Universitäts-Augenklinik Bonn

Anti-VEGF-Therapie: Lucentis

Frank G. Holz

www.augenklinik.uni-bonn.de

AAD 200623. März 2006Minisymposium 175

Neutralisierung von VEGFNeutralisierung von VEGF

Antikörperfragment: Ranibizumab = Lucentis

Antikörper: Bevacizumab = Avastin

Aptamer: Ranibizumab = Macugen

Daniel W. Miller, Silvia Vosseler, Nicolae Mirancea, Daniel J. Hicklin, Peter Bohlen , Frank G. Holz, Norbert E. Fusenig. Rapid Vessel Regression, Protease Inhibition, and Stromal Normalization uponShort-Term Vascular Endothelial Growth Factor Receptor 2 Inhibition in Skin CarcinomaHeterotransplants. American Journal of Pathology 2005;167:1389-1403

Blockade of VEGF receptor 2 (VEGFR-2)with the monoclonal antibody DC101

LucentisLucentis

MARINA-Studie okkulte und minimal klassische CNV

ANCHOR-Studie überwiegend klassische CNV

Reading center confirmsangiographic eligibility

Randomized 1:1:1

Sham(n=238)

Ranibizumab 0.3 mg(n=238)

Ranibizumab0.5 mg(n=240)

Minimally classic oroccult with no classic lesions

(n=716)

Investigator identifiespotential patients

Lucentis: MARINALucentis: MARINA--StudieStudieOkkulte + minimal klassische CNVOkkulte + minimal klassische CNV

2 4 6 8 10 12

Visit (months)-15

-10

-5

0

5

10

ETD

RS

lette

rs

Sham (n=238)Ranibizumab 0.3 mg (n=238)Ranibizumab 0.5 mg (n=240)

-10.4

+6.5+7.2 17.6 letter

benefit ***

16.9 letter benefit ***

Visual acuity mean change from baseline (letters)Visual acuity mean change from baseline (letters)

***P<0.0001 for all ranibizumab comparisons vs Sham from month 1 to month 24

Lucentis: MARINALucentis: MARINA--Studie 1 JahrStudie 1 Jahr

Lucentis: MARINALucentis: MARINA--StudieStudie

***p < 0.0001 vs. Sham

15,110,9

5,911,3

38,734,5

15,0

40,0 42,1

0

10

20

30

40

50

60

70

80

90

100

Baseline Month 12 Month 24

*** ******

***

Sham (n=238)

Ranibizumab 0.3 mg (n=238)

Ranibizumab 0.5 mg (n=240)

Patients with Patients with 20/4020/40 or better (%)or better (%)

*** ***

Reading center confirmsangiographic eligibility

Randomized 1:1:1

Predominantly classic lesions (n=423)

Investigator identifiespotential subjects

Verteporfin ShamPDT

ShamPDT

Shaminjection(n=143)

Ranibizumab 0.3 mg(n=140)

Ranibizumab0.5 mg(n=140)

Lucentis ANCHOR-StudieÜÜberwiegende klass. CNV: Lucentis vs. PDTberwiegende klass. CNV: Lucentis vs. PDT

Lucentis ANCHOR-StudieÜÜberwiegende klass. CNV: Lucentis vs. PDTberwiegende klass. CNV: Lucentis vs. PDT

Ranibizumab0.5 mg

Primary endpoint

Sham injection

0.3 mg

0 1 2 3 4 5 6 7 8 9 10 11 12Month

0.5 mg

Ranibizumab0.3 mg

PDT

Sham PDTVerteporfin

Sham

LucentisLucentis

ANCHOR

Patients losing <15 letters (%)

MARINA

Verteporfin(n=143)

64.3

Sham(n=238)

62.2

***p<0.0001 vs control

Ranibizumab0.3 mg(n=140)

Ranibizumab0.5 mg(n=139)

Ranibizumab0.3 mg(n=238)

Ranibizumab0.5 mg(n=240)

*** *** *** ***94.3 96.494.5 94.6

0

100

EXCITEEXCITE--StudieStudie

Month

Ranibizumab0.3 mg

Ranibizumab0.5 mg

0 1 2 3 4 5 6 7 8 9 10 11 12 23 24

Finalvisit

PrimaryEndpoint

Ranibizumab0.3 mg

LucentisLucentis PROTECTPROTECT--StudieStudieLucentisLucentis + PDT+ PDT

• Investigator discretion• Ranibizumab administered 1 hr after verteporfin PDT

1 2 3 4 5 6 7 8 9

PDT

0Month

Ranibizumab+

** ** **

Primary endpoint

LucentisLucentis + + PDT (PROTECTPDT (PROTECT--Studie)Studie)

Vorher

0,4

Nach 9 Monaten

0,6

Intraokulare EntzIntraokulare Entzüündungndung

MARINA ANCHOR

1 (0.7%)1 (0.7%)00002 (0.8%)2 (0.8%)2 (0.8%)2 (0.8%)00Intraocular inflammationIntraocular inflammation

000000000000VitritisVitritis

1 (0.4%)1 (0.4%)

1 (0.4%)1 (0.4%)

00

RanibizumabRanibizumab0.5 mg0.5 mg(n=239)(n=239)

00

1 (0.4%)1 (0.4%)

1 (0.4%)1 (0.4%)

RanibizumabRanibizumab0.3 mg0.3 mg(n=238)(n=238)

00

00

00

ShamSham(n=236)(n=236)

1 (0.7%)1 (0.7%)0000UveitisUveitis

000000IridocyclitisIridocyclitis

0 0 0000IritisIritis

RanibizumabRanibizumab0.5 mg0.5 mg(n=140)(n=140)

RanibizumabRanibizumab0.3 mg0.3 mg(n=137)(n=137)

VerteporfinVerteporfin(n=143)(n=143)MedDRAMedDRA

preferred termspreferred terms

Integrated safety summary

APTC arterial APTC arterial thromboembolicthromboembolic events: events: Pooled ANCHOR and MARINAPooled ANCHOR and MARINA

APTC* classificationAPTC* classificationSham or Sham or

vertaporfinvertaporfin(n=379) (n=379)

RanibizumabRanibizumab0.3 mg 0.3 mg (n=375)(n=375)

Ranibizumab Ranibizumab 0.5 mg 0.5 mg (n=379)(n=379)

Vascular death Vascular death 1 (0.3%)1 (0.3%) 2 (0.5%)2 (0.5%) 3 (0.8%)3 (0.8%)

NonNon--fatalfatalmyocardial infarction myocardial infarction 2 (0.5%)2 (0.5%) 2 (0.5%)2 (0.5%) 4 (1.0%)4 (1.0%)

NonNon--fatalfatalischemic stroke ischemic stroke 2 (0.5%)2 (0.5%) 2 (0.5%)2 (0.5%) 4 (1.0%)4 (1.0%)

NonNon--fatalfatalhemorrhage stroke hemorrhage stroke 00 00 00

TOTALTOTAL 5 (1.3%)5 (1.3%) 6 (1.6%)6 (1.6%) 11 (2.9%)11 (2.9%)

*Used during FDA COX-2 inhibitor advisory panel meetings Feb’05

Integrated safety summary*Antiplatelet Trialists’ Collaboration, BMJ 1994 Jan 8; 308(6921): 81

SchluSchlußßfolgerungenfolgerungenWirksamkeitWirksamkeit

•• AntiAnti--VEGFVEGF--Therapiestrategie bestTherapiestrategie bestäätigttigt•• Wirksamkeit Wirksamkeit üüber 2 Jahreber 2 Jahre•• Zunahme des Benefits gegenZunahme des Benefits gegenüüber Placebo ber Placebo üüber 2 ber 2

JahreJahre

SicherheitSicherheit•• Sicherheitsprofil okulSicherheitsprofil okulääre Nebenwirkungen +re Nebenwirkungen +•• ExtraokulExtraokulääres Sicherheitsprofil +res Sicherheitsprofil +

•• Keine Evidenz fKeine Evidenz füür systemische VEGFr systemische VEGF--InhibitionInhibition

AusblickAusblick•• Reduzierte Applikationsfrequenz?Reduzierte Applikationsfrequenz?•• Abbruchkriterien?Abbruchkriterien?•• Andere ApplikationssystemeAndere Applikationssysteme