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A phase I trial has begun investigating intravitreal injection with a complement inhibitor (POT-4, Potentia Pharmaceuticals) in patients with active choroidal neovascularization secondary to age-related macular degeneration. There is a solid scientific basis for developing complement inhibition as a therapeutic strategy, particularly for treating patients with early disease to prevent progression.
"In just the past few years, several lines of evidence derived from genetic, animal model, and clinical histopathology studies point to a pathophysiologic role of inflammation, and particularly inflammation mediated by the complement system, in all stages of AMD. [This drug] is being developed as a locally administered compound with the idea that it could ultimately be used to treat patients with very early disease and reduce the risk of progression leading to vision loss," said Dr. Slakter, a vitreoretinal specialist in private practice in New York and clinical professor of ophthalmology, New York University School of Medicine, New York.
"Thus far, [the drug] has demonstrated favorable activity and safety in preclinical testing. It is the first complement inhibitor to enter clinical testing, and we look forward to the results of the phase I study and further trials," he said.
Dr. Slakter explained that three pathways, known as the classical, alternative, and lectin pathways, make up the complement activation system, and all three pathways converge on and activate C3. This activation step normally is regulated by several inhibitory proteins, such as complement Factor H, to prevent excessive or inappropriate complement activation that would lead to unwanted destruction of host cells.
"Various factors have been identified as potential triggers for complement activation leading to AMD, and they variably affect the classical, alternative, and lectin pathways. However, C3 activation is a central point for all three pathways. Therefore, [the complement inhibitor] can prevent the generation of downstream active mediators regardless of the trigger or pathway stimulated," he said.
"Furthermore, considering all the evidence linking AMD with the complement system, the strongest link involves genetic polymorphism in the gene encoding complement Factor H. This information combined with understanding of the mechanism of [the drug] provides strong support for investigating it as a pharmacotherapy for modulating the complement system," Dr. Slakter said.