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.
