Age-related macular degeneration complement blocked by C5aR inhibitor

JPE1375 (Jerini Ophthalmic), a peptidomimetic inhibitor of the complement factor 5a receptor, blocks the mechanism that draws inflammatory cells into the disease process of age-related macular degeneration. When blocked, the numbers of neutrophils and macrophages decrease substantially and in turn the choroidal neovascularization also decreases.

Key Points

When blocked, the numbers of neutrophils and macrophages decrease substantially and in turn the choroidal neovascularization (CNV) also decreases, according to Anthony P. Adamis, MD, speaking at the annual meeting of the American Academy of Ophthalmology.

"There are very compelling data that complement appears to be involved in both early and late AMD," said Dr. Adamis, adjunct professor, Department of Ophthalmology and Visual Sciences, The University of Illinois at Chicago, and president and chief executive officer of Jerini Ophthalmic. "We do not understand very well mechanistically how complement is causing AMD. However, we do know that over-activation of the complement system is somehow leading to the development of the disease.

An important consideration in this type of therapy, Dr. Adamis explained, is that the complement cascade is part of the innate immune system and in the eye it prevents development of infection.

With this phenomenon in mind, he said, "Those of us who are thinking about blocking the complement cascade do so at our potential peril. We need to understand how much to block and where to block it."

Dr. Adamis and his group are looking at blocking inflammation associated with complement activation, which has been seen as a component of drusen and CNV. The investigators are specifically targeting the principal component of the complement cascade, C5aR, using a compound referred to as JPE1375. Preclinical studies have suggested that blocking this receptor on inflammatory cells may be useful in addressing complement-mediated diseases. Studies in preclinical models also have suggested that inactivation of the entire complement system predisposes eyes to develop endophthalmitis.

"Importantly, however, by blocking inflammation only, the membrane attack complex, which attacks bacteria, is allowed to function," Dr. Adamis said, adding that fine-tuning is potentially important to control rates of endophthalmitis.

The case for C5aR is there but is incomplete, he noted. C5aR has been identified in early-stage AMD drusen and in later AMD phases in CNV. Work in a model in which CNV was induced using laser showed that inhibiting C5aR results in suppression of CNV. By selective blockage, the numbers of neutrophils and macrophages that can infiltrate are reduced and the CNV can be reduced by about 50%, according to Dr. Adamis.

"When administered intravitreally in animals, it was effectively able to suppress neovascularization," Dr. Adamis said.

Besides development of CNV, geographic atrophy is another factor in vision loss in AMD. Multinucleated giant cells and macrophages are at the edge of the area of geographic atrophy, as reported previously by Shirley Sarks, MD.

"The close association with the boundary of the area of atrophy suggests that the inflammatory cells may actively influence the rate of development of the atrophic lesions. While these are indirect data, it is nice co-localization and indirect data to support that inflammatory cells play a role in geographic atrophy," Dr. Adamis said.

JPE1375 is a small molecule, and it has been reformulated into injectable sustained-release microspheres measuring only 40 μm in diameter. The formulation is stable in biologic fluids, under high temperatures, and with various solvents. In addition, the molecule is released over 6 months, which lowers the patient treatment burden. JPE1375 prevents C5aR from binding to C5a.

"JPE1375 is a small molecule that has interesting physicochemical characteristics. It is potent and stable and can be reformulated for extended release. We would like to administer this molecule no more often than twice a year," he explained.

In their research, Dr. Adamis and colleagues looked at complement-mediated diseases and the blocking of C5aR and inflammation to determine if the disease is affected. They studied models outside the eye such as neutropenia, peritonitis, fibrosis, rejection of kidney transplants, and myocardial infarction, as well as CNV. They found that when C5aR was blocked in all of the models, it had a beneficial effect on the outcome of the disease.

"With all those data, we are more confident to move forward with development of JPE1375. We have reformulated our compound into microspheres that can be injected through a 27-gauge needle; the microspheres will release drug over a 6-month period. When treating patients with early AMD or geographic atrophy, these patients may see well with monthly injections, but we wanted to reduce the treatment burden to no more than twice a year," he explained.

In addition to reducing the treatment burden, sustained release also should reduce dramatically the peak concentration in the eye and serum and lengthen the duration of drug exposure, which may be beneficial in a chronic disease such as AMD, he said.