Gene Therapy Trial for Geographic Atrophy Shows Limited Efficacy Despite Sustained Factor I Expression

The FOCUS Phase I/II clinical trial investigating PPY988, a novel gene therapy approach for geographic atrophy (GA), has revealed important findings about complement modulation in age-related macular degeneration (AMD), despite the program's early termination by Novartis.

The trial evaluated PPY988, a subretinal gene therapy designed to supplement complement factor I (CFI) protein in retinal layers affected by GA. While the therapy demonstrated successful protein expression, its therapeutic impact fell short of expectations, leading to important lessons for future complement-targeting treatments.

Key Findings and Biomarker Analysis

The study enrolled 31 subjects who received one of three doses of PPY988 via subretinal delivery. Comprehensive biomarker analysis revealed:

• A sustained two-fold increase in vitreous humor Factor I levels at week 36, maintained through week 96
• Reduction in complement activation marker Ba by approximately 2-fold at week 36
• Minimal impact on other complement activation products, suggesting limited therapeutic effect
• Comparable response between CFI rare variant carriers and non-carriers

Comparative Potency Analysis

In vitro studies comparing PPY988 with pegcetacoplan (Syfovre), a recently approved complement inhibitor, revealed crucial differences:

• Pegcetacoplan demonstrated significantly higher potency in controlling complement activation
• Factor I showed limited effectiveness at clinically achieved concentrations
• The findings suggest that increasing Factor I concentration alone may be insufficient for meaningful clinical benefit

Technical Insights and Sampling Methodology

The study provided valuable technical insights for future gene therapy trials:

• Successful implementation of serial vitreous sampling
• Impact of vitrectomy on protein levels requiring careful data interpretation
• Limited correlation between aqueous and vitreous humor biomarkers
• Need for protein level normalization in post-vitrectomy analyses

Implications for Future Research

While the PPY988 program did not advance to later-stage development, the study offers critical learnings:

• Validates complement modulation as a therapeutic strategy, given recent successes with other complement inhibitors
• Highlights the importance of potency considerations in gene therapy development
• Suggests potential opportunities for engineering more active regulatory proteins
• Emphasizes the need for robust preclinical potency assessments

The findings underscore that while gene therapy remains a promising approach for GA treatment, careful consideration must be given to achieving sufficient therapeutic potency. The study's comprehensive biomarker analysis provides a valuable framework for future complement-targeting therapies in ophthalmology.