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