Despite Mixed Trial Results and Stock Plunge, Apellis Keeps Commitment to Lead Candidate Pegcetacoplan

Despite a sharp dive in its stock price a day after reporting mixed topline results from two Phase III clinical trials of its lead candidate to treat geographic atrophy, Apellis Pharmaceuticals is staying focused on filing a New Drug Application for the candidate, pegcetacoplan, in the United States next year and building out its marketing and sales teams, cofounder and CEO Cedric Francois, MD, PhD, told analysts last week.

After the announcement last Thursday, Apellis’ stock crashed almost 40%, closing out the week just a shade under $35, recovering somewhat from an even greater plunge Friday morning. But the loss continued early in the week with the price dropping below $33.

Geographic atrophy (GA) is an advanced form of dry, or non-neovascular age-related macular degeneration (AMD) that leads to irreversible blindness. Several anti-VEGF treatments have been approved to treat the wet form of the disease, neovascular AMD, but no approved treatments exist for GA, which reportedly affects 5 million people worldwide. Apellis is betting that pegcetacoplan will be the first approved treatment for GA. Pegcetacoplan targets the C3 complement in the disease pathway.

Two Trials, Two Different Results

Progression of GA is measured in the growth of lesions in the back of the eye. Twelve-month results from the Phase III OAKS and DERBY trials showed that pegcetacoplan had different effects on lesion growth. The trials evaluated monthly and bimonthly injections of 15 mg/0.1 mL pegcetacoplan and sham injections.
In OAKS, monthly injections reduced lesion growth by 22% compared to sham (p=0.0003), while bimonthly injections yielded a 16% reduction vs. sham (p=0.0052). In DERBY, however, those reductions were 12% (p=0.075) and 11% respectively (p=0.0528), missing the prespecified primary endpoint.
“We are continuing to analyze the data to better understand why the data in DERBY looks different from OAKS and our previous FILLY study,” Dr. Francois said on the analysts’ call. FILLY was a Phase II study.

Potential Silver Linings

Combined data on eyes with extrafoveal lesions—lesions outside the fovea, the region in the center of the back of the eye responsible for sharp central vision—showed monthly and bimonthly pegcetacoplan treatments achieved 26% (p=0.0001) and 23% (p=0.0002) reductions vs. sham.

“We believe this outcome reinforces our leadership position on complement and offers yet more validation of our approach,” Dr. Francois said.
Dr. Francois also noted the studies’ safety findings “exceeded our expectations.” Two confirmed and one suspected cases of infectious endophthalmitis were reported for 6,331 total injections, as were 13 cases of intraocular inflammation—rates of 0.047% for the former and 0.21% for the latter. No cases of retinal vasculitis or retinal vein occlusion were reported.
“We believe that the data from OAKS, DERBY and our Phase II FILLY study provide a compelling and robust data set that supports approval despite the narrow miss in DERBY,” Dr. Francois told the analysts.

When pressed, Dr. Francois acknowledged that “we have much more work to do” in ferreting out the differences between the two trials.

Submission Strategy

“But,” he added, “what I would like to point out, which I think is really important and will help us in the submission strategy that we have, is that in 2015 we made a commitment to study this very complex disease of geographic atrophy with consistency”— that is, using the same patient population, study design and methods across the two Phase III and the Phase II FILLY trials.

“Consistency creates a data set in which the narrowness in DERBY becomes contextualized,” he said. “When you run a couple of Phase III clinical trials, you always get some differences, and this is one of those examples where, of course, it didn’t go the way we wanted to in DERBY, but where all the remainder of the data support our hypothesis.”

He noted Apellis is continuing to build it its ophthalmology commercial and medical affairs teams, hiring marketing and sales leaderships in the United States, and building out its teams and affiliates in Germany and Australia. It also plans to submit a marketing application for approval in Europe next year.

Apellis is also pursuing APL-0006, its investigative treatment for wet AMD that combines anti-VEGF properties with C3 inhibition, Dr. Francois said, with plans to submit an Investigative New Drug Application next year with the Food and Drug Administration.

And the company will report more analysis from OAKS and DERBY at upcoming ophthalmology meetings, he added.

In the meantime, as Dr. Francois said, the Apellis team has work to do.