The macula, a part of the retina, contains a high concentration of photoreceptor cells and is crucial for central vision. Age-related macular degeneration (AMD) is a degenerative disease that affects the macula as it ages, impacting the eye's posterior segment. This condition can lead to vision impairment or even blindness in the elderly. Late-stage AMD is categorized into two types: dry AMD (geographic atrophy (GA)), which accounts for 80-90% of cases, and wet AMD (exudative or neovascular AMD), making up 10-20% of cases. Approximately 90% of severe vision loss is due to wet AMD.

Currently, there are about 200 million AMD patients worldwide, and this number is expected to rise to 288 million by 2040 due to the aging population. According to Globaldata, the global AMD market size is projected to reach $27.5 billion by 2031.

Figure 1. Diagram of the fundus and macular cell tissue in normal subjects and patients with dry AMD or wet AMD [2].

Progress in New Treatments for GA

In dry AMD, the loss of photoreceptors and retinal pigment epithelial (RPE) cells in the macula leads to the atrophy of retinal tissue. In the late stages, the degeneration of RPE cells becomes confluent, resulting in severe vision loss, a condition known as geographic atrophy (GA) [3]. The development of GA is associated with the complement cascade, with C3, C5, and other complement inhibitors being potential therapeutic targets for GA.

In February 2023, The C3 complement inhibitor Pegcetacoplan (Syfovre), developed by Apellis, was the approved for GA. It is the first drug approved for GA by the FDA. In August 2023, the FDA approved Avacincaptad pegol (Izervay), a C5 inhibitor developed by Iveric Bio under Astellas. These two drugs are currently the only approved treatments for GA, but there is still room for improvement in their efficacy.

Pegcetacoplan (Syfovre)

Pegcetacoplan is a pegylated highly selective bicyclic peptide composed of 13 amino acids that inhibits the formation of C3 convertase, thereby blocking the complement pathway at its source. Bicyclic peptides combine the properties of antibodies, small-molecule drugs, and peptides, offering antibody-like affinity and precise targeting specificity. Additionally, their smaller molecular size allows for rapid and deep tissue penetration. After its launch in February 2023, Pegcetacoplan achieved annual sales of $275 million. In the Phase 3 OAKS trial, the group receiving monthly injections showed a 22% reduction in GA lesion growth after 12 months.

Figure 2. Structure of Pegcetacoplan

In June 2024, Apellis announced that Syfovre preserved visual function at 36 months in patients with GA secondary to AMD. These positive data from the GALE long-term extension study were presented at the Clinical Trials at the Summit (CTS) Meeting.

In a predefined microperimetry endpoint, patients treated continuously every month for 36 months (p=0.0156) and every other month (p=0.1233) developed fewer new scotomatous points compared to those in the sham crossover group (all p-values nominal). Scotomatous points indicate areas of the retina that have lost all light sensitivity and are no longer functional.

Figure 3. Pegcetacoplan Shows Visual Function Benefit in Prespecified Endpoint at 36 Months [4]

Avacincaptad pegol (Izervay)

Avacincaptad pegol is a novel complement C5 inhibitor. This drug is an RNA aptamer, a PEGylated oligonucleotide that binds to and inhibits the complement protein C5. By inhibiting C5, Avacincaptad pegol may prevent the cleavage of C5a and C5b, thereby reducing the formation of the membrane attack complex (MAC). In August 2023, Izervay received FDA approval for treatment of GA. The approval was based on results from the Phase 3 clinical trials GATHER1 and GATHER2. These trials demonstrated that after 12 months of monthly treatment, the growth of GA lesion area decreased by 27% and 14%, respectively.

Figure 4. Structure of Avacincaptad pegol (Izervay)

Conclusion

In the field of GA treatment, besides C3 and C5 complement inhibitors, other methods include the implantation of bionic retinal chips, cell therapy, and gene therapy. However, these treatments are currently in relatively early stages of development. At present, the only therapies that have achieved positive results in Phase 3 studies are intravitreal injections of C3 and C5 complement inhibitors. We look forward to more innovative therapies emerging in this field in the future.

Huateng Pharma, as a leading PEG linker supplier, can provide you with both polydispersed PEGs, monodispersed PEGs and multi-arm PEGs for your drug PEGylation need. We are ISO 9001 and EXCiPACT GMP certified, contact us at sales@huatengusa.com for your PEG inquiries. 

References:
[1] Fabre M, Mateo L, Lamaa D, Baillif S, Pagès G, Demange L, Ronco C, Benhida R. Recent Advances in Age-Related Macular Degeneration Therapies. Molecules. 2022; 27(16):5089.
[2] Qu S, Lin H, Pfeiffer N, Grus FH. Age-Related Macular Degeneration and Mitochondria-Associated Autoantibodies: A Review of the Specific Pathogenesis and Therapeutic Strategies. International Journal of Molecular Sciences. 2024; 25(3):1624.

[3] Thomas, C. N., Sim, D. A., Lee, W. H., Alfahad, N., Dick, A. D., Denniston, A. K., & Hill, L. J. (2022). Emerging therapies and their delivery for treating age-related macular degeneration. British Journal of Pharmacology, 179(9), 1908-1937.
[4] https://investors.apellis.com/news-releases/news-release-details/syfovrer-pegcetacoplan-injection-preserved-visual-function-36

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