- Introduction:

  - Geographic atrophy (GA) is a leading cause of blindness in adults over 50, affecting 196 million people globally.

  - GA involves progressive retinal degeneration due to photoreceptor, retinal pigment epithelium (RPE), and choriocapillaris loss.

  - Overactivation of the complement system is thought to play a key role in GA progression.

  - In 2023, the FDA approved two complement inhibitors, Syfovre (pegcetacoplan) and Izervay (avacincaptad pegol), for GA treatment.

- Syfovre (Pegcetacoplan):

  - C3 and C3b inhibitor approved in early 2023.

  - Phase III trials (OAKS and DERBY) showed a 22% and 19% reduction in GA lesion growth rate with monthly injections, and 18% and 16% with every-other-month (EOM) dosing over 24 months.

  - GALE extension study at 36 months showed further reduction in GA growth rate (25% monthly, 20% EOM).

  - No significant improvement in functional visual outcomes (e.g., BCVA, reading independence).

  - Safety concerns: Intraocular inflammation (0.24%), retinal vasculitis, infectious endophthalmitis (0.03%), ischemic optic neuropathy (1.7% monthly group), and new-onset exudative AMD (11-13% in treated groups).

- Izervay (Avacincaptad Pegol):

  - C5 complement inhibitor approved in late 2023.

  - GATHER2 trial showed a 14% reduction in GA growth rate with monthly dosing over 12 months, and 19% at 24 months with EOM dosing.

  - No significant improvement in visual function (BCVA, low-luminance BCVA).

  - Safety profile: No cases of intraocular inflammation, endophthalmitis, or retinal vasculitis reported.

  - Higher rates of macular neovascularization (4% at 12 months, 7% at 24 months) compared to sham.

- Safety Profiles:

  - Syfovre: Higher risk of intraocular inflammation, retinal vasculitis, and ischemic optic neuropathy.

  - Izervay: Lower risk of inflammation and infection but higher risk of macular neovascularization.

  - Both drugs carry a risk of converting to exudative AMD, which can be managed with anti-VEGF injections.

- Approach to Treatment:

  - Patient education is crucial, emphasizing the risks and limited impact on visual acuity.

  - Treatment decisions should be individualized based on disease stage, location, and patient comorbidities.

  - Syfovre may be more suitable for foveal-involving GA, while Izervay may be better for earlier-stage GA.

  - Close monitoring is essential after initial doses, especially for treatment-naïve eyes.

  - Financial and psychological burdens of repeated intravitreal injections should be considered.

- Conclusion:

  - Syfovre and Izervay represent significant advancements in GA treatment, offering hope for slowing disease progression.

  - Further research is needed to assess long-term efficacy, safety, and real-world outcomes.

  - Ongoing discussions in the retina community highlight the need for standardized guidelines and potential future therapeutic options.