What drugs are in development for Geographic Atrophy?

Introduction to Geographic Atrophy
Definition and Pathophysiology
Geographic Atrophy (GA) is an advanced form of dry age-related macular degeneration (AMD) characterized by progressive atrophy of the retinal pigment epithelium, photoreceptors, and underlying choriocapillaris. GA leads to irreversible vision loss when the atrophic lesions encroach upon the fovea, the region responsible for central, high-resolution vision. The underlying pathophysiology is multifactorial, involving chronic inflammation, oxidative stress, and dysregulation of the complement cascade. Genetic studies have highlighted variants, particularly in complement system regulators such as CFH, that predispose individuals to aberrant complement activation contributing to the progression of GA. Inflammatory mediators stimulate a faulty immune response in the macula, ultimately resulting in progressive cell death and tissue loss. This recognition of the central role of the complement system has driven significant research efforts to develop targeted therapeutics for GA.

Epidemiology and Impact
The incidence of GA increases with age, with prevalence estimates demonstrating significant impact among elderly populations. Approximately one million individuals in the United States and five million people worldwide are affected by GA, with rates increasing to nearly 25% in populations over age 90. The progressive loss of vision directly impacts patient quality of life, independence, and the ability to perform everyday tasks. Economic burdens, both direct and indirect, are substantial, and the need for effective, long-term treatment options continues to grow as the population ages.

Current Treatment Landscape
Existing Treatments and Limitations
Although the introduction of anti-vascular endothelial growth factor (anti-VEGF) therapies has dramatically changed the treatment of neovascular AMD, there remain no widely approved therapies that reverse or even halt the progression of GA. Recently, pegcetacoplan—an investigational, targeted inhibitor of complement component C3—was approved by the FDA under the brand name Syfovre for the treatment of GA. However, despite its favorable impact on reducing the progression of GA lesions as demonstrated in Phase 3 clinical trials (DERBY/OAKS), its efficacy is modest with only a reduced rate of lesion growth rather than functional improvement in vision. In addition, other published research has shown that even promising treatments may come with challenges such as the need for frequent intravitreal injections, potential for adverse ocular events (for example, conversion to neovascular AMD), and complex dosing regimens that may limit patient adherence in real-world settings.

Unmet Medical Needs
The absence of curative or robustly disease-modifying treatments in GA leaves a considerable unmet medical need. With GA being largely asymptomatic until central vision is affected, there is a critical need for therapies that not only slow lesion progression but also help preserve or improve retinal function. The chronic and progressive nature of GA calls for treatments that offer increased dosing intervals, minimal adverse effects, and solutions that ultimately provide significant visual benefit beyond reducing the anatomical progression. Moreover, the economic impact combined with the psychological and functional burden on patients underlines the necessity for novel treatment modalities that are both clinically effective and patient-friendly.

Drugs in Development
Key Drugs in Clinical Trials
Multiple agents are currently in development targeting various components of the pathogenic cascade in GA. Although several drugs have been designed to inhibit the complement pathway, other therapeutic strategies are also emerging. The following are some of the most prominent drugs under clinical evaluation or near clinical translation:

• Pegcetacoplan: Developed by Apellis Pharmaceuticals, pegcetacoplan is a targeted C3 inhibitor that has already received FDA approval. Nevertheless, its continued development and long-term studies remain part of the evolving landscape as researchers further assess its efficacy in slowing the progression of GA lesions over time using an intravitreal injection regimen. Despite its approval, pegcetacoplan’s fitted role in the broader treatment paradigm continues to be refined to ensure optimal dosing intervals and combination strategies with other approaches.

• Avacincaptad Pegol (Zimura®): This investigational drug is a complement component C5 inhibitor developed by Iveric Bio. In pivotal Phase 3 clinical trials (such as GATHER1 and GATHER2), avacincaptad pegol has demonstrated statistically significant reductions in the rate of GA lesion growth. For example, one trial reported a 14.3% reduction in the square root-transformed GA growth rate over 12 months. Post-hoc analyses have also revealed even greater reductions in specific subgroups, particularly in patients from defined geographic regions, making avacincaptad pegol one of the most promising agents in this therapeutic area.

• ANX007: Produced by Annexon, Inc., this agent is a selective inhibitor of C1q, the initiating molecule of the classical complement pathway. ANX007 has entered clinical trials—often in the context of combination studies—to assess its potential in mitigating immune-mediated damage in GA. Early clinical data indicate that using ANX007 as a standalone or additive therapy may block the early triggers of the complement cascade, possibly leading to meaningful clinical benefit by not only reducing anatomical lesion progression but also preserving retinal function over time.

• NGM621: A proprietary humanized immunoglobulin that exhibits potent binding to complement component C3, NGM621 is designed for intravitreal administration. Its development is based on the therapeutic rationale that strong and sustained C3 inhibition may provide a more durable suppression of the pathological complement activation underlying GA progression. Preclinical studies and early-phase clinical data have indicated favorable pharmacokinetics and dosing intervals, potentially allowing for every-eight-week dosing regimens, which would alleviate the treatment burden on patients.

• PAS-Nomacopan: Akari Therapeutics is pursuing a preclinical and early clinical development program for PAS-nomacopan, a long-acting version of nomacopan engineered using PASylation technology. This formulation is specifically designed to extend the dosing interval beyond three months while maintaining robust inhibition of complement C5 and leukotriene B4. The extended half-life and improved molecular properties have the potential to further reduce treatment frequency, addressing a major unmet need in GA treatment.

• Other Complement Inhibitors and Gene Therapy Approaches: In addition to the above agents, there are other novel therapeutic modalities under investigation. Some early-stage studies are exploring the delivery of complement regulatory proteins via gene therapy. For instance, approaches that involve the use of adeno-associated virus (AAV) vectors for local delivery of complement factor I or soluble complement regulators are being evaluated preclinically, with the aim of achieving continuous therapeutic levels without the need for frequent injections. Although these approaches are in earlier stages compared to the direct complement inhibitors, they represent an exciting new direction in GA therapy development.

Mechanisms of Action
From a mechanistic standpoint, the drugs in development target various nodes of the complement cascade, each with slightly different pharmacodynamic profiles:

• Direct Complement Inhibition at the C3 Level (Pegcetacoplan, NGM621): C3 is the central component of the complement cascade. Inhibition at this level provides broad suppression of complement activation, preventing the formation of pro-inflammatory fragments and the membrane attack complex (MAC) that drive retinal cell damage. Pegcetacoplan binds to C3 and blocks its conversion into C3a and C3b, mitigating inflammatory damage. Similarly, NGM621 is designed to interact with C3 with high affinity, offering the potential for a longer duration of action and a reduction in treatment frequency.

• Inhibition of the Terminal Complement Pathway (Avacincaptad Pegol, PAS-Nomacopan): Avacincaptad Pegol targets the C5 component of the complement cascade. By preventing the cleavage of C5 into C5a and C5b, it effectively reduces the generation of the potent inflammatory mediator C5a and the assembly of the MAC. This targeted approach allows for the suppression of inflammation while potentially maintaining upstream complement functions important for host defense. PAS-Nomacopan, by contrast, provides similar inhibition of C5 but with a modified pharmacokinetic profile that enables prolonged dosing intervals using innovative PASylation technology.

• Classical Pathway Inhibition (ANX007): ANX007 acts at the very beginning of the complement cascade by inhibiting C1q. Given that C1q is responsible for initiating the classical pathway (one of three complement activation pathways), its inhibition can prevent the downstream inflammatory cascade. This strategy may be particularly useful if early complement activation contributes heavily to the pathological process of GA, allowing for both anatomical preservation and functional benefits.

• Gene Therapy and Sustained Delivery Approaches: Beyond traditional protein therapeutics, advanced drug delivery modalities—such as gene therapy—are also being explored. In these approaches, the objective is to achieve continuous and sustained expression of complement regulators directly within the eye. This could potentially eliminate or reduce the need for repeated injections while maintaining therapeutic levels of the inhibitor over a long period. Although these strategies are currently at an early stage, they offer an exciting alternative to conventional drug administration.

Efficacy and Safety Data
There is a growing body of clinical and preclinical data that underpins the development of these drugs for GA:

• Pegcetacoplan: Phase 3 clinical trials (DERBY and OAKS) have reported statistically significant reductions in the growth rate of GA lesions. The primary efficacy endpoint was typically measured using fundus autofluorescence and square root transformation of the lesion area. Safety data from these trials indicate a generally favorable profile, although adverse ocular events such as conversion to neovascular AMD have been noted, emphasizing the need for careful patient selection and ongoing monitoring.

• Avacincaptad Pegol: Data from the GATHER1 and GATHER2 trials have demonstrated that avacincaptad pegol reduces the mean rate of GA growth by approximately 14–18% over 12 months compared to sham treatment. Notably, subgroup analyses have suggested even greater efficacy in defined patient populations. The safety profile appears robust with a low incidence of severe adverse events, although as with other intravitreal therapies, injection-related complications are an ongoing concern.

• ANX007: Early data from clinical studies with ANX007 show that selective inhibition of C1q can be safely achieved with intravitreal administration. While detailed efficacy data in terms of lesion size reduction are still emerging, preliminary observations are promising with respect to both anatomical preservation and potential functional benefits. The unique mode of action of ANX007 posits that early blockade of the classical complement pathway might offer benefits complementary to agents targeting downstream components, although further data are required.

• NGM621: In early-phase clinical studies, NGM621 has shown promising pharmacokinetic properties including sustained inhibition of C3 activity over extended dosing intervals. Initial efficacy signals suggest that robust inhibition of complement activity at the C3 level may lead to measurable decreases in GA lesion progression over the treatment period. Safety assessments to date have reported acceptable tolerability, supporting the continued clinical investigation of NGM621.

• PAS-Nomacopan: The long-acting PAS-nomacopan candidate has undergone preclinical evaluation demonstrating high levels of activity with a significantly extended half-life. Such modifications not only promise to reduce the frequency of intravitreal injections but also may lower the overall rate of adverse events by providing a more stable drug level in the retina. Although human data are still forthcoming, the preclinical safety and efficacy profile are encouraging and support further clinical development.

Across these programs, common endpoints are used to measure efficacy, including the change in lesion area assessed by high-resolution imaging techniques (e.g., fundus autofluorescence) as well as functional outcomes that, while challenging to capture in a slowly progressive disease such as GA, remain an important secondary consideration. Safety assessments have focused on both ocular and systemic events, with the overall tolerability of intravitreally administered agents typically favorable when compared to the potential devastating visual consequences of untreated GA.

Future Directions and Challenges
Emerging Therapies
The treatment landscape for GA is rapidly evolving, and several emerging approaches are under exploration. In addition to the established complement inhibitors, future therapies may include combination regimens that employ multiple agents targeting different aspects of the disease pathway. For example, combining a C3 inhibitor with a neuroprotective agent or an anti-inflammatory compound might yield synergistic effects in halting disease progression and preserving visual function.

There is also significant interest in developing therapies that work at a gene therapy level. These strategies aim to provide one-time interventions capable of ensuring sustained expression of complement regulators in the retina, potentially reducing or even eliminating the need for repeated intravitreal injections. Such an approach would represent a paradigm shift in how chronic degenerative diseases like GA are managed and could address critical issues regarding treatment adherence and patient quality of life.

Additionally, advancements in drug formulation technology, such as PASylation seen with PAS-nomacopan, are being continually optimized to extend the dosing interval and improve the pharmacodynamic profiles of therapeutic proteins. These technological innovations are expected to enable a more convenient and patient-friendly treatment regimen, which is of paramount importance in a chronic disease that primarily affects an elderly population.

Regulatory and Market Considerations
Regulatory agencies worldwide are recognizing the high unmet need in GA and have facilitated expedited pathways for these novel agents. Drugs such as avacincaptad pegol and pegcetacoplan have benefited from Fast Track designations and other regulatory mechanisms that allow for early and frequent communication with the agencies. Such measures help to identify potential safety signals sooner and optimize clinical trial designs to address the unique challenges of GA.

Market considerations include not only the clinical efficacy and safety of these agents but also challenges related to their cost-effectiveness, reimbursement strategies, and real-world adherence. Intravitreal injections, while effective, are invasive procedures that require repeated administration. This can impose significant healthcare costs and increase the burden on both patients and clinical practices. As a result, the potential for therapies that allow for longer dosing intervals is particularly attractive from a market perspective. Future market success is likely to depend on demonstrable improvements in both the anatomical progression of GA and, crucially, functional and quality-of-life outcomes for patients.

Another key challenge lies in educating clinicians and patients about the benefits and risks of these emerging therapies, particularly given the modest efficacy seen so far in slowing anatomical lesion growth. Effective communication of the clinical trial data and real-world benefits, balanced with clear information about potential adverse events, will be essential to ensure widespread acceptance and optimal use of these new treatments.

Moreover, combination therapies that target multiple pathways (e.g., complement inhibition coupled with neuroprotection) may gain traction in the future. However, such innovative approaches will necessitate more complex clinical trial designs and pose challenges related to drug–drug interactions and safety assessments. The path towards regulatory approval for combination therapies is often longer and more complicated than for monotherapies. Thus, while promising, these future directions must navigate both scientific and regulatory intricacies to achieve clinical translation.

Conclusion
In summary, the current development landscape for Geographic Atrophy is characterized by an array of promising drugs targeting various aspects of a complex pathological cascade. Complement inhibitors such as pegcetacoplan and avacincaptad pegol have advanced into late-stage clinical trials and, in some cases, regulatory approval, demonstrating statistically significant reductions in the progression of GA lesions while maintaining acceptable safety profiles. Agents with alternative complement blocking mechanisms, such as ANX007 targeting the classical pathway and NGM621 offering potent C3 inhibition with extended dosing intervals, are in active clinical development, with early data suggesting favorable efficacy and safety. Meanwhile, innovative formulations like PAS-nomacopan, designed through protein engineering to allow for prolonged dosing intervals, are preparing to bridge the gap between clinical efficacy and improved patient convenience.

Future directions in GA treatment appear to favor approaches that integrate sustained drug delivery—potentially through gene therapy or advanced molecular modifications—with combination regimens that might synergize complement inhibition with other neuroprotective or anti-inflammatory strategies. Regulatory agencies are responding to the significant unmet medical need in GA by providing accelerated pathways, although market challenges such as cost and frequent dosing remain. Ultimately, the success of these therapies will not only depend on their ability to slow anatomical progression but also on the translation of these benefits into meaningful improvements in visual function and quality of life for patients.

Overall, while the journey toward a definitive treatment for GA is complex and multifaceted, the current pipeline reflects a robust and diversified effort from the industry. The convergence of innovative drug development, sophisticated clinical trial designs, and supportive regulatory mechanisms provides hope that a meaningful breakthrough in the treatment of GA is on the horizon. Continued research into new therapeutic targets and delivery methods, combined with an evolving understanding of the disease’s pathophysiology, will further refine these strategies and ultimately lead to more effective management options for patients suffering from this blinding condition.