3. 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
3
4. 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
4
5. 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.
5
6. 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-VEGF6
7. Anti-VEGF
• there are mainly three injections available
with us for treatment.
• These are :
1-Lucentis (Ranibizumab)
2- Avastin (bevacizumab)
3-Macugen(pegaptanib)
7
11. 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
11
12. 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.
12
13. 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.
13
14. 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.
14
15. 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
15
16. 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.
16
17. 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.
17
18. 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?
18
19. 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
19
20. 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.
20
21. 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.
21
23. 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%
23
24. 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
24
25. DRUG COSTS :
• DRUG COSTS:
• Bevacizumab $ 45.00
• Ranibizumab $1594.92
25
26. 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.
26
27. 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
27
28. 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.
28
29. 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.
29
30. 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.
30
31. 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.
31
32. 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)
32
33. 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).
33
34. 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
34
35. 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.
35
