These two drugs emerged from the promising technological platforms of monoclonal antibodies.

Technology platforms of monoclonal antibodies are promising and allow the development of many new drugs, given the ease to develop drugs for mediators or receptors that were previously identified.

Current conditions for these drugs are exposed in the corresponding chapter.

Future prospects about their use in AMD are essentially made by process innovation, with adoption of optimized therapeutic schemes of combined therapy and improvement of intra-eye drug delivery.

Aptamers are oligonucleotide ligands that are selected for their high-affinity to bind molecular targets.

Pegaptanib sodium (Macugen^®; Eyetech Pharmaceuticals/Pfizer) is an RNA Aptamer directed against vascular endothelial growth factor (VEGF)-165, the VEGF isoform primarily responsible for pathological ocular neovascularization and vascular permeability.

“Pegaptanib therefore has the notable distinction of being the first aptamer therapeutic approved for use in humans, paving the way for future aptamer applications.”⁽¹⁾

Like the use of Lucentis^® and Avastin^® future prospects with the use of Macugen^® are essentially made by process innovation, with adoption of optimized therapeutic schemes of combined therapy.

The aflibercept, VEGF-Trap, results of a process of bioengineering where extramembrane fragments of receptors 1 and 2 of VEGF are merged to IgG1 FC fragment.

This recombinant fusion protein is a composite decoy receptor based on VEGF receptors VEGFR1 and VEGFR2.

The VEGF Trap (Regeneron Pharmaceuticals, Tarrytown, NY, USA) is an 110kDa soluble recombinant protein with the binding portions of VEGF receptor 1 and 2 fused to the Fc region of human IgG that binds all VEGF isoforms with a very high affinity (about 140 times that one of ranibizumab).

Aflibercept is a fully human soluble fusion protein that binds all forms of VEGF-A along with the related Placental Growth Factor (PlGF)⁽²⁾.

This high affinity fusion protein is used to block the biological activities of VEGF by preventing it to bind to its receptors.

VEGF-Trap effectively suppresses tumor growth and vascularization in vivo⁽³⁾.

In phase I, randomized, placebo-controlled trial of VEGF Trap administered intravenously for treatment of choroidal neovascularization, the Clinical Evaluation of Antiangiogenesis in the Retina (CLEAR)-AMD 1 group found a dose-dependent increase in systemic blood pressure with a maximum tolerated dose of 1mg/kg.

This dose resulted in the elimination of about 60% of excess retinal thickness after either single or multiple administrations.

CLEAR IT-1 was a phase I dose escalation study of a single intravitreal injection of various doses of VEGF Trap (0.05, 0.15, 0.5, 1, 2, and 4mg)⁽⁴⁾.

At 6 weeks, mean visual acuity gain was 4.8 letters and mean OCT central retinal thickness decreased from 298μm to 208μm across all groups.

Higher doses resulted in gaining more letters.

The potential benefit of VEGF Trap is its longer duration of action compared with single injections of other anti-VEGF agents because of its higher affinity and longer intravitreal half-life.

It seems that VEGF Trap would offer less frequent dosing resulting in fewer injections, lower cost and reduced risk of complications⁽⁵⁾.

From August 2007 it’s initiated a phase III global development program for VEGF Trap-Eye in wet AMD.

During the first year of the two phase III trials, the companies (Regeneron Pharmaceuticals, Inc. and Bayer HealthCare AG ) are evaluating VEGF Trap-Eye dosed 0.5 mg every 4 weeks, 2 mg every 4 weeks, or 2 mg every 8 weeks (following three monthly doses) in direct comparison with ranibizumab (Lucentis^® Genentech, Inc.) administered 0.5 mg every 4 weeks according to its U.S. label.

PRN dosing will be evaluated during the second year of each study.

Currently phase III clinical trials, VIEW 1 and 2 study will assess its efficacy and safety in patients with neovascular AMD.

The VIEW1 study (in the United States and Canada) and the VIEW2 study (in Europe, Asia Pacific, Japan, and Latin America)^(6,7) enrolled 1200 patients.

Despite Bevasiranib has been discontinued it’s worth mentioning because it was the first therapy based on the Nobel Prize-winning RNA interference (RNAi) technology to advance to phase III clinical trials.

Bevasiranib was a first-in-class small interfering RNA (siRNA) drug designed to silence the genes that produce vascular endothelial growth factor (VEGF).

“The decision to conclude the clinical program follows a review of preliminary trial data by the Independent Data Monitoring Committee, which found that although Bevasiranib showed activity when used in conjunction with Lucentis^® (ranibizumab, Genentech), the trial was unlikely to meet its primary endpoint.”⁽⁸⁾

The trial was COBALT for “Combination of Bevasiranib and Lucentis^® Therapies” for AMD.

It was a phase III, randomized, double-blinded, parallel-assignment study of the RNAi drug administered either every 8 or 12 weeks as a maintenance therapy following three injections of Lucentis^®(9).

It is a siRNA, 19 nucleotides in length, that inhibits the expression of the hypoxia-inductible gene RTP801.

This stress-response gene mediates the mammalian target of rapamycin (mTOR) pathway.

PF-04523655 has been shown to reduce the volume of choroidal neovascularization in a mouse model.

PF-04523655 has been shown to cause regression of CNV in experimental studies of mice and primates.

Intravitreal small-interfering RNA (siRNA) PF-04523655 (Quark; licensed to Pfizer) used to treat choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD) seems to be safe and well tolerated in an interim phase I analysis.

“No adverse events were observed up to the 3,000-µg dose”⁽¹⁰⁾.

Allergan has halted development of its siRNA-based wet age-related macular degeneration, Sirna-027 is the first chemically modified short interfering RNA (siRNA) targeting Vascular Endothelial Growth Factor Receptor-1 (VEGFR-1).

VEGFR-1 is found primarily on vascular endothelial cells and is stimulated by both VEGF and placental growth factor (PlGF), resulting in the growth of new blood vessels⁽¹¹⁾.

By targeting VEGFR-1, Sirna-027 is designed to reduce pathologic angiogenesis mediated by both VEGF and PlGF.

Development was halted for AGN-745 after the drug failed to meet a key efficacy endpoint in a phase II study.

The trial compared the effect of three different monthly doses of AGN-745 with Genentech’s antibody drug Lucentis^®, the standard of care for AMD, in treating the subfoveal choroidal neovascularization associated with the disease.

Both drugs were administered via intravitreal injection⁽¹²⁾.

Apparently no safety issues were associated with AGN-745, a chemically modified siRNA.

But since the drug did “not meet its efficacy hurdle” — improvement in visual acuity — Allergan opted to halt its development⁽¹³⁾.