New and emerging therapies for retinal diseases

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

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

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. 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. Anti-VEGFS

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

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. 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. 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. 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. 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. 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. Corticosteroids

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

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

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

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. Encapsulated cell technology (ECT)

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. 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. Nanostructured Tethadur

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

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. Anti-PDGFs

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. How can we dismantle NV?

49. PDGF antagonist (E10030), Ophthotech

50. Combined anti-VEGF/anti-PDGF treatment

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. 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. 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. Gene Therapy

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. 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. Gene therapy

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

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. 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. AAV2-sFlt01
• http://permalink.fliqz.com/aspx/permalink.aspx?at=2315379b313
6443fa353b26aaf11d582&a=375d1defb6aa477988c6708adf47c1e7

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. hESC
5 Days

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. 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. 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. 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

70. Topical therapy

71. 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

72. 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

73. 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

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

75. Inflammatory cytokines, VEGF and RVO

76. 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

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

78. 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

79. 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

80. 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

81. 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

82. 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

83. wAMD 77 y.o. female
with classic
CNVM

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

85. Thank you