Impact of Baseline Characteristics on Geographic Atrophy Progression in the FILLY Trial Evaluating the Complement C3 Inhibitor Pegcetacoplan

Steinle, Nathan; Pearce, Ian; Monés, Jordi; Metlapally, Ravi; Saroj, Namrata; Hamdani, Mohamed; Ribeiro, Ramiro; Rosenfeld, Philip J.; Lad, Eleonora M.

doi:10.1016/j.ajo.2021.02.031

Cited by 44 publications

(22 citation statements)

References 23 publications

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“…This C3 inhibitor, locally administrated via intravitreal injection, has proven to mitigate GA enlargement versus placebo treatment [ 153 ]. The FILLY study found that Pegcetacoplan treatment monthly resulted in a 29% of reduction of atrophic progression compared to sham controls, even after controlling for confounding factors [ 154 ]. To confirm APL-2 success, two phase 3 studies have completed enrolment (OAKS NCT03525613 and DERBY NCT03525600) and will define its efficacy and safety profile as a GA treatment.…”

Section: Resultsmentioning

confidence: 99%

Genetic Aspects of Age-Related Macular Degeneration and Their Therapeutic Potential

Stradiotto

Allegrini

Fossati

et al. 2022

IJMS

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Age-related macular degeneration (AMD) is a complex and multifactorial disease, resulting from the interaction of environmental and genetic factors. The continuous discovery of associations between genetic polymorphisms and AMD gives reason for the pivotal role attributed to the genetic component to its development. In that light, genetic tests and polygenic scores have been created to predict the risk of development and response to therapy. Still, none of them have yet been validated. Furthermore, there is no evidence from a clinical trial that the determination of the individual genetic structure can improve treatment outcomes. In this comprehensive review, we summarize the polymorphisms of the main pathogenetic ways involved in AMD development to identify which of them constitutes a potential therapeutic target. As complement overactivation plays a major role, the modulation of targeted complement proteins seems to be a promising therapeutic approach. Herein, we summarize the complement-modulating molecules now undergoing clinical trials, enlightening those in an advanced phase of trial. Gene therapy is a potential innovative one-time treatment, and its relevance is quickly evolving in the field of retinal diseases. We describe the state of the art of gene therapies now undergoing clinical trials both in the field of complement-suppressors and that of anti-VEGF.

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Section: Resultsmentioning

confidence: 99%

Genetic Aspects of Age-Related Macular Degeneration and Their Therapeutic Potential

Stradiotto

Allegrini

Fossati

et al. 2022

IJMS

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“…Overall, 47 prespecified genetic variants associated with AMD risk were not associated with GA lesion growth rate or response to treatment. In a post hoc analysis, there was a persistent effect of pegcetacoplan on GA growth even after controlling for known risk factors of GA in AMD, extrafoveal lesions and larger low luminance deficits [12]. In summary, the FILLY trial found that treatment of GA patients with intravitreal injections of pegcetacoplan was associated with a reduction in the rate of GA lesion growth, even after controlling for confounding factors.…”

Section: C3 Inhibitionmentioning

confidence: 86%

A Review of Completed and Ongoing Complement Inhibitor Trials for Geographic Atrophy Secondary to Age-Related Macular Degeneration

Halawa

Lin

Miller

et al. 2021

JCM

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Age-related macular degeneration (AMD) is a leading cause of irreversible blindness among older adults in the Western world. While therapies exist for patients with exudative AMD, there are currently no approved therapies for non-exudative AMD and its advanced form of geographic atrophy (GA). The discovery of genetic variants in complement protein loci with increased susceptibility to AMD has led to the investigation of the role of complement inhibition in AMD with a focus on GA. Here, we review completed and ongoing clinical trials evaluating the safety and efficacy of these studies. Overall, complement inhibition in GA has yielded mixed results. The inhibition of complement factor D has failed pivotal phase 3 trials. Studies of C3 and C5 inhibition meeting their primary endpoint are limited by high rates of discontinuation and withdrawal in the treatment arm and higher risks of conversion to exudative AMD. Studies evaluating other complement members (CFB, CFH, CFI and inhibitors of membrane attack complex—CD59) are ongoing and could offer other viable strategies.

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“…Nevertheless, they were associated with an unexpected increased incidence of new-onset neovascularization, identified to be dosedependent. The conversion from a nonexudative MNV to exudative MNV in these eyes has been suggested to be the main cause, and it may have an immunologic basis, but further study of these hypotheses is being pursued in an ongoing global phase 3 study [102][103][104]. Second, NGM621 is a humanized IgG1 monoclonal antibody engineered to potently inhibit the activity of C3, which was safe and well-tolerated in phase I trials [88].…”

Section: The Role Of Complementmentioning

confidence: 99%

Pathophysiology of Age-Related Macular Degeneration: Implications for Treatment

et al. 2022

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Age-related macular degeneration (AMD) is a complex, multifactorial, progressive retinal disease that affects millions of people worldwide and has become the leading cause of visual impairment in developed countries. The disease etiopathogenesis is not understood fully, although many triggers and processes that lead to dysfunction and degeneration of the retinal pigment epithelium (RPE) already have been identified. Thus, the lack of cellular control of oxidative stress, altered proteostasis, dysfunction of lipid homeostasis, and mitochondrial dysfunction form an internal feedback loop that causes the RPE to fail and allows accumulation of abnormal misfolded proteins and abnormal lipids that will form drusen. An inadequate antioxidant response, deficits in autophagy mechanisms, and dysregulation of the extracellular matrix (ECM) help to increase the deposition of abnormal drusen material over time. The drusen then act as inflammatory centers that trigger chronic inflammation of the subretinal space in which microglia and recruited macrophages also are involved, and the complement system is a key component. Choriocapillaris degeneration and nutritional influences are also classic elements recognized in the AMD pathophysiology. The genetic component of the disease is embodied in the recognition of the described risk or protective polymorphisms of some complement (mainly complement factor H, CFH) and ECM related genes (mainly age-related maculopathy susceptibility 2/high-temperature requirement protein A1, ARMS2/HTRA1). Carriers of the risk haplotype at ARMS2/HTRA1 have a higher risk of developing late AMD at a younger age. Finally, gut microbiota and epigenetics may play a role in modulating the progression to advanced AMD with the presence of local inflammatory conditions. Because of multiple implicated processes, different complex combinations of treatments will probably be the best option to obtain the best visual results; they in turn will differ depending on the type and spectrum of disease affecting individual patients or the disease stage in each patient at a specific moment. This will undoubtedly lead to personalized medicine for control and hopefully a future cure, which necessitates the continued unraveling of all the processes involved in the pathogenesis of AMD that must be understood to devise the combinations of treatments for different concurrent or subsequent problems.

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Impact of Baseline Characteristics on Geographic Atrophy Progression in the FILLY Trial Evaluating the Complement C3 Inhibitor Pegcetacoplan

Cited by 44 publications

References 23 publications

Genetic Aspects of Age-Related Macular Degeneration and Their Therapeutic Potential

Genetic Aspects of Age-Related Macular Degeneration and Their Therapeutic Potential

A Review of Completed and Ongoing Complement Inhibitor Trials for Geographic Atrophy Secondary to Age-Related Macular Degeneration

Pathophysiology of Age-Related Macular Degeneration: Implications for Treatment

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