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New and emerging therapies for retinal diseases

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New and emerging therapies for retinal diseases

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New and emerging therapies for retinal diseases

  1. 1. 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
  2. 2. Disclosures • No financial interests to disclose • Dr. Chiu has been a consultant to Alimera Sciences
  3. 3. 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
  4. 4. 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
  5. 5. Prevalence of diagnosed DM in US adults 2004 2008 http://apps.nccd.cdc.gov/ddtstrs/default.aspx
  6. 6. Prevalence of diagnosed DM in Maryland adults 2004 2008 2011 2004 http://apps.nccd.cdc.gov/ddtstrs/default.aspx 0 - 6.3 6.4 – 7.5 7.6 – 8.8 8.9 – 10.5 ≥ 10.6
  7. 7. 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
  8. 8. Anti-VEGFS
  9. 9. 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)
  10. 10. 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
  11. 11. RISE Mean change ETDRS letters 15 or more letters gained 36 mo 36 mo Sham +4.7 19.2% 0.3 mg +10.5 36.8% Mean change ETDRS letters 15 or more letters gained 36 mo 36 mo Sham +4.3 22.0% 0.3 mg +14.2 51.2% RIDE Sham group received Lucentis from mo 24-36
  12. 12. RIDE/RISE Lucentis 0.3 mg Sham Received macular laser 37.6% 72.0% Mean # of laser treatments 0.7 1.7 Received panretinal laser 0.8% 11.7% Progression of DR severity 11.2% 33.8% 24 month data
  13. 13. RIDE/RISE • Not so impressive findings • 23% treated patients still had central macular thickness of ≥ 250 microns • 40% had not achieved VA ≥ 20/40
  14. 14. In the real world… • Treatment burden • Cost • Patient tolerance • Do we really need to inject every month? • DRCR-net Protocol I
  15. 15. 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
  16. 16. 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
  17. 17. VISTA Mean change ETDRS letters 15 or more letters gained 12 mo 12 mo Sham +1.2 9.1% Monthly +10.5 32.4% Q 2mo (after 5 monthly) +10.7 33.3% VIVID Mean change ETDRS letters 15 or more letters gained 12 mo 12 mo Sham +0.2 7.8% Monthly +12.5 41.6% Q 2mo (after 5 monthly) +10.7 32.4%
  18. 18. 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
  19. 19. 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%
  20. 20. 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
  21. 21. Corticosteroids
  22. 22. Corticosteroids • Role of inflammatory cytokines BESIDES VEGF in DR • IL-6 • MCP-1 • Anti-VEGF therapy may not fully address the pathophysiology of DR VEGF Inflammatory cytokines Anti-VEGF *** * Corticosteroid * ***
  23. 23. 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 (?)
  24. 24. 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
  25. 25. Dexamethasone (Ozurdex) • Injectable biodegradable intravitreal implant, 3-6 mo duration of effect • $1300 per dose • FDA approved for DME June 2014
  26. 26. 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
  27. 27. MEAD study – pseudophakic/anticipated cataract surgery participants Ozurdex Sham % of pts with ≥ 15 letter gain 23.3 10.9 Mean change in VA from baseline +6.5 +1.7 % achieving ≥ 20/40 VA 29.1 17.8
  28. 28. 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
  29. 29. AMD • How far we have come • What do we do (with what we have) • Where we are going
  30. 30. 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)
  31. 31. 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)
  32. 32. 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 Mean change ETDRS letters at 2 years Total injection in the 2nd year Total injections over 2 years Eylea q 8 w +7.6 4.2 11.2 Lucentis q 4 w +7.9 4.7 16.5
  33. 33. 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
  34. 34. AMD – What do we do (with what we have) • 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”
  35. 35. 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 Mean change ETDRS letters at 2 years 15 or more letters gained (%) at 1 year Total # of injections over 2 years Monthly +9.1 34.5 22.0 PRN +7.9 30.2 13.3
  36. 36. AMD - Where are we going • Sustained release • Quest for the “Everlasting Gobstopper”
  37. 37. 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.)
  38. 38. Encapsulated cell technology (ECT)
  39. 39. 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)
  40. 40. 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
  41. 41. Nanostructured Tethadur
  42. 42. 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
  43. 43. 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
  44. 44. AMD – Where are we going • Beyond VEGF • Anti-Platelet derived growth factor (anti-PDGF) • Gene Therapy/Stem Cell • Topical therapy
  45. 45. 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
  46. 46. Anti-PDGFs
  47. 47. 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
  48. 48. How can we dismantle NV?
  49. 49. PDGF antagonist (E10030), Ophthotech
  50. 50. Combined anti-VEGF/anti-PDGF treatment
  51. 51. 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
  52. 52. 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
  53. 53. 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
  54. 54. Gene Therapy
  55. 55. Gene therapy • Therapy in which genetic material is introduced into cells to effect protein transduction by the cells 1. Compensate for structurally abnormal or missing genes 2. Also can be used to induce target host cells to secrete a naturally occurring or engineered therapeutic protein (as alternative to repeated injections)
  56. 56. Gene therapy • Desirable features of viral vectors 1. Able to introduce and transfer target cells with cDNA 2. No activation of immune response 3. Vector incapable of causing disease 4. Much of the vector’s genetic material can be replaced by the therapeutic gene • Adeno-associated virus (AAV)
  57. 57. Gene therapy
  58. 58. 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
  59. 59. Ongoing retinal gene therapy trials • Wet AMD • Leber’s congenital amaurosis • Stargardt’s disease • Choroidemia • Usher syndrome • Retinitis pigmentosa
  60. 60. 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
  61. 61. 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 Change in ETDRS letters # of rescue Lucentis Low dose +8.7 0.33 High dose +12.5 Control -3.5 3.00
  62. 62. AAV2-sFlt01 • http://permalink.fliqz.com/aspx/permalink.aspx?at=2315379b313 6443fa353b26aaf11d582&a=375d1defb6aa477988c6708adf47c1e7
  63. 63. 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
  64. 64. hESC 5 Days
  65. 65. 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
  66. 66. 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 N=18 Significantly improved Stable to insignificantly improved Worsened Visual acuity 10 7 1
  67. 67. 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
  68. 68. 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
  69. 69. Topical therapy
  70. 70. 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
  71. 71. 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 VA gain (ETDRS letters) ≥ 15 letter gain Mean # of injections Squalamine + Lucentis +10.4 48.3% 6.2 Lucentis monotherapy +6.3 21.2% 6.4
  72. 72. Retinal vein occlusion (RVO) • Aflibercept (Eylea) • Regeneron • FDA approved for BRVO, October 2014 • FDA approved for CRVO, September 2012 • VIBRANT study, Phase 3 % gaining ≥ 15 ETDRS letters Mean gain in ETDRS letters Eylea 53% +17.0 Laser (control) 27% +6.8
  73. 73. Retinal vein occlusion (RVO) • Similar results for the other anti-VEGFs • Lucentis 0.5 mg (CRUISE/BRAVO) • Avastin
  74. 74. Inflammatory cytokines, VEGF and RVO
  75. 75. 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 Mean # of bevacizumab reinjections Combination group 2.0 Bevacizumab alone 3.0
  76. 76. Maturi, et al. Clin Ophthalmol. 2014; 8: 1057– 1064
  77. 77. 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
  78. 78. DME Baseline + 1 year 20/160 20/60 + 2 years + 3 years 20/30 20/30 63 y.o. female with DM2 • Initial monthly Avastin injection • Subtenons kenalog injection • Retreated PRN • IVA q2 months • STK q 3-4 months
  79. 79. 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 20/200 + 1 year 20/40 + 2 years 20/30 DME
  80. 80. CRVO 56 year old male with BRVO • Did not show for scheduled Avastin injection for 1 month Baseline 20/60 + 1 month 20/100 AVASTIN #1 + 2 months 20/30 AVASTIN #2
  81. 81. 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 5+ months AVASTIN #3 6+ months 7+ months AVASTIN #4 20/30 20/30 20/40 AVASTIN #5
  82. 82. wAMD 77 y.o. female with classic CNVM
  83. 83. wAMD Baseline 1 month 20/400 20/200 AVASTIN #1 AVASTIN #2 2 months 3 months 20/200 20/100 AVASTIN #3 AVASTIN #4
  84. 84. Thank you

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