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
Disclosures
• No financial interests to disclose
• Dr. Chiu has been a consultant to Alimera Sciences
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
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
Prevalence of diagnosed DM in US adults
2004 2008
http://apps.nccd.cdc.gov/ddtstrs/default.aspx
Prevalence of diagnosed DM in Maryland adults
http://apps.nccd.cdc.gov/ddtstrs/default.aspx2004
2008 20112004
0 - 6.3
6.4 – 7.5
7.6 – 8.8
8.9 – 10.5
≥ 10.6
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
Anti-VEGFS
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)
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
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
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
RIDE/RISE
• Not so impressive findings• 23% treated patients still had central macular thickness of ≥ 250 microns
• 40% had not achieved VA ≥ 20/40
In the real world…
• Treatment burden• Cost
• Patient tolerance
• Do we really need to inject every month?• DRCR-net Protocol I
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
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
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%
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
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%
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 Avastintreated patients
• Rate of ATE (arteriothromboembolic events) was 2% Eylea, 4% Avastin, 5% Lucentis
• Results pending verification prior to publication
Corticosteroids
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 * ***
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 (?)
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
Dexamethasone (Ozurdex)
• Injectable biodegradable intravitrealimplant, 3-6 mo duration of effect
• $1300 per dose
• FDA approved for DME June 2014
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
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
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
AMD
• How far we have come
• What do we do (with what we have)
• Where we are going
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)
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)
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
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
• 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)
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
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
0.5 mg dose
AMD - Where are we going
• Sustained release• Quest for the “Everlasting Gobstopper”
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.)
Encapsulated cell technology (ECT)
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)
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 Tethadurparticles
• Animal studies – sustained release of bevacizumab for 6 months
Nanostructured Tethadur
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
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
AMD – Where are we going
•Beyond VEGF • Anti-Platelet derived growth factor (anti-PDGF)
• Gene Therapy/Stem Cell
• Topical therapy
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
Anti-PDGFs
Platelet derived growth factor (PDGF)
• What’s in a neovascularcomplex?• 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
How can we dismantle NV?
PDGF antagonist (E10030), Ophthotech
Combined anti-VEGF/anti-PDGF treatment
Fovista (Ophthotech)
Pericyte Anti-VEGF PDGF FovistaFovista bound
to PDGFFovista + 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
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
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
Gene Therapy
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)
Gene therapy
• Desirable features of viral vectors1. 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)
Gene therapy
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
Ongoing retinal gene therapy trials
• Wet AMD
• Leber’s congenital amaurosis
• Stargardt’s disease
• Choroidemia
• Usher syndrome
• Retinitis pigmentosa
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
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
AAV2-sFlt01
• http://permalink.fliqz.com/aspx/permalink.aspx?at=2315379b3136443fa353b26aaf11d582&a=375d1defb6aa477988c6708adf47c1e7
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
hESC
5 Days
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
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
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
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 lampalizumabtreated pts
• 44% reduction in GA progression in pts positive for CFI biomarker
• 57% of DNA tested pts were CFI+
• Phase 3 underway
Topical therapy
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
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
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
Retinal vein occlusion (RVO)
• Similar results for the other anti-VEGFs• Lucentis 0.5 mg (CRUISE/BRAVO)
• Avastin
Inflammatory cytokines, VEGF and RVO
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
Maturi, et al. Clin Ophthalmol. 2014; 8: 1057–1064
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
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
• Retreated
PRN
• IVA q2
months
• STK q 3-4
months
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
CRVO56 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
CRVO
46 y.o. male
with CRVO
• Initial
observation
no edema
Baseline
20/40
2 months
4+ months
20/80AVASTIN #1
20/60AVASTIN #2 +
STKAVASTIN #3
5+ months
AVASTIN #4
20/30
20/30 20/40AVASTIN #5
6+ months 7+ months
wAMD77 y.o. female
with classic
CNVM
wAMDBaseline 1 month
2 months 3 months
20/400 20/200
20/200 20/100
AVASTIN #1 AVASTIN #2
AVASTIN #3 AVASTIN #4
Thank you