Apellis finds that one of its twins is evil

A hit and a miss with pegcetacoplan in late-stage trials leaves Apellis with shrinking prospects.

Trial Results

The sellside did its utmost to put a positive spin on the mixed phase 3 data on Apellis’s geographic atrophy project intravitreal pegcetacoplan, released after market close yesterday. This morning's 42% fall in the group’s stock suggests that investors have taken a less rosy view.

Approval of the complement inhibitor is still just about possible, though the blockbuster forecasts appended to pegcetacoplan will surely have to be revised. But more was riding on pegcetacoplan than just approval; Apellis viewed it as a “pipeline in a product”, aiming to expand its use into similar eye conditions. This now looks less likely to work out.

Data from the twin Derby and Oaks trials, in a total of 1,258 patients with geographic atrophy, an advanced form of dry age-related macular degeneration, had been hotly awaited. This intravitreal form of pegcetacoplan has forecast 2026 sales of $1.2bn, according to Evaluate Pharma’s sellside consensus. 

The trials were identical in design, which makes it puzzling that Oaks hit, significantly decreasing the formation of new lesions versus sham treatment, whereas Derby did not. That Derby missed significance narrowly must be particularly galling for Apellis, which did not offer any explanation for the divergent results.

Topline phase 3 data on Apellis's pegcetacoplan
  Reduction in GA lesion growth at 1yr vs pooled sham
Trial Pegcetacoplan monthly P value Pegcetacoplan every other month P value
Oaks (637 pts) 22% 0.0003 16% 0.0052
Derby (621 pts) 12% 0.0528 11% 0.0750
Oaks + Derby (prespecified analysis) 17% <0.0001 14% 0.0012
Source: company release.

Pooling the data from Oaks and Derby resulted in statistically significant hits, but it is not clear that the FDA will accept pooled data, especially when one trial is clearly driving the positive combined result.

In any case the magnitude of lesion reductions yielded by this analysis falls short of the 20% threshold doctors would consider meaningful, as mentioned in Apellis’s R&D presentation in June. 

At least there is nothing on the safety side to stand in the way of approval. Exudations – leaking blood vessels in the eye, including the choroidal neovascularisations that were problematic in the phase 2 Filly trial – were seen in 6.0% of patients given pegcetacoplan monthly and 4.1% of those given it every other month, versus 2.4% for sham. 

Apellis wants to file with the FDA in the first half of next year. The regulator has shown itself to be lenient in some cases, so approval cannot be ruled out. Evercore ISI's Umer Raffat called the results “very much approvable”, pointing out that the lack of approved therapies for geographic atrophy. 

Getting doctors and payers on side with lacklustre data might be a tougher proposition.

Then there are Apellis’s later ambitions. The group's stated intention to become the number-one company in the retina space relies on it positioning pegcetacoplan as a therapy to prevent progression of intermediate AMD patients to wet AMD and dry AMD. A phase 3 study had been planned for 2022. 

Whether to go ahead with this is another decision for Apellis to make. 

More data from Derby and Oaks will be presented at the Retina Society meeting, which starts later this month. But it is already clear that pegcetacoplan has followed Roche’s lampalizumab and Gemini’s GEM103 in becoming a complement-targeting project with an unimpressive showing in geographic atrophy. 

The next most advanced agent for this disorder is Alkeus’s ALK-001, whose phase 3 Saga trial could report next year.

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