Complement inhibition as a therapeutic strategy in retinal disorders

ABSTRACT

Introduction: Dry age-related macular degeneration (AMD) and Stargardt Macular Dystrophy (STGD1) result in vision loss due to progressive atrophy of the macula and lack of effective treatments. Numerous studies have implicated complement-associated inflammation as a contributor to both diseases.

Areas covered: The complement factor D inhibitor, lampalizumab, failed to halt geographic atrophy (GA) progression in phase 3 studies. The complement factor 3 (C3) inhibitor, APL-2, has shown potential to reduce GA growth in a phase 2 trial, supporting advancement to phase 3 trials. The intravenous complement factor 5 (C5) inhibitor, eculizumab, failed to halt GA progression in a phase 2 study. Another C5 inhibitor, avacincaptad pegol, is delivered by intravitreal injection, and will be studied for safety and preliminary signs of efficacy for AMD and STGD1 patients in phase 2 trials. LFG316 (C5 inhibitor) and CLG561 (properdin inhibitor) failed to halt GA progression in phase 2 studies. A phase 1 trial is evaluating the effects of combining LFG316 and CL561. Complement inhibition by gene therapy will be explored in the phase 1 trial of HMR59 in AMD patients.

Expert opinion: While complement inhibition has not yet demonstrated the ability to halt GA progression in a phase 3 trial, further study is warranted.

KEYWORDS:

• Complement
• age-related macular degeneration
• geographic atrophy
• lampalizumab
• eculizumab
• avacincaptad pegol
• APL-2
• LFG316
• CL561
• Stargardt macular dystrophy

Article highlights

• Complement associated inflammation contributes to progression of age-related macular degeneration (AMD) and Stargardt macular dystrophy (STGD1). Various complement inhibitors are under investigation to slow down these degenerative diseases.

• The complement factor D inhibitor, lampalizumab, failed to halt geographic atrophy (GA) progression in phase 3 studies for AMD.

• The C3 inhibitor, APL-2, has shown potential to reduce GA growth in a phase 2 trial, supporting advancement to phase 3 trials.

• The intravenous C5 inhibitor, eculizumab, failed to halt GA progression in a phase 2 study.

• The C5 inhibitor, avacincaptad pegol, is delivered by intravitreal injection, and will be studied for safety and preliminary signs of efficacy for AMD and STGD1 patients in phase 2 trials.

• LFG316 (C5 inhibitor) and CLG561 (properdin inhibitor) failed to halt GA progression in phase 2 studies.

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Declaration of interest

T Ciulla has had previous employment and equity ownership in Ophthotech Corporation, and current employment and equity ownership in Spark Therapeutics. This work was undertake in his role as Volunteer Clinical Professor at Indiana University School of Medicine, and does not reflect the views or opinions of these corporations or management. P Dugel is on the scientific advisory board for Genentech, Roche, Alcon and Ophthotech. 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.

Reviewer disclosures

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

Additional information

Funding

This paper was not funded.