Researchers explore ways to enhance anti-VEGF therapy in AMD treatment

Pharmaceutical candidates in early-stage development target elements of the angiogenic cascade not covered by anti-VEGF injections.

Despite the success of intravitreal anti-VEGF therapy in treating age-related macular degeneration, serious concerns abound over the potential burden of repeated injections.

As greater understanding of the angiogenesis cascade leading to neovascularization secondary to AMD has emerged, researchers have taken a greater interest in potential combination therapies that might enhance the efficacy of anti-VEGF therapy.

Although still in the early stages of development, candidate drug therapies could offer the theoretical potential of enhancing anti-VEGF efficacy and, perhaps, leading to regression of choroidal neovascularization.

In continuing coverage of presentations from the Retinal Innovation Symposium in Newport Beach, Calif., which was sponsored in part by the Foundation Fighting Blindness, Ocular Surgery News offers a glimpse of what may be the next generation of therapeutics that defines treatment of retinal pathologies.

Boosting anti-VEGF therapy

Seminal studies conducted using anti-VEGF monotherapy — notably ANCHOR and MARINA, the two phase 3 pivotal trials that influenced the U.S. Food and Drug Administration in its review of Lucentis (ranibizumab, Genentech) — have demonstrated that the treatment is capable of inducing significant gains in visual acuity. However, in those studies, evidence emerged that anti-VEGF monotherapy does not result in regression of CNV.

There have been numerous attempts to refine how frequently anti-VEGF therapy should be re-administered; ANCHOR and MARINA employed monthly dosing paradigms while later studies have explored as-needed therapy and various treat-and-extend paradigms. Although improvement in visual acuity is possible with potentially fewer doses, the ability to eradicate CNV remains elusive. As a result, while anti-VEGF therapy is the current gold standard for wet AMD, it results in a three-line or better improvement in visual acuity in only about one-third of patients and requires persistent drug administration.

One prominent theory about the persistence of CNV holds that expression of platelet-derived growth factor (PDGF) at the site of neovascularization results in the recruitment of pericytes. These biologically active cells then attach themselves to the CNV, and render the CNV less reponsive to anti-VEGF agents.

Researchers at Ophthotech are testing an anti-PDGF therapy, called E10030, in combination with ranibizumab. This approach utilizes E10030 to selectively strip the protective pericytes from the CNV lesion while simultaneously exposing the CNV to ranibizumab. CNV that is stripped of pericytes by E10030 is much more reliant on VEGF for cell survival signals and therefore inhibiting VEGF in this more immature, pericyte-free state may allow for true CNV regression.

“We believe that inhibiting PDGF, and thus pericyte activity, in combination with anti-VEGF therapy may result in true CNV regression. This may translate into an enhanced anti-permeability effect and ultimately improved visual outcomes. In addition, this combination approach may reduce the number of treatments required to maintain those positive outcomes,” Samir Patel, MD, co-founder, president and CEO of Ophthotech, said at the symposium.

In a phase 1 dose-escalation study in 22 patients with wet AMD who had received no prior therapy, visual acuity improved by a mean 14 letters at 12 weeks. Overall, 59% of patients in the study improved by three lines of vision or more and CNV size decreased an average of 86%.

Based on the results of that trial, Ophthotech launched a phase 2 randomized controlled trial of E10030 combined with ranibizumab. According to a press release from the company, the trial will eventually enroll 444 patients in the U.S., Europe and Latin America

Ophthotech is heavily invested in other therapeutic modalities that might augment anti-VEGF activity. Its proprietary complement factor 5 inhibitor, ARC1905, is currently in separate phase 1 trials in patients with the wet form and the dry form of AMD. Ophthotech is also supporting an ongoing phase 1 study of an alpha-5 beta-1 agonist, volociximab, that is thought to disrupt fibronectin-integrin interaction during angiogenesis.

Complement immune system

As researchers look for mechanisms to boost therapeutic results in treating AMD, the complement immune system has become a frequent target. Recently emerging evidence has suggested that components of the complement immune system, when activated, contribute to inflammation that is important in the development of both dry and wet forms of AMD. Notably, complement factors may contribute directly to cell death or recruit additional immune system agents that cause cell death.

When activated at the retina, complement factor 3 (C3) appears to trigger a series of cleavages, as well as the recruitment of other immune mediators, namely complement factor 5 (C5), that result in lysis of retinal pigment epithelium. Strong evidence has emerged that C3 and C5 can be found in retinal drusen, suggesting they play a role in drusen formation.

A drug candidate named POT-4 (Potentia Pharmaceuticals, Alcon) offers the potential to block C3, thereby effectively shutting down downstream activation of associated complement factors. A phase 1 study of POT-4 was completed in late 2008, demonstrating that the drug was well-tolerated, with minimal side effects believed to be associated with injection of the drug.

The study also produced enough of a biological signal to warrant further investigation. Since the completion of the study, Potentia Pharmaceuticals entered into a licensing agreement with Alcon that will transfer development rights. The agreement also contains language that will allow Alcon to purchase shares of Potentia if certain developmental milestones are achieved. – by Bryan Bechtel

• Samir Patel, MD, can be reached at Ophthotech, 5 Vaughn Drive, Suite 106, Princeton, NJ 08540; 609-945-6050; email: samir.patel@ophthotech.com.