Redefining Preventable Blindness - Pharmacological Treatment of - - PowerPoint PPT Presentation

Redefining Preventable Blindness - Pharmacological Treatment of Age-Related Vision Loss

David T. Shima, PhD Rothes Professor of Translational Vision Research UCL Institute of Ophthalmology

The urgency to develop treatments for vision loss: wet AMD

Advanced stages of AMD

Age-Related Macular Degeneration

Neovascular AMD and Diabetic Retinopathy

• Leading causes of

blindness in aging adults in developed world

• Though distinct

pathogenesis, AMD and DR both linked to abnormal growth and behaviour of blood vessels

Angiogenic in vivo

Vascular Endothelial Growth Factor

Potent inducer of edema in the retina

Vascular Permeability Factor

Vascular Endothelial Growth Factor (VEGF)

VEGF and oxygen levels

VEGF levels correlate with hypoxia and ischemia-induced iris neovascularization

Anti-VEGF Ab Control

Arch Ophthalmol 1996;114:66-71

Toppling of the Barriers to Developing Drugs for AMD

• Late 1990s
• Treatments mainly surgical or laser-based
• Concept of repeat intravitreal injections was refuted
• No Investors
• 2000 Investment in Eyetech (Dotcom boom)
• 2000 Genentech announce clinical development of

Lucentis

• 2002 $750M Eyetech deal with Pfizer
• 2003 Genentech/Novartis deal

Progress for patients with wet AMD

• Pegaptanib (Macugen)
• Approved 2004
• Stabilize vision
• Ranibizumab (Lucentis)
• Approved 2006
• Reverse vision loss

Anti-VEGF in AMD

Rosenfeld et al, NEJM 2006:355;1419

3

The Impact of Drug Development

Source: Abbott Laboratories

2

Expectations for the Ophthalmic Drug Industry

$1.9 $2.9 $5.7 $2.5 $2.9 $3.8 $5.8 $4.0 $2.8

$0.0 $3.0 $6.0 $9.0 $12.0 $15.0 $18.0 $21.0 2000 2005 2010

Total = $4.4B Total = $8.6B Total = $19.3B Diabetic Retinopathy Macular Degeneration Anti-Inflamm Dry Eye Anti-Allergy Antibiotics Glaucoma

Source: S.G. Cowan/Braun and other industry sources

The challenges

• 1. The law of diminishing returns

Rosenfeld et al, NEJM 2006:355;1419

3

• 2. Cost and Time: 14.2 Years To Develop a Drug

14.2 years

DiMasi et al., J Health Economics 2003;22(2):151-185

8

• 3. Drug Approvals Are Not Keeping Pace With R&D Spending

R&D expenditures adjusted for inflation Source: Tufts Center for Drug Development 2005 5

The Development Gauntlet

13 Compounds

13

• 4. Cost effectiveness a must

• 5. Safety challenge grows

The ability to prevent death and prolong survival means survival is with co morbidity

Conclusions and Solutions?

• Expectations are high, but drug development is costly

and success rates are low

• With the growing ageing population, cost effectiveness

will play a major role in any success scenario

• With the growing ageing population, co-morbidities,

poly-pharmacy and safety concerns will be a challenge

• Explore the landscape in ophthalmic drug development

Pharmacological treatment of AMD and DR

• Anti-VEGF drugs (Macugen, Lucentis, Avastin) have

improved vision or prevented legal blindness in many tens

• f thousands of AMD patients
• Need to expand upon use in DR and vein occlusion
• Need for drug delivery to enable AMD prevention

approaches and chronic treatment of DR

• 60% of wet AMD eyes see 20/50 or worse despite Lucentis
• Need for combination and next generation treatments

Expanded use of VEGF antagonists for retinal disease

• Macugen
• Lucentis
• Avastin

Need for Advances in Drug Delivery for AMD and DR

• Current drugs require 9-12

injections/year based on pivotal studies

• Approx 5-6/yr in real world

setting

• Safety, inconvenience and

workload issues

• Diabetic retinopathy,

prevention strategies for wet AMD and treatment of severe dry AMD require advanced formulation

VEGF antagonists and safety risks

Potential for anti-VEGF therapeutic toxicity in humans

• Thrombosis
• Hemorrhage
• Hypertension
• Proteinuria
• Neural effects

Drug Delivery Strategies

• I-vation coil
• Surmodics
• Vitreal implants
• Posurdex
• Medidur

PLGA Microspheres

PLGA based commercial products

Target product profile

• Duration of release enables reduction to < 2

injections/yr

• Utilize components with known safety in ocular setting
• Must be syringable through 27 gauge needle
• Efficient load and low burst release

Reformulation to enable Prevention

• In vitro sustained release from microparticles

Drug Delivery enables strategies aimed at prevention of advanced AMD

Geographic atrophy

• Patients with central GA
• ~1M people in EU
• No treatments
• 50% legally blind in 2 years

All the buzz about Complement

• Complement pathway is involved in defense against

microbes

• Hypothesis is that unchecked, complement may

damage our own tissues

• Human genetic data have identified complement gene

polymorphisms linked to increased risk for AMD (CFH, CFB, C3)

• Risk is related to progression to advanced AMD
• Both wet AMD and geographic atrophy
• ~ 10 Complement antagonists in development for AMD

60% of patients treated with Lucentis still have disabling vision

Need for combination and next generation therapies

By 2003, clinical data suggested treated lesions did not regress

Extending the rationale for targets in the neovasculature

Combination therapy: a scientific rationale

Pericytes Endothelial Cells

Anti-pericyte

• r matrix

Anti-endothelium (Lucentis)

What about attacking the pericyte by blockade

• f PDGF-B?

Lectin/SMA

Anti-PDGFB (Day 20)

Lectin/SMA

Control ( Day 20)

E10030 (anti-PDGF-B) finished Phase 1

+21 Letters +27 Letters

Pre-combination therapy Post-combination therapy 1 month Post-combination therapy 2 month

20/80 20/32 20/25

Targeting the vessel

• VEGF (OSI-Eyetech,

Genentech, Regeneron)

• PDGF-B (Ophthotech)
• Delta-4 (Genentech,

Regeneron)

• α5β1 integrin (Jerini

Ophthalmic)

The integrin antagonist JSM6427 is entering Phase 2 clinical trials for Wet AMD

d7 d14 d21 d28 JSM6427 Vehicle

Future

• Anti-VEGFs have paved the way for the next

generation of treatments for age-related vision loss

• Challenges are significant
• Cost, Safety
• Clinical Trials
• Avastin
• Enabling technologies are critical
• Better biomarkers
• Diagnostics
• Drug Delivery

UCL Institute of Ophthalmology partners

• NIHR Biomedical Research Centre at Moorfields
• MRC
• Jerini Ophthalmic
• GSK