The complement system: a novel therapeutic target for age-related macular degeneration

ABSTRACT

Introduction

With the recent FDA approvals of pegcetacoplan (SYFOVRE, Apellis Pharmaceuticals) and avacincaptad pegol (IZERVAY, Astellas Pharmaceuticals), modulation of the complement system has emerged as a promising therapeutic approach for slowing progression of geographic atrophy (GA) in AMD.

Areas covered

This article reviews the current understanding of the complement system, its role in AMD, and the various complement-targeting therapies in development for the treatment of GA, including monoclonal antibodies, aptamers, protein analogs, and gene therapies. Approved and investigational agents have largely focused on interfering with the activity of complement components 3 and 5, owing to their central roles in the classical, lectin, and alternative complement pathways. Other investigational therapies have targeted formation of membrane attack complex (a terminal step in the complement cascade which leads to cell lysis), complement factors H and I (which serve regulatory functions in the alternative pathway), complement factors B and D (within the alternative pathway), and complement component 1 (within the classical pathway). Clinical trials investigating these agents are summarized, and the potential benefits and limitations of these therapies are discussed.

Expert opinion

Targeting the complement system is a promising therapeutic approach for slowing the progression of GA in AMD, potentially improving visual outcomes. However, increased risk of exudative conversion must be considered, and further research is required to identify clinical criteria and best practices for initiating complement inhibitor therapy for GA.

KEYWORDS:

• Age-related macular degeneration
• geographic atrophy
• complement
• inflammation
• pegcetacoplan
• avacincaptad pegol
• retina

Article highlights

• The complement system has recently emerged as a promising therapeutic target to slow progression of geographic atrophy (GA) in AMD.

• The complement system is a complex network of over 30 proteins that plays an essential role in the innate immune response, participating in immune surveillance and tissue homeostasis.

• The complement system consists of three distinct pathways. The classical pathway is triggered by IgG or IgM antibody-antigen complexes. The lectin pathway is triggered by recognition of specific carbohydrates on microbial surfaces. The alternative pathway is continuously activated through slow, spontaneous hydrolysis of complement component 3 (C3), requiring constant inhibition by endogenous regulatory proteins on host cell surfaces that pathogens do not possess.

• Activation of the complement cascade via any of these pathways produces a number of effector molecules that achieve three major outcomes: (1) opsonization of pathogens for phagocytosis, (2) production of anaphylatoxins that increase local vascular permeability and recruit inflammatory cells, and (3) target membrane damage resulting in cell lysis.

• There are multiple sites along the complement cascade that are targeted by investigational and recently-approved therapeutic agents.

• Two intravitreal complement inhibitors, pegcetacoplan (SYFOVRE, Apellis Pharmaceuticals), which targets C3, and avacincaptad pegol (IZERVAY, Astellas Pharmaceuticals), which targets C5, have recently been approved by the FDA to slow the progression of GA.

• Complement inhibitor therapy has notably been associated with increased risk of exudation in GA, although the impact on final visual acuity outcomes remains uncertain.

• Further research is necessary to identify clinical criteria and best practices for initiating complement therapy in GA.

Declaration of interests

T Ciulla is employed by, and holds stock options in, Clearside Biomedical and Viridian Therapeutics. He has been a consultant for Nanoscope and Ocuphire. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.