![Evidence from prospective studies:
TURF Trial
Aflibercept 2mg maintained mean VA improvements previously achieved with high-dose 2mg
ranibizumab and led to significant anatomic improvement and was required monthly in most
patients.
Wykoff CC et al. BJO. 2014 Feb 11. [Epub ahead of print]
TURF = aflibercepT for subjects with exudative AMD who were incomplete responders to mUltiple Ranibizumab anti-VEGF injections;](https://image.slidesharecdn.com/eyleaswitch-210509112533/85/Eylea-switch-19-320.jpg)
Eylea switch
- 1. CHALLENGING AMD: HOW LONG AMD NEED TREATMENT AJAY DUDANI MUMBAI RETINA CENTRE
- 2. HOW LONG n AMD CHRONIC DISEASE CAN STABILIZE AND CONTROL BUT IT DOESN’T HAVE AN END VISION IS LOST DUE TO INSUFFICIENT LONG TERM TREATMENT MOST ARE TREATED FOR 3 YRS SOME 10 YRS UNDERTREATMENT IS THE FIRST ENEMY GEOGRAPHIC ATROPHY IS LUXURY BECAUSE YOU HAVE AVOIDED SCARRING
- 3. TREAT AND EXTEND REGIMEN VISION MAINTENANCE WITH LONGER TREATMENT INTERVALS FLEXIBLE DOSING PERSONALISED TREATMENT TRIALS WITH 1200 PATIENTS REDUCE CLINIC VISITS TREAT PROACTIVELY PREVENT RELAPSES NO RISK 0F VISION LOSS 3- 4 MONTHLY INJECTIONS
- 4. RAP LESIONS WONDERFUL LESIONS DRAMATIC RESPONSE- MORPHOLOGICAL TREAT EARLY AND AGRESSIVELY PREDICTABLE TIME OF RELASE VERY OFTEN BILATERAL
- 5. TREX SPAIDE AND FREUND-10 YRS AGO INJECTION AT EACH VISITR INTERVAL IS EXTENDED WHEN NO ACTIVITY 2 WEEKS AT A TIME – 4 IN DME 6 WEEKS TO 8 TO 10 TO12 WEEKS RECURRING ACTIVITY –INTERVAL REDUCED BY 2 WEEKS LUCAS STUDY ATLAS- EYLEA TREX TREND CANTREAT RIVAL STUDY
- 6. META-ANALYSIS 26 000 PATIENTS TREAT AND EXTEND- 8.8 LETTER GAIN –FIRST YEAR-7.3 INJ 6.7 LETTERS IN –SECOND YEAR-4.9 INJ 5.4 LETTERS – THIRD YR- 4 INJ PRN- 3.5 LETTER GAIN – YEAR1---5.4 INJ 1.3 GAIN IN –YEAR 2—3.7 INJ 1.9 LETTER LOSS IN –YR 3 ---2.8 INJ
- 7. REAL WORLD EVIDENCE 5 YRS FOLLW UP60 MONTHS VISION IMPROVED AT 6 MONTHS REMAINED FOR 6 YR 40% PATIENTS INTERVAL OF 12 WEEKS – 1 YR REDUCTION IN NO OF INJECTIONS
- 8. Patients may be switched to EYLEA as a result of: Suboptimal response to other anti-VEGF treatments Scarring or other negative anatomical changes To reduce treatment burden Despite the encouraging results of multiple trials, many Lucentis and Avastin patients have recurrent fluid despite continued monthly injections1 Patients may have an initial suboptimal response or may develop resistance to anti-VEGF treatment over time1 Poor response to anti-VEGF treatment may lead to scarring and other negative anatomical changes2 – such damage can compromise the effectiveness of subsequent treatment Why Switch treatments? Yonekawa Y, Andreoli C, Miller J et al. Conversion to aflibercept for chronic refractory or recurrent neovascular age-related macular degeneratio n. Am J Ophthalmol 2013; 156 (1): 29–35. Daniel E, Toth CA, Grunwald JE et al. Risk of scar in the comparison of age-related macular degenera tion treatments trials. Ophthalmology 2014; 121 (3): 656-666.
- 9. Fully human fusion protein of key domains from human VEGF receptors 1 and 2 with human IgGFc Blocks all VEGF-A isoforms and placental growth factor (PlGF) High affinity - binds VEGF-A and PlGF more tightly than native receptors Aflibercept is specially purified and formulated for intravitreal injection Strict 1:1 stoichiometric binding Aflibercept maintains significant intravitreal VEGF-binding activity for 10–12 weeks after a single injection Aflibercept for intravitreal injection IgG=immunoglobulin G VEGFR1 VEGFR2 Fc Portion of IgG VEGF Trap Eye 2 3
- 10. Aflibercept 15 pM 16 pM 2890 pM 15 pM 26 pM Bevacizumab 854pM 1476 pM NB 706 pM 1323 pM Ranibizumab 675 pM 1140 pM NB 686 pM 845 pM VEGFR1 cell line VEGFR2 cell line NB: no detectable blocking under the assay conditions used Data on file, Regeneron Pharmaceuticals, Inc. IC50 at 20pM VEGF-A165 IC50 at 20pM VEGF-A121 IC50 at 20pM VEGF-A165 IC50 at 20pM VEGF-A121 IC50 at 40pM hPlGF2 Aflibercept Potently Blocks VEGF-A and Uniquely Binds PlGF
- 11. Unique Binding Mechanism of Aflibercept VEGF VEGF VEGF VEGF VEGF VEGF VEGF VEGF VEGF VEGF VEGF VEGF VEGF VEGF VEGF VEGF VEGF VEGF VEGF VEGF VEGF VEGF Aflibercept Bevacizumab Ranibizumab 1:1 stoichiometric binding Affinity maturation Bevacizumab can daisy-chain” or “paper-doll” with VEGF leading to large, multimeric conglomerates Two ranibizumab molecules can bind each VEGF dimer VEGF VEGF VEGF VEGF VEGF VEGF
- 12. Aflibercept suppresses intraocular VEGF for a mean of 71 days in wet AMD VEGF suppression in individual wet AMD patients* 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Individual patient Days after aflibercept injection 0 20 40 60 80 100 120 140 160 180 200 Definite VEGF suppression Uncertain suppression status Definite end of suppression Uncertain end of suppression Recommended 8-week injection interval Fauser S et al. Am J Ophthalmol. 2014;158(3):532–536. *Duration of complete suppression, as well as the end of suppression whenever definable.
- 13. Aflibercept binds strongly to both VEGF-A and PlGF1 Aflibercept suppresses VEGF-A in patients with wet AMD for almost twice as long as ranibizumab — VEGF-A was suppressed for a mean of 71 days with aflibercept versus 36 days with ranibizumab2,3 It is believed that the longer durability of effect for aflibercept will result in a greater possibility for extension of the treatment interval Implications for retinal disease management 1. Papadopoulos N, et al. Angiogenesis. 2012;15 (2):171–185. 2. Fauser S, et al. Am J Ophthalmol. 2014;158(3):532–536. 3. Muether PS, et al. Am J Ophthalmol. 2013;156(5):989–993.e2.
- 14. Monthly dosing has been shown to be highly effective in improving VA1,2 Anti-VEGF agents in retinal disease: Substantial gains in VA can be achieved 1. Brown DM, et al; ANCHOR Study Group. N Engl J Med. 2006;355(14):1432–1444; 2. Rosenfeld PJ, et al; MARINA Study Group. N Engl J Med. 2006;355(14):1419–1431; 3. Mitchell P. Macular Degeneration Foundation. 2011. Available at: http://www.mdfoundation.com.au/LatestNews/MDFoundationDeloitteAccessEconomicsReport%202011ExecSummary.pdf. Accessed February 2016; 4. Reginno CD, et al. Am J Ophthalmol. 2008;145:239–248; 5. CATT Research Group. N Engl J Med. 2011;364(20):1897–1908; 6. Chakravarthy U et al; The IVAN Study Investigators. Ophthalmology. 2012;119(7):1399–1411. PRN = pro re nata; T&E = treat-and-extend; VA = visual acuity. PIER4 Standard of care Fixed quarterly Inadequate treatment, efficacy compromised4 Proactive treatment CATT5 IVAN6 PRN Wet AMD Overwhelming management burden3 Monthly management burden remains5,6 Next-generation anti-angiogenic therapy ANCHOR1 MARINA2 Fixed monthly
- 15. In practice, patients are often monitored and treated less frequently than regimens used in clinical trials,1 and this can lead to inferior outcomes Reduced dosing frequency has been shown to lead to sub-optimal outcomes in wet AMD 1. Holz FG, et al. Br J Ophthalmol. 2015;99:220–226; 2. Lanzetta P, et al. Br J Ophthalmol. 2013;97:1497–1507. Mean change in visual acuity (ETDRS letters) Number of injections from baseline to month 12/week 52 0 SAILOR MONT BLANC SUSTAIN CATT EXCITE VIEW PIER HARBOR HARBOR CATT VIEW ANCHOR 1 2 3 4 5 6 7 8 9 10 11 12 13 0 4 5 6 7 8 9 10 11 12 VA results at: 3 months 12 months AFL 2 mg (every 8 weeksa) RBZ 0.5 mg (PRN/quarterlya) RBZ 0.5 mg (monthly) aAfter three monthly doses. AFL = aflibercept; RBZ = ranibizumab. Mean change in VA from baseline to month 12/week 52 by injection frequency2
- 16. Maximizing benefit, reducing burden Frequency of dosing with anti-VEGF agents is important If dosing is too high: OVER-TREATMENT If dosing is too low: UNDER-TREATMENT • Unnecessary burden on patients3 • Could compromise patient compliance → under-treatment • Extra burden on healthcare systems • Potential higher frequency of treatment-related adverse events • Sub-optimal efficacy outcomes1 − Vision loss/poor vision maintained − Underlying disease pathology • Burden of poor vision2 − Financial impact − Wide-ranging effects on QoL − Burden on family and caregivers QoL = quality of life. 1. Regillo CD. Retina Today. 2014; 2. Lotery A, et al. Br J Ophthalmol. 2007;91:1303–1307; 3. Monés J. Ophthalmologica. 2011;225:112–119.
- 17. Aflibercept 15 pM 16 pM 2890 pM 15 pM 26 pM Bevacizumab 854pM 1476 pM NB 706 pM 1323 pM Ranibizumab 675 pM 1140 pM NB 686 pM 845 pM VEGFR1 cell line VEGFR2 cell line NB: no detectable blocking under the assay conditions used IC50 at 20pM VEGF-A165 IC50 VEGF-A121 IC50 at 20pM VEGF-A165 IC50 at 20pM VEGF-A121 IC50 at 40pM hPlGF2 Reason for improved outcomes with aflibercept in SWITCH patients: Binding to VEGF and PlGF, Tighter binding and Durable VEGF suppression Heier JS, et al. Retinal Physician. 2009. Available at: http://www.retinalphysician.com/articleviewer.aspx?articleid=102898. Access Binds VEGF-A and PlGF with higher affinity than their native receptors Forms a stable, inert 1:1 complex with VEGF-A, binding both sides of the dimer and preventing interaction with other molecules Aflibercept suppresses intraocular VEGF for a mean of 71 days IgG = immunoglobulin G.
- 18. What is the evidence for switching patients to EYLEA therapy? Meta-analysis significant visual and anatomical improvements in eyes diagnosed with AMD for a median of 40-65 months Treatment regimens of 3 initial monthly doses followed by either PRN or 2q8 injections. The loading phase is of particular importance in maximizing fluid resolution. Seguin-Greenstein S, et al. J Ophthalmol. 2016
- 19. Evidence from prospective studies: TURF Trial Aflibercept 2mg maintained mean VA improvements previously achieved with high-dose 2mg ranibizumab and led to significant anatomic improvement and was required monthly in most patients. Wykoff CC et al. BJO. 2014 Feb 11. [Epub ahead of print] TURF = aflibercepT for subjects with exudative AMD who were incomplete responders to mUltiple Ranibizumab anti-VEGF injections;
- 20. 50% of patients had a reduction in subretinal fluid; 84% showed increase in VA, gain of 5.9 letters, CST improved 304.1 to 265.5 micrometers at 6 months. Singh et al. Br J Ophthalmol. 2014 Evidence from prospective studies: ASSESS Study
- 21. Chang AA et al. Ophthalmology. 2014;121(1):188-92. 33% had reduction in CRT of greater than 100 micrometers 45% of patients were fluid-free after three monthly aflibercept injections Evidence from prospective studies: Chang et al. 2014
- 22. What dosing regimen works in switch patients? — Switch to IVT-AFL allowed in both regimens a stabilization of morphological and functional parameters — Fixed regimen determines a greater reduction of CRT, fluid and PED height associated with a slight improvement in the BCVA — PRN RAN to T&E IVT-AFL switch resulted in a significant reduction in CRT and stabilization of VA with the same number of treatments given but with a mean of 1.5 less visits per patient — Both the 2q8 and PRN IVT-AFL regimens were effective in maintaining vision and anatomical outcomes in treatment-resistant nAMD patients. — The 2q8 regimen produced better visual outcomes with fewer injections than the PRN over 48 weeks — The loading phase is of particular importance in maximizing fluid resolution. 22 Seguin-Greenstein S, et al. J Ophthalmol. 2016 ARVO 2015 abstracts: Comparison of PRN and Fixed Regimen in the Switch of Aflibercept in Neovascular AMD (Daniele De Geronimo), Efficacy Outcomes and Treatmen t Burden of ‘As Required’ Ranibizumab to ‘Treat and Extend’ Aflibercept for Neovascular Age-Related Macular Degeneration: 12 Month Pre and Post Switch Analysis in Cli nical Practice (Archana Airody), Comparison of Aflibercept Treatment Regimes for Treatment-Resistant Neovascular Age-Related Macular Degeneration: 8-Weekly vs an ‘ As-Needed’ Regime (Wijeyanthy Wijeyakumar)
- 23. Summary Switching between anti-VEGF treatments showed positive results in patients with refractory or recurrent wAMD. Aflibercept is unique due to its longer half-life in the eye and higher binding affinity to VEGF compared to other anti-VEGF agents, such as bevacizumab and ranibizumab — Similar to ranibizumab and bevacizumab, aflibercept binds to multiple isoforms of VEGF-A; however, aflibercept has been specifically designed to also bind PlGF — VEGF-A is bound more tightly by aflibercept than by bevacizumab, ranibizumab, or native VEGF receptors — Binding of VEGF-A to aflibercept is 45–92x tighter than to bevacizumab and ranibizumab Majority of studies support switching to aflibercept based on improved anatomical outcomes, reductions in intraretinal and subretinal fluid, and extended injection intervals Papadopoulos N, Martin J, Ruan Q et al. Binding and neutralization of vascular endothelial growth factor (VEGF) and related ligands by VEGF Trap, ranibizumab and bevacizumab. Angiogenesis 2012; 15: 171–185.
- 24. SEVEN –UP STUDY SEVEN YR OUTCOMES IN RANIBIZUMAB ARM OF ANCHOR,MARINA AND HORIZON ROFAGA ET AL OPHTHALMOLOGY NOV 2013 LONGTERM OUTCOMES AT 7-8 YRS RANIBIZUMAB FOR CNVM DUE TO AMD PRIMARY END POINT BCVA OF 20/70 OR BETTER
- 25. SEVEN UP-RESULTS AT 7.3 YEARS (6.3-8.5) 37% EYES HAD 20/70 OR BETTER VISION 23% EYES BCVA 20/40 OR BETTER 37% EYES BCVA 20/200 OR WORSE 43% EYES HAD STABLE OR IMPROVED VISION 34% EYES HAD DECLINED VISION 8.6 LETTERS MEAN OF 6.8 LUCENTIS IN 3.4 YRS
- 26. SEVEN UP -RESULTS SD OCT SHOWED LEAKAGE IN 68% EYES 46% WERE RECEIVING ONGOING LUCENTIS MACULAR ATROPHY WAS SEEN IN 98% EYES ON FAF MEAN AREA 9.4 MM SIGNIFICANT CORRELATION TO POOR VISION(P<0.0001)
- 27. SEVEN UP CONCLUSIONS AFTER 7 TO 8 YEARS OF LUCENTIS ONE THIRD OF PATIENTS SHOWED GOOD VISUAL OUTCOMES ANOTHER THIRD HAD POOR OUTCOMES ALMOST HALF THE EYES WERE STABLE ONE THIRD DECLINED BY 15 LETTERS OR MORE Lucentis prevents scarring and keeps vessels reopenable by altering the natural course wet AMD(40% EYES HAD NO FIBROTIC LESIONS)
- 28. CASE 1-MYOPIC CNVM 65 YR LADY ONE EYED VISION 6/6 N8 HIGH MYOPE LATTICE LASERED PSEUDOPHAKIC MYOPIC CNVM 2009 15 PRN AVASTINS LAMELLAR MACULAR HOLE VISION TODAY 6/9P N10 SWITCH TO ACCENTRIX 9 MONTHLY INJECTIONS
- 29. MYOPIC CNVM 2010
- 34. CASE 2-PED OCCULT CNVM 75 YR EYE SURGEON VISION 6/24 N36 IN OS -2009 LARGE GIANT PED OS OTHER EYE SOFT CONFLUENT DRUSENS 22 PRN LUCENTIS FED UP AND DROPPED OFF TREATMENT PED SPONTANEOUS COLLAPSE 6/60 GOT HIS OTHER EYE CATARACT SURGERY REFUSED EYLEA SWITCH
- 35. OCCULT CNVM
- 39. CASE 3 -BILATERAL WET AMD -60 INJ -9 YRS FOLLOW UP 69 YR LADY LE CNVM IN 2009 REFUSED TREATMENT 6/60 RE CNVM 2010 6/9 N8 55 PRN LUCENTIS TILL DATE LAST -15/7/2015 RE RECURRENCES LE HEALED 6 INJ LUCENTIS PRN RE VISION 6/18 N 24 LE 6/24 N36 EYLEA SWITCH DONE LESION HEALING 2 EYLEAS AT 2 MONTHLY PRN LAST EYLEA 9 MONTHS AGO NOW SWITCH BACK TO ACCENTRIX
- 44. 3/14 6/14
- 45. LESION MORPHOLOGY THICK CHOROID-PACHYCHOROID EXUDATIVE MACULOPATHY POINTED CONICAL PED-IPCV RESPONSE TO ANXIOTYTICS –CSCR ADV- OCTA
- 46. Case 4-Occult CNVM 15 YR STUDY –RAP 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 LUCENTIS TACHYPHYLAXIS? RE AFTER SWITCH TO EYLEA -6 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
- 47. COMPARE PRE AND POST VEGF -RAP PRE VEGF EYE—PL POST VEGF 6/9 N12 DOES THE LEAK EVER STOP STARTS AS FLOOD THEN A DRIZZLE ENDS AS A MINOR TRICKLE VEGF IS THE DRIVER ANTIVEGF IS THE GLUE WATERPROOFING THE RETINA DR FIXIT
- 48. Fundus Photos R eye L eye
- 49. Serial angiography-RE Sep 20 05 (FF A) May 2006 (ICG) Oct 20 08 (FFA) RAP LESION
- 50. Serial OCTs - PEDs with fluid Sep 05 – PDT d one May 06 – post lucentis – 3 injections at 2 mon thly intervals May 06 – fluid 6 mo nths later – Lucenti s started
- 51. Serial OCTs May 07 – Fluid 8 months a fter last injection – needed injection every 3 months si nce.. Jan 09 – eg of OCT post in jection March 09 – fluid in 3 months – Thicke ning of same paraf oveal area every 3 months
- 52. Serial OCT’s – Last injection July13 July 2013 – pre- injection Feb’13 - extra foveal site
- 53. Serial SLO photos Nov 2010 Mar 2009 Sep 2008 July 2013
- 57. ANTI VEGF SIDE -EFFECTS DID IT LEAD TO CHORIODAL ATROPHY GEOGRAPHIC ATROPHY GLAUCOMA HEART ATTACK HYPERTENSION CENTRAL SCOTOMAS SLOW READING SPEED LOSS OF CONTRAST SENSITIVITY EXTENT AND TREAT