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thwart wet AMD in two ways. Pegpleranib blocks a different protein, PDGF, which is also implicated in unwanted blood vessel growth. According to Ophthotech’s website, there is room for improvement over the current standards. The company cites clinical studies that anti-VEGF treatments alone lose effectiveness after a year in about 20 percent of patients, and a majority of patients taking the drugs never gain back “significant” vision. Long-term follow-ups from the NIH’s CATT and other studies show that the benefit of anti-VEGF therapy tends to wane over time. (Ophthotech officials declined requests for comment.)
Ophthotech’s Phase 2 results of a pegpleranib-ranibizumab combination showed patients could read an average of 4.1 more letters more on a visual acuity chart than patients on ranibizumab alone after 24 weeks of treatment. (The results were published on Monday in the peer-reviewed journal Ophthalmology.) To put that in perspective, Regillo, of Wills Eye, says he wants to see a pegpleranib combination provide a boost of “at least 3 or 3.5 letters” over single-drug therapy before he considers using the combination on newly diagnosed patients.
Clark cautions that any improvement less than 5 letters—a full line on the chart—“[won’t] be that exciting in terms of broad acceptance in clinical practice,” and Regillo says less than three letters would be more “noise” than signal.
Ophthotech’s Phase 3 pegpleranib-ranibizumab study, which is treating patients for a full year, will produce data by the end of the 2016. In a recent research note, Leerink Partners analyst Joseph Schwartz estimated as much as $1.26 billion in peak U.S. sales if pegpleranib comes through.
The company could also earn up to $700 million in payments from Novartis if the drug wins approval and is cleared for reimbursement in various European countries. (Novartis holds rights to pegpleranib in Europe and owns partial rights to ranibizumab.)
At least two things make observers wary of Ophthotech’s upcoming data. First, skeptics wonder if the difference between the pegpleranib-ranibizumab combination and ranibizumab alone on patients’ vision will be as large as it was in Ophthotech’s Phase 2 trial. Second, a rival combination therapy from Regeneron, which also aimed to block VEGF and PDGF, failed a mid-stage trial last month.
“When you hear about the same [drug] target not working, that has to create some skepticism,” Regillo says. (Regillo has received research grants from several wet AMD drug developers and is a Genentech consultant.)
In a recent report on retinal diseases, Leerink estimated that pegpleranib, if approved, would cost $1,500 a vial. With all the handwringing over AMD drug prices and insurers’ growing restrictions, how many doctors will prescribe it? And how would they use it?
“[The potential cost] is a concern,” Regillo says. “I’m going to use the least amount of drug to get whatever benefit this combination derives.”
Regillo speculates he might use a pegpleranib combination first, up to six times, then switch back to a single drug to maintain the gains from the combo therapy. He also notes that wet AMD patients with 20/40 vision or better likely won’t need a combo therapy. Clark agrees, saying the best theoretical use might be to eliminate damage to the eye in severe cases as quickly as possible.
Shulman says that if Ophthotech’s Phase 3 studies show patients with severe cases improve rapidly, she might be persuaded to use a combo therapy rather than aflibercept alone as she does now. Additionally, Feistmann says, there are still many people that don’t respond to anti-VEGF therapy. “Hopefully [pegpleranib] will help the non-responders so we have an extra tool in our toolkit,” he says. (Both Shulman and Feistmann disclose that they own Roche stock.)
With eye doctors feeling pressure to control costs, Ophthotech’s upcoming data won’t just have to be good. They’ll have to be good in ways that save patients time and hassle and save the healthcare system money. (Sometimes those goals overlap, sometimes they don’t.)
The most substantial burden for wet AMD patients—typically 65 years or older—is coming into the office for monthly injections, Shulman says. If a combination therapy can reduce office visits by lasting longer per dose, the price might be right. The more clear-cut the benefits are, the more likely the next generation of AMD therapy—whether it comes from Ophthotech or elsewhere—will make the cut with doctors who would love nothing more than to escape the spotlight.