Ophthotech’s Final Try at Combo Eye Drug Comes up Short

Xconomy New York — 

It wasn’t too long ago that Ophthotech was running a group of clinical trials being perhaps as closely watched as any in the ophthalmology field, studies that had a chance to change the way a common form of vision loss, age-related macular degeneration (AMD), is treated. But those days are a distant memory now. All three of the trials have failed.

Ophthotech (NASDAQ: OPHT) said this morning that its experimental pegpleranib (Fovista) failed the third of three Phase 3 trials in patients with the “wet” or more damaging and fast-moving form of AMD. The drug, when given in combination with one of two other wet AMD drugs, aflibercept (Eylea) or bevacizumab (Avastin), didn’t lead to any benefit on patients’ vision compared to aflibercept or bevacizumab alone after a year of treatment. In December, the drug, when combined with ranibizumab (Lucentis) in two separate Phase 3 trials, didn’t fare any better than ranibizumab alone.

Specifically, Ophthotech said today that in the 640-patient trial, called OPH1004, patients on combination therapy could read an average of 9.42 more letters on a standard visual acuity chart after a year of treatment than they could at the start of the study. Patients on bevacizumab or aflibercept alone read 9.04 letters, meaning the drug led to an average gain of just 0.38 letters, a result that wasn’t statistically significant. A pegpleranib combination also failed to produce any clinically meaningful benefit on any other secondary measures, Ophthotech said.

Due to the results, Ophthotech will stop treating patients who are in the second year of the OPH1004 study.

Ophthotech shares fell about 13 percent in pre-market trading Monday morning. Such a small dip on results from such a significant trial is a reflection of just how far expectations had already fallen for pegpleranib in 2017. Ophthotech itself said in a statement just last month that the trial had a “low likelihood of success” given previous results. When the first two studies failed in December, Ophthotech shares fell more than 80 percent. They closed as high as $78.53 apiece in December 2015. Shares closed at $2.55 apiece on Friday and exchanged hands early Monday morning at $2.20.

The news all but seals the fate of pegpleranib, which had a chance to become a mainstay treatment in a large and growing market. AMD affects more that 2 million Americans, a number expected to grow to nearly 5.5 million by 2050 as the population ages, according to the National Eye Institute. About 10 to 15 percent of those patients have the wet form, when abnormal blood vessels form in the eye and leak fluid, ultimately causing potentially significant vision loss. The market for AMD treatments has exploded the past several years. Until recently, the standard of care was laser therapies that didn’t actually improve patients’ vision. That method has been replaced by injectable pharmaceuticals. Two drugs, aflibercept (from Regeneron Pharmaceutials) and ranibizumab (from Genentech/Novartis), are specifically approved for the condition. The most widely used drug for wet AMD, bevacizumab (Avastin), is prescribed off label. These drugs are given frequently, as often as every month.

These wet AMD drugs—which block a protein called VEGF and stop abnormal blood vessels from forming—can restore some vision, prevent further damage to the eyes, and stop people from going blind. But they aren’t cures, and there is room for improvement. Ophthotech was trying to show that adding another drug, pegpleranib, that worked by a different, potentially complementary mechanism (it blocks a different protein, PDGF), might restore even more vision for patients. Perhaps the drug could be used just a few times when a patient is first diagnosed for wet AMD; or perhaps pegpleranib could be useful for people who don’t respond to other treatments.

Either would’ve been a huge opportunity. Aflibercept and ranibizumab generate more than $7 billion in worldwide sales combined. They also cost about $2,000 a dose and are a big strain on Medicare, which spent about $2.63 billion combined on aflibercept ($1.3 billion) and ranibizumab ($1.33 billion) in 2014, or roughly 12 percent of the $21.5 billion it spent on its so-called Part B program, which governs drugs administered in hospitals and clinics. That’s one of the reasons several ophthalmologists voiced concern to Xconomy about the potential effect on costs of a second, likely expensive pegpleranib injection.

Pegpleranib, however, has now failed to produce in three different studies, likely spelling the end of the road for the drug. Ophthotech has been able to survive the failures thanks to the pile of cash it raised in its IPO, in subsequent stock offerings, and through a big pegpleranib partnership deal with Novartis. The company still had $196.4 million in the bank as of June 30. But it has significantly changed its strategy, cut a bunch of jobs, and several of its former top executives are gone— former CEO David Guyer switched roles to executive chairman, for example, and ex-president Samir Patel is no longer with the company. Ophthotech is now pursuing treatments for rare eye diseases with limited or no treatment options, and aims to use its cash to buy experimental drugs to add to its pipeline. It recently announced plans to test its most advanced treatment, a drug called avacincaptad pegol (Zimura)—already in clinical trials for two different forms of AMD—on the rare Stargardt disease.