Spektrum der Augenheilkunde

, Volume 19, Issue 6, pp 317–325 | Cite as

Anti-Angiogenese bei neovaskulärer Makuladegeneration: Neue therapeutische Strategien

  • U. Schmidt-Erfurth
  • A. Aue
  • M. Georgopoulos
  • C. Kiss
  • R. Michels
  • S. Richter-Müksch
  • S. Sacu
  • C. Simader
  • C. Vécsei
  • P. -V. Vécsei-Marlovits
  • J. Wagner
  • S. Michels
Übersichtsarbeiten

Antiangiogenesis in neovascular macular degeneration: New therapeutical strategies

Zusammenfassung

Hintergrund

Die Behandlungsmöglichkeiten bei der neovaskulären altersbezogenen Makuladegeneration (AMD) haben sich in den letzten Jahren grundlegend geändert. Pharmakologische Strategien dominieren das Spektrum der therapeutischen Möglichkeiten. Als Optionen stehen hier zur Verfügung: Medikamente mit gezielter antiproliferativer Wirkung, sogenannte Anti-VEGF-Substanzen, die Behandlung mit Verteporfm bei der Photodynamischen Therapie (PDT), der intravitreale Einsatz von Triamcinolon, sowie Kombinationen der einzelnen Methoden.

Resultate

Bei den Anti-VEGF-Substanzen ist Macugen in den USA bereits zur Behandlung der feuchten AMD zugelassen. Es handelt sich um ein Aptamer, das spezifisch den Wachstumsfaktor VEGF 165 bindet. Im VISION Trial wurden Patienten mit allen Läsionstypen und -größen mit intravitrealem Macugen und 6-wöchigen Injektionen über 2 Jahre behandelt. Mit 8,5 Behandlungen über 1 Jahr blieb der Visus bei 70% der Patienten stabil im Vergleich zu 55% in der Kontrollgruppe. Mit 16 Behandlungen über 2 Jahre hielt sich diese Visusstabilisierung, allerdings nur wenn kontinuierlich weiter injiziert wurde. Eine Zunahme der Sehkraft von 3 Zeilen und mehr war bei 6% aller Patienten nachweisbar. Der Behandlungseffekt war unabhängig von Läsionstyp und-größe, jedoch homogener bei Patienten mit einer minimal klassischen Komponente. Als unerwünschte Komplikationen traten Endophthalmitiden auf (1,3% im 1. Jahr), sowie traumatische Verletzungen von Linse und Netzhaut.

Bei Lucentis handelt es sich ebenfalls um eine Anti-VEGF-Substanz. Das Medikament ist ein humanisiertes Antikörperfragment, das alle Isotypen des VEGF-Gefäßfaktors bindet. In der Phase-III-Studie MARINA wurden Patienten mit minimal klassischer oder rein okkulter CNV mit intravitrealer Lucentisgabe in 4-wöchigen Intervallen behandelt. Zum Follow-up nach 1 Jahr waren 94,5% der Patienten stabil hinsichtlich des Visus. Die durchschnittliche Visusveränderung lag im Mittel bei +1,2 Zeilen. 25% aller Patienten zeigten einen Zugewinn an Sehkraft von mindestens 3 Zeilen in der Dosisgruppe von 0,3 mg Lucentis. In der FOCUS-Studie wurde PDT mit Lucentis kombiniert gegen PDT-Monotherapie getestet. In einer Population mit minimal klassischer und vorwiegend klassischem Läsionstyp zeigten 90,5% aller Patienten einen stabilen Visus nach 1 Jahr. Der durchschnittliche Visusanstieg lag im Mittel bei einer Zeile, und 24% aller Patienten wiesen einen Anstieg der Sehkraft von mindestens 3 Zeilen auf. Lediglich 1,3 PDT-Behandlungen waren erforderlich für ein komplettes Sistieren der exsudativen Aktivität. Auch in der Macugen-Studie wiesen vor allem Patienten mit vorwiegend klassischer Neovaskularisation ein verbessertes Ergebnis in Kombination mit der Photodynamischen Therapie auf.

Anecortave ist ein chemisch modifiziertes Steroid, das mit verschiedenen Wachstumsfaktoren interagiert. In einer prospektiven Studie erzielte die Monotherapie mit Anecortave verglichen mit einer PDT-Monotherapie vergleichbare Resultate mit 45% gegen 49% Stabilisierungen.

Die Photodynamische Therapie mit Verteporfin allein als Monotherapie erweist sich am effizientesten bei kleinen, vorwiegend klassischen choroidalen Neovaskularisationen (CNV). Bei der Mehrzahl der gemischten oder vorwiegend okkulten Membranen und der größeren Läsionstypen wird eine Kombination mit intravitrealem Steroid empfohlen. Große interventionelle Studien zeigten, dass 90% der kombiniert behandelten Patienten stabil bleiben und 30% einen Visusanstieg aufwiesen. Der durchschnittliche Visus zeigte einen mittleren Anstieg von +1,1 Zeilen. Bei einer Gabe von 25 mg kristallinem Triamcinolon trat bei 26% der Patienten ein Anstieg des intraokularen Drucks auf, der bei 90% der Augen durch lokale Medikation einstellbar und passager war. 50% der behandelten Augen zeigten eine Kataraktprogredienz mit konsekutiver Operation des Grauen Stars in dieser älteren Bevölkerungsgruppe.

Perspektiven

Mit pharmakologischer Intervention ist es erstmals gelungen nicht nur Visusstabilisierungen bei der Mehrzahl der Patienten zu erreichen, sondern auch Visusverbesserungen. Besonders Anti-VEGF-Substanzen scheinen geeignet, eine relativ rasche und wirksame Beeinflussung der neovaskulären Aktivität zu erreichen. Die hohe Rate an Visusverbesserungen zeigt ein beträchtliches Erholungspotenzial der makulären Netzhaut an. Mit einer gezielten Indikation und einem weiteren Anpassen der Behandlungsparameter hat sich die Prognose bei der neovaskulären AMD entscheidend verbessert.

Summary

Background

Treatment options in neovascular age-related macular degeneration have changed substantially over the last years. Pharmacologic strategies dominate the spectrum of therapeutic interventions. Available alternatives include: Substances with a specific antiproliferative effect, so-called anti-VEGF drugs, the use of verteporfm in photodynamic therapy, an intravitreal application of triamcinolon, as well as the combination of these modalities.

Results

Among anti-VEGF agents, Macugen was the first approved drug to treat neovascular AMD in the US. The substance is an aptamer specifically binding to the VEGF isotype 165. The VISION trial included patients with all lesion types and sizes which were treated with intravitreal Macugen in 6-week intervals over two years. Using 8.5 treatments over one year, visual acuity remained stable in 70% of treated eyes as compared to 55% of control eyes. With a total number of 16 treatments vision remained stable at that level over two years, however, only if treatment was continuously added during the second year. An increase in v.a. by 3 or more lines was documented in 6% of eyes. The treatment effect was unrelated to the lesion type and size, but was more reliable in eyes with minimally classic lesions. Adverse events included endophthalmitis (1.3% during the first year) as well as traumatic cataract and retinal detachment.

Lucentis acts as an anti-VEGF substance as well. The substance consists of a humanized antibody fragment binding all isotypes of VEGF in general. In a phase III study, the MARINA trial, patients with minimally classic or purely occult CNV were treated with 4-weekly Lucentis injections. 94.5% of Lucentis-treated patients were stable in terms of vision after a follow-up of one year. The mean change in v. a. was +1.2 lines. 25% of eyes demonstrated an improvement in vision of at least 3 lines and more in the dose group of 0.3 mg. The FOCUS trial tested PDT combined with Lucentis versus PDT alone. In a population with minimally classic and predominantly classic lesions, 91% of all eyes presented with stable vision at the one year visit. Mean v. a. improved by one line and 24% of all patients improved by 3 lines and more. Only 1.3 PDT treatments were needed to obtain complete resolution of leakage. An improved outcome with a PDT combination was also noted in the Macugen trial.

Anecortave is a modified steroid interacting with multiple growth factors. A prospective trial offered similar results for PDT as well as anecortave monotherapy, 49% versus 45% vision stabilization.

PDT alone given as a monotherapy appears to be most effective in small predominantly classic lesions. In the majority of the mixed or predominantly occult membranes and particularly in larger lesions, a combination with an intravitreal steroid is recommended. Large interventional studies have shown that 90% of patients receiving PDT and intravitreal triamcinolon will have stable vision and 30% appear to improve by at least three lines. Mean visual acuity improved by 1.1 lines. With a dose of 25 mg of triamcinolon, the intraocular pressure increased in 26% of eyes, transiently and well controlled by topical medication in 90%. 50% developed a progression in cataract development in this elderly population.

Perspective

Using pharmacologic intervention, treatment of neovascular AMD is able, for the first time, to offer stabilization in the vast majority of patients and improvement for a large group. Particularly anti-VEGF agents may be adequate to obtain a rapid and efficient impact on neovascular activity. Based on an appropriate indication and a further improvement of parameters, the prognosis in neovascular AMD has dramatically improved.

Schlüsselwörter

Antiangiogenese Endothelialer Wachstumsfaktor VEGF Macugen Lucentis Anecortave Acetate Verteporfm Triamcinolon 

Key words

Antiangiogenesis vascular endothelial growth factor VEGF Macugen Lucentis Anecortave Acetate Verteporfin Triamcinolon 

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Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  • U. Schmidt-Erfurth
    • 1
  • A. Aue
    • 1
  • M. Georgopoulos
    • 1
  • C. Kiss
    • 1
  • R. Michels
    • 1
  • S. Richter-Müksch
    • 1
  • S. Sacu
    • 1
  • C. Simader
    • 1
  • C. Vécsei
    • 1
  • P. -V. Vécsei-Marlovits
    • 1
  • J. Wagner
    • 1
  • S. Michels
    • 1
  1. 1.Klinik für Augenheilkunde und Optometrie, Medizinische Universität WienWienÖsterreich

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