AMD Combination Therapy Disappoints in Phase 3

Article

The billion-dollar combination of pegpleranib and ranibizumab failed to meet primary endpoints in studies for the treatment of age-related macular degeneration.

Pegpleranib (Fovista/Ophthotech) failed to significantly improve upon ranibizumab’s (Lucentis/Genentech) results when the two were combined, pharmaceutical giant Novartis announced yesterday. Novartis holds the rights to market the two age-related macular degeneration (AMD) treatments outside of the United States.

Ophthotech sponsored the studies, OPH1002 and OPH1003. Differences in best corrected visual acuity (BCVA) were the primary metric. The randomized, double-blind clinical trial studies followed over 1,200 combined patients for the course of a year, comparing safety and efficacy of pegpleranib 1.5mg in combination with ranibizumab versus ranibizumab monotherapy in patients 50 years old or older with neovascular AMD.

At month 12, separation between the two treatment courses was marginal-to-nonexistent. Patients in the combination group showed BCVA improvements of 10.74 and 9.91 in OPH 1002 and 1003, respectively. Patients on ranibizumab alone improved by 9.82 and 10.36, amounting to a wash.

Fovista is a first-of-its-kind anti-platelet derived growth factor (anti-PDGF) drug that, according to Novartis’s press release, “selectively binds to PDGF-BB and PDGF-AB homo and hetero-dimers, respectively, thereby disrupting the interaction with their cognate tyrosine kinase receptors” in order to strip pericytes from the underlying endothelial cells and potentially leave them “in an unprotected and vulnerable state, thereby increasing their sensitivity to the effects of VEGF blockade.” When paired with an anti-vascular endothelial growth factor (anti-VEGF) such as ranibizumab, it is believed that it should make the former more effective.

The joint licensing and development deals surrounding pegpleranib involve major dollars and major players. Novartis pledged a billion dollars, including $200 million outright, to Ophthotech in 2014 in order to secure ex-U.S. marketing rights. More than a decade earlier, in 2003, Novartis had purchased the same rights to Lucentis off of Genentech (which itself became part of Roche in 2009). Just last year, Genentech/Roche exercised an option to split Fovista’s international marketing rights with Novartis.

Ophthotech announced in July that they had completed recruitment for phase 3 trials of Fovista in combination with aflibercept (Eylea/Regeneron) and bevacizumab (Avastin/Genentech). Those drugs, like Lucentis, are common and competing anti-VEGF agents.

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