الفهرس 
Vascular Endothelium Growth Factor (VEGFOnly 14 pages are availabe for public view
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Abstract
Vascular Endothelium Growth Factor (VEGF) is the key signal used by oxygen-hungry cells to promote growth of blood vessels. It binds to specialized receptors on the surfaces of endothelial cells and directs them to build new vessels creating a new path for blood to flow. This is the process used for designing treatment of excessive or pathological angiogenesis. By selectively inhibiting the growth of new blood vessels, cells can be starved and controlled. Using drugs to block the formation of VEGF or the binding of VEGF to its receptors is used now effectively in treatment in many eye diseases (ANTI -VEGF drugs).
Anti-VEGFs could be endogenous, dietary or exogenous factors. The exogenous are different group of drugs including chemically synthesized short strands of RNA (aptamers) such as pegaptanib sodium, monoclonal antibodies such as bevacizumab, antibody derivatives such as ranibizumab.
There are different strategies for inhibiting VEGF pathway. The two primary strategies include inhibiting either the VEGF ligand (ligand antibodies or soluble receptors) or the VEGF receptor (tyrosine kinase inhibitors) or receptor antibodies.
In Ophthalmology the most commonly used anti-VEGFs are Macugen, (pegaptanib sodium), Avastin (bevacizumab) and Lucentis (ranibizumab sodium). Avastin is not FDA approved for ophthalmic use.
The most commonly eye diseases in which VEGF and anti- VEGFs have significant roles are age related macular degeneration, myopic choroidal neovascularization, proliferative diabetic retinopathy, diabetic macular edema, retinal vein occlusion, corneal neovascularization, trachoma, neovascular glaucoma and pterygium.
Bevacizumab vs. Ranibizumab vs. Pegaptanib:
These three available anti-VEGF medications were not introduced at the same time, nor are used with the same frequency.
Avastin (bevacizumab) entered the market first. Its particle is too big to penetrate the retina and it was never designed for intravitreal injection. The drug is not approved for ophthalmic use.
The drug remains the most commonly used anti-VEGF because of availability, efficacy and cost. Most people started off with Avastin, and because of its cost and the possibility of dividing one vial into multiple patients, treatment became affordable and the results were satisfactory.
Next, Macugen (pegaptanib sodium,) was introduced. It is an oligonucleotide (aptamer) which binds to extra-cellular VEGF, inhibiting its binding to VEGF receptors and suppressing pathological angiogenesis.
The drug was approved in (2004) for treatment of neovascular AMD, given by intravitreal injection, but it failed to gain popularity. Although this was shown to decrease the risk of vision loss significantly compared to no treatment, it is felt to be relatively ineffective compared to the newer treatments
Lastly, Lucentis (ranibizumab) entered the market at the end of 2006. Unlike bevacizumab, it is approved for treating ocular conditions.
Ranibizumab (Lucentis®), is a recombinant humanized monoclonal antibody that binds (VEGF-A), and prevents their interaction with its receptors (VEGFR-1, VEGFR-2), inhibiting angiogenesis, and vascular leakage in the retina.
The drug was approved in (2006) for treatment of neovascular AMD, as an intravitreal injection once a month for three months, followed by a monthly monitoring. It is re-administered if a patient loses more than five letters visual acuity.
Definitely, the drugs have changed since Lucentis came in because it was an approved drug, and can be used more formally. whereas every time Avastin is used, the ophthalmologist has to explain to a patient that it is an unapproved drug. But the patients who can’t afford Lucentis don’t care about label (off-label use).
Of all the anti-Age Related Macular Degeneration options available today, Lucentis, on the strength of the MARINA and ANCHOR trials, scores over all the other approved therapies, in terms of efficacy. Despite its proved efficacy, its cost can be an obstacle for regular use.
Repeated injections and follow-up with Lucentis are challenging because of the cost. It is better to explain to the patient all the available treatment options and the associated costs and allow the patient to choose.
Because of the life threatening adverse events such as stroke and heart attack which might occur with use of Avastin, the FDA has issued a caution concerning Avastin prohibiting the use of Avastine in certain conditions.
Lucentis is the first drug proven in clinical trials to maintain and improve vision in patients with predominantly classic CNV secondary to AMD. Vision improvement with Lucentis treatment increases the ability of patients. It offers patients the possibility to gain some vision and independence by restoring the ability to perform everyday activities.
The pivotal studies used in the regulatory submissions for Lucentis showed a remarkable response among wet
AMD patients. Approximately 95% of Lucentis-treated patients maintained their vision; More than 68% of Lucentis-treated patients gained some vision. To date, this gain in vision has been sustained at two years with monthly Lucentis treatment.
The large MARINA and ANCHOR trials, and now the SAILOR follow-up study, confirm that Lucentis is safe and effective for neovascular AMD. The risk at the 0.5mg dose would seem quite small and balanced by the large vision benefit.
Genentech Pharmaceuticals (the manufacturer of both Lucentis and Avastin) has refused to sponsor a head to head trial comparing the two drugs.
The National Eye Institute is sponsoring the Comparison of AMD Treatment Trials Study (CATT Study), a multicenter, randomized, double-masked, clinical trial designed to assess the efficacy of bevacizumab compared to ranibizumab therapy and will be conducted in 44 clinical centers throughout the United States. Early results are expected in 2011
Lucentis Clinical Trials
FOCUS: It is a Phase I/II randomized, single-masked study evaluating the safety, tolerability and efficacy of Lucentis in combination with Photodynamic Therapy (PDT) in 162 patients with predominantly classic subfoveal wet AMD. In this study, patients were randomized 2:1 to receive (PDT) followed by either 0.5 mg injections of Lucentis or sham injections for 23 months.
MARINA: It is Phase III, multicenter, randomized, double-masked, sham-injection-controlled study to investigate the efficacy and safety of Lucentis in 716 patients diagnosed with minimally classic or occult with no classic choroidal neo-vascularization secondary to AMD. Patients received
monthly intravitreal injections of Lucentis 0.3mg or 0.5mg or sham injections.
ANCHOR: A study to use Anti-VEGF Antibody for treatment of predominantly classic CNV in AMD. It is a randomized, multicenter, double masked, active treatment controlled Phase III study comparing two different doses of Lucentis to PDT in 423 patients.
PIER: A Phase IIIb, multicenter, randomized, double-Masked, sham injection-controlled study of the efficacy and safety of Lucentis in 187 subjects with subfoveal choroidal neovascularization with or without classic CNV secondary to AMD. In this trial, Lucentis is administered monthly for three doses followed by doses once every three months for two years.
SAILOR: A larger study recruiting patients to evaluate the safety of the two different dosages of Lucentis. The SAILOR study was a phase IIIb follow-up study to the MARINA and ANCHOR studies to evaluate the long-term safety and efficacy of Lucentis in a large population of patients with all subtypes of neovascular AMD.
BRAVO: The phase 3 BRAVO study, was a multicenter, study to evaluate the safety and efficacy of 6 monthly injections of Lucentis compared to monthly sham (control) injections in patients with macular edema due to BRVO. Patients treated with the two doses of Lucentis (0.3mg or 0.5mg) showed a statistically significant improvement in BCVA at 6 months compared to control treatments. The BRAVO results in RVO are milestone for anti angiogenic therapy.
CRUISE: Is another phase III trial of Lucentis for CRVO. It is expected to be completed later this year.
RAVE (Rubeosis Anti-VEGF): It is an ongoing one year, FDA phase open label clinical trial designed to test the
safety and efficacy of nine monthly Lucentis injection of 0.5 mg in ischemic CRVO.
The improvement seen in this small trial may imply the macular edema present in ischemic CRVO is mediated in large part by VEGF. While the intermediate results of Lucentis in ischemic CRVO are encouraging, longer-term follow-up to determine if neo-vessels develops at a later time point is required.
Further studies are needed in order to elucidate the role of intravitreal Lucentis in the ischemic form of CRVO, and its efficacy in preventing conversion from the perfused to the ischemic form of the disease.
IN THIS STUDY
Ranibizumab (Lucentis) has been reviewed as regarding its Development, Pharmacology and Mechanism.
Preclinical Studies, Lucentis Phase I/ II Preparatory Studies, Lucentis Phase III Efficacy studies, and Lucentis Phase III Safety Studies have been overlooked.
Lucentis Phase III Patient Reported Outcomes and some Studies involving the use of Lucentis in Ocular diseases have been discussed.