How does Pegcetacoplancompare with other treatments for AMD?

Overview of Age-related Macular Degeneration (AMD)

Definition and Types
Age-related macular degeneration (AMD) is a degenerative ocular condition that primarily impacts the central region of the retina—the macula—leading to significant central vision loss in the elderly population. Its hallmark features include the presence of drusen, retinal pigment epithelium (RPE) alterations, and macular atrophy. AMD is broadly classified into two types:
• Dry AMD (nonexudative) is characterized by gradual RPE and photoreceptor degeneration often accompanied by geographic atrophy (GA), a late-stage irreversible loss of retinal tissue.
• Wet AMD (exudative or neovascular) is marked by abnormal blood vessel growth (choroidal neovascularization) underneath the retina, leading to leakage, hemorrhage, and rapid vision loss.

These distinctions are crucial as they influence both clinical management and the treatment options available. While wet AMD has historically been managed with anti-vascular endothelial growth factor (anti-VEGF) therapies, dry AMD had long been considered untreatable until the advent of therapies targeting the complement cascade, such as pegcetacoplan.

Current Treatment Landscape
In current clinical practice, the treatment of AMD varies considerably between its forms. For wet AMD, intravitreal injections of anti-VEGF agents – including ranibizumab (Lucentis®), aflibercept (Eylea®), bevacizumab (Avastin® off-label), and the more recently introduced faricimab – have become the standard of care. These agents aim to inhibit abnormal blood vessel growth and vascular leakage, thereby preserving visual acuity and sometimes even improving it on a monthly or bimonthly dosing regimen.
Dry AMD, particularly when it progresses to geographic atrophy (GA), has long posed a treatment challenge because neurodegenerative changes in the retina are irreversible. Historically, patients have been managed with nutritional supplementation (e.g., AREDS formula) aimed at slowing progression, but these measures do not reverse damage. Emerging therapies now target specific pathogenic mechanisms, such as modulation of the complement system that drives inflammation and tissue degeneration. In this context, pegcetacoplan has garnered significant attention as it is the first FDA-approved treatment specifically for GA, marking a breakthrough for the nonexudative form of AMD.

Pegcetacoplan: A New Treatment Option

Mechanism of Action
Pegcetacoplan represents a novel therapeutic approach because it targets the complement cascade at its central component, C3. By binding to C3 and its activation fragment C3b, pegcetacoplan prevents further cleavage into downstream effectors that result in inflammation, cellular damage, and ultimately atrophy of the retinal tissue. This upstream inhibition modulates the overactivation of the complement system—a pathophysiological driver in dry AMD—thereby reducing inflammatory processes and slowing the progression of GA. Unlike anti-VEGF therapies that block angiogenic factors involved in new blood vessel formation, pegcetacoplan acts on the innate immune response implicated in the chronic degeneration seen in dry AMD. This difference in mechanism directly addresses one of the key unmet needs in AMD management: a treatment option beyond the reduction of aberrant vascular permeability and neovascularization.

Clinical Trial Results
Multiple clinical trials have evaluated the efficacy and safety of pegcetacoplan in patients with GA secondary to AMD. In phase II (FILLY) and phase III studies (DERBY and OAKS), pegcetacoplan administered intravitreally on a monthly or every-other-month schedule demonstrated a statistically significant reduction in GA lesion growth. For instance, in the OAKS trial, monthly administration resulted in a 21–22% reduction in lesion growth, and every-other-month dosing achieved approximately a 16% reduction relative to sham treatment. Although these trials did not show clear differences in traditional visual acuity endpoints over the study duration—owing largely to the slow progression of GA and the use of anatomic endpoints—the slowed progression of atrophy suggests potential long-term benefits in preserving central vision. Furthermore, subgroup analyses indicate that the treatment effect may be more pronounced in extrafoveal lesions compared to subfoveal involvement, an observation that could guide patient selection strategies in clinical practice. The clinical trials, though encouraging, also noted some safety concerns, such as an increased incidence of conversion to exudative (wet) AMD in a subset of treated patients. In summary, the clinical results demonstrate that pegcetacoplan effectively slows GA lesion expansion in dry AMD with an acceptable safety profile, though careful monitoring is necessary.

Comparison with Other AMD Treatments

Efficacy Comparison
When comparing therapeutic efficacy, it is important to note that the mechanisms and clinical outcomes of pegcetacoplan differ fundamentally from those of established anti-VEGF therapies. Anti-VEGF agents, such as ranibizumab and aflibercept, are designed to inhibit neovascularization by blocking VEGF—a key driver in wet AMD pathophysiology. Their efficacy in wet AMD is well-documented through improvements in best-corrected visual acuity (BCVA) and reductions in intraretinal fluid accumulation. However, these anti-VEGF agents have limited or no efficacy in dry AMD, where vascular proliferation is not the primary concern.

Pegcetacoplan, by contrast, directly targets the complement system in dry AMD. Its ability to slow GA progression represents a breakthrough in addressing the underlying inflammatory and degenerative processes that occur in atrophic AMD. Clinical trial data from the FILLY, DERBY, and OAKS studies suggest that pegcetacoplan slows the expansion of atrophic lesions by about 16–22%, a statistically significant difference compared to sham injections. Despite this anatomical benefit, some clinical trials reported that improvements in visual function (e.g., BCVA) remain less pronounced over the study period. These findings are consistent with the notion that anatomical preservation may precede measurable functional gains, especially in a slowly progressive disease such as GA. Therefore, compared to anti-VEGF treatments—which rapidly improve vision in wet AMD but are not effective in dry AMD—pegcetacoplan provides a complementary therapeutic approach for dry AMD by targeting disease progression at a molecular level.

Safety and Side Effects
Safety profiles between pegcetacoplan and other AMD treatments also differ significantly owing to their unique mechanisms of action. Anti-VEGF therapies have generally been well-tolerated with ocular complications—including endophthalmitis, retinal detachments, or increased intraocular pressure—being relatively rare with strict adherence to injection protocols. In contrast, pegcetacoplan is associated with a distinct set of safety considerations. While the clinical trials established an acceptable overall safety profile, there is an observed increased incidence of new-onset exudative AMD (conversion to wet AMD) in the pegcetacoplan-treated group. For instance, in the DERBY and OAKS trials, conversion rates of approximately 6–12% were noted in treated eyes compared to lower rates with sham treatment. This conversion risk requires careful patient selection and monitoring, particularly in those with preexisting risk factors for neovascularization.

Other local adverse effects commonly observed with intravitreal injections, such as injection site reactions, are comparable between pegcetacoplan and anti-VEGF drugs; however, the risk–benefit balance is influenced by the fact that pegcetacoplan is addressing a previously untreatable aspect of AMD. Ongoing analyses and post-marketing surveillance will help to further characterize these risk profiles. In summary, while anti-VEGF therapies exhibit well-established ocular safety profiles in the treatment of wet AMD, pegcetacoplan’s safety profile must be interpreted in the context of its novel mechanism, with particular vigilance towards potential conversion risk and compliance with follow-up care.

Cost and Accessibility
Cost is a particularly critical factor when evaluating treatments for AMD. Anti-VEGF treatments, though effective for wet AMD, involve repeated intravitreal injections that can be expensive and require frequent visits to specialized centers. Many healthcare systems have developed protocols and reimbursement strategies given the high burden of these treatments. Although biosimilar and off-label alternatives (such as bevacizumab) exist, the cost–effectiveness debate among anti-VEGF agents remains a key consideration.

Pegcetacoplan, as the first drug approved specifically for GA in dry AMD, enters a market with a significant unmet need; however, its cost is also high, with estimates suggesting that the per-injection cost could be around 2000 USD or more. As a result, accessibility may be limited by economic and system-level factors, particularly in areas with tight healthcare budgets. Cost–effectiveness analyses that consider quality-adjusted life years (QALYs) and overall economic burden are needed to contextualize the potential long-term benefits of slowing GA progression relative to the high drug cost. In addition, the cost barrier may drive further comparisons with other investigational and emerging therapies targeting complement activity or alternative pathways in AMD. In summary, while pegcetacoplan adds a critical therapeutic option for the dry AMD segment, its cost and the financial implications for both patients and healthcare providers require thorough economic evaluations and policy considerations to enhance future accessibility.

Future Directions and Considerations

Ongoing Research and Trials
Future developments in AMD treatment are robust, as numerous clinical trials continue to refine our understanding of treatment regimens for both dry and wet AMD. For pegcetacoplan, additional data from ongoing studies such as the GALE extension study and various phase 4 real-world evidence projects will further elucidate its long-term efficacy, safety, and impact on visual function. Other investigational therapies targeting different components of the complement cascade (e.g., avacincaptad pegol and gene therapy approaches such as AAVCAGsCD59) are complementary to pegcetacoplan and reflect the vibrant research landscape. These ongoing studies will clarify the optimal dosing regimens, long-term effects, and potential for combined therapy approaches that address both anatomical preservation and functional improvement.

Potential for Combination Therapies
Given the multifactorial nature of AMD pathophysiology, there is growing interest in combination therapies that integrate the benefits of targeting different pathways. For instance, while anti-VEGF agents have clear benefits in neovascular AMD, combining them with complement inhibitors like pegcetacoplan in patients with mixed pathology or early converters to exudative AMD might enhance overall outcomes. In addition, studies investigating cellular therapies, retinal implants, and gene therapies are opening the door toward restoring lost function in advanced disease stages. Integrating pegcetacoplan with complementary approaches that address oxidative stress, inflammation, and neuroprotection holds promise for more holistic management strategies. The potential synergistic effect of combination therapies could not only improve visual outcomes but also offer a customized approach based on individual patient risk factors and genetic profiles.

Economic and Policy Implications
The introduction of a high-cost therapy like pegcetacoplan has important implications for healthcare policy and economic decision-making. As numerous new agents emerge in the treatment landscape for AMD, policymakers and healthcare providers must balance the clinical benefits of slowing disease progression against the financial impact on healthcare systems. Economic evaluations that incorporate cost–utility and cost-effectiveness analyses are essential to determine whether the long-term benefits of delaying GA progression translate into sufficient improvements in quality of life and reduced burden on healthcare resources.

Furthermore, reimbursement policies, patient access programs, and the development of biosimilars will be critical in ensuring that innovations in AMD treatment, such as pegcetacoplan, become accessible to a broader patient population. With increasing competition from other investigational complement inhibitors and gene therapies, transparent pricing strategies and real-world efficacy data will shape future policy decisions. In addition, long-term clinical outcomes and patient-reported outcome measures (PROMs) will be essential for assessing the value of these treatments in routine clinical practice.

Detailed Conclusion
In summary, while AMD remains a leading cause of irreversible vision loss among the elderly worldwide, the evolving treatment landscape is now offering options for both wet and dry forms of the disease. Traditional anti-VEGF agents are highly effective for neovascular AMD but have historically left the dry form, particularly geographic atrophy, with limited treatment options. Pegcetacoplan, a novel C3 complement inhibitor, fills this critical gap by directly targeting the chronic inflammation and complement overactivation that underlies dry AMD. Clinical evidence from the FILLY, DERBY, and OAKS studies suggests that pegcetacoplan significantly slows the growth of GA lesions, providing an anatomical benefit that may eventually translate into preservation of visual function. Although this treatment shows promise, it also comes with specific safety concerns—most notably the increased risk of conversion to wet AMD—and a high cost that may limit its immediate accessibility.

Comparing pegcetacoplan with other treatments reveals several key points. First, in terms of efficacy, while anti-VEGF therapies deliver rapid improvement in vision for wet AMD, pegcetacoplan offers a breakthrough by slowing the degeneration seen in dry AMD. Second, the safety profile differs in that anti-VEGF agents have a long track record of minimal ocular side effects, whereas pegcetacoplan requires monitoring for potential exudative conversion and other intravitreal injection-related reactions. Third, the economic implications and cost–effectiveness parameters for pegcetacoplan are still being evaluated, with initial indications suggesting that its high cost must be weighed against the clinical benefit of slowing GA progression—a benefit that may accrue over many years.

Looking forward, ongoing research and expansion of clinical trials will provide a clearer picture of pegcetacoplan’s long-term impact and its potential role in combination therapies. The integration of pegcetacoplan with other modalities, such as anti-VEGF agents for mixed AMD forms or gene therapies targeting specific genetic risk factors, is an exciting area of development that may yield synergistic benefits. Economic evaluations and policy decisions will further determine how this new therapy fits within the broader public health framework, ensuring that its innovative benefits are accessible while maintaining sustainable healthcare budgets.

Ultimately, the advent of pegcetacoplan marks a substantial step forward in the treatment of AMD—specifically addressing an unmet need for patients with dry AMD. Its mechanism of action, clinical trial success in slowing GA progression, and promise in combination with other treatments offer a new avenue for preserving vision and enhancing quality of life in a disease that has long been a leading cause of blindness. As further evidence emerges from extended trials and real-world use, the precise role of pegcetacoplan will become clearer, enabling clinicians, patients, and policymakers to make informed decisions based on a balance of efficacy, safety, cost, and long-term outcomes.