How does Pozelimabcompare with other treatments for AMD?

Introduction to Age-related Macular Degeneration (AMD)

Definition and Types of AMD
Age-related macular degeneration (AMD) is a progressive ocular disease that affects the macula, a small yet critical part of the retina responsible for central vision. It is the leading cause of irreversible vision loss among people over 50 in industrialized countries. AMD is broadly divided into two primary types. The first is the dry (nonexudative) form, also referred to as geographic atrophy (GA), characterized by the gradual degeneration of retinal pigment epithelium (RPE) cells and photoreceptors. The process is often associated with the accumulation of drusen—yellow deposits under the retina—and is marked by a slow but steady loss of central vision. In contrast, the wet (neovascular or exudative) form is marked by the growth of abnormal blood vessels from the choroid into the retina. This neovascularization, driven largely by vascular endothelial growth factor (VEGF), leads to rapid vision loss due to leakage, bleeding, and subsequent scarring of the macular region.

Current Treatment Landscape
The therapeutic approaches to AMD vary considerably based on the type of AMD. For wet AMD, the current standard of care is based on repetitive intraocular injections of anti-VEGF agents. Agents such as ranibizumab, aflibercept, bevacizumab, and more recently faricimab have been used extensively to inhibit abnormal blood vessel growth and vascular permeability, leading to stabilization or improvement of vision as evidenced in large pivotal clinical trials (e.g., MARINA, ANCHOR, VIEW studies). Despite their success in wet AMD, these drugs do not impact the progression of the dry form of AMD.
For dry AMD—especially geographic atrophy—there is a significant gap in effective therapies. Nutritional supplementation, as recommended by the Age-Related Eye Disease Study (AREDS), has been the mainstay of treatment, offering only a modest slowing of progression in a subset of patients. In light of this an unmet clinical need, newer strategies have begun to focus on the role of inflammation and complement dysregulation implicated in dry AMD. Several investigational agents, including complement inhibitors and neuroprotective agents, are in early to mid-stage clinical trials. In this context, pozelimab—a monoclonal antibody that targets complement factor C5—emerges as a novel approach to addressing the inflammatory component of dry AMD.

Pozelimab as a Treatment Option

Mechanism of Action
Pozelimab is a fully human IgG4P monoclonal antibody developed using proprietary humanized antibody (VelocImmune®) technology. Its primary mechanism of action is the inhibition of complement factor C5—a key component of the terminal complement cascade involved in producing inflammatory mediators. By binding with high affinity to both the wild-type and variant forms of C5, pozelimab prevents its cleavage into C5a and C5b, thereby potentially halting the formation of the membrane attack complex and the subsequent inflammatory responses that contribute to retinal cell damage.
This approach is particularly relevant in the context of dry AMD or geographic atrophy. In these patients, dysregulation of the complement system and chronic low-grade inflammation are thought to accelerate degeneration of the RPE and photoreceptors. Unlike anti-VEGF agents, which address only the neovascular component of wet AMD, pozelimab’s action in modulating complement-induced inflammation offers a promising strategy to slow progression in dry AMD—a disease form with very few treatment options at present.

Clinical Trial Results
A recently registered clinical trial is exploring the subcutaneous administration of pozelimab (either in combination with cemdisiran, a C5‐inhibiting siRNA, or as monotherapy) in adult participants with geographic atrophy secondary to AMD. Although full data from this trial have yet to be published, its design is intended to assess the effectiveness, safety, and tolerability of pozelimab in slowing the progression of atrophic lesions. Other publications on pozelimab have focused on its application in complement-mediated diseases like CHAPLE (CD55-deficient protein-losing enteropathy), where it has demonstrated rapid normalization of specific biomarkers and a tolerable safety profile when complemented with vaccination protocols to mitigate infection risks.
For AMD, the rationale is that by inhibiting complement-mediated inflammation, pozelimab may help limit further destruction of retinal cells that occurs in early and intermediate stages of dry AMD. If effective, this would represent a shift in the current paradigm, where most drugs do not halt or reverse the underlying degeneration but merely slow it. At this stage, comparative data of visual acuity gains or lesion size reductions compared to anti-VEGF treatments or nutritional supplementation are still awaited, but the focus remains on filling the therapeutic gap in nonexudative AMD.

Comparative Analysis of Treatments

Efficacy Comparisons
In comparing pozelimab with other treatments for AMD, several factors must be considered—most notably the distinction between efficacy in wet versus dry AMD.
For wet AMD, widely used anti-VEGF agents (ranibizumab, aflibercept, bevacizumab) have repeatedly demonstrated robust efficacy in improving or stabilizing vision. These agents work by directly inhibiting VEGF, thereby reducing neovascularization and fluid accumulation. Multiple studies have shown gains of upwards of 12–15 ETDRS letters in many patients. However, while these drugs are excellent at addressing new blood vessel formation, they do not influence the inflammatory or complement-mediated pathways that are key drivers in dry AMD.
Conversely, nutritional supplementation (e.g., AREDS formulations) has been shown to slow the progression of dry AMD modestly, with a relative risk reduction in progression to advanced disease of around 25% in appropriate patients, but without any improvement in visual acuity.
Pozelimab, with its complementary mechanism targeting the inflammatory cascade via C5 inhibition, is not competing head-to-head with anti-VEGF agents in wet AMD; rather, it is potentially the first drug to offer disease-modifying efficacy in dry AMD. Early trials are investigating if pozelimab can slow the enlargement of geographic atrophy lesions. While anti-VEGF therapies have robustly improved short-term vision outcomes in neovascular AMD, they have had no impact on dry AMD. Should pozelimab prove effective in its role, its benefits would be measured in terms of preventing further RPE degeneration and maintaining retinal integrity over long periods. In this sense, its efficacy would be complementary to rather than directly comparable with anti-VEGF therapies.
It is also important to note that other investigational complement inhibitors, such as pegcetacoplan, have shown promising results in reducing the progression of geographic atrophy. Pozelimab’s effectiveness will ultimately be compared with these agents based on endpoints such as changes in lesion size, the rate of progression, and ultimately, quality of life and functional vision outcomes.

Safety Profiles
The safety profiles of the current mainstay treatments for AMD differ significantly based on their mechanisms and routes of administration.
Anti-VEGF agents require repeated intravitreal injections. In addition to being invasive, these injections carry risks such as endophthalmitis, retinal detachment, intraocular pressure elevation, and cataract formation. Systemic side effects are low but not negligible. Moreover, the frequency of injections required (often monthly or bi-monthly) heightens the risk of injection-related complications over time.
Nutritional supplements, such as those used in AREDS formulations, are noninvasive and generally safe. However, their effect sizes are limited, and some components (e.g., beta-carotene) may be contraindicated in certain populations (such as smokers) due to potential safety concerns.
Pozelimab, on the other hand, is administered subcutaneously, thereby avoiding the injection-site ocular risks inherent to intravitreal anti-VEGF administration. Its systemic complement inhibition mechanism does carry a distinct safety consideration: the risk of infections, particularly with encapsulated organisms like Neisseria meningitidis. This risk is managed in clinical practice by vaccinating patients prior to starting treatment. Data from studies in other complement-mediated diseases suggest that aside from the infection risk, pozelimab is generally well tolerated with a mild-to-moderate profile of adverse events.
Thus, compared with the repetitive invasive deliveries of anti-VEGF therapies, pozelimab may offer a more convenient and potentially safer route for patients with nonexudative AMD if its long-term systemic safety profile is confirmed. In addition, the safety of complement inhibition will be critically examined in the AMD population since retinal tissue and systemic immune homeostasis may have unique sensitivities.

Cost-effectiveness Analysis
Cost-effectiveness is an important dimension when comparing AMD treatments. Anti-VEGF therapies, while clinically effective in wet AMD, are among the most expensive treatments available. Studies comparing ranibizumab and aflibercept have shown high cost-per-QALY ratios, sometimes mitigated by the use of off-label agents such as bevacizumab, which offers similar efficacy at a fraction of the cost.
For dry AMD, where the primary treatment has historically been nutritional supplementation, the direct costs are lower, but the overall cost-benefit is limited by the modest efficacy in preventing progression.
The overall economic benefit of a novel agent like pozelimab will depend on several factors. First, if pozelimab can slow or halt the progression of geographic atrophy, it could reduce the long-term burden of vision loss, including the need for additional supportive care, surgical interventions, or rehabilitation services. Second, if combined therapy (such as with cemdisiran) further boosts its efficacy, the upfront cost might be offset by a substantial reduction in downstream costs associated with blindness. Although no direct cost-effectiveness data for pozelimab in AMD are yet available, its production method (using VelocImmune® technology) and the possibility of less frequent systemic dosing may eventually render it economically competitive compared with the high cumulative cost of chronic intravitreal injections.
In summary, while anti-VEGF treatments are currently the most cost-intensive and effective for wet AMD, the potential use of pozelimab in dry AMD could be cost-saving in the long term if it successfully delays or prevents progression to advanced stages that incur significant health system and societal costs.

Future Directions and Research

Ongoing Research on Pozelimab
The clinical evaluation of pozelimab in AMD is still in its early stages. Ongoing trials such as the study described are designed to assess its efficacy, safety, and tolerability in patients with geographic atrophy. These studies will need to detail key endpoints such as changes in retinal lesion size, visual acuity maintenance, and functional outcomes over extended periods. Additional research is expected to refine the dosing regimen, explore combination therapy approaches (specifically pozelimab in combination with cemdisiran, which may provide a dual inhibitory effect on the complement cascade), and establish the biomarker profiles that predict treatment response.
Research on pozelimab in other indications (for instance, in CHAPLE disease) provides important preliminary safety and efficacy data that will guide its application in AMD. However, dedicated studies in AMD—addressing disease-specific challenges and patient heterogeneity—are essential for determining where pozelimab will fit in the clinical landscape compared to established anti-VEGF therapies and investigational complement inhibitors like pegcetacoplan.

Emerging Treatments and Innovations
The overall treatment landscape for AMD is evolving rapidly with numerous novel approaches under investigation. For wet AMD, the focus continues to shift toward drugs with extended durability, such as faricimab, and novel delivery methods that reduce the injection frequency (port delivery systems are one example). In contrast, for dry AMD, the absence of any approved therapy has spurred intense research into complement inhibition, neuroprotection, and even cellular therapies including RPE transplantations.
Emerging pharmacologic agents—such as pegcetacoplan and avacincaptad pegol—also target the complement cascade, but at different points along the pathway. Comparisons between these agents and pozelimab will likely be made on efficacy in slowing geographic atrophy progression, safety profiles (in terms of systemic immunosuppression and infection risk), and dosing convenience. Furthermore, research is also exploring personalized medicine approaches whereby patient genetics (such as polymorphisms in CFH, ARMS2, or other complement-related genes) might guide treatment selection.
Innovations in imaging and functional assessments will also allow for more precise monitoring of treatment efficacy. The integration of advanced optical coherence tomography (OCT) techniques and retinal function measurements may refine the endpoints used in future trials, giving better insight into how complement inhibition with pozelimab compares with and possibly complements existing therapies.
There is also great interest in combining different therapeutic modalities—such as pairing anti-VEGF treatments with complement inhibitors—to address both the neovascular and inflammatory aspects of AMD. While anti-VEGF therapies effectively tame neovascularization, they do little to modify the underlying degenerative process in dry AMD. Pozelimab may fill this gap if future studies confirm that complement blockade slows the slow march toward geographic atrophy. This combined approach holds potential for a more comprehensive treatment strategy that not only improves visual acuity but also preserves retinal structure over the long term.

Conclusion
In general, AMD remains a major cause of vision loss with a bifurcated therapeutic landscape: effective anti-VEGF agents dominate the treatment of wet AMD, while dry AMD (geographic atrophy) lacks truly effective therapies. The standard anti-VEGF agents (ranibizumab, aflibercept, bevacizumab, brolucizumab) provide robust short-term gains through inhibition of VEGF-driven neovascularization but do not alter the course of complement-driven inflammation and degeneration seen in dry AMD. Nutritional supplementation (AREDS) and lifestyle modifications can slow progression in selected patients with dry AMD, but these measures offer only a marginal benefit.
Pozelimab introduces a novel therapeutic mechanism by targeting complement factor C5 to mitigate the chronic inflammatory cascades implicated in dry AMD. Early clinical trials (e.g., the study described) are assessing whether pozelimab, particularly when used in combination with agents such as cemdisiran, can slow geographic atrophy progression, thereby offering a treatment option for a patient population with very limited choices. Its mechanism of action is distinct from that of anti-VEGF drugs, meaning that while it may not compete directly in the realm of neovascular AMD, it holds promise particularly in addressing the unmet needs in nonexudative AMD.
From an efficacy standpoint, whereas anti-VEGF agents have repeatedly demonstrated their ability to improve visual acuity in wet AMD, pozelimab’s promise lies in its potential to preserve retinal structure and slow vision loss in dry AMD—a goal that has not yet been achieved by other therapies. Safety remains a critical consideration; while the intravitreal delivery of anti-VEGF agents imposes risks related to repeated ocular injections, pozelimab’s systemic administration avoids these complications. Nonetheless, systemic complement inhibition carries its own set of challenges, particularly related to the risk of serious infections—a risk that can be mitigated through vaccination protocols.
Economically, anti-VEGF therapies for wet AMD are high-cost interventions that have spurred considerable cost-effectiveness debates, with agents such as bevacizumab emerging as a lower-cost alternative despite their off-label use. Should pozelimab demonstrate efficacy in slowing the progression of dry AMD, its long-term cost-effectiveness will depend on its ability not only to maintain vision and quality of life but also to reduce the broader healthcare and societal costs associated with advanced vision loss. Early indications based on production technology and dosing regimens suggest that pozelimab may eventually be a competitive option in this regard, but definitive economic assessments await data from further-phase trials.
Future directions in AMD therapy are poised to embrace combination regimens and personalized medicine strategies. As ongoing research continues to define the role of complement inhibition in retinal diseases, pozelimab could become an integral component of a broader therapeutic arsenal—potentially used in combination with anti-VEGF agents or neuroprotective strategies to comprehensively address both the neovascular and degenerative mechanisms involved in AMD. With innovations in diagnostic imaging and a better understanding of genetic risk factors, future clinical trials will refine the selection of patients who stand to benefit most from pozelimab, thereby optimizing treatment outcomes.
In conclusion, the available evidence shows that while anti-VEGF agents provide substantial benefits in wet AMD, their inability to address the underlying inflammatory and complement-mediated damage in dry AMD represents a significant unmet need. Pozelimab, by virtue of its targeted inhibition of C5, may offer a promising alternative or adjunct therapy specifically for geographic atrophy. Its unique mechanism, potential for safer subcutaneous administration, and the possibility of reducing the overall long-term cost burden render it an interesting candidate to fill a significant gap in current AMD treatment. However, several questions remain regarding its long-term efficacy, safety, and economic viability. Ongoing clinical trials and future research will be crucial in determining where pozelimab fits in the evolving treatment paradigm for AMD and whether it can fulfill its promise as a complementary or standalone therapy for this challenging disease.