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RETINA CONSERVATIONS: A Conversation With Cedric Francois, MD, PhD

The complement inhibitor APL-2 has potential as an effective treatment for geographic atrophy.

Cedric Francois, MD, PhD
IMAGE COURTESY DR. FRANCOIS

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Cedric Francois, MD, PhD, founder and CEO of Apellis Pharmaceuticals, speaks with Retinal Physician about the efforts of Apellis in the development of the complement inhibitor APL-2, the phase 2 FILLY trial, and past studies of complement inhibitors.

Q. Can you talk about the interesting history of Apellis and its relationship with Potentia? There were some fascinating twists and turns in that relationship.

A. In 2001, we founded Potentia Pharmaceuticals, which became the first group to test complement-inhibiting drug candidates for age-related macular degeneration (AMD) in that disease. In 2009, Alcon entered into a licensing and option-to-purchase agreement with Potentia Pharmaceuticals to develop the lead program at Potentia, POT-4, to treat geographic atrophy (GA). Alcon was subsequently acquired by Novartis.

In 2014, Potentia regained the rights to its programs. Apellis then brought the Potentia program back in house and modified the molecule to become APL-2, a new chemical entity, which was expected to behave well when injected intravitreally. In 19 months, APL-2 went through preclinical development, an IND application, and a phase 1 trial, and it reached the milestone of a first patient dosed in a 246-patient phase 2 clinical trial (FILLY).

Q. Was it the development of the complement inhibitor APL-2 that brought Apellis back into the ophthalmic arena?

A. Very much so. While Apellis never lost faith in the potential of complement inhibition at the level of C3, the APL-2 molecule was better suited for intravitreal injections.

Q. Regarding complement inhibitors, Genentech’s lampalizumab did well in phase 2 but failed in phase 3. How does APL-2 differ in complement inhibition from lampalizumab? How does it differ from Ophthotech’s avacincaptad pegol (Zimura)?

A. APL-2 targets complement factor C3, which is the central component of the complement cascade and allows the broadest possible inhibition. Lampalizumab is a partial complement inhibitor at factor D. This difference may explain why we are seeing a highly statistically significant effect with APL-2.

The 12-month data for our phase 2 trial in GA for APL-2 showed a 29% reduction in GA lesion growth for “all-comer GA patients” in the monthly dosing group, regardless of genotype profile. By comparison, phase 2 clinical data for lampalizumab indicated positive results for people with a specific genetic biomarker (mutation in complement factor I [CFI]), and less positive results for unmutated CFI patients, who represented approximately 57% of clinical trial participants.

In addition, we saw an increased effect over time, with a reduction in GA lesion growth from month 6 to 12 of closer to 50%. Finally, because we only studied 1 eye per subject in the primary endpoint analysis, we had an opportunity to compare study eyes to contralateral eyes in subjects with bilateral GA. Here too, we saw a statistically significant difference between study eye and contralateral eyes in monthly dosed patients, as well as, again, an increased effect from month 6 to 12.

Regarding the other complement inhibitors you mention, Zimura is a PEGylated aptamer targeting complement factor C5. While we wish Ophthotech success, unfortunately, C5 inhibition has not worked in the past. Antibodies against C5 were both tested when administered systemically (the COMPLETE trial by Philip J. Rosenfeld, MD, PhD) and also when administered intravitreally (phase 2, Novartis). Because of those findings, it would be surprising in our opinion if other approaches targeting C5 or downstream of C5, like genetically enhancing the expression of CD59, were to be effective.

Q. APL-2 was generally given high marks for its phase 2 FILLY trial results for reducing progression in GA targeting the C3 level. Yet, many were puzzled that there was such a high incidence of wet AMD, especially at the high dose. Do you have an explanation for that?

A. First, I want to stress that we take new-onset exudations seriously and will always place patient safety first. In our study at 18 months, 1% of sham patients, 9% of patients dosed every other month, and 21% of patients dosed monthly developed new-onset exudation. It is worth noting that in patients who were dosed every other month (as opposed to every month), the incidence of new-onset exudation was similar to what would have been expected from natural history.

In patients receiving monthly APL-2, the rate of new-onset wet AMD was higher, and in the sham group, it was lower than would have been expected. Importantly, these cases were generally mild and immediately treated with anti-VEGF agents. We are satisfied with the overall safety profile and we plan to enroll largely the same patient population in phase 3 as we did in phase 2.

With regards to the mechanism, the new-onset exudation (wet AMD) seems to reflect a biological effect from the injection of the drug, with a clear appearance of dose-response between monthly and every-other-month injections. While we are further investigating etiology, we believe that new-onset exudations may be a manifestation of neovascularization, possibly from pre-existing type 1 membranes, as part of a healing response in the retina.

We believe that retinal cells that accumulate too much C3 product become a target for phagocytosis by microglia and macrophages. APL-2 prevents C3 deposition and gives retinal cells a chance to remove preformed C3 product. This may switch macrophages and microglia from a phagocytotic into a repair phenotype, which is known to be associated with neovascularization. When neovascularization is aggressive, vessels may not have time to mature, which can make them leaky. This is what we suspect was observed in the FILLY trial.

Q. The Apellis pipeline revolves exclusively around APL-2, both in ocular (GA and wet AMD) and non-ocular applications. Is this all about the many opportunities for complement inhibition?

A. Apellis has other molecules in development, including a compound called APL-9, which is designed for intravenous administration in systemic indications, as well as other preclinical programs. However, it is correct that Apellis is currently highly focused on complement factor C3, which has opened a wide range of opportunities in multiple therapeutic areas.

Q. Apellis recently raised $150 million through a public offering and is now a publicly traded stock. How will those funds be used?

A. In addition to helping fund phase 3 with APL-2, the financing will be used to initiate phase 3 trials with APL-2 in paroxysmal nocturnal hemoglobinuria, a rare, chronic, life-threatening blood disorder, and advance development in other indications, such as complement-dependent nephropathies.

Q. Your plans for phase 3 emulate the goals of the phase 2 trial, but on a large scale. Is this the “safest” route to FDA approval, given recent disappointing phase 3 trial results in retinal disease?

A. The fewer changes made from phase 2 to phase 3, the more likely it is that the study will repeat the phase 2 findings. The fact that APL-2 showed efficacy, both when comparing the study eyes between groups as well as when comparing the study eyes to the fellow eyes in the same patients, gives us confidence that the observed effects were real.

Q. What might challenge complement inhibition in GA?

A. It’s too soon to tell. For now, our job is to stay focused on solidifying at least one effective approach that slows down or stops the growth of atrophy in these patients, a goal that has remained elusive. RP