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Good Morning

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Anti-VEGF Intravitreal Injections

Speaker: Dr.Ala’ Abu-FarsakhSupervised by : Dr. Wafa’ Al-Sakaji

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VEGF

• VEGF is a short form for Vascular Endothelial Growth Factor, which is responsible for growth of blood vessels. Besides having a role in normal vascular growth, VEGF is also responsible for many retinal diseases by causing new vessels growth and by increasing leakage and thus causing retinal swelling

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VEGF-A

• VEGF-A is a chemical signal that stimulates angiogenesis in a variety of diseases, especially in cancer. Bevacizumab was the first clinically available angiogenesis inhibitor in the United States

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Anti-VEGF

• The anti-VEGF agents block the VEGF molecules and thus benefit the patients by decreasing the abnormal and harmful new blood vessels formation and by decreasing the leakage and swelling of the retina.

• This leads to stabilization of vision and even improvement in vision in many cases.

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Anti-VEGF

• These agents are being used for many eye diseases, especially for :

• -wet form of AMD (Age related Macular Degeneration).• -CNVM (Choroidal Neo Vascular Membrane). -Severe Diabetic Retinopathy. -Macular Edema (swelling) -Vascular Blocks. -Neovascular Glaucoma (NVG). -Vitreous Hemorrhage, etc. These retinal diseases, which were earlier considered incurable,

or had very poor results with existing treatments are now being tackled with good results with these anti-VEGF agents.

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Anti-VEGF

• there are mainly three injections available with us for treatment.

• These are :

1-Lucentis (Ranibizumab) 2- Avastin (bevacizumab) 3-Macugen(pegaptanib)

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• Age Related Macular Degeneration (AMD)

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Choroidal/Sub-Retinal Neo-Vascular Membrane (CNVM/SRNVM

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Diabetic Macular Edema

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Evolution of Anti VEGF :

• Evolution of Anti VEGF Macugen (pegaptanib sodium, Eyetech/Pfizer), Off-label use of Avastin (bevacizumab, Genentech) ,Lucentis (ranibizumab, Genentech) That not only slowed vision loss or maintained current visual acuity, but also offered the potential to improve and even restore functional vision.

• Others :Anecorative acetate RNA interference, VEGF Trap

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Pegaptanib

• Pegaptanib sodium injection (brand name Macugen) is an anti-angiogenic medicine for the treatment of neovascular (wet) age-related macular degeneration (AMD).

• It was discovered by Gilead Sciences and licensed in 2000 to EyeTech Pharmaceuticals.

• Approval was granted by the U.S. Food and Drug Administration (FDA) in December 2004.

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Pegaptanib

• Pegaptanib is a anti-VEGF molecule, a single strand of nucleic acid that binds with specificity to a particular target. Pegaptanib specifically binds to VEGF 165, a protein that plays a critical role in angiogenesis (the formation of new blood vessels) and increased permeability (leakage from blood vessels), two of the primary pathological processes responsible for the vision loss associated with neovascular AMD.

• Pegaptanib is administered in a 0.3 mg dose once every 6 weeks by intravitreal injection.

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Safety profile of pegaptanib

• Results:• As in years 1 and 2, pegaptanib was well tolerated in year 3.

Adverse events were mainly ocular in nature, mild, transient and injection-related. Serious adverse events were rare. No evidence of systemic safety signals attributed to vascular endothelial growth factor inhibition arose in year 3. There were no findings in relation to vital signs or electrocardiogram results suggesting a relationship to pegaptanib treatment.

• Conclusion:• The 3-year safety profile of pegaptanib sodium was

favourable in patients with NV-AMD.

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Bevacizumab : Avastin

• Bevacizumab : • Bevacizumab Intravitreal bevacizumab (IVB)

(Avastin,Genentech) Humanized monoclonal antibody to all forms of VEGF- A .

• FDA-approved for adjunct intravenous antiangiogenic treatment of metastatic colorectal cancer in 2004. It was initially studied for the treatment of exudative AMD with intravenous delivery, with Promising results

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Bevacizumab : Avastin

• Bevacizumab binds directly to VEGF to form a protein complex which is incapable of further binding to VEGF receptor sites (which would initiate vessel growth) effectively reducing available VEGF.

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Bevacizumab : Avastin

• Bevacizumab has recently been used by ophthalmologists in an off-label use as an intravitreal agent in the treatment of proliferative (neovascular) eye diseases, particularly for choroidal neovascular membrane (CNV) in AMD. Although not currently approved by the FDA for such use, the injection of 1.25-2.5 mg of bevacizumab into the vitreous cavity has been performed without significant intraocular toxicity.

• Many retina specialists have noted impressive results in the setting of CNV, proliferative diabetic retinopathy, neovascular glaucoma, diabetic macular edema, retinopathy of prematurity and macular edema secondary to retinal vein occlusions.

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Avastin safety profile

• Can a drug for which a Food and Drug Administration (FDA) warning has been issued be safe? The question of safety using off label intravitreal bevacizumab (Avastin ‐Genentech, South San Francisco, California, USA; Roche AG, Basle, Switzerland) is a concern among ophthalmologists around the globe. This is one of the key aspects of The international intravitreal bevacizumab safety survey: using the internet to assess drug safety worldwide published by A Fung et al. Why else would 70 centres from 12 countries voluntarily report on >7000 injections in >5000 patients using an internet based questionnaire within just 6 ‐months?

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Ranibizumab : Lucentis

• Ranibizumab : • Ranibizumab During the same time period, intravitreal

ranibizumab (Lucentis, Genentech) A fab fragment of the bevacizumab humanized monoclonal antibody, was undergoing US FDA clinical trial testing for neovascular AMD in 2006 at 0.5mg intravitreally.

• Results from these clinical trials suggested that treatment of exudative AMD with Intravitreal ranibizumab was superior with rates of visual improvement not previously achieved to those reported in the pegaptanib phase III trials

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Ranibizumab : Lucentis

• trade name (Lucentis) is a monoclonal antibody fragment (Fab) derived from the same parent mouse antibody as bevacizumab (Avastin). It is much smaller than the parent molecule and has been affinity matured to provide stronger binding to VEGF-A.

• It is an anti-angiogenic that has been approved to treat the "wet" type of age-related macular degeneration (AMD, also ARMD), a common form of age-related vision loss.

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Ranibizumab : Lucentis

• Ranibizumab sells for $1,593 per dose, compared to bevacizumab, which can be prepared for macular degeneration treatment in doses that cost $42. Clinical trials have shown both to be equally effective; however there were some reports of infection after dividing bevacizumab into smaller doses.

• Ranibizumab was developed by Genentech and is marketed in the United States by Genentech and elsewhere by Novartis,under the brand name Lucentis.

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Ranibizumab : Lucentis

• Clinical Indications:• Wet ARMD• Central retinal vein occlusion• Diabetic Macular Edema

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Safety profile of ranibizumab :

• Safety profile of ranibizumab Serious ocular adverse events in 2 year MARINA study for ranibizumab 0.5 mg:

• Endophthalmitis – 1.3% • Uveitis – 1.3% .• Retinal tear – 0.4%• Lens damage – 0.4%

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Safety profile of ranibizumab :

• • Safety profile of ranibizumab Serious ocular

adverse events in 1 year ANCHOR study for ranibizumab 0.5 mg :

• Endophthalmitis – 1.4 %• Uveitis – 0.7% • There was no increase in systemic adverse

effects such as HTN, arterial thromboembolism in either study

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DRUG COSTS :

• DRUG COSTS:• Bevacizumab $ 45.00 • Ranibizumab $1594.92

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Avastin vs. Lucentis

• The primary pharmacokinetic difference between intraocular Bevacizumab and Ranibizumab is the very large difference in systemic half-lives, i.e. 2 hours for Ranibizumab versus 20 days for Bevacizumab.

• Since Bevacizumab was designed as a cancer treatment, the long systemic half-life is considered to be a positive feature (allowing greater exposure time of the tumor to the drug), while the same long half-life is a negative feature in intraocular treatment, since it has no benefit outside of the eye and may in fact be detrimental.

• Although the systemic exposure with both drugs is very low, Ranibizumab has a much lower average systemic exposure , so it may be has lesser chance of systemic adverse events.

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Avastin vs. Lucentis• The National Eye Institute (NEI) of the National Institutes of Health (NIH) announced

in October 2006 that it would fund a comparative study trial of ranibizumab (Lucentis) and bevacizumab (Avastin) to assess the relative safety and effectiveness in treating AMD.

• This study, called the Comparison of Age-Related Macular Degeneration Treatment Trials (CATT Study), enrolled about 1,200 patients with newly diagnosed wet AMD, randomly assigning the patients to one of four treatment groups.The CATT Study was conducted at 47 clinical sites throughout the United States, following the patients for 2 years.

• Initial results of the study showing essentially similar outcomes using either drug at one year were formally published after peer review in the New England Journal of Medicine on May 19, 2011.

• Similar results in this cohort were maintained at two years, with bevacizumab showing no inferiority to ranibizumab, although a statistically non-significant trend to improved visual outcomes from injections given monthly rather than as required was noted with both drugs

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Avastin vs lucentis• But, this same study(CATT) raised concerns that Avastin was NOT as safe at

Lucentis. The study showed a “number needed to harm” of 12 in favor of Lucentis. What this means is that for every 12 patients treated with Avastin instead of Lucentis, 1 would develop a bad systemic outcome. And that is a pretty scary number.

Here at Queen’s University, we studied more than 1,500 of our patients who received either drug. We found that patients who got an eye injection with Avastin were 12 times more likely to develop serious inflammation in the eye.

• We also noticed a trend towards the possibility of patients developing a stroke within 30 days of getting an eye injection with Avastin. In our(CATT) study this was NOT statistically significant but this concern was also noted in a large study of over 40,000 patients in the US which showed a 22% higher risk of stroke for those using Avastin. These are significant results.

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Anti-VEGF side effects

• Side effects:• The most common side effects in clinical trials were

conjunctival hemorrhage, eye pain, vitreous floaters, increased intraocular pressure, and intraocular inflammation.

• Although there is a theoretical risk for arterial thromboembolic events in patients receiving VEGF-inhibitors by intravitreal injection, the observed incidence rate was low (< 4%) and similar to that seen in patients randomized to placebo.(althought lesser also in ranibizumab)

• Serious adverse events related to the injection procedure occurred with an incidence rate of less than 1% and included endophthalmitis, retinal detachment, and traumatic cataracts.

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Elevated I.O.P

• In conclusion, Hoang and colleagues' study provides more evidence for potential sustained ocular hypertension after repeated anti-VEGF injections. Although it seems logical that this is more likely to occur in patients with preexisting glaucoma, this study did not find such a correlation; therefore, all patients should be monitored.

• Moreover, it is unclear whether the risk is the same with ranibizumab and bevacizumab, but sustained ocular hypertension can occur with either agent. Therefore, ophthalmologists -- especially those who administer these agents -- should be aware of this potential side effect and be ready to treat it accordingly.

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Eylea(Aflibercept)

• Eylea (aflibercept, Regeneron) just received FDA approval for treatment of Wet Macular Degeneration.(BAYER)

• Eylea works by a similar mechanism as Lucentis and Avastin (blocks Vascular Endothelial Growth Factor or VEGF). Instead of being an antibody to the VEGF molecule, it is a fusion protein consisting of portions of the receptors for the VEGF molecule (VEGFR-1, VEGFR-2), thereby binding and blocking VEGF.

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Eylea(Aflibercept) Indications

• EYLEA is indicated for the treatment of patients with:

• Neovascular (Wet) Age-Related Macular Degeneration (AMD)

• Macular Edema Following Central Retinal Vein Occlusion (CRVO)

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Eylea(Aflibercept) Indications

• Neovascular (Wet) Age-Related Macular Degeneration (AMD)

• The recommended dose for EYLEA is 2 mg (0.05 mL or 50 microliters) administered by intravitreal injection every 4 weeks (monthly) for the first 12 weeks (3 months), followed by 2 mg (0.05 mL) via intravitreal injection once every 8 weeks (2 months).

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Eylea(Aflibercept) Indications

• Macular Edema Following Central Retinal Vein Occlusion (CRVO)

• The recommended dose for EYLEA is 2 mg (0.05 mL or 50 microliters) administered by intravitreal injection once every 4 weeks (monthly

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Eylea(Aflibercept)

• BOTTOM LINE: Eylea is a new drug mainly for Wet AMD that may be helpful in patients that do not completely respond to Lucentis and Avastin. It has the potential of lasting effect longer than Lucentis and Avastin, but so far the evidence is not terribly strong and the visual acuity results are not different.

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Thank You