Anti-vascular endothelial growth factors (VEGF) agents (Lucentis, Eylea, and off-label Avastin) are the current standard of care in the treatment of wet age-related macular degeneration (AMD). Although a majority of wet AMD patients achieve maintenance of visual acuity with these agents, only a minority experience improvement in visual acuity, defined as gaining at least 15 letters of vision. Fovista, a novel platelet-derived growth factor (PDGF) inhibitor administered as an adjunctive therapy to current VEGF inhibitors, has been aiming to address the unmet need of improvement in vision superior to that achieved with current anti-VEGF agents. Due to the synergistic efficacy demonstrated by Fovista in combination with Lucentis in a 24-week Phase IIb study—a 62% benefit over Lucentis monotherapy—retinal specialists had been anticipating Fovista to be a welcome addition to their wet AMD treatment armamentarium.

However, in one of the most eagerly awaited late-phase trials in the Ophthalmology therapy area in recent years, Ophthotech and Novartis announced on December 12, 2016 that adjunctive Fovista did not improve visual acuity among wet AMD patients relative to Lucentis monotherapy at 12 months. Based on two pivotal Phase III studies, the combination therapy demonstrated a non-significant average gain of 10.24 letters of vision vs. 10.01 letters for monthly Lucentis monotherapy. Though a third Phase III study is still ongoing with Fovista in combination with Eylea and Avastin, it currently seems unlikely that these results would be sufficient to support regulatory approval and launch of Fovista for wet AMD.

In addition to the effect of these results on Ophthotech—the company’s share price dropped over 80% following announcement of the results—they also impacted Novartis’s Ophthalmology portfolio. Novartis, looking to counter the stiff competition to the Lucentis franchise from Regeneron/Bayer’s Eylea, acquired ex-U.S. licensing and commercialization rights to Fovista from Ophthotech in May 2014 in a deal valued at as much as $1 billion. Novartis’s hopes are likely now pinned on the Phase III therapy RTH-258, a VEGF inhibitor with the possibility of less-frequent dosing than current therapies, another substantial unmet need in wet AMD, with results expected in 2017.

Overall, it appears that adjunctive anti-PDGF therapies may have a bleak future in wet AMD. Topline data from Regeneron’s Phase II study of REGN-2176-3, a coformulation of a PDGF inhibitor with Eylea, announced in September 2016 demonstrated no additional efficacy above Eylea treatment alone. Ohr Pharmaceutical’s squalamine, another adjunctive therapy targeting PDGF, VEGF, and basic fibroblast growth factor (bFGF) in Phase III development as an eye drop formulation for wet AMD, demonstrated efficacy in only a subset of patients with specific lesion types in a Phase II trial.

In an effort to meet the need for therapies with improved efficacy over currently available VEGF inhibitors, the focus in the market will likely now shift to another set of combination therapies in Phase II development for wet AMD—angiopoietin-2 inhibitors combined with VEGF inhibitors—such as RG-7716 by Roche and REGN-910-3 by Regeneron/Bayer. Results from these trials are expected in 2017.

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