Discov. 2007;6(6):437-442. → Structurally different from originally licensed biopharmaceutical → Intended to improve performance while preserving mechanism of action → Examples Infliximab and adalimumab Filgrastim and pegfilgrastim → Not considered to be biosimilar Second-Generation (or Biobetter) Generic Drugs → Small-molecule drugs, that are less complex than biosimilars → Manufacturing process is several orders of magnitude less complex → Regulated under different legislation
  13. 5 ‘Similar’ DoesNot Equal ‘Same’ ‘‘Similar’ DoesNot Equal ‘Same’ - Let’s look at Manufacturing Processes
  14. Biologics: Drug Substance Production Process START Vectors to insert the gene Gene sequence coding for protein Host cells to grow the protein END Biophysical characteristics of final drug substance Lengthy and complex purification process Fermentation with very precise culture conditions Factors influencing properties of the molecule: • Time, pH, temperature, culture media, oxygen levels/lactic acid accumulation Properties most frequently affected: • Carbohydrates, ratios of charged species, aggregates Factors influencing properties of the molecule/product: • Removal of host cell DNA and proteins • Removal of fragments and aggregates • Concentration of the protein • Final formulation buffer Liu HF et al. mAbs. 2010;2;(5):480-499 Li F. et al. mAbs 2010;2(5):466-477
  15. Manufacturing Biologics – why is it so difficult ? • A biological typically requires around 250 in process tests during manufacturing as compared to around 50 for routine generics • To ensure high quality and consistency in final product , high level of monitoring and testing required during production.
  16. Biologics Manufacturing Control at EveryStep In ProcessTestingData From EveryProcess Step CellBank Bioreactor Harvest Chromatography 1, 2, 3 Virus Filter Concentration Bottling FinalTests Purification Cell Culture Final Dosage Form Forcomparability, the innovator hasarich testing database from every in process step of every batch, the biosimilar only hasaccessto the finalproduct
  17. Biosimilars and Twins: Identical DNA, Minor differences in Features • Theactive ingredient of abiosimilar can at best only resemblethat of the innovator product • How an innovator makesits biologic can never be duplicated down to the last detail; abiosimilar is made using cells, materials and processesthat differ from the innovator product • Thisis true even if abiologic and its biosimilar start from the samegenetic blueprint, in much the sameway asidentical twins, despite the same genes, have different fingerprints
  18. Different vectors to insert the gene Different host cells to grow the protein Different fermentation/culture conditions Different downstream processing Different biophysical characteristics in final product
  19. Accumulated Experience and Knowledge Generates Sustainable Quality and Predictability YEAR 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 Innovator Development Discovery and Target Validation Cell Line, Process Development Process Characterization, Validation Process monitoring, Scale and Site changes, Comparability Protocols, Process consistency Assurance Characterization of Molecule, Structure /Function Studies, Justify and Establish Specifications Deep understanding of Product Properties, Comparability Protocols to assure consistent product Non-clinical Studies Ph 1 clinic als Phase 2 Clinicals Phase 3Clinicals BLA/ MAA Clinical Studies for additional Indications Pre-Approval SafetyDatabase Post-Approval Safety Database, Post-Approval Phamacovigilence, Post- Marketing Observational Stuides, Post-Marketing Safety Studies YEAR 1 2 3 4 5 Biosimilar Development Cell Line, Process Development, Characterization Analytical Characterization, Establsih Specifications Non- Clinical Studies Clinical studies BLA/ MAA Pre-Approval SafetyDatabase
  20. 5 ‘Similar’ DoesNot Equal ‘Same’ Small Alterations Can Make a BIG Difference
  21. Manufacturing Biosimilars Even small changes in production – minor equipment and environmental variations can : • Cause significant changes in behavior of cells • Change in the fragile 3-dimensional structure of the protein • Change in quantity of acid-base variants and glycosylation • Impact the safety and effectiveness of the Biologic
  22. 23 Concept of Interchangability
  23. Interchangeability “Biosimilar to the U.S.-licensed reference biological product … expected to produce the same clinical result as the reference product in any given patient.” “For a biological product that is administered more than once to an individual, the risk in terms of safety or diminished efficacy of alternating or switching between use of the biological product and the reference product will not be greater than the risk of using the reference product without such alternation or switch” cations/TherapeuticBiologicApplications/Biosimilars/ucm411418.htm. Accessed 19th Feb 2016 Note : The interchangeable product may be substituted for the reference product without the intervention of the health care provider who prescribed the reference product. (biosimilar drug should neither increase AEs nor decrease efficacy when switched from the reference drug)
  24. 5 ‘Similar’ DoesNot Equal ‘Same’ Approvals
  25. Steps involved in Approval of Similar Biologic Physicochemical data Pre-clinical Studies Clinical (PK/PD) studies Confirmatory clinical safety and efficacy studies Safety and Immunogenicity Data • One or more adequately powered, randomized, parallel group, blinded confirmatory clinical safety and efficacy trials are desirable based on the comparability established during preclinical and PK / PD studies • Pharmacodynamic Studies • Toxicological Studies • Both pre-approval and post- approval assessment of safety is desired to be conducted for similar biologic. • Regarding pre-approval safety assessment, comparative pre-approval safety data including the immunogenicity data is required for all similar biologics
  26. • Strong need for regulations governing biosimilars • Implementation of an abbreviated licensure pathway for biological products presents challenges, given the associated scientific & technical complexities • European Union has regulations in place for quite some time for approving biosimilars • US & India have recently covered these under their respective Acts by bringing in applicable guidelines for their evaluation & overall regulation Status of Regulations for Biosimilars Globally
  27. 28 Strength of Evidence
  28. Strength of Evidence Meta- analysis Randomized Clinical Trials Cohort studies Case control studies Case reports Editorials/Expert Opinions Animal research/ In-vitro studies 1 2 3 4 5 Levels of evidence 311/evidence-based-decission- making.aspx?ModuleName=coursecontent&PartID=4&SectionID=-1. Accessed on 30th Sept 2016 Currently all the data of Ranibizumab biosimilar fall into this level Ranibizumab Innovator
  29. Occult CNVM 15 YR STUDY – BILATERAL RAP -45 INJECTIONS • 82 year old male • Strong family history of AMD • LE – Diagnosed with AMD 14 years ago(2001), Underwent 2 TTT’s, 3 PDT’s with IVTA, now has macular scar with Vn of HM RE – Has had 1 PDT (Nov 2005) for extra foveal RAP lesion and 36 injections of Lucentis in the past 11 year • OCT MONTHLY • EXTENT AND TREAT-ONLY INJECT WHEN FLUID • LUCENTIS TACHYPHYLAXIS? • RE AFTER SWITCH TO EYLEA -6 EYLEA INJ OVER 5 YRS • Repeat eylea after 4 months ON PRN BASIS • LAST EYLEA 2WEEKS AGO AFTER 12 MONTHS • VISION 6/9 N6 • GEOGRAPHIC ATROPHY
  31. Fundus Photos R eye L eye
  32. Serial angiography-RE Sep 2005 (FFA) May 2006 (ICG) Oct 2008 (FFA) RAP LESION
  33. Serial OCTs - PEDs with fluid Sep 05 – PDT done May 06 – post lucentis – 3 injections at 2 monthly intervals May 06 – fluid 6 months later – Lucentis started
  34. Serial OCTs May 07 – Fluid 8 months after last injection – needed injection every 3 months since.. Jan 09 – eg of OCT post injection March 09 – fluid in 3 months – Thickening of same parafoveal area every 3 months
  35. Serial OCT’s – Last injection July13 July 2013 – pre- injection Feb’13 - extra foveal site
  36. Serial SLO photos Nov 2010 Mar 2009 Sep 2008 July 2013
  38. Summary • Anti-VEGF medications have revolutionized the treatment of exudative AMD over the past 2 decades and patients with a potentially blinding disease have been able to regain vision. • While there is still no clear-cut best treatment regimen, evidence suggests individualized treatments may be safer and more efficient. • The "treat and extend" protocol seems to offer the most favorable alternative to the monthly regimen with a goal being to extend the interval between visits to maintain an exudation-free macula with the fewest number of visits and injections • There still remain several unanswered questions regarding nAMD treatment such as the interval by which "treat and extend" protocols should be extended at each visit, how
  39. Ranibizumab vs biosimilar Parameter Bio-similar Study Ideal Standard Duration of the Study Just 3 months Minimum of 1 year follow up is necessary and ideally landmark studies like CATT & IVAN have taken the 2 year follow up to compare the safety between bevacizumab and ranibizumab. Endpoint % of patients with loss of <15 letters Current studies evaluate BCVA gain Number of Patients in the study The study with Bio-similar has only 100 patients. Biosimilar arm 75 and ranibizumab arm 25. A minimum of 30 patients is required in any arm of a trial for statistical significance and the ranibizumab arm is under –represented. Sample sizes for most H2H studies of Anti-VEGF have been around 200- 300 patients Ranibizumab and its biosimilar have been studied in one single trial and that too in patients of AMD only. Accessed on 19/02/2016
  40. RE-ENACT Study (Retrospective, Multicentre, Observational study on Wet AMD) 45 Did not capture the complete information on adverse events in the medical records and hence, not analyzed in this subgroup
  41. 5 ‘Similar’ DoesNot Equal ‘Same’ Safety??
  42. Recent Report of Eye Inflammation with Rbz Biosimilar, Company Recalls Batch for QC Testing 48 Patel D. Patients report eye inflammation, Intas recalls its drug batch. The Indian Express. April 3, 2017. http:// patients-report-eye-inflammation-intasrecalls-its-drug-batch-4596914/. Accessed April 11, 2017 With some patients reporting Inflammation in their eyes due to Rbz Biosimilar, the company has advised the docs to not to use any drug of this of this particular batch. It has also recalled this batch from the market to undergo internal testing at its QC lab
  43. VRSI Issued Alert on Ranibizumab Biosimilar Second Time In a Row 49 Dear Members, there had been reports of Intraocular Inflammation from various parts of India after IV Rbz Biosimilar of a company. Company has advised not to use Rbz Biosimilar Inj. of batch no 18020020. VRSI is gathering more facts on this situation. It is advised that all members to be alert and exercise abundance of precaution with other batches of the biosimilar also. Please report any adverse Incidents to VRSI at
  44. FDA Inspection of Biosimilar Plant 50 Observation-1: Lab reports are deficient in that they do not include complete record of all data obtained during testing Observation-2: Appropriate controls are not exercised over computers or related systems. There was failure to maintain backup file of data entered into computer or related system foiaelectronicreadingroom/ucm567595.pdf
  45. 51 • Observation-10: Building used in mfgd., processing, packing or holding of drug products are not free of infestation by birds • Observation-11: Cell bank were not maintained under appropriate storage monitoring conditions designed to maintain viability and prevent contamination and records of the vials from the cell bank and storage conditions were not maintained FDA Inspection of Biosimilar Plant ryinformation/cderfoiaelectronicreadingroom/ucm567595.pdf
  46. USFDA – approved innovator Manufacturing Site 52
  47. Summary • With patent expiration of innovator products, biosimilars will increasingly become available • Awareness of the deviations between biosimilars & innovator products in terms of efficacy, safety & immunogenicity is essential for proper prescription & safety of the patients • How similar is similar enough?
  48. Thank you