![AMD is a major cause of world blindness
Neovascular
AMD
~10% of all patients with AMD have the Neovascular form (~2.5 million
people worldwide); however, AMD is responsible for 90% of severe
visual loss due to AMD
Potentially as
debilitating as
arthritis, COPD,
and AIDS
AMD
AMD affects 20-25 million people worldwide,
and 2.3% of people
≥65 years of age in Europe3
Aging
population
In 2013, there were an estimated
841 million people worldwide ≥60 years of age, which is expected to rise
to
2 billion by 2050
1. Ferris FL, et al. Arch Ophthalmol 1984;102:1640-2; 2. Chopdar A, et al. Br Med J 2003;326:485-8; 3. Augood CA, et al. Arch Ophthalmol 2006;124:529-35; 4. Vision Problems in the US: Prevalence of
Adult Vision Impairment and Age-Related Eye Disease in America. http://www.preventblindness.net/site/DocServer/VPUS_2008_update.pdf [Accessed May 2014]; 5. Williams RA, et al. Arch
Ophthalmol 1998;116:514-20; 6. Ivers RQ, et al. J Am Geriatr Soc 1998;46:58-64;
2. http://www.un.org/en/development/desa/population/publications/pdf/ageing/WorldPopulationAgeing2013.pdf [Accessed May 2014]](https://image.slidesharecdn.com/mypreferredmoleculeforthemanagementofnamd3-210506094815/85/My-preferred-molecule-for-the-management-of-NEOVASCULAR-AMD-DR-AJAY-DUDANI-2-320.jpg)
My preferred molecule for the management of NEOVASCULAR AMD-DR AJAY DUDANI
- 1. My preferred molecule for the management of nAMD Ranibizumab And why do I choose it over Biosimilars??
- 2. AMD is a major cause of world blindness Neovascular AMD ~10% of all patients with AMD have the Neovascular form (~2.5 million people worldwide); however, AMD is responsible for 90% of severe visual loss due to AMD Potentially as debilitating as arthritis, COPD, and AIDS AMD AMD affects 20-25 million people worldwide, and 2.3% of people ≥65 years of age in Europe3 Aging population In 2013, there were an estimated 841 million people worldwide ≥60 years of age, which is expected to rise to 2 billion by 2050 1. Ferris FL, et al. Arch Ophthalmol 1984;102:1640-2; 2. Chopdar A, et al. Br Med J 2003;326:485-8; 3. Augood CA, et al. Arch Ophthalmol 2006;124:529-35; 4. Vision Problems in the US: Prevalence of Adult Vision Impairment and Age-Related Eye Disease in America. http://www.preventblindness.net/site/DocServer/VPUS_2008_update.pdf [Accessed May 2014]; 5. Williams RA, et al. Arch Ophthalmol 1998;116:514-20; 6. Ivers RQ, et al. J Am Geriatr Soc 1998;46:58-64; 2. http://www.un.org/en/development/desa/population/publications/pdf/ageing/WorldPopulationAgeing2013.pdf [Accessed May 2014]
- 3. Pathogenesis of AMD 1. Augustin AJ, Kirchhoff J. Expert Opin Ther Targets 2009;13:641-51; 2. Kijlstra A, et al. Age-Related Macular Degeneration: Immunological Factors in the Pathogenesis and Therapeutic Consequences. In: Pleyer U, Foster JV, Uveitis and Immunological Disorders. Heidelberg: Springer, 2009. p. 73-85
- 4. Treatment advances in AMD Pre-1980 No treatment Early 1980’s Thermal Laser Early 2000s Photodynamic Therapy 2006 onwards Anti-VEGF Therapy 2018 and beyond Vision Loss Halt disease progression Stabilize and optimize vision 1.Kent C. Rev Ophthalmol 2009. 2. DM et al. N Eng Journal Medicine. 2006;355:1432-44
- 5. 1. www.ema.europa.eu/docs/en_GB/document _library/EPAR_-_Scientific_Discussion/human/000715/WC500043550.pdf; 2. Ranibizumab prescribing information, www.ema.europe.eu; 3. Aflibercept® prescribing information, www.fda.gov; 4. Dixon JA et al. Expert Opin Investig Drugs 2009;18:1573-80; 5. Tew WP et al. Clin Cancer Res 2010;16:358-66; 6. Bevacizumab® prescribing information, www.ema.europe.eu; 7. Zhu Q et al. Ophthalmology 2008;115:1750-5 Note :* Bevacizumab is an unapproved drug for the ocular usage * Considering Anti-VEGFs there are 3 molecules that are available
- 6. Chronologically multiple studies prove the efficacy and safety of Ranibizumab Numerous clinical trials1-15 Including: ANCHOR, CABERNET, CATT, EXCITE, GEFAL, HARBOR, HORIZON, IVAN, MARINA, PIER, SAILOR, SEVEN UP, SUSTAIN, VIEW 1, VIEW 2 Trials of fixed and individualized dosing regimens1,3,4,6-15 Fixed: monthly or quarterly (ranibizumab 0.3 mg and 0.5 mg) Individualized: PRN or treat/wait and extend Tolerability14 Up to 7 years after treatment initiation, ranibizumab has been well tolerated, with low incidence of serious ocular and non-ocular AEs Efficacy12,13 Monthly treatment or prompt / earlya PRN treatment resulted in significant increases in VA, which were maintained 1. http://clinicaltrials.gov/show/NCT00061594 (ANCHOR); 2. http://www.clinicaltrials.gov/ct2/show/NCT00454389 (CABERNET); 3. http://clinicaltrials.gov/ct2/show/NCT00593450 (CATT); 4. http://clinicaltrials.gov/ct2/show/NCT00275821 (EXCITE); 5. http://clinicaltrials.gov/ct2/show/NCT01170767 (GEFAL); 6. http://clinicaltrials.gov/ct2/show/NCT00891735 (HARBOR); 7. http://www.clinicaltrials.gov/ct2/show/NCT00379795 (HORIZON); 8. http://www.controlled-trials.com/ISRCTN92166560 (IVAN); 9. http://clinicaltrials.gov/ct2/show/NCT00056836 (MARINA); 10. http://clinicaltrials.gov/ct2/show/NCT00090623 (PIER); 11. http://clinicaltrials.gov/ct2/show/NCT00251459 (SAILOR); 12. http://clinicaltrials.gov/ct2/show/NCT01256827 (SEVEN UP); 13. http://clinicaltrials.gov/ct2/show/NCT00331864 (SUSTAIN); 14. http://clinicaltrials.gov/ct2/show/NCT00509795 (VIEW1); 15. http://clinicaltrials.gov/ct2/show/NCT00637377
- 7. In the figure, a number of landmark randomized clinical trials that have brought a paradigm change in the management of neovascular age-related macular degeneration, and led to the approval (by United States Food and Drug Administration) of therapeutic agents such as ranibizumab and aflibercept, among others, have been chronicled. There has been an extensive evidence and wealth of data that supports the safety and efficacy of Ranibizumab Timeline of major milestones in the field of pharmacotherapeutics for age-related macular degeneration
- 8. Results: The Marina Study -10.4 -14.9 2 14 16 18 22 24 4 6 8 0 10 5 0 5 -10 -15 -20 ETDRS letters Month Ranibizumab 0.5 mg (n = 240) Ranibizumab 0.3 mg (n = 238) +5.4 +6.6 +6.5 +7.2 12 10 20 Sham (n = 238) Ranibizumab (0.3mg) Ranibizumab (0.5mg) Sham Injection Primary Endpoint (Loss of < 15 letters) 12 (24) months 94.5% 94.6% 62.2% BCVA letters at 12 (24) months +6.5 +7.2 -10.4 Philip J. Rosenfeld et al. N Eng J Med 2006: 355;14-17
- 9. Results: The Anchor Study ETDRS letters Month Ranibizumab 0.5 mg (n = 140) Ranibizumab 0.3 mg (n = 140) Verteporfin (n = 143) -9.6 -9.8 2 10 12 14 16 18 20 22 24 6 8 4 0 15 10 5 0 -5 -10 -15 +11.3 +10.7 +8.1 +8.5 Verteporfin PDT + SHAM inj SHAM PDT + RZB (0.3 mg) SHAM PDT + RZB (0.5 mg) Mean change in BCVA after 2 years -9.8 8.1 10.7 % of patients with improvement of > 15 letters inVA after 2 years 6.3 34.3 41 David M et al. American Academy of Ophthalmology 2009;116:57-65
- 10. SUSTAIN: patients who received most frequent retreatment with ranibizumab had poorest VA maintenance BCVA, best-corrected visual acuity; ETDRS, Early Treatment Diabetic Retinopathy Study; PRN, pro re nata; SE, standard error; VA, visual acuity Holz F, et al. Ophthalmology 2011;118:663-71. Figure reprinted from Holz F, et al. Safety and efficacy of a flexible dosing regimen of ranibizumab in neovascular age-related macular degeneration: the SUSTAIN study. Ophthalmology 2011;118:663-71, Copyright 2011, with permission from Elsevier
- 11. EXCITE: profile of patients on quarterly treatment shows that there is a variable response to treatment BCVA, best-corrected visual acuity; ETDRS, Early Treatment Diabetic Retinopathy Study; SE, standard error Eldem B, et al. Presented at ARVO, May 3-7, 2009, Fort Lauderdale, FL, USA: Poster D1107 0 1 2 3 4 5 6 7 8 9 10 11 12 Gained/not maintained n = 80 Gained/maintained n = 99 No initial gain n = 44 15 Month Mean BCVA change from baseline (ETDRS letters ± SE) 10 5 0 -5 -10 -15 Treatment: ranibizumab quarterly (0.3 + 0.5 mg), pooled Response: ranibizumab injection
- 12. HARBORa: individualized ranibizumab dosing results in clinically meaningful VA gains, which are sustained over 24 months aNote that the primary efficacy endpoint of HARBOR was not met. Primary endpoint: non-inferiority of 0.5 mg PRN vs 0.5 mg Monthly (4 letter margin) BCVA, best-corrected visual acuity; ETDRS, Early Treatment Diabetic Retinopathy Study; OCT, optical coherence tomography; PRN, pro re nata Faber D, et al. Presented at ARVO Annual Meeting, May 9, 2013, Seattle, WA, USA: Poster #6308
- 13. Pooled VIEW 1 & 2: visual gains with monthly ranibizumab dosing were maintained when switched to PRN dosing 0 1 2 3 4 5 6 7 8 9 10 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80 84 88 92 96 Mean change from baseline (BCVA) Letters Week +8.7 +7.9 PRN: 4.7 injections Patients switched to capped PRN regimen BCVA, best-corrected visual acuity; PRN, pro re nata Schmidt-Erfurth U, et al. Ophthalmology 2014;121:193-201
- 14. Long-term follow-up (SEVEN-UP): vision decline remains a long-term risk of neovascular AMD, requiring further treatment ap < 0.005 vs SEVEN-UP Year 7.3; bp < .0001 vs SEVEN-UP Year 7.3; cp < .001 vs SEVEN-UP Year 7.3; AMD, age-related macular degenration; ETDRS, Early Treatment Diabetic Retinopathy Study; SEM, standard error of the mean Rofagha S, et al. Ophthalmology 2013;120:2292-9; Image reproduced from Rofagha S, et al. Seven-year outcomes in ranibizumab-treated patients in ANCHOR, MARINA, and HORIZON. Ophthalmology 2013;120:2292-2299 (Copyright © 2013 American Academy of Ophthalmology. Reprinted with permission from Elsevier)
- 15. Biologics: A wide range of products such as vaccines, blood and blood components and recombinant therapeutic proteins that prevent, treat or cure a disease Manufacturing biologics demands stringent conditions for • Standardization • Characterization • Purification • Maintenance of quality (Efficacy and Safety) Biosimilar: A biopharmaceutical drug designed to have active properties similar to one that has previously been licensed Manufacturing Biosimilars aims at designing structural analogues to the innovator molecule There may be minute differences(Chemical analogues) that go unnoticed
- 16. • Biosimilars - the size and complexity of proteins make it virtually impossible to produce an exact copy of an originator, hence the name “similar” • A major concern with biosimilars is that small (undetectable) differences compared with originator products might lead to unexpected immunogenicity in patients Biosimilars .....only “Similar” not “Identical” Bridges Jr SL, White DW, Worthing AB. American College of Rheumatology. The science behind biosimilars: entering a new era of biologic therapy. Arthritis Rheum. 2018;70(3):334-44. Brinks V. Immunogenicity of biosimilar monoclonal antibodies. Generics and Biosimilars Initiative Journal (GaBI Journal). 2013 Dec 1;2(4):188-93.
- 17. Manufacturing Biosimilars is not only size but complexity https://www.gene.com/stories/building-biologics
- 18. There is a significant difference in the focus of Manufacture of Biologics and Biosimilars Innovator medication focus on Robust evidence based on Clinical studies Biosimilars focus on Analytical Studies for the chemical characterization Kiss S, Fine HF, Krawitz J. Coming of Age: Biosimilars. Ophthalmic Surgery, Lasers and Imaging Retina. 2018 Mar 21;49(3):162-5.
- 19. Note :* Bevacizumab is an unapproved drug for the ocular usage Corticosteroids Laser Bevacizumab* Ranibizumab Aflibercept Biosimilars Wealth of Data Damage to the Peripheral area Damage due to prolonged systemic presence ? IOP/Cataract risk ? Safely and efficacy evidence At a glance we can compare the available treatment modalities for the management of DME
- 20. Thus Ranibizumab • As it is safe for the Eye , and approved for AMD • It has a long history to prove its safety and efficacy • It has been proven beneficial , not only in reduction in CST but also gaining BCVA • It has a wealth of data , been beneficial in all the regimen
- 21. 78 yr lady one eyed other lost to AMD/PCV? 75 prn Ranibizumab over 10 yrs Today 6/18 and needs injection 2-3 monthly Feb 2011
- 22. 78 yr lady one eyed other lost to AMD/PCV? 75 prn Ranibizumab over 10 yrs Today 6/18 and needs injection 2-3 monthly Feb 2012
- 23. 78 yr lady one eyed other lost to AMD/PCV? 75 prn Ranibizumab over 10 yrs Today 6/18 and needs injection 2-3 monthly Jan 2013
- 24. 78 yr lady one eyed other lost to AMD/PCV? 75 prn Ranibizumab over 10 yrs Today 6/18 and needs injection 2-3 monthly Mar 2014
- 25. 78 yr lady one eyed other lost to AMD/PCV? 75 prn Ranibizumab over 10 yrs Today 6/18 and needs injection 2-3 monthly Jan 2015
- 26. 78 yr lady one eyed other lost to AMD/PCV? 75 prn Ranibizumab over 10 yrs Today 6/18 and needs injection 2-3 monthly Feb 2016
- 27. 78 yr lady one eyed other lost to AMD/PCV? 75 prn Ranibizumab over 10 yrs Today 6/18 and needs injection 2-3 monthly Apr 2017
- 28. 78 yr lady one eyed other lost to AMD/PCV? 75 prn Ranibizumab over 10 yrs Today 6/18 and needs injection 2-3 monthly Jan 2018
- 29. 78 yr lady one eyed other lost to AMD/PCV? 75 prn Ranibizumab over 10 yrs Today 6/18 and needs injection 2-3 monthly Jan 2019
- 30. 78 yr lady one eyed other lost to AMD/PCV? 75 prn Ranibizumab over 10 yrs Today 6/18 and needs injection 2-3 monthly Jan 2020
- 31. This is a case which portrays the evolution of treatment of AMD over a time period of 15 Years Patient details 88 year old male Known complaint and Strong family history of AMD Vision details Eye Past Present (Jan 2019) LE Diagnosed with AMD 18 years ago (2001) VA limited to HM RE Diagnosed CNVM 15 years ago (2004) Current VA= 6/12
- 32. Left Eye (Since 2002) Right Eye (Since 2005) • 5 PDTs with IVTA • 1 PDT given Nov 2005 for extrafoveal RAP lesion • 5 TTTs • Followed by 36 injections of Ranibizumab * for a span of 11 years • Followed up with monthly OCT • Treat and extend regime deployed thoroughly • Therapy switched to Aflibercept 5 years ago • 6 injections given till date • Aflibercept injections repeated every 4 months (PRN regime) • Last injection given in Jan 2019(time interval of 12 months) • Current Observation • Current situation shows Macular scar • Geographic atrophy Visual Acuity results • HM • 6/9 Treatment regime deployed * Note: This patient was the first patient in India to receive Ranibizumab injection, this was imported on compassionate basis
- 35. Milestones of treatment(Fundus Photos) Sep 2005 FFA
- 36. Milestones of treatment(Fundus Photos) May 2006 ICG RAP LESION
- 37. Milestones of treatment(OCT Images) Sept 2005 1St PDT Done
- 38. Milestones of treatment(OCT Images) May 2007 Fluid 8 months after last injection – needed injection every 3 months since..
- 39. Milestones of treatment(OCT Images) Mar 2009 Fluid in 3 months – Thickening of same parafoveal area every 3 months
- 40. Milestones of treatment(OCT Images) Feb 2013 Extra foveal site
- 41. Milestones of treatment(Serial SLO images) Sept 2008
- 42. Milestones of treatment(Serial SLO images) Mar 2009
- 43. Milestones of treatment(Serial SLO images) Nov 2010
- 44. Milestones of treatment(Serial SLO images) July 2013
- 45. Milestones of treatment (Consolidated Report) 16 May 2016
- 46. OCT and Fundus Photo 06/10/2018 OCT and Fundus Photo 09/01/2019 Right Eye
- 47. OCT and Fundus Photo 06/10/2018 OCT and Fundus Photo 09/01/2019 Right Eye