New and Emerging Therapies for Retinal Diseases

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New and Emerging Therapies for Retinal Diseases Toufic Melki, M.D. Richard Chiu, D.O. Retina Centers of Washington Locations in Rockville, Arlington, and Georgetown University

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Disclosures No financial interests to disclose Dr. Chiu has been a consultant to Alimera Sciences

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Outline I. Diabetic Macular Edema A. Anti-VEGF therapies B. Corticosteroids and role of inflammatory mediators in DR 1. Ozurdex 2. Iluvien II. AMD A. Sustained delivery devices B. Platelet derived growth factor inhibition (anti-PDGF therapy) C. Gene therapy D. Complement cascade inhibition E. Squalamine topical therapy III. RVO A. Anti-VEGF therapies and differences with DME, wAMD therapy B. Corticosteroids IV. Case presentations

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Diabetic macular edema 26 million Americans with diabetes 2 million new cases of DM diagnosed every year 19% of current diabetics are undiagnosed About 10% of patients with DM develop DME in their lifetime 72,000 new cases of DME diagnosed each year

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Prevalence of diagnosed DM in US adults 2004 2008 http://apps.nccd.cdc.gov/ddtstrs/default.aspx

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Prevalence of diagnosed DM in Maryland adults http://apps.nccd.cdc.gov/ddtstrs/default.aspx 2004 2008 2011 2004 0 - 6.3 6.4 – 7.5 7.6 – 8.8 8.9 – 10.5 ? 10.6

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Diabetic macular edema “Standard of care” Focal/grid laser ETDRS Clinically significant diabetic macular edema Focal/grid laser decreased 3-year risk of moderate vision loss from 24% to 12% Visual acuity did not improve

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Ranibizumab(Lucentis) for DME FDA approved for diabetic macular edema (DME) in August 2012 Monthly injection 0.3 mg dose (different than 0.5 mg used for RVO and AMD) $1100 per dose (vs $1900 for 0.5 mg)

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RIDE and RISE studies 36 month Phase III studies for MONTHLY injection of ranibizumab 759 patients VA ranging from 20/40 to 20/320 OCT > 275 microns Focal laser allowed at 3 months

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RISE RIDE Sham group received Lucentis from mo 24-36

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RIDE/RISE 24 month data

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RIDE/RISE Not so impressive findings 23% treated patients still had central macular thickness of ? 250 microns 40% had not achieved VA ? 20/40

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In the real world… Treatment burden Cost Patient tolerance Do we really need to inject every month? DRCR-net Protocol I

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Aflibercept (Eylea) FDA approved for diabetic macular edema (DME) in July 2014 2 mg dose (same as RVO and AMD dose) Monthly injection x 5 doses, Q 2 months thereafter $1850 per dose

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VIVID (EU and Japan)/VISTA (US) studies Phase III studies comparing Eylea 2.0 mg MONTHLY and Q2 MONTHS (after 5 initial monthly injections) to sham VIVID 461 patients, VISTA 466 patients 3 year study “Rescue” laser given if VA declined >=15 letters at any 1 visit or >= 10 letters in 2 consecutive visits

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Bevacizumab (Avastin) $42 per dose for intravitreal Cost of treatment for colon CA is $40,000-100,000 annually Efficacy in wAMD demonstrated to be comparable in CATT study

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BOLT study 24 month prospective study for bevacizumab (Avastin) Mean change in BCVA Treatment (q 6 weeks) +8.6 letters Laser -0.5 letters 15 letter or more gain Treatment group 32% Laser group 4%

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DRCR.net Protocol T NIH sponsored studying comparing 660 patients randomly assigned to treatment with Eylea, Lucentis, and Avastin Identical retreatment criteria AAO 2014 “Teaser” for 12 month data Eylea treated patients significantly better by 2 ETDRS letters than Lucentis and Avastin treated patients Eylea treated patients received one fewer injection than Lucentis and Avastin treated patients Rate of ATE (arteriothromboembolic events) was 2% Eylea, 4% Avastin, 5% Lucentis Results pending verification prior to publication

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Corticosteroids Role of inflammatory cytokines BESIDES VEGF in DR IL-6 MCP-1 Anti-VEGF therapy may not fully address the pathophysiology of DR

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Fluocinolone (Iluvien) Alimera Sciences Non-biodegradable implant, releases 0.2 mcg/day 3 year duration of effect Previously rejected by FDA in 2011 citing adverse events (IOP, glaucoma) In use in several E.U. countries FDA approval September 2014 for DME previously treated with corticosteroids s significant IOP elevation Available in US 1st quarter 2015, cost $8000 (?)

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FAME study Two 3 year Phase III studies for Iluvien 15 letter or more gain Treatment group 28.5-32.4% Sham 13.4% 82-88% of phakic patients received cataract surgery 38-42% required IOP lowering meds 4.8-8.1% required glaucoma surgery

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Dexamethasone (Ozurdex) Injectable biodegradable intravitreal implant, 3-6 mo duration of effect $1300 per dose FDA approved for DME June 2014

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MEAD study 3 year phase III study Retreatment allowed q 6 mo Mean 4.1 injections over 3 year study period Adverse outcomes 59% treated patients needed cataract surgery (vs 7% in sham group) 41% required IOP lowering medication 0.7% needed glaucoma filtration surgery

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MEAD study – pseudophakic/anticipated cataract surgery participants

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Corticosteroids Consider using if/when DME patients are: Pseudophakic or anticipating cataract surgery Post-vitrectomy Unable to maintain near monthly follow-up/injections frequently required for anti-VEGF treatment Poorly responsive or tachyphylactic to anti-VEGF monotherapy

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AMD How far we have come What do we do (with what we have) Where we are going

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AMD – How far have we come Bloch SB, et al. Am J Ophthalmol 2012; 153: 209-213 Population based observational study, Denmark Incidence of legal blindness from AMD decreased by 50% from 2000-2010 Most of the decrease occurring after 2006 (i.e. after introduction of anti-VEGF therapy)

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AMD – How far have we come MARINA study Monthly ranibizumab (Lucentis) injection x 2 years +10.7 ETDRS letters -14.9 letters with sham -9.8 letters with photodynamic therapy (ANCHOR)

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AMD – How far we have come VIEW1/VIEW2 Phase III study comparing aflibercept (Eylea) to ranibizumab (Lucentis) Year 1: Eylea q 8 weeks (after 3 initial monthly doses) vs Lucentis q 4 w Year 2: PRN with monthly evaluation

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AMD – What do we do (with what we have) CATT 2 key questions Comparison of bevacizumab (Avastin) with ranibizumab (Lucentis) Monthly vs PRN dosing of each 24 month results Monthly dosing favored over PRN 2.4 letters Switching to PRN after 1 year of monthly injection resulted in -2.2 letters over continued monthly dosing VA outcomes slightly favor Lucentis (1.4 letters) but was not statistically significant

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IVAN (“British CATT”) 2 key questions Comparison of bevacizumab (Avastin) with ranibizumab (Lucentis) Continuous (monthly) vs discontinuous (PRN) 24 month results (The Lancet, 382: 1258-1267) Bevazicumab (-1.37 letters) was “neither inferior nor non-inferior to ranibizumab” Discontinuous (-1.63 letters) was “neither inferior nor non-inferior to continuous” AMD – What do we do (with what we have)

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AMD- What do we do (with what we have) HARBOR study Ranibizumab (Lucentis) 0.5 mg vs 2.0 mg (“high dose”) Monthly vs PRN after 3 monthly doses Retreatment if OCT demonstrated fluid or if VA decreased by ? 5 letters 24 month results No significant difference between 0.5 mg and 2.0 mg dose In year 2, PRN treated group had similar visual outcomes with average of 9.9 weeks between injections 0.5 mg dose

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AMD - Where are we going Sustained release Quest for the “Everlasting Gobstopper”

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AMD – Where are we going Encapsulated Cell Technology (Neurotech) Genetically engineered RPE cells line which can be modified to produce specified protein Encapsulated non-biodegradable delivery device Initial device produced ciliary neurotrophic factor (CNTF) for retinitis pigmentosa and dry AMD Adaptable to produce all classes of biotherapeutics (anti-VEGF, PDGF, etc.)

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Encapsulated cell technology (ECT)

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AMD – Where are we going Wet AMD/ECT VEGF receptor decoy (NT-503) – Affinity for VEGF similar to aflibercept (Eylea) Phase 1 Dose escalation studies Double implant vs single 2 line gain with double implant at 10 months 150 micron decrease in central subfield on OCT with double implant vs 50 micron with single Phase 2 study with new generation implant with 2-3x release rate Future implants could combine more than 1 therapy (e.g. anti-VEGF + anti-PDGF)

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AMD – Where are we going Nanostructured Tethadur (pSivida) Implantable silicone porous silicone wafer Diameter of pores “tuned” to affect sustained release “Tube of tennis balls” Faster release with ping pong balls Slower release with tennis balls Drug (e.g. Avastin, Eylea, etc) withdrawn from vial and mixed with Tethadur particles Animal studies – sustained release of bevacizumab for 6 months

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Nanostructured Tethadur

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AMD – Where are we going Port delivery system (PDS) Developed by Genentech in collaboration with ForSight VISION 4 Subconjunctival implant, placed in pars plana 10 minute procedure Minimally invasive office based refill procedure Phase 1 study Lucentis Average improvement of 2 lines at 1 year Average 4-5 refills in 12 months Phase 2 underway Higher dose Goal of 4 month interval

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AMD – Where are we going MicroPump (Replenish) Battery Drug reservoir chamber Refill port accessible with transconjunctival 31 g needle Intraocular canula releases microdose into vitreous cavity Phase 1 study

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AMD – Where are we going Beyond VEGF Anti-Platelet derived growth factor (anti-PDGF) Gene Therapy/Stem Cell Topical therapy

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Anti-platelet derived growth factor therapy The problem with anti-VEGF monotherapy Withdrawal or undertreatment results in recurrent neovascularization in a vast majority because: Anti-VEGF treatment decreases vascular permeability… BUT does not cause regression of the NV complex

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Platelet derived growth factor (PDGF) What’s in a neovascular complex? Endothelial cells “bricks and mortar” Expresses PDGF Pericyte recruitment Pericytes “armor against anti-VEGF” Promotes endothelial cell survival through chemical signaling Inflammatory cells Anti-VEGF therapy

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How can we dismantle NV?

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PDGF antagonist (E10030), Ophthotech

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Combined anti-VEGF/anti-PDGF treatment

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Fovista (Ophthotech) Pericyte Anti-VEGF PDGF Fovista Fovista bound to PDGF Fovista + Anti-VEGF combination therapy Pericyte coverage protects NV complex from anti-VEGF induced disruption Fovista is injected Fovista binds PDGF leading to stripping away of pericytes Regression of NV complex! Ophthotech.com

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Fovista (Ophthotech) Phase 2 study 24 week endpoint Comparison of Fovista/Lucentis vs Lucentis monotherapy +10.6 letters for combination therapy +6.5 for Lucentis monotherapy Development of subretinal fibrosis 10% in combination group 51% in Lucentis monotherapy group Phase 3 study underway

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Anti-PDGF Also being developed by: Neurotech using Encapsulated Cell Technology (ECT) implants MedImmune as a combination anti-VEGF/anti-PDGF injection with goal of lasting 6 months REGN2176-3 (Regeneron) combination with aflibercept (Eylea) in Phase 1 studies DE-120 (Santen) anti-VEGF/anti-PDGF in Phase 1 studies

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Gene Therapy

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Gene therapy Therapy in which genetic material is introduced into cells to effect protein transduction by the cells Compensate for structurally abnormal or missing genes Also can be used to induce target host cells to secrete a naturally occurring or engineered therapeutic protein (as alternative to repeated injections)

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Gene therapy Desirable features of viral vectors Able to introduce and transfer target cells with cDNA No activation of immune response Vector incapable of causing disease Much of the vector’s genetic material can be replaced by the therapeutic gene Adeno-associated virus (AAV)

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Gene therapy

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Gene therapy Advantages of the eye It’s small (i.e. low volume, large effect) Immunologically privileged Low systemic side effects Direct delivery of therapy

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Ongoing retinal gene therapy trials Wet AMD Leber’s congenital amaurosis Stargardt’s disease Choroidemia Usher syndrome Retinitis pigmentosa

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AAV2-sFlt01 Intravitreal Therapy (Genzyme/Sanofi) Induces expression of a modified VEGF receptor 1 (VEGFR1) Preclinical primate models Binds VEGF with high affinity Expresses VEGFR1 for at least 18 months after 1 injection

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AAV2-sFlt01 Subretinal therapy (Avalanche Biotech) Phase 1 study (6 pts) treated with low/high dose plus control arm 2 initial monthly Lucentis injections Day 380

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AAV2-sFlt01 http://permalink.fliqz.com/aspx/permalink.aspx?at=2315379b3136443fa353b26aaf11d582&a=375d1defb6aa477988c6708adf47c1e7

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Stem cell transplantation hESC (human embryonal stem cell) Pluripotent (any germ layer) Derived from human embryos (blastocyst stage) 5 days after feritilization Results in destruction of embryo iPSC (induced pluripotent stem cell) Derived from adult cells More tumorigenic than ESC (teratoma formation) Amniotic and cord blood stem cells Multipotent

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hESC 5 Days

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Stem cell transplantation Ocata Therapeutics (formerly Advanced Cell Technology) Phase 1/2 studies – primary endpoint of safety and tolerability Mean 22 months follow up, 3 dose cohorts (50K, 100K, 150K cells) Human embroynal stem cell (hESC) derived RPE cells 9 pts c Stargardt’s/9 pts c dry AMD (VA ? 20/400 in worse vision cohorts and ? 20/100 in better vision cohort) Wills, Bascom Palmer, UCLA

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Stem cell transplantation Safe, well tolerated (i.e. no rejection by immune system or teratoma formation) Stargardt’s: HM to 20/800 dAMD: +7 ETDRS letters

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Complement cascade inhibition Geographic atrophy Loss of macular RPE Pathophysiology Complement cascade hyperactivity (?) Chronic inflammation/overactivation of immune system in macula Complement factor H and I (CFH and CFI) work together to deactivate the cascade that triggers inflammatory response and cell death Genetic polymorphisms in CFH, CFH are associated with advanced AMD risk

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Complement cascade inhibition Lampalizumab (Genentech) Inhibits alternative complement cascade by targeting Complement Factor D MAHALO study, Phase 2 study Sham vs monthly injection Primary endopoint – change in GA area Relationships between genetic polymorphisms with treatment assessed RESULTS: 20.4% reduction in GA progression in ALL lampalizumab treated pts 44% reduction in GA progression in pts positive for CFI biomarker 57% of DNA tested pts were CFI+ Phase 3 underway

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Topical therapy

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Squalamine Originally derived from dogfish shark liver, now chemically synthesized Inhibits both VEGF and PDGF Initial wet AMD trials Intravenous infusion Weekly x 4 weeks, monthly thereafter Effective gains in VA/maintenance of VA RAPID plasma clearance – posterior ocular therapeutic concentration requires > 1 IV infusion treatments per week

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Squalamine eye drops Ohr Pharmaceutical Rapid uptake Trough levels >> threshold to inhibit angiogenesis Phase 2 IMPACT study 9 month data Topical squalamine/Lucentis injection vs sham/Lucentis injection Initial Lucentis injection and PRN injection thereafter

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Retinal vein occlusion (RVO) Aflibercept (Eylea) Regeneron FDA approved for BRVO, October 2014 FDA approved for CRVO, September 2012 VIBRANT study, Phase 3

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Retinal vein occlusion (RVO) Similar results for the other anti-VEGFs Lucentis 0.5 mg (CRUISE/BRAVO) Avastin

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Inflammatory cytokines, VEGF and RVO

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Combination treatments Intravitreal bevacizumab (Avastin)/dexamethasone (Ozurdex) Maturi, et al. Clin Ophthalmol. 2014; 8: 1057–1064 6 month study Initial Avastin followed by Ozurdex vs sham PRN Avastin injection q month

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Maturi, et al. Clin Ophthalmol. 2014; 8: 1057–1064

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Conclusions Most patients with wet AMD, DME, RVO can now benefit from effective and proven treatments Many patients still fall through the cracks Poorly responsive Undertreated Overall burden of treatment Knowledge is power

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DME 20/160 20/60 20/30 20/30 Baseline + 1 year + 2 years + 3 years 63 y.o. female with DM2 Initial monthly Avastin injection Subtenons kenalog injection RetreatedPRN IVA q2 months STK q 3-4 months

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67 y.o. male with DM2 Initial monthly Avastin injection Subtenons kenalog injection Retreated PRN IVA q 2-4 months STK q 3-4 months Baseline + 1 year + 2 years 20/200 20/40 20/30 DME

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CRVO 56 year old male with BRVO Did not show for scheduled Avastin injection for 1 month 20/60 20/100 20/30 AVASTIN #1 AVASTIN #2 Baseline + 1 month + 2 months

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CRVO 46 y.o. male with CRVO Initial observation no edema Baseline 20/40 2 months 4+ months 20/80 AVASTIN #1 20/60 AVASTIN #2 + STK AVASTIN #3 5+ months AVASTIN #4 20/30 20/30 20/40 AVASTIN #5 6+ months 7+ months

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wAMD 77 y.o. female with classic CNVM

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wAMD Baseline 1 month 2 months 3 months 20/400 20/200 20/200 20/100 AVASTIN #1 AVASTIN #2 AVASTIN #3 AVASTIN #4

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Thank you