Ophthalmic Surgery, Lasers and Imaging Retina

Practical Retina Free

Geographic Atrophy: Clinical Impact and Emerging Treatments

Hershel R. Patel, MS, MD; Seenu M. Hariprasad, MD; David Eichenbaum, MD

I am pleased to announce that beginning in 2015, Howard F. Fine, MD, MHSc, will join Seenu M. Hariprasad, MD, as co-section editor of the Practical Retina column. Under Dr. Hariprasad’s leadership, the Practical Retina column has become a highly popular feature in OSLI Retina. As the publication frequency increases from six to 10 issues of OSLI Retina per year, a second editor is warranted. I welcome Dr. Fine’s contributions to Practical Retina.

— Carmen A. Puliafito, MD OSLI Retina Editor-in-Chief

Seenu M. Hariprasad

Seenu M. Hariprasad
Practical Retina Editor

Geographic atrophy remains an important cause of permanent vision loss despite historic progress made in managing vitreoretinal diseases over the past decade. Fortunately, our understanding of age-related macular degeneration pathophysiology has reached a level that has allowed us to embark on several clinical trials to discover treatments to manage this difficult disease. Availability of animal models and advances in imaging (OCT and autofluorescence) have aided in the possibility of upcoming breakthrough treatments for GA.

Drs. Patel and Eichenbaum discuss a wide variety of treatment approaches, including neuroprotection, LDL-lowering agents, antibodies binding amyloid, anti-inflammatories, visual cycle modulators, and stem cell transplantation. Although many of these approaches are in the early stage, the community is encouraged by the progress of the Genentech lampalizumab development program entering phase 3 this year.

I am certain that the insights and review of this complex topic provided by Drs. Patel and Eichenbaum will be valued by the community.


Hershel R. Patel

Hershel R. Patel

David Eichenbaum

David Eichenbaum

Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in the developed world. Severe central visual impairment develops as a result of neovascular derangement (wet AMD) or non-neovascular abnormalities (dry AMD). Slight alterations in central visual acuity can have profound effects on activities of daily living such as reading or driving. Dry AMD, which constitutes 85% to 90% of cases, is clinically associated with large confluent drusen formation and hyperpigmentation, with subsequent resorption of drusen and eventual loss of retinal pigment epithelium (RPE), choriocapillaris, and photoreceptors, leading to geographic atrophy (GA).1,2 This advanced stage of dry AMD is responsible for 20% of all cases of legal blindness in North America.3

Although there is no current treatment to specifically target the onset or progression of GA, improved understanding of the underlying pathophysiology has spawned potential new therapies that are currently undergoing evaluation in clinical trials (Table, pages 10 and 11).4 Although the probable initial insult has been characterized, halting progression to GA will likely require augmentation of multiple molecular pathways. Broad classes of therapeutics under study include pharmacologic approaches to preserving and restoring RPE cells and photoreceptors, maintaining blood flow to the choriocapillaris, reducing beta-amyloid accumulation, preventing or reducing oxidative damage, reducing accumulation of retinal toxins, and minimizing inflammatory damage (Figure, page 12).4

Agents Currently in Clinical Development for Dry Age-Related Macular DegenerationAgents Currently in Clinical Development for Dry Age-Related Macular Degeneration

Table:

Agents Currently in Clinical Development for Dry Age-Related Macular Degeneration

Prevention

It remains important to counsel patients about modifiable risk factors that may allow for a better final visual outcome. These factors include smoking, hypertension, and body mass index, and controlling these factors has been reported to reduce the risk of developing AMD by 50%.5

Oxidative stress

Antioxidants and neuroprotective drugs are two classes of drug that can reduce stress by free radical damage. Nutritional supplements have been employed for their antioxidant properties as preventative therapy for AMD. The AREDS formulation includes 500 mg vitamin C, 400 IU vitamin E, 15 mg beta-carotene, 80 mg zinc oxide, and 2 mg cupric oxide.6 While there are no reported adverse effects associated with consumption of the AREDS formulation, beneficial effects were seen only in relation to reduction of the risk of progression to wet AMD. Vitamin supplementation has not shown a reduction in the risk of progression to central GA.7

Neuroprotection

Brimonidine tartrate (Alphagan-P; Allergan, Irvine, CA) is an alpha-2 adrenergic receptor agonist that has been shown in animal studies to protect retinal function after acute ischemia. It confers protection on retinal ganglion cells, bipolar cells, and photoreceptors in models of ischemia, ocular hypertension, retinal phototoxicity, and partial optic nerve crush.8 Activation of alpha-2 adrenergic receptors potentially slows neuronal loss by reducing apoptosis.9 Brimonidine tartrate has been tested in a randomized, double-blind phase 2 trial as an intravitreal implant inserted at day 1 and month 6. A 200-µg and a 400-µg implant were tested using the fellow eye as a control in a sham arm. At the 2-year mark, the data appear to show efficacy, with less expansion of baseline GA area in a dose-dependent pattern.10 Allergan is now enrolling the prospective placebo-controlled phase 3 BEACON study of the 400-µg brimonidine implant injected quarterly for 24 months.11

LDL-lowering agents

Many risk factors for the development of cardiovascular disease parallel those of AMD, including genetics, smoking, hypertension, and hyperlipidemia. Aberrant accumulations of lipids play an important role in the pathogenesis of both diseases. There has been a logical conjecture that statins may be useful for prevention and treatment. Longitudinal studies to date have not consistently demonstrated a benefit of statin therapy on the advancement of GA. The dose and duration of therapy are factors not often considered by these studies. In addition, no randomized, controlled trials with long-term follow-up have been undertaken, leaving the beneficial effects of statins for AMD unclear.12

Amyloid

Drusen formation along the basal surface of the RPE is a long-known significant risk factor for AMD, and the resorption of these drusen are the clinical sign identified before the progression to GA. The mechanisms associated with drusen resorption are believed to be associated with the development of GA. Drusen contain immunomodulatory molecules and components that are common to glomerulone-phritis, atherosclerosis, and Alzheimer’s disease. Beta-amyloid has been shown to be a common protein between the neuritic plaques in Alzheimer’s disease and drusen in AMD.13 GSK933776 (Glaxo-SmithKline) is currently being investigated in a phase 2 multicenter, randomized, double-masked trial for GA secondary to dry AMD. This drug is a humanized monoclonal antibody administered via an intravenous infusion that binds with high affinity to the beta-amyloid N terminus. In addition, the Fc portion of GSK933776 is designed to reduce complement fixation and Fc receptor binding, which theoretically provides additional anti-inflammatory effects.14

Choroidal circulation, perfusion

The choriocapillaris provides all of the metabolic needs of the photoreceptors, including 90% of the oxygen consumed by the photoreceptors in the darkness. Clinical studies suggest that choroidal blood flow is compromised in age-matched control subjects with AMD. Lack of perfusion of the chorio-capillaris has been suggested as a potential cause of reticular drusen, which are a common phenotypic hallmark that portends a high risk for progression to GA.4,15 MC-1101 (MacuClear, Plano, TX) is a topically applied vasodilator that increases nitric oxide concentrations. MC-1101 was shown in preliminary studies to increase choroidal blood flow as measured with laser Doppler flow studies greater than five-fold in 1 hour after 1.0% administration. MacuClear is currently recruiting 60 patients for a phase 2/3 sham-controlled, double-masked, randomized, controlled trial for MC-1101 1.0% dosed twice daily.16,17

Visual cycle modulators

Fenretinide (Sirion Therapeutics, Tampa, FL), also known as N-(4hydroxyphenyl) retinamide, is designed to modulate the visual cycle and prevent toxic accumulation of lipofuscin in the RPE. It is an orally ingested vitamin A derivative that competitively binds retinol-binding protein (RBP) and subsequently decreases retinol bioavailability.18 Dose-dependent reductions in serum RBP-retinol with associated reduced lesion growth rates have been reported in a placebo-controlled, randomized, double-masked 2-year trial with 246 patients at a dose of 300 mg. The same study found a 45% decreased incidence of choroidal neovascularization compared to placebo.19 Despite encouraging results, changes in the manufacturing process during the trial have resulted in the U.S. Food and Drug Administration rejecting the data for review. Unless funding is acquired for a repeat trial, this drug will likely not come to market.20

Anti-inflammatory agents

Anti-inflammatory agents target or inhibit a variety of proteins involved in the immunologic inflammatory process. These include matrix metalloproteinase (a protein vital for cellular migration), mTOR (a vital cellular proliferation protein), and the complement cascade (an innate pro-inflammatory/immunologic protein family). Lampalizumab (Genentech, South San Francisco, CA) is an intra-vitreally injected monoclonal antibody that blocks factor D in the complement cascade. The multicenter, randomized, single-masked phase 2 MAHALO trial enrolled 129 patients, and those in the treatment arm of the study showed a 20.4% reduction rate in the area of GA at 18 months. Remarkably, 57% of the 93 patients in the treatment arm were positive for the complement factor I biomarker. In this subgroup, monthly lampalizumab was associated with a 44% decrease in rate of disease progression at 18 months (P < .005). In those treated every other month, the rate of disease progression decreased by 18% (P = .23). The enhanced treatment effects of lampalizumab associated with the complement factor I biomarker emphasize the potential importance of genotype identification in future targeted therapies.21

Prevention of RPE, photoreceptor loss

A great deal of controversy has surrounded the transplant and harvesting of embryonic stem cells. In January 2012, a landmark study by Schwartz et al published in Lancet offered the first description of human embryonic stem cell transplant into human subjects with retinal disease. In that study, MAO9-hRPE cells (human embryonic stem-cell-derived retinal pigmented epithelial cells; Advanced Cell Technology, Marlborough, MA) were transplanted subretinally. Safety was demonstrated in the two patients, one with Stargardt’s disease and another with GA, with no evidence of hyperproliferation, tumorigenesis, ectopic tissue formation, or rejection after 4 months.22 A phase 1/2 clinical trial is currently recruiting participants with one or more areas with greater than 250 µm of GA. Four cohorts are planned, with each receiving between 50,000 to 200,000 cells.23

Conclusion

GA remains an important cause of irreversible blindness in North America, and challenges remain in fully understanding the underlying pathophysiology, identification of an appropriate animal model, and a primary clinical endpoint correlated to visual acuity.4 Despite this, 15 years of work and clinical trials by many scientists and physicians have resulted in numerous potential treatments. Although stem cell therapy shows a great deal of promise based on preliminary reporting, it is still in its infancy. Pharmacologic therapy, however, is progressing, with anti-inflammatory lampalizumab therapy entering phase 3 trials this year. With improvements in the efficiency of molecular science and the clinical trial networks, the future has never been brighter for patients with GA.

References

  1. Lim LS, Mitchell P, Seddon JM, Holz FG, Wong TY. Age-related macular degeneration. Lancet. 2012;379(9827):1728–1738. doi:10.1016/S0140-6736(12)60282-7 [CrossRef]
  2. Bhutto I, Lutty G. Understanding age-related macular degeneration (AMD): relationships between the photoreceptor/retinal pigment epithelium/Bruch’s membrane/choriocapillaris complex. Mol Aspects Med. 2012;33(4):295–317. doi:10.1016/j.mam.2012.04.005 [CrossRef]
  3. Sunness JS. The natural history of geographic atrophy, the advanced atrophic form of age-related macular degeneration. Mol Vis. 1999;5:25.
  4. Holz FG, Strauss EC, Schmitz-Valckenberg S, van Lookeren Campagne M. Geographic atrophy: clinical features and potential therapeutic approaches. Ophthalmology. 2014;121(5):1079–1091. doi:10.1016/j.ophtha.2013.11.023 [CrossRef]
  5. Tomany SC, Wang JJ, Van Leeuwen R, et al. Risk factors for incident age-related macular degeneration: pooled findings from 3 continents. Ophthalmology. 2004;111(7):1280–1287. doi:10.1016/j.ophtha.2003.11.010 [CrossRef]
  6. Coleman HR, Chan CC, Ferris FL 3rd, Chew EY. Age-related macular degeneration. Lancet. 2008;372(9652):1835–1845. doi:10.1016/S0140-6736(08)61759-6 [CrossRef]
  7. Chew EY, Clemons TE, Agrón E, et al. Age-Related Eye Disease Study Research Group. Long-term effects of vitamins C and E, ß-carotene, and zinc on age-related macular degeneration: AREDS report no. 35. Ophthalmology. 2013;120(8):1604–1611. doi:10.1016/j.ophtha.2013.01.021 [CrossRef]
  8. Damico FM, Gasparin F, Scolari MR, Pedral LS, Takahashi BS. New approaches and potential treatments for dry age-related macular degeneration. Arq Bras Oftalmol. 2012;75(1):71–6.
  9. Tatton W, Chen D, Chalmers-Redman R, Wheeler L, Nixon R, Tatton N. Hypothesis for a common basis for neuroprotection in glaucoma and Alzheimer’s disease: anti-apoptosis by alpha-2-adrenergic receptor activation. Surv Ophthalmol. 2003;48Suppl 1:S25–37 doi:10.1016/S0039-6257(03)00005-5 [CrossRef]
  10. ClinicalTrials.gov Identifier: NCT00658619. Safety and Efficacy of Brimonidine Intravitreal Implant in Patients With Geographic Atrophy Due to Age-related Macular Degeneration (AMD). http://clinicaltrials.gov/ct2/show/NCT00658619?term=NCT00658619&rank=1
  11. ClinicalTrials.gov Identifier: NCT02087085. A Safety and Efficacy Study of Brimonidine Intravitreal Implant in Geographic Atrophy Secondary to Age-related Macular Degeneration (BEACON). http://clinicaltrials.gov/ct2/show/study/NCT02087085?term=brimonidine+geographic&rank=2
  12. Tsao SW, Fong DS. Do statins have a role in the prevention of age-related macular degeneration?Drugs Aging. 2013;30(4):205–213. doi:10.1007/s40266-013-0061-4 [CrossRef]
  13. Johnson LV, Leitner WP, Rivest AJ, Staples MK, Radeke MJ, Anderson DH. The Alzheimer’s A beta -peptide is deposited at sites of complement activation in pathologic deposits associated with aging and age-related macular degeneration. Proc Natl Acad Sci U S A. 2002;99(18):11830–11835. doi:10.1073/pnas.192203399 [CrossRef]
  14. Leyhe T, Andreasen N, Simeoni M, et al. Modulation of beta-amyloid by a single dose of GSK933776 in patients with mild Alzheimer’s disease: a Phase I study. Alzheimers Res Ther. 2014;6(2):19. doi:10.1186/alzrt249 [CrossRef]
  15. Schmitz-Valckenberg S, Alten F, Steinberg JS, et al. Geographic Atrophy Progression (GAP) Study Group. Reticular drusen associated with geographic atrophy in age-related macular degeneration. Invest Ophthalmol Vis Sci. 2011;52(9):5009–5015. doi:10.1167/iovs.11-7235 [CrossRef]
  16. Chiou C. Is dry AMD treatable?Retina Today. May2012. http://bmctoday.net/retinatoday/2012/05/article.asp?f=is-dry-amd-treatable
  17. Mathis AE. Hope for dry AMD?Retinal Physician. http://www.reti-nalphysician.com/articleviewer.aspx?articleID=107893
  18. Schmitz-Valckenberg S, Mössner A, Fleckenstein M, Wiedemann P, Holz FG. [Therapy approaches for geographic atrophy]. Ophthalmologe. 2010;107(11):1016–1019. doi:10.1007/s00347-010-2160-5 [CrossRef]
  19. Mata NL, Lichter JB, Vogel R, Han Y, Bui TV, Singerman LJ. Investigation of oral fenretinide for treatment of geographic atrophy in age-related macular degeneration. Retina. 2013;33(3):498–507. doi:10.1097/IAE.0b013e318265801d [CrossRef]
  20. http://www.amd.org/research/dry-amd-research/dry-amd-clinical-trials/52-fenretinide-pill.html
  21. Roche. Investor update. August 27, 2013. http://www.roche.com/investors/ir_update/inv-update-2013-08-27.htm
  22. Schwartz SD, Hubschman JP, Heilwell G, et al. Embryonic stem cell trials for macular degeneration: a preliminary report. Lancet. 2012;379(9817):713–720. doi:10.1016/S0140-6736(12)60028-2 [CrossRef]
  23. ClinicalTrials.gov Identifier: NCT01344993. Safety and Tolerability of Sub-retinal Transplantation of hESC Derived RPE (MA09-hRPE) Cells in Patients With Advanced Dry Age Related Macular Degeneration (Dry AMD). http://clinicaltrials.gov/ct2/show/NCT01344993?term=MA09&rank=4

Agents Currently in Clinical Development for Dry Age-Related Macular Degeneration

DrugManufacturerStructure, Administration RouteMechanism of ActionPatient PopulationClinical Study Phase, Identifier
Antioxidants
  AREDS210National Eye InstituteDietary supplement: lutein/ zeaxanthin, DHA/EPAPatients with AMDPhase 3 (n = 4,000) started Sep 2006, now complete (NCT00345176); addition of lutein and zeaxanthine did not significantly reduce progression to advanced AMD
  OT-55148Othera Pharmaceuticals, Exton, PADisubstituted hydroxylamine; topical solutionIs converted to TEMPOL-H, a potent free-radical scavenger and antioxidantPatients with geographic atrophyPhase 2 (n = 11) started Mar 2006, complete Mar 2011 (NCT00306488); limited treatment benefit for GA
  Omega-3 fatty acidWills Eye InstituteAREDS 2 Vitamin formula, 1 g; Eye Omega Advantage, 2gPatients with AREDS category 3 or 4 disease. Category 3: Many medium sized drusen or ≥ 1 large drusen in one or both eyes; Category 4: Geographic atrophy or CNV in one eye.Phase 3 (n = 100) currently recruiting; started Jul 2012; expected completion, Feb 2013 (NCT01653184)
  Omega-6:omega-3 ratio and progression of AMDUniversity of Alberta, CanadaAREDS vitamins or equivalentPatients with wet AMD in one eye and early/intermediate dry AMD in fellow eyePhase 3 (n = 200) started Mar 2012, expected completion Mar 2014/2017 (NCT00987129)
  Lutein and omega-3 fatty acids (LUTEGA)University of Jena, GermanyLutein, zeaxanthin, omega-3 fatty acids (MPOD)Patients with nonexudative AMDPhase 3 (n = 172) completed Sep 2011. After 1 year, increase in MPOD and VA was seen (NCT00763659); LUTEGA2 (n = 80), a continuation and crossover of LUTEGA, completed Dec 2012.
  Lutein (Nutrof)University Hospital, Bordeaux, FranceLutein and zeaxantin (increase in MPOD)Patients whose parents had a history of wet AMDPhase 1 (n = 120) started Jan 2011; status: currently recruiting (NCT01269697)
  Lutein and zeaxanthinPeking University, ChinaChanges in MPOD during 96 weeksPatients with AMDPhase 2/3 (n = 162) started Jun 2010, expected completion June 2012; status: currently recruiting (NCT01528605)
  Lutein and zeaxanthinPeking University, ChinaChanges in MPOD and multifocal electroretinogramsPhase 1/2 (n =1 20) started Sep 2009, status: currently recruiting (NCT01048476)
Visual cycle modulators
  FenretidineSirion Therapeutics, Tampa, FLSynthetic retinoid derivative; oralPrevents the transport of retinol to the RPEGeographic atrophyDevelopment terminated
  ACU-442951Acucela Inc, Bothell, WASmall non-retinoid molecule; oralInhibits conversion of alltransretinyl ester to 11-cis-retinol via the isomerase RPE65. Prevents accumulation of A2EGeographic atrophy; Primary endpoint is change from baseline in total area of GA lesionsPhase 2 safety study (n = 84) started in Oct 2009. Fast Track Status granted in March 2010, study completed (NCT01002950). Phase 2/3 (n = 440) currently recruiting, estimated completion by Jul 2016 (NCT01802866).
  ALK-001AlkeusDeuterium-enriched Vitamin ASlows the formation of A2E and lipofuscinDry AMDPreclinical
Anti-inflammatory agents
  Fluocinolone (Illuvien)Alimera Sciences, Alpharetta, GACorticosteroid; IVTNon-bioerodible polyimide tube containing 180 µg corticosteroidGeographic atrophyPhase 2 (n = 40) started Dec 2008, estimated completion Dec 2014; status: currently recruiting (NCT00695318)
  Glatiramer acetate(Copaxone)Teva Pharmaceuticals, Kfar-Saba, IsraelImmuno-modulatorDownregulates inflammatory cytokinesGeographic atrophy (halting progression, including progression to wet AMD)Status of two clinical trials (NCT00466076 and NCT0054133) unknown
  Sirolimus (Rapamycin)Wyeth, Madison, WISubconjunctivalInhibits mTOR and HIF-1a, anti-inflammatory and immunosuppressantPatients with geographic atrophy. Enrolling patients with bilateral geographic atrophy. Enrolling patients with progressively worsening central geographic atrophyPhase 1/2 (n = 11) complete:.subconjunctival sirolimus was not effective in delaying progression of geographic atrophy (NCT0076649); phase 1/2 study (n = 15) started Sep 2011, expected completion July 2014 (NCT01445548); phase 2 study (enrolling by invitation, so far n = 50), expected completion Dec 2014 (NCT01675947).
  LFG316Novartis Pharmaceutical Corporation, New Hanover, NJIVT12 monthly dosesGrowth of lesions in patients with geographic atrophyPhase 2 (n = 120) started Jan 2012, expected completion Jun 2014 (NCT01527500)
  POT-4Potentia Pharmaceuticals, Louisville, KY; Alcon Research, Fort Worth, TXCyclic 13-amino acid peptide; IVTInhibits conversion of complement C3 to C3a/bWet AMD (prolongation of anti-VEGF effects of ranibizumabPhase 1 complete (NCT00473928)
  AL-78898AAlcon, Fort Worth, TXInhibits conversion of complement C3 to C3a/bPatients with geographic atrophyPhase 2 (n = 120) currently recruiting, started Jun 2012, expected completion Apr 2012 (NCT01603043)
  Eculizumab (SOLIRIS)Alexion Pharmaceuticals, Cheshire, CTHumanized monoclonal antibody; IVInhibits the complement cascade at C5Dry AMDPhase 2 (n = 60) failed to demonstrate efficacy with primary outcome measure at predefined 6-month endpoint (NCT00935883)
  ARC-1905Ophthotec, Princeton, NJAnti-C5 pegylated aptamer; IVTInhibits downstream complement activationDry AMDPhase 1 (n = 50) started Jul 2009, estimated completion Nov 2012; current status unknown (NCT00950638)
  FCFD4514S (lampalizumab)Genentech/Roche; South San Francisco, CAAnti-factor D Fab; IVTInhibits complement Factor DGeographic atrophyMAHALO, a phase 1b/2 safety and efficacy study (n = 143) is now complete (NCT01229215). An open-label extension study (n = 90) is ongoing; expected completion Aug 2014 (NCT01602120).
Amyloid
  RN6G (PF-4382923)Pfizer Inc, New York, NYHumanized monoclonal antibody; IVPrevents accumulation of amyloid ß 40/42Patients with advanced dry AMD, including geographic atrophyPhase 2 efficacy study (n = 276) recruiting, expected completion Jul 2014 (NCT01577381). Two phase 1 (n = 57 and n = 24) safety and tolerability studies (NCT01003691, NCT00877032) complete.
  GSK933776GlaxoSmithKline, Research Triangle Park, NCHumanized monoclonal antibody, IVModulation of amyloid levels ßPatients with geographic atrophy secondary to dry AMDPhase 2 (n = 162) started Jun 2011, currently recruiting, estimated completion Mar 2014 (NCT01342926)
Choroidal circulation/perfusion
  Trimetazidine52Institute de Recherches Internationales, Servier, FranceAnti-ischemic agentPatients with soft drusen and/or RPE abnormalities in study eye and CNV in the fellow eyePhase 3 (n = 1,086) ISRCTN99532788
  MC-1101MacuCLEAR Inc, Plano, TXAntihypertensive, vasodilator, antiinflammatory, antioxidant; 1% ophthalmic solution TIDPrevents rupture of Bruch’s membranePatients with geographic atrophyPhase 2/3 (n = 60) currently recruiting, started Jul 2012, expected completion Jul 2014 (NCT01601483).
  UF-021 (Ocuseva)Sucampo Pharmaceuticals, Tokyo, JapanProstaglandin analog; isopropyl unoprostone; ophthalmic solutionIncreases retinal and choroidal blood flowPatients with retinitis pigmentosa or dry AMDPhase 2 (n = 112) started Jun 2011 in Japan for retinitis pigmentosa (NCT01379560). A US trial in patients with dry AMD is planned.
Neuroprotectants
  CNTF/NT50153,54Neurotech, Lincoln, RIEncapsulated cell technologyEncapsulated human cells genetically modified to secrete ciliary neurotrophic factor (CNTF)Phase 2 (n = 48) completed Oct 2009 (NCT00447954)
  AL-8309B (tandospirone)Alcon Research, Fort Worth, TXSelective serotonin 1A agonistProtects retina from light damage; topicalGeographic atrophyPhase 3 GATE trial (NCT00890097) discontinued in 2012 due to lack of efficacy
  Brimonidine tartrateAllergan, Irvine, CAα2-adrenergic agonist; IVT implantStimulates production of neurotrophic factorsGeographic atrophy area at month 12 in patients with bilateral geographic atrophyPhase 2 (n = 119) started May 2008, estimated completion Apr 2011 (NCT00658619); phase 2 safety extension study (n = 215) started Feb 2010, estimated completion Feb 2014
  RNA-144101University of KentuckyInhibitor of toll-like receptor 3 (TLR3)Geographic atrophy (NCT01093170)Study withdrawn prior to enrollment
Stem cell therapy
  CNTO2476Janssen Research/ Centocor IncHuman umbilical tissue-derived cells (hUTC); subretinal injection using the iTrack Model 275 micro catheterSingle dosePatients with visual acuity impairment associated with geographic atrophy secondary to AMDPhase 1/2a (n = 56) started Sep 2010, expected completion Aug 2017 (primary endpoint completion Sep 2013 (NCT01226628)
  MA09-hRPEAdvanced Cell TechnologySubretinal transplantation of human embryonic stem cell-derived retinal pigmented epithelial (MA09-hRPE) cellsPatients with advanced dry AMDPhase 1/2a (n = 12) started Apr 2011, expected completion Jul 2013 (NCT01344993)
  MA09-hRPEAdvanced Cell TechnologySubretinal transplantation of human embryonic stem cell-derived retinal pigmented epithelial (MA09-hRPE) cellsPatients with Stargardt>s macular dystrophyPhase 1/2 studies (both n = 12) currently recruiting; NCT01345006 started Apr 2011, expected completion Sep 2013; NCT01469832 started Nov 2011, expected completion Apr 2014
  HuCNS-SCStemCell Inc., Newark, CASubretinal transplantation of human neural stem cellsPatients with retinal degenerative diseases such as AMDPhase 1/2 (n = 16) started June 2012, expected completion Aug 2014 (NCT01632527)

Hershel R. Patel, MS, MD, can be reached at USF Eye Institute, 12901 Bruce B. Downs Blvd., MDC 21, Tampa, FL 33612; 516-318-5567; email: hershelrpatel@gmail.com.

David Eichenbaum, MD, can be reached at Retina Vitreous Associates of Florida, 12903 N 56th St, Tampa, FL 33617; 727-323-0077; email: deichenbaum@retinavitreous.com.

Disclosures: Dr. Patel has no relevant financial disclosures. Dr. Eichenbaum is an investigator, speaker and consultant to Genentech; an investigator for Ophthotech; a speaker and consultant for Allergan Retina; and an equity holder in Hemera Biosciences.

10.3928/23258160-20150101-01

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