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The point on antiangiogenic drugs Francesco Bandello, Francesca Menchini Department of Ophthalmology University of Udine, Italy. European Frontiers in Ocular Pharmacology Catania, January 18, 2008. History of neovascular AMD therapy. 2006. 2005. ‘60s. 2000. 2004. Laser. Lucentis.

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The point on antiangiogenic drugs francesco bandello francesca menchini department of ophthalmology university of udin

The point on antiangiogenic drugs

Francesco Bandello, Francesca Menchini

Department of Ophthalmology

University of Udine, Italy

European Frontiers in Ocular Pharmacology

Catania, January 18, 2008


History of neovascular amd therapy

History of neovascular AMD therapy

2006

2005

‘60s

2000

2004

Laser

Lucentis

Avastin

Photodynamic therapy (PDT)

with verteporfin

Macugen


Introduction

Introduction

  • Limits of conventional therapies for exudative AMD:

    • Efficacy limited to selected CNV subtypes

    • Absent (laser photocoagulation) or limited (PDT) selectivity on the healthy surrounding retina

    • Efficacy on already formed new vessels (do not prevent recurrences)

  • Need for new treatment modalities that target not only

    established new vessels but prevent new vessels growth

  • Recent improved knowledge of biomolecular mechanisms at the basis of CNV development


Vegf historical note 1

VEGF: historical note (1)

  • “Factor X“

    • diffusible factor responsible for retinal and iris neovascularization in proliferative retinopathy

      Michaelson. Trans Ophthalmol Soc UK, 1948

  • “Tumor vascular permeability factor”

    • First isolated from guinea pig ascites

    • 50.000 times more potent than histamine in increasing vascular permeability

      Senger et al. Science 1983


Vegf historical note 2

VEGF: historical note (2)

  • VEGF was cloned and expressed in 1989

  • Recognized as a potent stimulator of endothelial cell growth in vitro and neovascularization in vivo

    Leung et al. Science 1989

    Keck et al. Science 1989

    Ferrara et al, Biochem Biophys Res Commun 1989

  • Hypothesis that VEGF might play a role in the regulation of physiological and pathological growth of blood vessels


Vegf family

VEGF family

  • Collection of related protein isoforms derived from the same gene

    • VEGF 121

    • VEGF 165

    • VEGF 189

    • VEGF-B

    • VEGF-C

    • VEGF-D

    • VEGF-E

    • Placenta growth factor

VEGF-A


Vegf family1

VEGF family

  • VEGF isoforms have different affinity to heparine, that translates into an ability to interact with heparan sulfate proteoglycan on cell surface and basement membrane

    Houck et al. J Biol Chem 1992


Vegf isoforms

VEGF isoforms

  • VEGF 121, the smallest isoform, does not bind heparin and is freely soluble

  • The largest isoform, VEGF 189, is found in cell surfaces and stored in basement membranes


Regulation of vegf gene expression

Regulation of VEGF gene expression

  • Oxigen tension plays a key role in VEGF gene expression

  • Exposure to low PO2 in different circumstances induces VEGF m-RNA expression

    Semenza. Annu Rev Med, 2003

  • Several major growth factors (TGF-α, TGF-β, IGF-I, PDGF) and inflammatory cytokines up-regulate VEGF m-RNA expression

    Frank et al. J Biol Chem 1995

    Warren et al. J Biol Chem 1996

    Cohen et al. J Biol Chem 1996


Role of vegf in physiological conditions 1

Role of VEGF in physiological conditions (1)

  • In vitro VEGF promotes growth of vascular endothelial cells derived from arteries, veins and lymphatics

  • In mice VEGF gene delection leads to early death in utero due to grossly deficient blood vessels

    Carmeliet et al. Nature 1996

  • VEGF is essential in embryonic angiogenesis, including retinal vasculature

  • VEGF is required not only for proliferation but also for survival of endothelial cells

    Gerber et al. Development 1999

  • VEGF is required for skeletal growth and endochondral bone formation


Role of vegf in physiological conditions 2

Role of VEGF in physiological conditions (2)

  • Embryogenesis

  • Ovulation

  • Bone growth

  • Wound healing

  • Collaterals in ischemic heart and limbs

  • Neurotrophysm


Vegf and the eye 1

VEGF and the eye (1)

  • VEGF and its receptors are expressed in normal eye (particularly in the RPE)

  • Primary source of VEGF are neural cells, including ganglion, Muller and RPE cells

    Miller et al. Am J Pathol 1994

  • VEGF is trophic for the choriocapillaris and required for the maintenance of the choriocapillaris fenestrae


Role of vegf in pathologic conditions

Role of VEGF in pathologic conditions

  • VEGF m-RNA is expressed in the vast majority of human tumours

  • VEGF blockade with anti-VEGF antibodies decreases tumour perfusion, vascular volume, interstitial fluid pressure

    Kim et al. Nature 1993

  • VEGF levels are elevated in ocular fluid in patients with diseases characterized by hyperpermeability and neovascularization


Vegf a and angiogenesis

VEGF-A and angiogenesis

Endothelial cells activation

VEGF-A

Basement membrane degradation

Endothelial cells proliferation and migration

Vessels formation, elongation, proliferation

VEGF 165/120:

25:1 new vessels

2:1 normal

New vessels-associated pericytes maturation

Griffioen and Molema. PharmacolRev. 2000;52:237.


Vegf proinflammatory effect

VEGF: proinflammatory effect

  • VEGF receptors are expressed on inflammatory cells1

  • Inflammatory cells produce and release VEGF2-5

  • Inflammatory cells are involved in BRB break and neovascularization5

Leucocytes recruitment

1. Barleon B et al. Blood. 1996;87:3336-3343. 2. Gaudry M et al. Blood. 1997;90:4153-4161.

3. Iijima K et al. Kidney Int. 1993;44:959-966. 4. Mohle R et al. ProcNatl Acad Sci USA. 1997;94:663-668

.

5. Ishida S et al. J Exp Med. 2003;198:483-489.


The angiogenic cascade

The angiogenic cascade

Basement

membrane

Proliferation

Proteolysis

Migration

Increased VEGF expression

Other angiogenic

growth factors e.g. bFGF

Hypoxia

Migrating endothelial cells form new blood vessels in formerly avascular space

Vascular endothelial cell

1. Aiello LP et al. N Engl J Med. 1994;331:1480-1487. 2. Campochiaro PA et al. Mol Vis. 1999;5:34. 3. Dvorak HF et al. Am J Pathol. 1995;146:1029-1039.

4. Ferrara N. Recent Prog Horm Res. 2000;55:15-35. 5. Miller JW. Am J Pathol. 1997;151:13-23. 6. Miller JW et al. Am J Pathol. 1994;145:574-584.

7. Pe’er J et al. Lab Invest. 1995;72:638-645. 8. Spilsbury K et al. Am J Pathol. 2000;157:135-144.


Pathogenesis of cnv

Pathogenesis of CNV

  • Initial stimulus:

  • Choriocapillaris flow reduction

  • Lipofuscin accumulation

  • Oxidative stress

  • Bruch’s membrane alteration

VEGF

Ambati et al. Surv Ophthalmol. 2003

Witmer et al. Prog Retin Eye Res. 2003


Vegf 164 165 blockage inhibits pathologic retinal neovascularization in animal model

VEGF164(165) blockage inhibits pathologic retinal neovascularization in animal model

p<0,01

0,6

Murin VEGF 164 is equivalent

to human VEGF165

0,4

Area (mm2)

0,2

0

Control

Selective VEGF164

block

Non selective VEGF block

Ishida S et al, J Exp Med 2003


Vegf 164 165 blockage has no effect on physiologic retinal revascularization in animal model

VEGF164(165) blockage has no effect on physiologic retinal revascularization in animal model

Murin VEGF 164 is equivalent

to human VEGF165

p<0,01

30

20

Area (mm2)

10

0

Control

Selective VEGF164

block

Non selective VEGF block

Ishida S et al, J Exp Med 2003


Principal anti vegf compounds

Principal anti-VEGF compounds

  • Selective:

    • Macugen (Pegaptanib sodium)

  • Non selective:

    • Ranibizumab (Lucentis)

    • Bevacizumab (Avastin)


Macugen mechanism of action

Macugen: Mechanism of action

Basement

membrane

Proliferation

Proteolysis

Migration

VEGF165

Other angiogenic

growth factors

Hypoxia

VEGF

Pegaptanib acts here

  • Binds to VEGF165

    • Inhibits permeability

    • Inhibits neovascularization

Vascular endothelial cell

1. Ambati J et al. Surv Ophthalmol. 2003;48:257-293.

2. Miller DW et al. In: Holz FG et al. Age-Related Macular Degeneration. Springer-Verlag; 2004.

3. Singerman LJ, Miller DG. Pharmacological treatments for AMD [Review of Ophthalmology Web site]. Available at: www.revophth.com/index.asp?page=1_422.htm. Accessed July 20, 2004.

4. Sorbera LA et al. Drugs of the Future. 2002;27:841-845.


Macugen

Macugen

  • Aptamer, selective inhibitor of VEGF 165

  • VISION (VEGF Inhibition Study In Ocular Neovascularization)

  • Efficacy for any lesion subtypes

  • Mean number of injection at 24 months: 16

  • Therapeutic efficacy comparable to PDT

  • Mean visual loss at 2 year: 9-10 ETDRS letters

  • Visual improvement: 6%


Macugen 24 months results

Macugen: 24 months results

Mean visual acuity

45% Relative benefitP<0.01*

Visual acuity (letters)

Year 2

Year 1

Weeks

DC=discontinued, *Nominal P Value


Macugen 24 months results visual loss

Macugen: 24 months resultsVisual loss

30

26.5%

MACUGEN 0.3 mg-DC (n=132)

67% relative difference

P<0.05*

MACUGEN 0.3 mg-0.3 mg (n=133)

20

% of patients with visual loss ≥15 letters

15.8%

10

0

54

60

66

72

78

84

90

96

102

End of year 1

End of year 2

Weeks

DC=discontinued, *Nominal P Value


Efficacy cnv subtypes

Efficacy: CNV subtypes

Mean visual acuity change at 1 year

Pegaptanib 0,3 mg (n=294)

-4

-20

Sham injection (n=296)

p<0,01

-3

-15

p<0,05

p<0,001

-2

-10

VA change in letters

VA change in lines

-1

-5

n=72

n=76

n=110

n=101

n=112

n=119

0

0

Predominantly classic

Minimally classic

Occult


V i s i o n early lesions vs all patients

V.I.S.I.O.N. Early lesions vs all patients

All patients

Early lesion

Pegaptanib 0,3 mg (n=30)

Pegaptanib 0,3 mg (n=294)

80

Usual care (n=35)

Usual care (n=296)

80

70

57

55

60

47

% pazienti

33

40

23

20

20

20

6

2

0

0

<15

lettere

≥0

lettere

≥15

lettere

<15

lettere

≥0

lettere

≥15

lettere


The bevacizumab revolution

The bevacizumab revolution

  • Recombinant, humanized full-leght antibody, against all VEGF isoforms

  • FDA-approved for metastatic colorectal cancer in combination with 5FU (off-label)

  • Systemic dose 400 x intravitreal dose

  • Anecdotal reports (case series) on safety and efficacy

  • Anatomical and function improvement on the short-term

  • Different doses used (1 mg-2,5 mg)

  • Cost: 50-100$ vs 995$ (Macugen) and 2120$ (Lucentis)


The bevacizumab revolution1

The bevacizumab revolution

  • Toxicity studies done in rabbit, pig, cow, and monkey

  • No toxicity at standard dose

  • Some evidence of toxicity at 5x-10x standard dose (probably pH related)

  • Bevacizumab detected in 11.8% of patients’ serum following IVT injection

  • May be significant given 20-day half life in serum (compared with 0.5-day half life of ranibizumab)


Lucentis and avastin different and developed on parallel timelines

Lucentis® and Avastin™: different and developed on parallel timelines

Lucentis

(48 kDa)

(E. coli vector to mass produce)

Insertion ofmurineanti-VEGF-Asequences into a humanFAb framework

rhu Fab v1

Anti-VEGF-AMurine MAb(~150 kDa)

Affinitymaturation (140x)

Humanization

Humanization

Insertion of murineanti-VEGF-A sequences into a full-length human IgG

Avastin

(149 kDa)

(CHO cell vector to mass produce)


Bevacizumab catt trial

Bevacizumab: CATT Trial

  • Comparison of AMD Treatment Trials (CATT) supported by National Eye Institute

  • 40 centers

  • 1200 patients (enrollment starting in January 2008)

  • 300 pts: monthly ranibizumab

  • 300 pts: monthly bevacizumab

  • 300 pts: PRN ranibizumab

  • 300 pts: PRN bevacizumab


Lucentis

Lucentis

MARINA / ANCHOR = New Gold Standard


Ranibizumab mechanism of action

Ranibizumab: Mechanism of action

Basement

membrane

Proliferation

Proteolysis

Migration

VEGF110, VEGF121, VEGF165

Other angiogenic

growth factors

Hypoxia

VEGF

Ranibizumab acts here

  • Acts early in the cascade1

  • Attacks disease in two ways

    • Inhibits permeability2

    • Blocks angiogenesis3

  • Penetrates retina to block all VEGF isoforms4

Vascular endothelial cell

1. Lowe J et al. Invest Ophthalmol Vis Sci. 2003; vol. 44. E-ARVO abstract 1828.

2. Gaudreault J et al. Invest Ophthalmol Vis Sci. 2003; vol. 44. E-ARVO abstract 3942. 3. Krzystolik MG et al. Arch Ophthalmol. 2002;120:338-346.4. Mordenti J et al. Toxicol Pathol. 1999;27:536-544.


Marina and anchor study design

MARINA and ANCHOR study design

Investigator identifiespotential subjects

Investigator identifiespotential patients

Reading center confirmsangiographic eligibility

Reading center confirmsangiographic eligibility

Predominantly classic lesions (n=423)

Minimally classic oroccult with no classic lesions (n=716)

Randomized 1:1:1

Randomized 1:1:1

Visudyne

Sham

PDT

Sham

PDT

Ranibizumab

0.5 mg(n=240)

Sham

(n=238)

Ranibizumab 0.3 mg(n=238)

Sham

injection(n=143)

Ranibizumab 0.3 mg(n=140)

Ranibizumab

0.5 mg(n=140)

MARINA

ANCHOR

Rosenfeld et al, N Engl J Med 2006; 355(14): 1419

Brown et al, N Engl J Med 2006; 355(14): 1432


Marina and anchor patients losing 15 letters from baseline

MARINA and ANCHOR :Patients losing <15 letters from baseline

Visudyne

Sham

Lucentis 0.5 mg

MARINA

ANCHOR

Patients (%)

***

***

***

***

96.4

95

100

90

89.9

65.7

64.3

62

53

0

Month 12

Month 24

Month 12

Month 24

Rosenfeld et al, N Engl J Med 2006

Brown et al, N Engl J Med 2006

***p<0.0001 vs. sham


Marina and anchor mean change in va over time

MARINA and ANCHOR:Mean change in VA over time

Lucentis

0.3 mg (n=238)

MARINA

Sham (n=238)

Lucentis

0.5 mg (n=240)

ANCHOR

Visudyne

(n=143)

Lucentis

0.3 mg (n=238)

Lucentis

0.5 mg (n=240)

Rosenfeld et al, N Engl J Med 2006

Brown et al, N Engl J Med 2006

***p<0.0001 vs. sham or Visudyne


Marina and anchor patients gaining 15 letters from baseline

MARINA and ANCHOR: Patients gaining ≥15 letters from baseline

***

***

33

34

4

5

Visudyne

Sham

Lucentis 0.5 mg

Patients (%)

100

MARINA

ANCHOR

***

***

41.0

40.3

5.6

6.3

0

Month 12

Month 24

Month 12

Month 24

Rosenfeld et al, N Engl J Med 2006; 355(14): 1419

Brown et al, N Engl J Med 2006; 355(14): 1432

***p<0.0001 vs. sham


Marina and anchor maintain baseline va or gain 0 letters

MARINA and ANCHOR : Maintain baseline VA or gain ≥0 letters

Visudyne

Sham

Lucentis 0.5 mg

Patients (%)

MARINA

ANCHOR

100

***

85

***

***

71

70

Data to be added when available from CSR

34

29

25

0

Month 12

Month 24

Month 12

Month 24

Rosenfeld et al, N Engl J Med 2006; 355(14): 1419

Brown et al, N Engl J Med 2006; 355(14): 1432

***p<0.0001 vs. sham


The point on antiangiogenic drugs francesco bandello francesca menchini department of ophthalmology university of udin

MARINA and ANCHOR: Incidence of ocular serious AEs at 24 months

MARINA

ANCHOR


Marina and anchor arterial thromboembolic events ates

MARINA and ANCHOR: Arterial thromboembolic events (ATEs)

ANCHOR

MARINA


Efficacy conclusions

Efficacy conclusions

  • Lucentis (ranibizumab 0.5 mg dose), on average rapidly improves VA and sustains improvement over 24 months in patients with CNV lesions of all types:

    • over 70% of Lucentis-treated patients gained more than 0 letters in VA compared with baseline

    • over 33% of Lucentis-treated patients gained 15 letters or more in VA compared with baseline


Safety conclusions

Safety conclusions

  • Lucentis is well tolerated in studies for up to 24 months in duration

  • Low rate of ocular and non-ocular serious adverse events in both clinical trials

  • APTC ATEs occurred in a small number of patients in Lucentis and control groups across both trials


Lucentis posology overview of rationale

Lucentis posology:overview of rationale

MARINA & ANCHOR  Monthly injections

  • Limits of monthly regimen:

    • Cost

    • Time consuming for pts and

    • medical personnel

    • Long-term side effects (?)


How can we use anti vegfs most optimally in clinical practice

How can we use Anti-VEGFs most optimally in clinical practice?

  • It is easy to decide when to treat, but:

  • How do we determine when to stop treating?

    • Evidence?

    • Functional changes?

    • Anatomical changes?


How can we use anti vegfs most optimally in clinical practice1

How can we use Anti-VEGFs most optimally in clinical practice?

  • How do we determine when to stop treating?

    EVIDENCE

  • Subanalysis of MARINA and ANCHOR reveals that 30% of treated pts who did not gain vision at 4 months, at 12 months are 3 line gainers if treatment is continued


How can we use anti vegfs most optimally in clinical practice2

How can we use Anti-VEGFs most optimally in clinical practice?

  • How do we determine when to stop treating?

    FUNCTION

  • ETDRS refraction impractical in clinical practice

  • AMD vision variability (SRF, RPE detachment)

  • Vision gain and loss lags anatomy


How can we use anti vegfs most optimally in clinical practice3

How can we use Anti-VEGFs most optimally in clinical practice?

  • How do we determine when to stop treating?

    ANATOMY

  • How does anti-VEGFs work?

  • Anti-VEGF essentially dry out fluid (usually CNV remains perfused)

  • What is the most sensitive tool to assess the anatomy?

    • OCT?

    • FA?


Pier study design

PIER study design

0

0

1

2

3

4

5

6

7

8

9

10

11

12

23

24

Month

Lucentis®

0.5 mg

Sham

Primaryendpoint

Finalvisit

PIER 12 months


Pier primary end point mean change in va over 12 months

PIER: Primary End PointMean change in VA over 12 months

10

5

0

-5

-10

-15

0

ETDRS letters

-0.2

1

2

3

4

5

6

7

8

9

10

11

12

16.1 letterdifference***

-16.3

Month

Sham (n=63)

Lucentis® 0.5 mg (n=61)

PIER 12 months

***p<0.0001 vs sham


Sustain the gain monthly and quarterly regimen

Proportion sustaining gain* (%)

Sustain the gain*: Monthly and quarterly regimen

100

  • High rate of 40%of patients in PIER still sustained vision improvement with quarterly dosing suggesting that not all patients need monthly dosing

69

64

40

0

ANCHOR

MARINA

PIER

*Visual acuity change from month 3 at each monitoring visits ≥-5 letters


Observation from phase iii trials a biphasic treatment effect

Observation from phase III trials: a biphasic treatment effect

Maintain the gain

Mean change from baseline (letters)

Gain Vision


Number of injections needed to sustain the gain

Number of injections neededto sustain the gain*

# Injections

Month (after initial 3 month loading)

On average, 8.1 injections will be needed in the first 12 months of treatment (3 loading doses + 5.1 in the 9 month maintenance phase)

*Results based on drug-disease model


Pronto study

24 motnhs, open-label, prospective, single center, non randomized trial to evaluate an OCT-guided, variable-dosing regimen with IV Lucentis

3 monthly injections then re-treatment if one of the following:

5 letters visual loss with presence of macular fluid on OCT

Increase in OCT central Rth of at least 100µm

New-onset classic CNV

New macular hemorrhage

Persistence macular fluid at least one month after the previous injection

PrONTO Study


The point on antiangiogenic drugs francesco bandello francesca menchini department of ophthalmology university of udin

PrONTO: 12 months results

  • Mean VA gain: 9.3 letters

  • 82.5% stabilization, 35% ≥3 lines gain

  • Initial Rth decrease on OCT precedes visual acuity

    improvement

  • Mean number of injections: 5.6

  • Mean retreatment time: 4.3 months


Sustain trial va oct guided flexible dosing

SUSTAIN trial: VA / OCT guided flexible dosing

Finalvisit

Loading phase

Primaryendpoint

  • Maintenance phase

Month

0

1

2

3

4

5

6

7

8

9

10

11

12

Ranibizumab0.5 mg

VA / OCT guided dosingor flexible dosing


Approved eu lucentis posology

Approved [EU] Lucentis posology

Lucentis treatment is initiated with a loading phase of one injection per month for 3 consecutive months, followed by a maintenance phase in which patients should be monitored for VA on a monthly basis. If the patient experiences a loss of greater than 5 letters in VA (ETDRS or one Snellen line equivalent), Lucentis should be administered. The interval between two doses should not be shorter than 1 month


Udine experiences

Udine experiences

Anti-VEGF treatment


The point on antiangiogenic drugs francesco bandello francesca menchini department of ophthalmology university of udin

Case 1

Baseline

VA: 20/100

3 injections

on a monthly basis

3 months

VA: 20/125

No reinjection

6 months

VA: 20/160


The point on antiangiogenic drugs francesco bandello francesca menchini department of ophthalmology university of udin

Case 2

Baseline

VA: 20/50

3 injections on

a monthly basis

3 months

VA: 20/25

No re-injection

6 months

VA: 20/25

4th injection


The point on antiangiogenic drugs francesco bandello francesca menchini department of ophthalmology university of udin

Case 3

Baseline

VA= 20/63

1 month post Lucentis

VA= 20/32


Treatment of exudative amd future perspectives

Treatment of exudative AMD: future perspectives

  • Pathogenic mechanisms:

    • Inflammation

    • Cytokines expression (VEGF)

  • PDT

    • Neovascular tissue thrombosis

    • Hypoxia

    • Inflammation

    • VEGF up-regulation

  • Anti-VEGF

    • New vessels growth

    • Surrounding retinal tissue invasion

PDT

+

Anti-inflammatory drugs

+

Anti-VEGF

Combo therapy


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