Medikamentöse Therapieansätze für die nicht neovaskuläre AMD

Zusammenfassung

Hintergrund Die nicht neovaskuläre (trockene) altersbedingte Makuladegeneration (AMD) ist bis heute nicht behandelbar. Dieser Artikel fasst die klinischen Forschungsansätze für eine medikamentöse Therapie zusammen und analysiert, warum diese nicht zum Erfolg geführt haben.

Material und Methoden Literatur und Datenbankrecherche.

Ergebnisse Insgesamt ist die Zahl der verfolgten Therapieansätze begrenzt. Nur die Reduktion von Lipofuscinablagerungen und Drusen ist spezifisch für die AMD. Weitere Ansätze sind die Modulation der Entzündung und Neuroprotektion. Derzeit konnte mit keinem der Verfahren in einer konfirmatorischen Studie das Voranschreiten der AMD gestoppt oder verlangsamt werden.

Diskussion Um die Chancen für Entwicklungserfolge zu erhöhen, muss der aktuell begrenzte pharmakologische Target Space durch die Anwendung molekularer Netzwerkanalysen erweitert werden. Da bei der trockenen AMD der Visus oft nicht der primär betroffene Parameter ist, muss flankierend die Perspektive Betroffener näher untersucht werden, um sinnvolle Therapieziele jenseits des Visus zu definieren.

Abstract

Background Non-neovascular age-related macular degeneration (AMD) is not yet treatable. This article summarises current clinical research approaches. The reasons for the current lack of success are analysed.

Methods Literature and databank search.

Results The number of therapeutic approaches and mechanisms is limited. Only reduction in lipofuscin containing deposits is specific for AMD. Further approaches include modulation of inflammation and neuroprotection. Confirmatory studies have failed to demonstrate efficacy in AMD, i.e. slowing or stopping AMD progression.

Discussion To increase the probability of success for future developments, the pharmacological target space needs to be broadened. This may be achieved by application of molecular network analyses. As visual acuity is commonly not primarily affected by non-neovascular AMD, research on patient perspective is required to define reasonable target profiles for future therapies.

Schlüsselwörter

altersbedingte Makuladegeneration - geografische Atrophie - Pharmakologie der Netzhaut - Sehzyklus - Komplementsystem

Key words

age-related macular degeneration - geographic atrophy - retinal pharmacology - visual cycle - complement system

• Literatur

• 1 Johnen S, Koutsonas A. Trockene AMD – zelluläre und gentherapeutische Behandlungsansätze. Klin Monatsbl Augenheilkd 2019;
• 2 Holz FG, Bindewald-Wittich A, Fleckenstein M. et al. Progression of geographic atrophy and impact of fundus autofluorescence patterns in age-related macular degeneration. Am J Ophthalmol 2007; 143: 463-472 doi:10.1016/j.ajo.2006.11.041
• 3 Fleckenstein M, Schmitz-Valckenberg S, Lindner M. et al. The “diffuse-trickling” fundus autofluorescence phenotype in geographic atrophy. Invest Ophthalmol Vis Sci 2014; 55: 2911-2920 doi:10.1167/iovs.13-13409
• 4 Tanna P, Strauss RW, Fujinami K. et al. Stargardt disease: clinical features, molecular genetics, animal models and therapeutic options. Br J Ophthalmol 2017; 101: 25-30 doi:10.1136/bjophthalmol-2016-308823
• 5 Mata NL, Lichter JB, Vogel R. et al. Investigation of oral fenretinide for treatment of geographic atrophy in age-related macular degeneration. Retina 2013; 33: 498-507 doi:10.1097/IAE.0b013e318265801d
• 6 Acucela Inc.. Acucela announces top-line results from phase 2b/3 clinical trial of emixustat (25.05.2016). Im Internet: https://www.businesswire.com/news/home/20160525006550/en/Acucela-Announces-Top-Line-Results-Phase-2b3-Clinical Stand: 28.04.2019
• 7 Dugel PU, Novack RL, Csaky KG. et al. Phase II, randomized, placebo-controlled, 90-day study of emixustat hydrochloride in geographic atrophy associated with dry age-related macular degeneration. Retina 2015; 35: 1173-1183 doi:10.1097/IAE.0000000000000606
• 8 Ma L, Kaufman Y, Zhang J. et al. C20-D3-vitamin A slows lipofuscin accumulation and electrophysiological retinal degeneration in a mouse model of Stargardt disease. J Biol Chem 2011; 286: 7966-7974 doi:10.1074/jbc.M110.178657
• 9 Kaufman Y, Ma L, Washington I. Deuterium enrichment of vitamin A at the C20 position slows the formation of detrimental vitamin A dimers in wild-type rodents. J Biol Chem 2011; 286: 7958-7965 doi:10.1074/jbc.M110.178640
• 10 [Anonymous] Clinicaltrials.gov search on studies with ALK-001. Im Internet: https://clinicaltrials.gov/ct2/results?cond=&term=ALK-001
• 11 Vision Medicines. Vision Medicines Overview of VM200: An aldehyde trap molecule in IND enabling studies for Stargardt disease (19.10.2016). Im Internet: http://visionmedicines.com/pdf/VM200-Overview-Presentation.pdf Stand: 28.04.2019
• 12 Russell S, Bennett J, Wellman JA. et al. Efficacy and safety of voretigene neparvovec (AAV2-hRPE65v2) in patients with RPE65-mediated inherited retinal dystrophy: a randomised, controlled, open-label, phase 3 trial. Lancet 2017; 390: 849-860 doi:10.1016/S0140-6736(17)31868-8
• 13 Hageman GS, Anderson DH, Johnson LV. et al. A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration. Proc Natl Acad Sci U S A 2005; 102: 7227-7232 doi:10.1073/pnas.0501536102
• 14 Anderson DH, Mullins RF, Hageman GS. et al. A role for local inflammation in the formation of drusen in the aging eye. Am J Ophthalmol 2002; 134: 411-431
• 15 Gehrs KM, Jackson JR, Brown EN. et al. Complement, age-related macular degeneration and a vision of the future. Arch Ophthalmol 2010; 128: 349-358 doi:10.1001/archophthalmol.2010.18
• 16 Gold B, Merriam JE, Zernant J. et al. Variation in factor B (BF) and complement component 2 (C2) genes is associated with age-related macular degeneration. Nat Genet 2006; 38: 458-462 doi:10.1038/ng1750
• 17 Hageman GS, Hancox LS, Taiber AJ. et al. Extended haplotypes in the complement factor H (CFH) and CFH-related (CFHR) family of genes protect against age-related macular degeneration: characterization, ethnic distribution and evolutionary implications. Ann Med 2006; 38: 592-604
• 18 Hughes AE, Orr N, Esfandiary H. et al. A common CFH haplotype, with deletion of CFHR1 and CFHR3, is associated with lower risk of age-related macular degeneration. Nat Genet 2006; 38: 1173-1177 doi:10.1038/ng1890
• 19 Seddon JM, George S, Rosner B. et al. CFH gene variant, Y402H, and smoking, body mass index, environmental associations with advanced age-related macular degeneration. Hum Hered 2006; 61: 157-165 doi:10.1159/000094141
• 20 Yaspan BL, Williams DF, Holz FG. et al. Targeting factor D of the alternative complement pathway reduces geographic atrophy progression secondary to age-related macular degeneration. Sci Transl Med 2017; 9
• 21 Holz FG, Sadda SR, Busbee B. et al. Efficacy and safety of lampalizumab for geographic atrophy due to age-related macular degeneration: Chroma and Spectri phase 3 randomized clinical trials. JAMA Ophthalmol 2018; 136: 666-677 doi:10.1001/jamaophthalmol.2018.1544
• 22 Apellis Pharmaceuticals Inc.. Study to compare the efficacy and safety of intravitreal APL-2 therapy with sham injections in patients with geographic atrophy (GA) secondary to age-related macular degeneration (02.10.2018). Im Internet: https://clinicaltrials.gov/ct2/show/NCT03525600?term=NCT03525600&rank=1 Stand: 31.03.2019
• 23 Apellis Pharmaceuticals Inc.. Company Presentation: APL-2 in GA: Phase II FILLY Trial 18-Month Results (26.06.2018). Im Internet: http://investors.apellis.com/system/files-encrypted/nasdaq_kms/assets/2018/10/01/10-34-27/Apellis-RDDay-_Final.pdf Stand: 28.04.2019
• 24 Yehoshua Z, de Amorim Garcia Filho CA, Nunes RP. et al. Systemic complement inhibition with eculizumab for geographic atrophy in age-related macular degeneration: the COMPLETE study. Ophthalmology 2014; 121: 693-701 doi:10.1016/j.ophtha.2013.09.044
• 25 Bandello F, Sacconi R, Querques L. et al. Recent advances in the management of dry age-related macular degeneration: a review. F1000Res 2017; 6: 245 doi:10.12688/f1000research.10664.1
• 26 Wong WT, Dresner S, Forooghian F. et al. Treatment of geographic atrophy with subconjunctival sirolimus: results of a phase I/II clinical trial. Invest Ophthalmol Vis Sci 2013; 54: 2941-2950 doi:10.1167/iovs.13-11650
• 27 Zhang K, Hopkins JJ, Heier JS. et al. Ciliary neurotrophic factor delivered by encapsulated cell intraocular implants for treatment of geographic atrophy in age-related macular degeneration. Proc Natl Acad Sci U S A 2011; 108: 6241-6245 doi:10.1073/pnas.1018987108
• 28 Chew EY, Clemons TE, Jaffe GJ. et al. Effect of ciliary neurotrophic factor on retinal neurodegeneration in patients with macular telangiectasia type 2: a randomized clinical trial. Ophthalmology 2019; 126: 540-549 doi:10.1016/j.ophtha.2018.09.041
• 29 Allergan. A safety and efficacy study of Brimonidine intravitreal implant in geographic atrophy secondary to age-related macular degeneration (BEACON) (23.04.2019). Im Internet: https://clinicaltrials.gov/ct2/show/NCT02087085?term=NCT02087085&rank=1 Stand: 28.04.2019
• 30 Csaky K, Ferris 3rd F, Chew EY. et al. Report from the NEI/FDA endpoints workshop on age-related macular degeneration and inherited retinal diseases. Invest Ophthalmol Vis Sci 2017; 58: 3456-3463 doi:10.1167/iovs.17-22339
• 31 European Medicines Agency. Letter of support for intermediate Age Related Macular Degeneration (AMD) biomarker and novel clinical endpoint development (15.02.2018). Im Internet: https://www.ema.europa.eu/en/documents/other/letter-support-intermediate-age-related-macular-degeneration-amd-biomarker-novel-clinical-endpoint_en.pdf Stand: 31.03.2019