ANTI VEGF

Anant Srivastava

WHAT IS AMD?

Age-related macular degeneration (AMD) is an eye condition that affects a tiny part of the retina at the back of your eye, which is called the macula.

CAUSES OF AMD
Age Gender Gene Smoking Sunlight Eating Habits

SYMPTOMS
Difficulty with reading small print with your reading glasses. Straight lines start to look wavy or distorted Blurred Vision

EYE : PARTS EFFECTED

Macula Pinhead size specialized area in retina contains millions of specialized photoreceptor cells called Cones. These cone cells function best in bright light levels and allow you to see fine detail for activities such as reading and writing and to recognize colors. During AMD the Macula gets damaged or become malfunction & thereby causes blurred vision.

TYPES OF AMD

Dry AMD Wet AMD

AMD EPIDEMIOLOGY

10% Wet AMD

90% Dry AMD

DRY AMD

The commonest type of AMD (90%) Develops very slowly and causes a gradual change in your central vision.

Caused over a long period of time.

At worst situation it causes a blank patch in the center of the vision. But doesn't effect the peripheral vision . Hence never leads to total blindness.

WET AMD
About 10-15% who develop AMD have Wet AMD. Develops over a very short period of time. Causes damage to central vision making the central vision hampered.

CASCADE OF WET AMD

Lack of Oxygen in the Retinal Cells

Tending to leak the fluid & blood under retina causing more damage & impairs the vision.

Blood vessel start growing in the Macula from the layer under Retina

Opposite effect by body as new blood vessels are unstable.

The body respond to deliver more of oxygen & nutrients to the cells making new vessels to grow

TREATMENTS : A PROPHYLACTIC APPROACH

There is no treatment for AMD, but can be done is to prevent the AMD from further loss of visions.

Dry AMD
Anti Oxidants with zinc Supplements AREDS Formula Therapy Omega 3 Fatty acids (DHA & EPA)

Wet AMD
Anti VEGF Treatments Laser Treatments (Not used as of now)

ANGIOGENESIS
The process by which new blood vessels forms from the existing vessel networks. The process starts when there is a lack of oxygen in a tissue. Followed by new vessels to grow to compensate the depleted oxygen. This is a normal physiological process in body which helps to combat the oxygen requirement. Occurs in various part of organ & tissue where the oxygen is deprived.

VEGF

V.E.G.F., stands for Vascular Endothelial Growth Factor. Is a protein that occurs naturally within the body. Bodily tissues release this protein to signal the need for additional oxygen.

In other words, VEGF release is an indicators for Angiogenesis (Formation of new blood vessels)

VEGF : A POWERFUL MEDIATOR OF ANGIOGENESIS

Hypoxia in Tissue

Formation of New Blood Vessels (Angiogenesis)

Stimulate Protein (VEGF) Release

VEGF Binding with Tissues to compensate Lack of Oxygen

ANTI VEGF
Anti-vascular endothelial growth factor medications (Anti-VEGFs) are substances that stop blood vessels from forming or growing. Works by targeting a protein (VEGF) that is needed when new blood vessels forms. Blocking this protein slows the growth of the abnormal blood vessels. This slows the vision loss linked to wet AMD.

ANTI VEGF BRANDS

Avastin
Lucentis (2006)

Eylea (2011)

Macugen (2004)

ANTI VEGF TREATMENTS

Brand Name
Macugen

Generic Name
Pegaptanib

Company
Pfizer

Lucentis
Avastin Eylea

Ranibizumab
Bevacizumab Alfibercept

Novartis Pharma
Roche pharma Regeneron Pharma/S.A.

MACUGEN
The first anti-angiogenic or anti-VEGF medication used to treat wet AMD Approved by FDA in 2004. Therapy 6 weeks for up to two years. Newer Anti VEGF agents had shown much better efficacy. Now, Not used frequently for Wet AMD treatment.

LUCENTIS

Approved by FDA in Year 2006 for treating Wet AMD. Therapy Monthly eye Injection, maintains the vision upto 12 months in 95% of participants. Apart from inhibiting Angiogenesis also helps to reduce the leakage of fluids in Macula.

AVASTIN

A newer anti-VEGF but is approved as a treatment for colon and rectal cancer. Avastin is molecularely very similar to Lucentis. Not approved to used in the eye. Reason why ophthalmologist use for treating Wet AMD
Similar molecule Dramatic Cost difference.

CATT STUDY
Comparison of Age-Related Macular Degeneration

Treatment Trials (CATT Study)

Objective A comparative study between Lucentis & Avastin to assess the relative safety and effectiveness in treating AMD. No. of Patient Enrolled 1200 with newly Diagnosed Wet AMD. Centers & Duration 47 Centers & 2 Years. Result There was no significant difference between the both the treatments of Lucentis & Avastin.

EYLEA

Eylea is the most recent anti-VEGF therapy on the market . Approval status Approved by FDA in Nov 2011.

Benefits Less frequency of Dosage as compared to other.

Eylea is a protein that binds with the active forms of VEGF (VEGF-A) and placental growth factor (PIGF), another molecule involved in the formation of new blood vessels.

S/E OF ANTI - VEGF

Changes in vision, or trouble seeing. Inflammation of different parts of the eye. Bleeding. Eye discharge. Eye pain or discomfort. Increased IOP. Increased sensitivity to light. Headache. Painful urination.

CLINICAL TRIALS

Clinical trials regarding the intravitreal injection of anti-VEGF agents

Ranibizumab Bevacizumab Pegaptanib Aflibercept

Shown excellent results in the treatment of angiogenic pathologies including

Choroidal Neovascularization Macular Edema (ME) Proliferative Diabetic Retinopathy (PDR) Neovascular Glaucoma (NVG)

RVO (Retinal Vein Occlusion)

CRVO (Central Retinal Vein Occlusion) BRVO (Branched Retinal Vein Occlusion)

CRUISE Trial

BRAVO Trial

CRUISE & BRAVO STUDY

Two recent phase III clinical trials for RVO. In both the Central Retinal Vein Occlusion (CRUISE) study and the Branch Retinal Vein Occlusion (BRAVO) study. Subjects who received intravitreal injections of Ranibizumab showed a statistically significant improvement in visual acuity compared to subjects in the sham group.

CRUISE STUDY

The CRUISE study was a 12-month clinical trial that evaluated the efficacy and safety of anti-VEGF injections in the treatment of macular edema secondary to CRVO (Central Retinal Vein Occlusion).

CRUISE researchers examined 392 subjects from 95 U.S. locations.

Subjects divided into 3 Groups
0.3 Ranibizumab 0.5 Ranibizumab Sham Injection

Duration of Treatment Every month for first six month. Result Visual acuity improvement of three or more lines was observed in 46% of the subjects in the 0.3mg ranibizumab group, 48% of the subjects in the 0.5mg ranibizumab group, and 17% of the subjects in the sham group. Improvements were maintained in both treated groups at 12 months.

BRAVO STUDY

The BRAVO study was a 12-month clinical trial that evaluated the efficacy and safety of anti-VEGF injections in the treatment of macular edema secondary to BRVO (Branch retinal vein Occlusion).

BRAVO researchers examined 397 subjects from 93 U.S. locations. Subjects divided into 3 Groups in 1:1:1 ratio
0.3 Ranibizumab 0.5 Ranibizumab Sham Injection

Duration of Treatment Every month for first six month.

Result At six-month follow-up, a visual acuity improvement of three or more lines was observed in 55.2% of the subjects in the 0.3mg ranibizumab group, 61.1% of the subjects in the 0.5mg ranibizumab group, and 28.8% of the subjects in the sham group.

The RESTORE Study

The RESOLVE Study

READ-2 Study

CTs for DME

The DA VINCI Study

RESOLVE STUDY

Objective To study the safety and efficacy of ranibizumab in Diabetic Macular Edema (DME).

Conclusion Ranibizumab is effective in improving BCVA (best Corrected Visual Acuity) and is well tolerated in DME.

RESTORE STUDY

Objective To demonstrate superiority of ranibizumab 0.5 mg monotherapy or combined with laser over laser alone based on mean average change in Best-Corrected Visual Acuity (BCVA) over 12 months in diabetic macular edema (DME). Conclusion Ranibizumab monotherapy and combined with laser provided superior visual acuity gain over standard laser in patients with visual impairment due to DME. Visual acuity gains were associated with significant gains in VFQ-25 scores.

READ 2 STUDY

Objective To study two-year outcomes of the Ranibizumab for edema of the macula in diabetes II. Participant 126 patients with DME Groups

0.5 ranibizumab Focal or grid laser photocoagulation Combination of 0.5 mg RBZ and focal or grid laser.

Conclusion Intraocular injections of RBZ provided benefit for patients with DME for at least 2 years, and when combined with focal or grid laser treatments, the amount of residual edema was reduced, as were the frequency of injections needed to control edema.

DA VINCI STUDY

Objective To determine whether different doses and dosing regimens of intravitreal vascular endothelial growth factor (VEGF) Trap-Eye are superior to focal/grid photocoagulation in eyes with diabetic macular edema (DME).

Participant A total of 221 diabetic patients with clinically significant macular edema involving the central macula.
Conclusion Intravitreal VEGF Trap-Eye produced a statistically significant and clinically relevant improvement in visual acuity when compared with macular laser photocoagulation in patients with DME.

ANTI VEGF : INDIAN PERSPECTIVE

ARMD: FINANCIAL BURDEN WORLDWIDE

Yearly financial burden of age-related macular degeneration patients worldwide

LIMITATION OF ANTI-VEGF IN INDIA

Firstly, the treatment is invasive and involves intravitreal injection of these drugs. Secondly, multiple such treatments are required at four to six-week intervals for a period of two years. Thirdly and most importantly, most of these drugs are too expensive for the general masses and are unaffordable in developing nations.

ESTIMATED COST OF ANTI VEGF IN INDIA

Comparison of total estimated cost for different anti-vascular endothelial growth factor drugs

ANTI VEGF TREATMENT & INDIAN ECONOMY

The 60+ years age group is at risk for ARMD and constitutes 7.5% of the Indian population (75 million). About one million of them will suffer from ARMD (considering a 1.5% prevalence). Wet ARMD will constitute about 10% of these cases (0.1 million) and will require treatment. Considering that about 18 to 22% of the Indian population is below the poverty line, they cannot afford these treatments.
Source : http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2636001/

ANTI VEGF TREATMENT & INDIAN ECONOMY

Indias per capita income is a mere $720 (compared to $43740 of the United States). Hence, Indians cannot afford these treatments, unless costs are covered by insurance companies or sponsored by government agencies.

Source : http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2636001/

ALTERNATIVE FOR ARMD TREATMENT IN

INDIA Photodynamic Therapy with Verteporfin. Transpupillary Thermotherapy

*A single treatment with verteporfin costs approximately Rs. 65000 and required on an average 2 to 3 treatments.

Source : http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2636001/

THANK YOU