A closely watched experimental treatment for a leading cause of blindness slowed the death of retinal cells in a large, late-stage study, a finding that the drug's maker, Apellis Pharmaceuticals, said Thursday will support an application to the Food and Drug Administration for approval.
But results from a second, similarly sized clinical trial showed no significant benefit to treatment over a sham eye injection, raising questions about why two studies designed to be essentially identical produced conflicting results.
The split outcome could also make Apellis' case to regulators more difficult, inserting doubt into a development program that's viewed as critically important for the Waltham, Massachusetts-based biotech company.
The two Phase 3 studies, respectively dubbed OAKS and DERBY, tested monthly or every-other-month eye injections of Apellis' drug pegcetacoplan in 1,258 patients with geographic atrophy, a progressive and irreversible form of vision loss that develops from age-related macular degeneration, or AMD.
In OAKS, both treatment regimens reduced the growth of lesions in the retina significantly more than sham injections after one year of study. But in DERBY, neither did.
In an interview, Apellis CEO Cedric Francois emphasized the "totality of the data" support the use of treatment with pegcetacoplan. An analysis of the two Phase 3 studies combined, which Apellis had planned for beforehand, showed a significant difference between treatment and sham injection overall for both monthly and every-other-month dosing.
"Yes, we had a narrow miss in DERBY. But we have a highly statistically significant readout in OAKS, which is further supported by our Phase 2 clinical trial," said Francois, referring to another study that first read out results in 2017.
Apellis only released summary results from the two trials Thursday. More detailed data will be presented at a future medical meeting, the company said, and the studies will continue for another year to further assess other secondary measures, like the drug's impact on visual acuity and reading speed. Additional data, which Apellis is still evaluating, could help answer why the two trials produced divergent results.
While there are several effective medicines for the "wet" form of advanced AMD, none are available for geographic atrophy, which affects approximately 1 million Americans, according to data cited by Apellis. The company believes pegcetacoplan can be the first, and now plans to submit an application for FDA approval in the first half of next year.
An approved treatment could mean much to people with the disease, who have nothing to slow the steady degradation of their vision. The death of retinal cells in the macula — responsible for central vision — typically results in a loss of ability to see clearly and to see colors, in addition to causing dark splotches in the eye's sight.
"Once these retinal cells have died, they cannot be revived," said Jeffrey Heier, an investigator in the Apellis trials and the director of retinal research at the Ophthalmic Consultants of Boston, in an email. "Therefore, the goal is to slow the progression of the disease. Even when central vision is already lost, there is benefit to preserving as much vision as possible."
Study results suggested a greater benefit to treatment in patients whose eye lesions were outside the fovea, a central region of the macula that's dense with photoreceptor cells. Slowing the growth of lesions into the fovea could potentially help preserve some core vision.
Treatment appeared to cause a lower-than-expected rate of a side effect involving leakage from retinal blood vessels. There were two confirmed, and one suspected, cases of a serious kind of infection in treated eyes, but no changes in vision were reported as a result.
"The safety profile is better than any of us had hoped for," said Francois.
Still, the negative result from DERBY muddies the positive finding in OAKS. Additionally, the percentage reduction in lesion growth versus sham injections in the latter trial — 22% for monthly injections and 16% for every other month — was lower than what Apellis reported in its smaller Phase 2 study.
An approval, should the FDA grant one, would greatly buoy Apellis, which earlier this year won its first drug OK for a systemically infused version of pegcetacoplan, now sold as Empaveli for the treatment of a rare blood disorder called paroxysmal nocturnal hemoglobinuria. As geographic atrophy affects many more people, investors and analysts on Wall Street expect the first treatment for the eye condition could earn its developer billions of dollars in sales.
The market reaction to the' data could also affect the broader biotech industry, which draws momentum from smaller companies like Apellis proving they can discover and develop new therapies. Writing in a note to clients earlier this week, Umer Raffat, an analyst at Evercore ISI, said the readout is "considered one of the biggest catalysts in entire biopharma this fall."
Shares in Apellis fell by nearly 40% at the start of market trading Friday, cutting almost $2 billion from the company's valuation.
Several other companies, including Iveric Bio, NGM Biopharmaceuticals and Anexxon Biosciences, are also developing geographic atrophy treatments.
All three are following a similar scientific hypothesis as Apellis, which views geographic atrophy as the result of excessive activation of the complement system, an arm of the body's innate immune defenses.
The positive findings from OAKS, Apellis' Francois said, are both evidence of complement system's role in AMD and serve as a bridge to the company's broader ambitions to target complement in a wider range of eye, rare and neurological diseases.
"It is the first of many where we are going to see the therapeutic potential of controlling complement," he said.
Note: This story has been updated to clarify characterization of results from the DERBY study, and to include the market reaction Friday to Apellis' results.