THERAPY LIMITATIONS

Agents that block the activity of platelet derived growth factor (PDGF) offer a new front in the battle against age-related macular degeneration (AMD). Ongoing clinical trials suggest this approach could help overcome some of the limitations of current anti-VEGF therapy, Donald J D’Amico MD told a session of the World Ophthalmology Congress in Tokyo.

While there is no doubt that treatment of exudative AMD with anti-VEGF agents including ranibizumab (Lucentis) and bevacizumab (Avastin) has provided considerable benefits, recent follow-up studies indicate that the effects of these agents can diminish over time, noted Dr D’Amico, professor and chairman of ophthalmology at Weill Cornell Medical
College and ophthalmologist-in-chief at the New York Presbyterian Hospital.

He cited two studies in particular to support his point. The Seven Up study (Ophthalmology, 2013 Nov;120(11):2292-9.) looked at long-term outcomes seven to eight years after initiation of intensive ranibizumab therapy from three well-known clinical trials, ANCHOR, MARINA and HORIZON. Patients tended to show marked improvement in the initial three- or four-month treatment period, followed by a plateau effect. The study found that after long-term anti-VEGF therapy, a significant percentage of patients had regressed with poor visual outcomes.

Flexible treatment schedule

The SECURE study (Ophthalmology. 2013;120(1):130-139) also looked at long-term results of treatment with ranibizumab. That study followed more than 200 patients for two years who received ranibizumab on a flexible treatment schedule. In that study, patients also showed improvements in the beginning stages, then tended to lose best-corrected visual acuity over the longer term.

These and related findings have given rise to the concept of anti-VEGF resistance. Cancer researchers first reported this phenomenon more than 10 years ago. Research implicates pericytes, cells that produce vascular endothelial growth factor to proliferating endothelial cells, as an important factor in anti-VEGF resistance. PDGF in turn drives the recruitment of pericytes.

It now appears that drugs that inhibit PDGF could help reduce neovascularisation, particularly when administered with anti-VEGF agents, said
Dr D’Amico.

An international Phase II randomised, double blind study compared the efficacy of ranibizumab alone versus ranibizumab plus a platelet derived growth factor inhibitor, Fovista (Ophthotech). Patients receiving the combination showed statistically significant clinical responses compared to those receiving ranibizumab alone. In particular, patients in the combination groups showed a mean gain of 10.6 letters from baseline, compared with 6.5 letters for those on monotherapy. Fovista was well tolerated, with no
safety concerns.

The hope is that such combined therapy approaches could help to overcome limitations of current therapy, extending the duration of effect and even creating the conditions for regression of choroidal neovascularisation, he noted.

Clinical trials

A Phase III study of ranibizumab/Fovista combination therapy is now under way. Initial results from that study could appear as early as 2016. The company also announced clinical trials with Fovista in combination with bevacizumab, and Fovista in combination with aflibercept (Eylea, Regeneron). Regeneron, for its part, is reported to be collaborating with Bayer to develop its own PDGF-inhibitor for possible combination therapy
with aflibercept.

Ophthotech has another drug in development, Zimura, that is designed to interrupt the macular disease process at another step in the disease process, complement-mediated inflammatory component. The new compound is a chemically synthesised aptamer that inhibits complement factor C5, a central component of the complement cascade believed to be involved in the development of AMD.

Improvements in visual acuity

In a Phase II clinical trial that combined Zimura and anti-VEGF treatment, treatment naïve patients showed improvements in visual acuity throughout the 24-week study. Additional clinical trials are planned to evaluate the complement inhibitor in the treatment of geographic atrophy, and in patients with anti-VEGF resistant exudative AMD.

Ophthotech announced recently that the company would collaborate with Novartis to develop Fovista commercially. Novartis will provide as much as $1bn dollars to support clinical development and clinical trials of the drug. If and when the drug gains regulatory approval, Novartis would have the right to market the drug outside of the US, while Ophthotech would retain American marketing rights.

Donald J D’Amico: djd2003@med.cornell.edu