# Presentation: 730641

## Pegaptanib Benefit Risk Profile

- Donald J. D’Amico, MD
- Harvard Medical School
- Massachusetts Eye and Ear Infirmary
- FDA Advisory Panel          August 27, 2004

## Disclosures for Donald J. D’Amico, MD

- Consultant to
- 	a) Eyetech Pharmaceuticals
- 	       Safety Committee Member; Later Chair,
- 	       then Scientific Advisory Board Member
- 	b) Alcon Laboratories
- 		  Anecortave Safety Committee Chair
- 		  Retina Experts Advisory (Anecortave)
-            RAC (Surgical Advisory Group)
- 	c) Iridex Corporation
-            Safety Committee Member for
- 		      PTAMD (laser for drusen) and
-                Transpupillary Thermotherapy Trials

## Four Perspectives Relevant to Pegaptanib Benefit Risk Profile 

- 1)  Member of Pegaptanib Safety Committee
- 2)  Career-long interest in clinical and  	laboratory research in endophthalmitis 	and the retinal effects of intravitreal 	medications
- 3)  An academic in the field of retinal 	diseases and therapy
- 4)	  Practicing retinal specialist at MEEI

## Neovascular AMD – A Debilitating Disease

| 
20/40 | Driving privileges
Reading newspaper print |
| --- | --- |
| 
20/80 | 
Difficulty reading large print |
| 
20/200 or worse | Legal blindness
Face recognition is difficult
Ability to live independently
   is threatened |

## Meta-Analysis of Major Prevalence Studies in U.S., Europe, and Australia (1990-2001)

## Leading Causes of Blindness in U.S. Adults (Patients Age 40 Years or Older)

**54.4% AMD**

**Cataract**

**Glaucoma**

**Diabetic Retinopathy**

**Other**

## Prevalence of Blindness and Low Visionin U.S. Adults Age 40 Years or Older

- The Near Present (Year 2000 Census)
- 	937,000 Blind (0.78%)
- 		   _2.4 Million with Low Vision (1.98%)_
- 	         3.3 Million with Visual Impairment (2.76%)
- In the Future (2020)
-  (**↑** 70%)     1.6 Million Blind (1.1%)
-  (**↑**  60%)    _3.9 Million with Low Vision (2.5%)_
-                    5.5 Million with Visual Impairment (3.6%)

**Causes and Prevalence of Visual Impairment Among Adults in the United States, Arch Ophthalmol. 2004; 122:477-485**

## Neovascular AMD: An Unmet Medical Need

| Surgical/ Laser Therapies | Pharmacological Therapies |
| --- | --- |
| Laser Photocoagulation | Anti-VEGF agents (intravitreous) |
| PDT:  VisudyneTM, SnET2 |          Pegaptanib, RhuFAB |
| Surgery | Anecortave (post juxtascleral) |
|      Removal | Triamcinolone (intravitreous) |
|      Translocation | Squalamine (intravenous) |
|       360° retinotomy vs. limited | Prinomastat (oral) |
| Transpupillary Thermotherapy | Thalidomide (oral) |
| Feeder Vessel Treatment | Interferon alfa (subcutaneous) |
| Radiation | Combination strategies |
| RPE Transplantation |     PDT + Triamcinolone (intravit) |

-   ■*Effective**	**  **	** *■*Ineffective** **	**       *■*Ongoing study*

## AMD: Established Therapies

- Thermal laser photocoagulation
- Beneficial in patients with extrafoveal, juxtafoveal, and subfoveal lesions
- However, the immediate treatment-related visual loss has greatly limited its application to subfoveal lesions
- Photodynamic therapy with VisudyneTM
- FDA-approved for subfoveal predominantly classic lesions

## PDT with VisudyneTM in association with an intravitreous injection of Triamcinolone

- AMD: Evolving Clinical Practice

- +

## Intravitreous Injection Therapy in Current Practice

- Routinely employed for:
- Endophthalmitis
- Retinal Detachment
- CMV Retinitis
- Recent expanded use:
- Diabetic Macular Edema
- Retinal Vein Occlusions
- Uveitis
- AMD (with PDT)

## Pegaptanib Sodium Injection

-   Pharmacotherapy: Potential Advantages
*General* Treatment at a molecular level
- Improved targeting of disease process
- Limitation of collateral damage that occurs with larger scale interventions
*Pegaptanib* Based on extensive basic science into the most widely accepted, central disease processes in AMD (neovascularization, leakage), with consistency across multiple experimental models and studies

## Independent Safety Committee Monitoring

- Potential systemic side-effects of anti-VEGF drug administration
- Potential ocular drug-related side-effects of intravitreal anti-VEGF administration
- Potential mechanical side-effects or complications from intravitreous injection procedure

## Serious Ocular Adverse Events

- Endophthalmitis 12 cases
- Incidence rate comparable to published series
- 1 with severe visual loss (0.1%)
- 9 of these patients continued to receive study medication after endophthalmitis treatment
- The incidence rate is trending downward
- Retinal Detachment 5 cases
- 3 non-rhegmatogenous likely related to underlying macular degeneration
- 2 rhegmatogenous detachments were repaired
- Traumatic cataract 5 cases
- All surgically repaired without sequelae

## Pegaptanib Sodium: Safety

- Context:  7,545 intravitreous injections performed in 1,190 patients by 117 centers worldwide
- No evidence of systemic side effects
- No evidence of ocular drug-related side effects
- Ocular adverse events related to the route of administration were seen
- Majority were mild and transient
- Serious AEs were infrequent and manageable
- Conclusion:  A favorable safety profile that may be further improved by education

## Severe Vision LossDecrease ≥ 30 Letters (6 or more lines)

|  | Severe Vision Loss
% pt/year |
| --- | --- |
| Sham | 22 |
| Pegaptanib 0.3 mg | 9.5 |

## Severe Vision LossDecrease ≥ 30 Letters (6 or more lines)

|  | Severe Vision Loss
% pt/year |
| --- | --- |
| Sham | 22 |
| Pegaptanib 0.3 mg | 9.5 |
| Endophthalmitis | 0.1 |
| Retinal Detachment | 0.1 |
| Cataract | 0 |

## Pegaptanib Sodium: Efficacy

- Significant reduction in moderate and severe vision loss compared with sham
- Promotion of vision stability and gain in a proportion of patients
- Efficacy with broad based entry criteria including a range of subfoveal neovascular AMD lesions
- Benefit of intravitreous pegaptanib therapy was early and sustained

## Baseline and Week 54 Snellen Visual Acuity

**Baseline**

**Week 54**

**0.3 mg **

**Sham **

**Wilcoxon rank sum test for 0.3 mg vs Sham is <0.0001**
****3 patients had baseline Snellen score better than 20/40**

## Prevention of Severe Vision Loss (SVL)

- Pegaptanib potentially prevents SVL event in 15,000 more patients per year in the U.S. compared with usual care*

*57% reduction in the rate of SVL with pegaptanib*

***Assumption: 120,000 new treatment-eligible patients with exudative AMD per year**

## Prevention of Blindness in Treated Eye

- Pegaptanib potentially prevents treated eye blindness in an additional 22,800 patients per year in the U.S. compared with usual care*

***Assumption: 120,000 new treatment-eligible patients with exudative AMD per year**

*38% reduction in the rate of treated eye blindness with pegaptanib*

## Pegaptanib Benefit Risk Profile

- Conclusions
- Pegaptanib will have a significant impact on AMD, in regard to both a) individual patients with AMD lesions that would become amenable to treatment, and b) in its effects on visual function and its preservation in the aging US population
- The positive results indicate the beginning, and not the limit, of pharmacotherapy for AMD
- The benefits of pegaptanib therapy for AMD strongly outweigh the risks