Apellis turns up mixed results in closely watched eye disease tests. Are the data strong enough for approval?
Looking to scuffle with rare disease giant and now AstraZeneca subsidiary Alexion, little Apellis scored a breakthrough win earlier this summer for its own complement factor inhibitor drug. Apellis, though, always had its eyes on bigger fish, but a first glimpse at pivotal data for a major indication has muddied the waters.
In two Phase III studies testing pegcetacoplan in patients with geographic atrophy, Apellis’ drug nailed the primary endpoints in one test but flopped the same checkpoints in a “carbon copy” study, according to topline data released Thursday.
Geographic atrophy is an advanced form of dry age-related macular degeneration with no approved therapies that affects around 5 million patients worldwide — including around 1 million in the US — and is a leading cause of blindness.
An approval here could spell blockbuster sales for pegcetacoplan, a complement C3 inhibitor now marketed as Empaveli for paroxysmal nocturnal hemoglobinuria (PNH) — which is exactly why analysts and investors have kept such a close eye on these studies. In June, Evaluate Pharma pegged the drug’s potential market in GA at $1.2 billion in 2026.
In the Phase III OAKS trial, pegcetacoplan injected in the eye reduced the rate of GA lesion growth by 22% (p=0.0003) and 16% (p=0.0052) compared with pooled sham injection in patients administered a monthly and once-every-other-month dose of the drug, respectively, after a year, Apellis said.
Taken alone, that’s great news for Apellis. But the second trial toplined Thursday — the Phase III DERBY study — painted a murkier picture of the drug’s efficacy.
In that trial, pegcetacoplan failed to significantly cut lesion growth rate compared with sham in both cohorts, posting rates of 12% (p=0.0528, just over the standard benchmark of p=0.05) and 11% (p=0.075), respectively. That’s a concern since the studies were mirror images of one another and offered contradicting pictures of whether Apellis’ drug works in this indication.
In an attempt to bridge the gap between the two studies, Apellis offered results from a prespecified analysis combining the primary endpoints from both studies to determine overall significance. The biotech said monthly doses of the drug in both studies cut lesion growth by 17% overall (p=<0.0001) and a once-every-other-month dose cut lesion growth by 14% (p=0.0012) compared with sham.
A failed study is a black mark on any drug’s record, but CEO Cedric Francois said the totality of pegcetacoplan’s efficacy and safety data — which includes results from the Phase II FILLY trial — could offer a compelling case for regulators. The company expects to file for approval as soon as the first half of 2022.
“You have to look at these data in terms of the totality of data that we have assembled,” he told Endpoints News. “The entire data package that we have presents a very strong case for approval.”
In terms of why the studies diverged so greatly, Francois didn’t have much to offer, saying: “If you run the same trial 20 times, you’ll get 20 different results.”
Francois highlighted the safety data for pegcetacoplan in DERBY and OAKS, with just 6% of patients reporting exudations from the eye in the monthly dose cohorts and 4.1% in the every-other-month cohorts. There were two confirmed cases of infectious endophthalmitis and another suspected case among 6,331 injections administered during the studies. Meanwhile, there were 13 cases of intraocular inflammation reported and no retinal vasculitis or retinal vein occlusion reported.
“We came into this program with a drug that we believed would have to be given every month to patients, where there was concern that we may have an increased rate of exudation that was going to be a problem,” Francois said. “The safety here is so good that this is a drug that you’ll want to give to all patients with GA.”
Another potential boon to the drug’s case was its effect on what are called extrafoveal lesions, which are early signs of the disease prior to central vision being affected. In a combined exploratory analysis, pegceptacoplan cut the rate of growth for those lesions by 26% (p=<0.0001) for the once-monthly cohorts and 23% (p=0.0002) for the once-every-month cohorts.
So that leaves the ball in the FDA’s court, and it’s unclear exactly how regulators will absorb these conflicting results. It wouldn’t be the first time that missing a primary endpoint hasn’t torpedoed a drug’s chances, and the unmet clinical need and strong safety data could be enough to push the drug over the finish line.
If the FDA does cooperate, it would be the culmination of Apellis’ yearslong drive for GA, a disease Francois described as a “forest fire” in the eye that has so far confounded drug developers. Way back in 2017, Roche saw its own chances in GA collapse after its antibody lampalizumab flopped a key test in GA patients.
But Apellis believes complement factor inhibition could be key, which explains why Alexion — now a part of AstraZeneca — has been dabbling here with its own C5 inhibitor franchise. Empavelis’ approval in PNH in May marked the first major challenge to Alexion’s Soliris, a blockbuster drug for which PNH is the single largest indication.
Prior to its acquisition, Alexion was busy switching most of its patients over to follow-up drug Ultomiris, which sports a matching PNH approval and is working to quickly expand its label to match the older drug.