Download Anti VEGF Agents in Retinal Disorders – Current Scenario

Retina
5HWLQD
Anti VEGF Agents in Retinal
Disorders – Current Scenario
Charu
Ch
h
Gupta
G t
MS
Charu Gupta MS, Cyrus M. Shroff MD
Shroff Eye Centre, New Delhi
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is a group of proteins involved in the regulation
of angiogenesis, lymphangiogenesis and vascular
permeability.
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Blinding complications of retinal diseases like neovascular
age related macular degeneration, diabetic retinopathy,
vascular occlusions are mainly due to pathologic ocular
angiogenesis. There was a major breakthrough by Ferrara
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$" "" <' neovascularization1.
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agents for treatment of retinal diseases like neovascular
age related macular degeneration, diabetic retinopathy,
vascular occlusions has become the gold standard and has
shown good results. With widespread availability and usage
it is important to use these agents safely and judiciously.
Properties of VEGF
1. Stimulates angiogenesis
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factor
3. Increases vascular permeability
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5. Neuroprotective action
Pathological role of VEGF
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psoriasis and rheumatoid arthritis. In the eye, it has a major
role in most of the pathologic angiogenic conditions like:
Anti-VEGF agents
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Anti-VEGF agents in retinal disorders
<ZJ> " " ! # various ocular conditions2,3. The most common indications
presently are:
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Anti VEGF agents in Age related macular
degeneration
Indications
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classic, minimally classic and occult lesions.
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3. Extrafoveal lesions in combination with thermal laser
treatment.
www. dosonline.org l 33
Retina: Anti VEGF Agents in Retinal Disorders – Current Scenario
Pretreatment ( 5/60, N36)
Post anti VEGF Monotherapy (6/12, N8)
Figure 1: Pretreatment and Posttreatment FFA and OCT of a patient with predominantly classic CNVM. Patient received loading dose of
Anti VEGF injection followed by 2 more injections on a PRN basis. Patient has been subsequently stable for 2 years after last injection
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antibody Ranibizumab In the treatment of Neovascular
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of predominantly Classic CHORoidal Neovasularization
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of patients lost fewer than 15 letters of visual acuity when
treated with ranibizumab compared with approximately
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one third of patients treated with ranibizumab improved
vision by gaining 15 or more letters compared with 5% of
controls2,4,5.
Treatment Protocol
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was the standard treatment protocol. It undoubtedly was
! # ! X a very happy situation for both the doctor and patient.
34 l DOS Times - Vol. 20, No. 5 November, 2014
Trials were then conducted to see if the frequency of
injection can be reduced with minimal or no compromise
(P 6 and Treat and Extend7
regimen have been designed to work out dosing schedules
for ranibizumab so that a lesser number of injections are
required in the maintenance phase without losing out on
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Based on clinical trials and the experience of treating retinal
physicians an initial loading dose – monthly injections for
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PrONTO trial
Optical coherence tomography (OCT) is able to
accurately detect the earliest manifestations of recurrent
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increased retinal thickening, appearance of intraretinal
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then evaluated at monthly intervals using OCT for signs
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within the macula. In the 37 patients who completed the
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in visual acuity score was 10.7 letters. Baseline vision was
maintained by 78% of patients, and improved by 15 letters
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but with the mean frequency of dosing reduced by more
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Treat and Extend Regimen (TER)
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injections until the signs of exudation have resolved with
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The treatment interval is then sequentially lengthened by
1 to 2 weeks, as long as there are no signs of recurrent
exudation, till a maximum of 12 weeks. When recurrent
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the treatment interval is again extended as explained above.
The Treat and Extend regimen demonstrated favorable
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after initial loading dose to maintain visual gain seen in
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(Figure 1).
Follow up
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those situations a decision is often taken to combine the
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Anti VEGF agents in CNVM due to other pathologies
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associated with
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These patients usually do not require a loading dose and
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plays an important role in an accurate diagnosis and follow
up of the pathology.
Anti VEGF agents in Diabetic retinopathy
Indications
1. Diabetic macular edema – often followed up
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diabetic retinopathy
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glaucoma.
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It is important to rule out any retinal traction prior to
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: /--€ !# cases of diabetic retinopathy. In cases of active proliferative
diabetic retinopathy or iris neovascularization he found
a rapid response to intravitreal bevacizumab8. Though
the biologic effect is transient, bevacizumab, may have
an adjunctive role with pan retinal photocoagulation in
cases with severe neovascularization and macular edema.
Furthermore, they found that preoperative administration
of intravitreal bevacizumab in severe cases of proliferative
$ $! " causing an involution of vessels.
Ranibizumab and bevacizumab, have both been found
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visual acuity and reducing macular thickness, in a series
of randomized and non randomized trials. Recent reports
from contolled clinical trials: Read trial (Ranibizumab
for Edema of the Macula in Diabetes), Resolve trial
(Ranibizumab in Diabetic Macular Edema with Center
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Retina: Anti VEGF Agents in Retinal Disorders – Current Scenario
Diabetic macular Edema) have all found ranibizumab
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acuity and reducing macular thickness9,10. Results of the
phase III Restore trial showed that Ranibizumab alone and
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`/-LA- @!} # `//€¡ 53%, respectively) and ranibizumab + laser (22.9% and
44.9%) versus laser alone (8.2% and 23.6%).
BRAVO and Cruise trial
Treatment Protocol
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X ranibizumab injection compared with sham in patients
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month 6 was 12.7 letters in patients who received 0.3 mg
ranibizumab, 14.9 letters in patients who received 0.5 mg
ranibizumab, and 0.8 letters in those who received sham
injections.
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standardized. Complete metabolic workup with emphasis
on good control of blood sugar levels, blood pressure and
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and OCT is done to plan out treatment and prognosticate.
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patients to check for regression of vessels or if there is a
clinical suspicion of a new vessel developing.
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injections monthly to dry the macula and then focal laser
photocoagulation is added. If macular edema recurs
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laser sitting. In cases with massive macular edema or
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intravitreal corticosteroids if there is no contraindication to
the latter.
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Retinal venous occlusions
Indications
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but with documented increase in macular edema.
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36 l DOS Times - Vol. 20, No. 5 November, 2014
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In 397 patients randomized, the mean gain from baseline
at month 6 was 16.6 letters in patients receiving 0.3 mg of
ranibizumab, 18.3 letters in those receiving 0.5 mg, and
7.3 letters in those receiving sham injection.
Treatment Protocol
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resolution of the macular edema which is predominantly
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issue so very often multiple injections are required.
Thorough systemic workup of the patient especially the
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edema and retinal perfusion status periodically.
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schedules. In practice, most physicians will probably give
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basis can be extended past 3 months without recurrence
of edema, the physician will know the treatment can be
stopped because there is no active drug in the eye after 3
months.
In patients with persistent edema, however, treatment
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decide to add grid or sector laser photocoagulation. When
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be applied more precisely and at lower power in retinal
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is added if any neovascularisation develops and quite often
earlier if extensive capillary nonperfusion are seen, though
there is no study to validate this.
Post Avastin Endophthalmitis
VEGF Trap (Aflibercept)
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# `/8 } # # # compared to ranibizumab12.
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respectively. 94% and 95% of patients treated with 2mg
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as did 94% of patients treated with ranibizumab. In an
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from baseline was +8.4 letters at week 52 and +7.6 letters
at week 96 with a mean 11.2 injections over the 2 years
of study, including 4.2 injections in year 2. In eyes treated
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baseline was +8.7 letters at week 52 and +7.9 letters at
week 96, with a mean of 16.5 injections over the two years
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result was also good.
Decreased frequency of treatment while retaining the safety
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approved. The recommended dose is 2.0mg every 8 weeks
after an induction period of 3 monthly injections.
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group (n=35, 1.9 percent) compared with the ranibizumab
group (n=2, 0.3 percent) and that the magnitude of this
difference was especially noticeable when analyzing the
oldest pool of patients. This could be attributed to the
longer systemic half life.
Potential side effects and problems
<ZJ> " " " $# management of macular degeneration, diabetic retinopathy
and venous occlusive disease but ocular and systemic
safety concerns do exist.
Figure 2: Photo showing a patient with endophthalmitis who
presented 3 days Post intravitreal Anti VEGF injection.
Ocular
Endophthalmitis is a concern in any intravitreal procedure.
Multiple large retrospective studies have demonstrated an
incidence of one out of every 5,000 injections (0.02%).
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virulent Streptococcal species as the causative organism.
Severe eye pain, with or without decreased vision, in the
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# * _* " ! most common ocular signs (Figure 2). Early vitrectomy is
usually advisable.
Strict injection protocol with prepping of ocular surface
with povidone iodine is advocated worldwide. In the
Indian scenario, administration of injection in the operation
theatre under aseptic measures with pre and post injection
antibiotics is preferred.
The paucity of compounding pharmacies in India and
# _ practice of multiple use vials. There is also a potential risk
for contamination of bevacizumab during the aliquoting
process, during transportation from the pharmacy to the
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deviation from established protocols has led to widespread
contamination of bevacizumab lots. It is important for
physicians to become aware of their supplying pharmacy’s
procedures for the above and check with them regularly to
www. dosonline.org l 37
Retina: Anti VEGF Agents in Retinal Disorders – Current Scenario
$$$#$<$!@
should be used within 2 weeks.
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"$""#_##
(trace to 1+) as compared to the sham or photodynamic
therapy group. Transient increase in intraocular pressure,
post injection, was seen with all the drugs. The intraocular
pressure usually returned to normal within a week.
Sustained elevations in intraocular pressure elevation
occurs in 3.5 percent to 11 percent of patients receiving
ZJ> " retinal detachment have been reported.
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one cause of decreased vision in patients undergoing
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patients with unusually large (i.e., tall) pigment epithelial
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Systemic
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(bevacizumab) given to patients with colorectal cancer,
can lead to life threatening complications such as gastro
intestinal perforation, wound healing complication,
haemorrhage, arterial thromboembolic events (stroke or
heart attack), hypertension, proteinuria and congestive
heart failure. However, patient receiving bevacizumab
for eye conditions are healthier than cancer patients and
receive a tiny fraction of the dose which is administered
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in these studies. However, there is compelling clinical trial
subgroup analysis and pharmacokinetic data pointing to
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drugs.
;< * ! " serious adverse events associated with bevacizumab
compared with ranibizumab even though there was no
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recently demonstrated in their pharmacokinetic study
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that ranibizumab has a lower systemic exposure due
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accumulation, while ranibizumab did not.
38 l DOS Times - Vol. 20, No. 5 November, 2014
Clinical trials designed to answer this question will have to
#+-*---$
powered to detect a meaningful difference for these rare
events.
High risk groups
+ <"{"=8
2. History of stroke
3. Recent cardiovascular intervention
4. Diabetics with
proteinuria
uncontrolled
hypertension
and
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dose (0.3mg) of Ranibizumab is preferred.
Future trends
The future of treatment of neovascular disease lies in
making a drug or a combination of them which are effective
with no short term or long term safety concerns and easily
administered. Ocuserts and pellets for sustained release of
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done for steroids.
References
1.
Ferrara N, Houck K, Jakeman L, Leung DW. Molecular and biological
properties of the vascular growth factor family of proteins. Endocr
Rev 1992;13:18-32.
2. Heier JS. Treatment of neovascular age-related macular degeneration
with ranibizumab. In: Peyman GA, Meffert SA, Conway MD (eds):
Vitreoretinal Surgical Techniques. Informa UK Ltd, 2007; 652-57.
3. Avery RL,Pieramici DJ. Bevacizumab in the treatment of ocular
disease. In: Peyman GA,Meffert SA,Conway MD (eds): Vitreoretinal
Surgical Techniques. Informa UK Ltd, 2007; 658-65.
4. Rosenfeld PJ, Brown DM, Heier JS, et al. Ranibizumab for
Neovascular Age-Related Macular Degeneration. N Engl J Med
2006;355:1419-31.
5. Brown DM, Kaiser PK, Michels M, et al. Ranibizumab versus
*
‚"!`[^`
‚
Engl J Med 2006;355:1432-44.
6. Lalwani GA, Rosenfeld PJ, Fung AE, et al. A variable-dosing regimen
with intravitreal ranibizumab (Lucentis) for neovascularage-related
macular degeneration: year two of the PrONTO Study. Am J
Ophthalmol 2009;148:43–58.
7. Gupta OP, Shienbaum G, Patel AH, et al. A Treat and Extend
Regimen Using Ranibizumab for Neovascular Age-Related Macular
Degeneration -Clinical and Economic Impact. Ophthalmology
2010;117:2134–40.
8. Avery RL, Pieramici DS, Rabena MD et al. Intravitreal bevacizumab
in the treatment of proliferative diabetic retinopathy. Ophthalmology
2006;113:363-71.
9. Nguyen QD, Shah SM, Khwaja AA, et al Two-Year Outcomes of the
Ranibizumab for Edema of the mAcula in Diabetes (READ-2) Study.
Ophthalmology 2010;117:2146–51.
10. Mitchell P, Bandello F, Schmidt-Erfurth U, et al. The RESTORE
study: ranibizumab monotherapy or combined with laser versus
laser monotherapy for diabetic macular edema. Ophthalmology.
2011;4:615-25.
^
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`!„{!
`
` " †
_"‡_ edema from central vein occlusion. Ophthalmic Surg Lasers Imaging
2005;36:336-9.
12. Bayer Healthcare and Regeneron initiate phase 3 global
development. www.viva.vita.bayer healthcare.com.