Flush with an infusion of $47.5 million in financing earlier in the year, Apellis Pharmaceuticals is moving forward to develop agents that inhibit complement factor C3 to prevent geographic atrophy (GA) in dry age-related macular degeneration and a host of other diseases.

Apellis’s lead candidates are APL-1 and APL-2, both of which are derivatives of compstatin, a small peptide inhibitor of complement factor C3. The goal is to inhibit local inflammation, tissue damage and dysregulation of the adaptive immune system.

Besides the GA trial, Apellis also has clinical programs to treat paroxysmal nocturnal hemoglobinuria (PNH) as well as chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF). Both APL-1 and APL-2 are currently being tested in Phase I and Phase II clinical trials, and APL-2 has received Orphan Drug Designation from the Food and Drug Administration to treat PNH.
“Even through our endpoint is reducing the rate of progression, we are very interested in knowing if we are doing something more profound in these patients that might in the future reduce the need for treatments.”
Cedric Francois, MD, PhD

Cedric Francois, MD, PhD, Apellis founder and chief executive officer, provides insights into APL-1 and APL-2 and the company’s Phase II trial of APL-2 for treatment of GA in AMD, known as the FILLY trial. “That has something to do with our affinity for horses since we are based in Kentucky,” Dr. Francois says of the trial title.

The mechanism of action in his own words:
APL-1 and APL-2 are both molecules derived from a class of compounds, called compstatin derivatives discovered at the University of Pennsylvania. They bind to complement factor C3 and through steric hindrance, prevent C3 from becoming engaged in the complement cascade. Both of these molecules have been tested in macular degeneration.

The difference between them is that APL-1 is the smallest active peptide, and APL-2 is a derivative of APL-1 that has a longer half life in the eye and will hopefully allow for once-a-month or once-every-other month injections in patients with geographic atrophy.

The role complement factor C3 plays in AMD:
It is still very much a question today why, if it is the case, is uncontrolled complement activation a problem in macular degeneration? Simplistically, this is an issue between two possible pathways. The first is that uncontrolled complement activation damages the retina; an inhibitor to protect the retina acts in a direct cause and effect. In that case, inhibitors of complement factor C5 should work well, because the way in which the complement factor inflicts direct damage on the retina typically goes through C5.

The other way in which the complement factor can be detrimental to the eye is through immunity regulation; so, indirectly, where other adapted immune elements like neutrophils and macrophages are important causes of damage to the retina, complement is really an important regulator of that immune dysfunction. If that is the mechanism by which complement is a problem in the retina, then complement factor C3 is a preferred target to C5.

What is unique about C3 is its central role in how it blocks all the downstream effects of the cascade regardless of the source of activation. In that way, you don’t have to worry about the intricacies of how the complement affects the retina because the goal is to shut the cascade down.
Long Story Short:

Formal study title:  Study of APL-2 Therapy in Patients with Geographic Atrophy (FILLY). ClinicalTrials.gov Identifier: NCT02503332.

What AMD has in common with other diseases that ALP-2 targets:

What ties these seemingly different programs together is the underlying immunology. Apellis believes that complement as a regulator of immunity is much more important than as a direct insult or destroyer of tissues.

In the underlying immunology at work in IPF, COPD, PNH or macular degeneration, the principal difference between them is the tissue where this immune reaction takes place and the antigens that are involved in this immune process. Inhibiting C3 is a unique way of interfering with the vicious cycle that underlies these conditions.

Status of the current clinical trail in AMD:
With more than 180 of the planned 240 patients currently enrolled, FILLY trial enrollment is almost complete. By the summer of 2017 the trial should provide answers as to whether monthly or every-other-monthly injections of APL-2 in patients with GA can slow disease progression.

The trial design is similar to that of the MAHALO trial of lampalizumab (Genentech), with the object of comparing pathways. But FILLY is not a head-to-head trial; lampalizumab is a factor D inhibitor, and the object of FILLY is to determine how C3 behaves in these patients.

The big question the FILLY aims to answer:
Whether the rate of progression of atrophy in the eyes of patients with dry AMD can be slowed. If it can, it would set up a confirmatory trial.

A point worth adding:
The objective is to explore the immune process that drives the disease. Apellis is much more interested in disease modulation than in symptomatically treating the disease.

“Even through our endpoint is reducing the rate of progression, we are very interested in knowing if we are doing something more profound in these patients that might in the future reduce the need for treatments,” Dr. Francois says.  RS