CEO Glenn Sblendorio told BioWorld that, except for a phase I/II trial in Von Hippel-Lindau syndrome that was prompted by "a request we had a while back" from the National Eye Institute, the latest failure with Fovista (pegpleranib) "closes the book" on the anti-platelet-derived growth factor (PDGF) therapy, and Ophthotech Corp. will focus instead on complement 5 inhibitor Zimura (avacincaptad pegol) in eye diseases along with shopping for new assets.

Mean change in visual acuity at 12 months was not achieved in the study investigating the superiority of Fovista in combination with Eylea (aflibercept, Regeneron Pharmaceuticals Inc.) or Avastin (bevacizumab, Roche AG) anti-vascular endothelial growth factor (VEGF) therapy compared to Eylea or Avastin monotherapy for the treatment of wet age-related macular degeneration (AMD). Specifically, adding 1.5 mg of Fovista to an Eylea or Avastin regimen did not result in benefit as measured by the mean change in visual acuity at the 12-month time point, the company said. Ophthotech will stop treating patients who are in the second year of the study known as OPH1004, which enrolled about 640 patients with wet AMD.

Two previous phase III trials with Fovista in the same indication failed as well. In December 2016, Ophthotech disclosed the bad news from a pair of experiments known as OPH1002 and OPH1003, testing for the superiority of Fovista combined with another anti-VEGF drug, Lucentis (ranibizumab, Roche AG) in wet AMD. Also in anti-PDGF efforts, in late September of last year, Tarrytown, N.Y.-based Regeneron reported on the CAPELLA study testing Eylea co-formulated with rinucumab in AMD. The trial turned up no improvement in best corrected visual acuity compared to intravitreal Eylea injection monotherapy at 12 weeks, the primary endpoint. Raymond James analyst Chris Raymond said in a report that "management has consistently talked this combination down" in favor of its Eylea/anti-angiopoietin2 duo, which has reached phase II trials not only in AMD but also in diabetic macular edema. (See BioWorld Today, Oct. 3, 2016.)

"Early on, we did not really spend a lot of time with Zimura" because phase III trials with Fovista took up the company's resources, said Ophthotech's Sblendorio. But a phase I/II trial in wet AMD that was "uncontrolled – I have to be very specific here – did show a positive result of about 60 percent three-line gain" on the Early Treatment Diabetic Retinopathy Study, or ETDRS, chart, he said. "What we would like to do there is a small phase IIa trial to see if we can replicate those data, and then make decisions on how we move that [effort] forward."

Along with wet AMD, the company is enthused about treating orphan eye indications with Zimura, including Stargardt disease and idiopathic polypoidal choroidal vasculopathy (IPCV), a form of macular degeneration largely prevalent in Asians. A small but encouraging trial in IPCV was done in the past, too. Phase IIa studies in all three are expected to start before the end of the year. Leerink analyst Joseph Schwartz, in a July 26 report, noted that "importantly, the company decided to stop its phase IIa Zimura monotherapy study in wet AMD and re-initiate a new phase IIa study with an amended protocol that will include treatment-naive patients (vs. treatment-experienced [patients enrolled] previously)." Schwartz had given the latest-to-report Fovista experiment only a 25 percent chance of success. Ophthotech's Chief Operating Officer Keith Westby has "a lot of fingerprints on this [Zimura] protocol," Sblendorio said. Westby told BioWorld that the previous design came about when Fovista was still a going concern. "Opening [the Zimura study] up to treatment-naïve patients will allow us to enroll it faster," he said, though to talk about the sought label would be "premature."

Price tags high in BD

Among other firms working in the space, New York-based Ohr Pharmaceutical Inc. this spring said it was amending the phase II trial underway investigating squalamine in wet AMD (the MAKO Study) to enable efficacy analyses by the end of calendar 2017 or early 2018.

The study remains a multi-center, randomized, double-masked, placebo controlled clinical trial. Over 200 study subjects would continue to receive their assigned study treatment of monthly Lucentis and either squalamine or placebo drops twice daily, and undergo scheduled visits and assessments through nine months. The primary endpoint will be an assessment of visual acuity at nine months. Ohr execs hope to confirm benefits seen in the phase II IMPACT study. Squalamine acts against the development of aberrant neovascularization by inhibiting multiple growth factors, including VEGF, PDGF, and basic fibroblast growth factor. (See BioWorld Today, Feb. 9, 2015.)

For Ophthotech in Stargardt, "four or five" would-be competitors are developing drugs, including one effort in gene therapy and others in small-molecule, systemic approaches, Sblendorio said. "We're aware of the landscape. We believe that intravitreal injection is a way to get the drug very directly to the area affected." There's also an ongoing study with Zimura in dry AMD, a "very large disease," that's been enrolling "for some time [but] progressing very slowly until we have an opportunity to see the results of a competitor's trial that come out later this year," he said. The competitor is Basel, Switzerland-based Roche AG, conducting the SPECTRI phase III study with lampalizumab, a humanized monoclonal antibody fragment targeting complement factor D.

On the topic of business development, Sblendorio said during the second-quarter earnings conference call with investors that company officials "have looked at a lot of different opportunities. I think the focus has been on back of the eye, and as we generated more data in the area of orphan [diseases], we did look at a number of [those]. We haven't found anything that fits our strategy and there's a whole bunch of reasons as to why. One, it could have been knocked out because of diligence. Two, value expectations on a lot of these assets were much higher than we expected. We continue to look. I think what we had seen over the first six months is a lot of inbound possibilities" that can be further refined in the months ahead, he said.

Shares of Ophthotech (NASDAQ:OPHT) closed Monday at $2.71, up 16 cents.