A Cost-Effectiveness Analysis of Pegcetacoplan for the Treatment of Geographic Atrophy.

PURPOSE: To evaluate the cost-effectiveness of the treatment of geography atrophy (GA) with intravitreal pegcetacoplan and to identify utility-measurement surrogates. DESIGN: Cost analysis based on data from a published study. SUBJECTS: None; based on data from published sham control compared with 2 treatment groups in the index study. METHODS: Costs were based on 2022 Medicare reimbursement data. Specific outcomes were extrapolated from the DERBY and OAKS trials. Assumptions were made for the lifetime analysis based on a theoretical logistic growth model of the atrophy. OUTCOME MEASURES: Cost, cost utility, cost per quality-adjusted life-year, and cost per area of GA (in US$). RESULTS: The costs to treat GA in every month (EM) and every-other-month (EOM) treatment groups over the 2 years as reported were $70 000 and $34 600, respectively. The costs per area of delaying GA for 2 years in all patients were $87 300/mm2 (EM) and $49 200/mm2 (EOM), and in initially extrafoveal patients, $53 900/mm2 (EM) and $32 100/mm2 (EOM). The costs per day of delaying GA for 2 years were $295 (EM) and $170 (EOM); the marginal cost (EM vs. EOM) per retinal pigment epithelium cell saved was $30. The modeled lifetime costs were $350 000 (EM) and $172 000 (EOM), or $309 000/mm2 (EM) and $180 000 (EOM) /mm2. The modeled time to 95% atrophy at 13 years was delayed by 2.5 years (EM) and 2.1 years (EOM). The costs/quality-adjusted life-year gained based on modeled visual loss with 95% atrophy were $706 000 (EM) and $397 000 (EOM). CONCLUSION: Treatment of GA with intravitreal pegcetacoplan EOM was more cost effective than EM. Treatment of extrafoveal lesions yielded greater utility than the treatment of the entire group. As atrophy progression approaches an upper limit, the marginal cost/benefit ratios increase. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Diagnosis and Management of Patients With Geographic Atrophy Secondary to Age-Related Macular Degeneration: A Delphi Consensus Exercise.

Geographic atrophy (GA) is a progressive and irreversible retinal disease with no comprehensive recommendations for diagnosis or monitoring. We used a Delphi approach to determine consensus in key areas around diagnosis and management of GA. A steering committee of eight retina specialists developed two sequential online surveys administered to eye care professionals (ECPs). Consensus was defined as agreement by ≥ 75% of respondents. Up to 177 ECPs from eight countries completed one or both surveys. Consensus was achieved in several topics related to diagnostic imaging, including the use of optical coherence tomography, and the urgent need for treatments and beneficial interventions to reduce the associated burden. Currently, low-vision aids and smoking cessation are considered the most beneficial interventions. We demonstrate consensus for diagnosis and management of patients with GA including best practices in patient identification and monitoring, and unmet needs. [Ophthalmic Surg Lasers Imaging Retina 2023;54:589-598.].

Treatment of dry age-related macular degeneration: A review.

Age-related macular degeneration is a global disease with a significant societal impact. The advent of anti-vascular endothelial growth factor therapy (anti-VEGF) has revolutionised the treatment of neovascular age-related macular degeneration (nAMD). Dry age-related macular degeneration (dAMD) is being investigated for possible therapeutic options. The therapeutic categories undergoing clinical trials include complement pathway inhibitors, visual cycle modulators, reduction of toxic byproducts, antioxidative therapy, neuroprotective agents, laser therapy, surgical options, gene therapy, stem cell therapy, and miscellaneous treatments. Two intravitreal anti-complement factors (pegcetacoplan and avacincaptad pegol) have recently shown phase 3 clinical trial evidence of a reduction in the growth of geographic atrophy. In this review, we provide an update on treatment options currently undergoing clinical research trials for the management of dAMD and preventing the progression of Geographic Atrophy (GA).

The Role of Inflammation in Age-Related Macular Degeneration-Therapeutic Landscapes in Geographic Atrophy.

Age-related macular degeneration (AMD) is the leading cause of vision loss and visual impairment in people over 50 years of age. In the current therapeutic landscape, intravitreal anti-vascular endothelial growth factor (anti-VEGF) therapies have been central to the management of neovascular AMD (also known as wet AMD), whereas treatments for geographic atrophy have lagged behind. Several therapeutic approaches are being developed for geographic atrophy with the goal of either slowing down disease progression or reversing sight loss. Such strategies target the inflammatory pathways, complement cascade, visual cycle or neuroprotective mechanisms to slow down the degeneration. In addition, retinal implants have been tried for vision restoration and stem cell therapies for potentially a dual purpose of slowing down the degeneration and restoring visual function. In particular, therapies focusing on the complement pathway have shown promising results with the FDA approved pegcetacoplan, a complement C3 inhibitor, and avacincaptad pegol, a complement C5 inhibitor. In this review, we discuss the mechanisms of inflammation in AMD and outline the therapeutic landscapes of atrophy AMD. Improved understanding of the various pathway components and their interplay in this complex neuroinflammatory degeneration will guide the development of current and future therapeutic options, such as optogenetic therapy.

RPE-Directed Gene Therapy Improves Mitochondrial Function in Murine Dry AMD Models.

Age-related macular degeneration (AMD) is the most common cause of blindness in the aged population. However, to date there is no effective treatment for the dry form of the disease, representing 85-90% of cases. AMD is an immensely complex disease which affects, amongst others, both retinal pigment epithelium (RPE) and photoreceptor cells and leads to the progressive loss of central vision. Mitochondrial dysfunction in both RPE and photoreceptor cells is emerging as a key player in the disease. There are indications that during disease progression, the RPE is first impaired and RPE dysfunction in turn leads to subsequent photoreceptor cell degeneration; however, the exact sequence of events has not as yet been fully determined. We recently showed that AAV delivery of an optimised NADH-ubiquinone oxidoreductase (NDI1) gene, a nuclear-encoded complex 1 equivalent from S. cerevisiae, expressed from a general promoter, provided robust benefit in a variety of murine and cellular models of dry AMD; this was the first study employing a gene therapy to directly boost mitochondrial function, providing functional benefit in vivo. However, use of a restricted RPE-specific promoter to drive expression of the gene therapy enables exploration of the optimal target retinal cell type for dry AMD therapies. Furthermore, such restricted transgene expression could reduce potential off-target effects, possibly improving the safety profile of the therapy. Therefore, in the current study, we interrogate whether expression of the gene therapy from the RPE-specific promoter, Vitelliform macular dystrophy 2 (VMD2), might be sufficient to rescue dry AMD models.

Lateral gain is impaired in macular degeneration and can be targeted to restore vision in mice.

Macular degeneration is a leading cause of blindness. Treatments to rescue vision are currently limited. Here, we study how loss of central vision affects lateral feedback to spared areas of the human retina. We identify a cone-driven gain control mechanism that reduces visual function beyond the atrophic area in macular degeneration. This finding provides an insight into the negative effects of geographic atrophy on vision. Therefore, we develop a strategy to restore this feedback mechanism, through activation of laterally projecting cells. This results in improved vision in Cnga3-/- mice, which lack cone function, as well as a mouse model of geographic atrophy. Our work shows that a loss of lateral gain control contributes to the vision deficit in macular degeneration. Furthermore, in mouse models we show that lateral feedback can be harnessed to improve vision following retinal degeneration.

Survival of an HLA-mismatched, bioengineered RPE implant in dry age-related macular degeneration.

Cell-based therapies face challenges, including poor cell survival, immune rejection, and integration into pathologic tissue. We conducted an open-label phase 1/2a clinical trial to assess the safety and preliminary efficacy of a subretinal implant consisting of a polarized monolayer of allogeneic human embryonic stem cell-derived retinal pigmented epithelium (RPE) cells in subjects with geographic atrophy (GA) secondary to dry age-related macular degeneration. Postmortem histology from one subject with very advanced disease shows the presence of donor RPE cells 2 years after implantation by immunoreactivity for RPE65 and donor-specific human leukocyte antigen (HLA) class I molecules. Markers of RPE cell polarity and phagocytosis suggest donor RPE function. Further histologic examination demonstrated CD34+ structures beneath the implant and CD4+, CD68+, and FoxP3+ cells in the tissue. Despite significant donor-host HLA mismatch, no clinical signs of retinitis, vitreitis, vasculitis, choroiditis, or serologic immune response were detected in the deceased subject or any other subject in the study. Subretinally implanted, HLA-mismatched donor RPE cells survive, express functional markers, and do not elicit clinically detectable intraocular inflammation or serologic immune responses even without long-term immunosuppression.

Simultaneous perception of prosthetic and natural vision in AMD patients.

Loss of photoreceptors in atrophic age-related macular degeneration (AMD) results in severe visual impairment. Since the low-resolution peripheral vision is retained in such conditions, restoration of central vision should not jeopardize the surrounding healthy retina and allow for simultaneous use of the natural and prosthetic sight. This interim report, prespecified in the study protocol, presents the first clinical results with a photovoltaic substitute of the photoreceptors providing simultaneous use of the central prosthetic and peripheral natural vision in atrophic AMD. In this open-label single group feasibility trial (NCT03333954, recruitment completed), five patients with geographic atrophy have been implanted with a wireless 2 x 2 mm-wide 30 µm-thick device, having 378 pixels of 100 µm in size. All 5 patients achieved the primary outcome of the study by demonstrating the prosthetic visual perception in the former scotoma. The four patients with a subretinal placement of the chip demonstrated the secondary outcome: Landolt acuity of 1.17 ± 0.13 pixels, corresponding to the Snellen range of 20/460-20/565. With electronic magnification of up to a factor of 8, patients demonstrated prosthetic acuity in the range of 20/63-20/98. Under room lighting conditions, patients could simultaneously use prosthetic central vision and their remaining peripheral vision in the implanted eye and in the fellow eye.

Does Age-Related Macular Degeneration (AMD) Treatment Influence Patient Falls and Mobility? A Systematic Review.

PURPOSE: Age-related macular degeneration (AMD), a leading cause of irreversible blindness, increases fall risk through impaired central vision. Falls place an enormous economic burden on healthcare systems. We hypothesized that AMD treatments may reduce patients' falls risk. This systematic review (ID #: 172623) synthesized the current understanding of wet and dry AMD treatments' impact on patient falls and mobility, connecting these two public health issues. METHODS: On April 17, 2020, PubMed, Scopus, CINAHL, and the Cochrane Central Register of Controlled Trials were queried. Clinical trials and observational studies were included, while non-English and non-primary studies were excluded. Two authors screened, extracted data, and assessed bias using RoB-2 and ROBINS-I. A third author served as a tie breaker. RESULTS: This database search resulted in 3,525 studies, with an additional 112 identified through bibliography review. Ten articles met eligibility criteria. Most studies featured the outcome of interest as a secondary outcome (n = 4) and patient-reported adverse events (n = 5), rather than a primary focus (n = 2). Ten out of the 11 outcomes had a moderate to serious risk of bias. No two studies used the same instrument to measure falls or mobility. CONCLUSION: Despite the potential positive impact of AMD treatments on patient falls and mobility, quality data on this relationship are lacking. This work underscores the need to broaden ophthalmologic research outcomes beyond visual parameters to include patient-centred, functional measures. Incorporating standardized methods to track falls and screen for difficulty with walking and balance would enable evaluation of AMD treatments on functional outcomes, potentially helping guide management.

Treatments for dry age-related macular degeneration: therapeutic avenues, clinical trials and future directions.

Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in the developed world. The identification of the central role of vascular endothelial growth factor (VEGF) in the pathogenesis of neovascular AMD and the introduction of anti-VEGF agents as gold-standard treatment, have drastically changed its prognosis-something yet to be seen in dry AMD. Several therapeutic avenues with a wide variability of targets are currently being investigated in dry AMD. The approaches being investigated to reduce the rate of disease progression include, (1) drugs with antioxidative properties, (2) inhibitors of the complement cascade, (3) neuroprotective agents, (4) visual cycle inhibitors, (5) gene therapy and (6) cell-based therapies. A number of early phase clinical trials have provided promising results, with many more ongoing and anticipated in the near future. In this review, we aim to provide an update of the interventional trials to date and future prospects for the treatment of dry AMD.

One-Year Follow-Up in a Phase 1/2a Clinical Trial of an Allogeneic RPE Cell Bioengineered Implant for Advanced Dry Age-Related Macular Degeneration.

Purpose: To report 1-year follow-up of a phase 1/2a clinical trial testing a composite subretinal implant having polarized human embryonic stem cell (hESC)-derived retinal pigment epithelium (RPE) cells on an ultrathin parylene substrate in subjects with advanced non-neovascular age-related macular degeneration (NNAMD). Methods: The phase 1/2a clinical trial included 16 subjects in two cohorts. The main endpoint was safety assessed at 365 days using ophthalmic and systemic exams. Pseudophakic subjects with geographic atrophy (GA) and severe vision loss were eligible. Low-dose tacrolimus immunosuppression was utilized for 68 days in the peri-implantation period. The implant was delivered to the worst seeing eye with a custom subretinal insertion device in an outpatient setting. A data safety monitoring committee reviewed all results. Results: The treated eyes of all subjects were legally blind with a baseline best-corrected visual acuity (BCVA) of ≤ 20/200. There were no unexpected serious adverse events. Four subjects in cohort 1 had serious ocular adverse events, including retinal hemorrhage, edema, focal retinal detachment, or RPE detachment, which was mitigated in cohort 2 using improved hemostasis during surgery. Although this study was not powered to assess efficacy, treated eyes from four subjects showed an increased BCVA of >5 letters (6-13 letters). A larger proportion of treated eyes experienced a >5-letter gain when compared with the untreated eye (27% vs. 7%; P = not significant) and a larger proportion of nonimplanted eyes demonstrated a >5-letter loss (47% vs. 33%; P = not significant). Conclusions: Outpatient delivery of the implant can be performed routinely. At 1 year, the implant is safe and well tolerated in subjects with advanced dry AMD. Translational Relevance: This work describes the first clinical trial, to our knowledge, of a novel implant for advanced dry AMD.

Geographic atrophy: where we are now and where we are going.

PURPOSE OF REVIEW: Age-related macular degeneration (AMD) affects a significant percentage of the elderly population and end-stage disease classified by either geographic atrophy (GA) or neovascular AMD (nvAMD) is one of the leading causes of vision loss worldwide. Despite the fact that there are currently treatments for nvAMD, there are no treatments in practice to prevent disease onset or progression of GA. This topic is at the forefront of ophthalmic research demonstrated by the recent advances in disease characterization, genetic and environmental risk factor classification, biomarker discovery and mechanism of pathogenesis categorization. There are also numerous clinical treatment trials underway, targeting proposed pathways and biomarkers associated with GA that are promising. RECENT FINDINGS: With several clinical trials of potential treatments underway and numerous recent publications on disease diagnosis and classification, the understanding of GA pathogenesis has increased substantially. Although the exact mechanism of pathology is still elusive, recent literature has highlighted the utilization of current and new ophthalmic imaging modalities and discovery of objective and functional markers that can lead to earlier diagnosis and treatment. SUMMARY: Herein, we will provide an overview and discussion of the current status of GA including advances in mechanism of pathogenesis, diagnosis, classification and current treatment modalities.

Emerging treatments for geographic atrophy in age-related macular degeneration.

PURPOSE OF REVIEW: This review describes therapeutic research programs for geographic atrophy (GA) due to age-related macular degeneration (AMD). We highlight clinical trial data from phase I, II, and III studies. RECENT FINDINGS: There are currently no treatments for GA, a form of advanced AMD that causes significant visual morbidity. Currently, therapeutic candidates are being developed to delay further progression of GA or even attempt to reverse some of the damage. The approaches to therapy range from molecular targets to cell transplantation. Studies of these novel treatment approaches have demonstrated varying degrees of success. The progress in understanding the disease pathophysiology as well as clinical trial data is reviewed. SUMMARY: There are promising new treatments to prevent GA progression as well as some that may reverse the disease course.

Emerging Therapies in Nonexudative Age-Related Macular Degeneration in 2020.

ABSTRACT: Age-related macular degeneration (AMD) is one of the most common causes of severe vision loss in the developed world. Advanced forms of AMD are seen in primarily 2 types, exudative AMD involving the presence of choroidal neovascularization and nonexudative or dry AMD with geographic atrophy. For the latter, the combination of vitamins and minerals known as the Age-Related Eye Disease Study-2 formulation has been shown to decrease the rate of progression of nonexudative to exudative AMD, as no other treatments are currently approved for nonexudative AMD. This review will highlight upcoming treatments for nonexudative AMD. Six upcoming agents have shown results at least in the 2A phase. This includes intravitreal agents that are inhibitors of integrin (Risuteganib), intravitreal agents that disrupt the complement pathway (Zimura, APL-2), neuroprotective implants (Brimonidine DDS), a subcutaneous injectable (Elamipretide), and photobiomodulation (Valeda Light Delivery System).

Safety and Efficacy of Subretinally Administered Palucorcel for Geographic Atrophy of Age-Related Macular Degeneration: Phase 2b Study.

PURPOSE: To evaluate safety and successful use of a novel subretinal delivery system and suprachoroidal surgical approach and safety and activity of human umbilical tissue-derived cells (palucorcel) via a novel delivery system in patients with geographic atrophy (GA). DESIGN: Multicenter, open-label phase 2b study. PARTICIPANTS: Participants were 55 to 90 years with GA secondary to age-related macular degeneration (AMD) and best-corrected visual acuity (BCVA) of 20/80 to 20/800. Exclusion criteria included neovascular AMD in the intervention eye, glaucoma with intraocular pressure of 25 mmHg or more, or other significant ophthalmologic conditions. METHODS: Participants received a subretinal injection of palucorcel, 3.0 × 105 cells in 50 µl, using the custom-designed delivery system and surgical procedure. MAIN OUTCOME MEASURES: Safety assessments included treatment-emergent adverse events (AEs), immunologic assessments, and ophthalmologic evaluations. Efficacy was evaluated as change in mean number of BCVA letters from baseline, proportion of participants gaining 15 BCVA letters or more, and growth rate of GA lesions at 12 months. RESULTS: Surgery and palucorcel administration were performed in 21 participants at 8 sites by 8 different surgeons. At baseline, median total area of GA was 13.4 mm2 and median BCVA was 43 letters in the intervention eye. Eye-related AEs occurred in 76% of participants (16/21), including conjunctival hemorrhage (n = 5), retinal hemorrhage (n = 4), and vitreous floaters (n = 4). Most AEs were mild and resolved within 1 month. No serious AEs, no retinal detachment or perforation, and no significant changes in intraocular pressure occurred. At month 12, mean change in BCVA from baseline was -5.9 letters correct (standard deviation, 13.0 letters correct) in the intervention eye and -3.7 letters correct (standard deviation, 9.0 letters correct) in the fellow eye. No participants showed improvement of 15 letters or more in the intervention eye, and 3 participants lost more than 15 letters by month 1. No apparent effect of treatment was observed. CONCLUSIONS: Palucorcel was delivered successfully to the targeted subretinal site using a novel delivery system and suprachoroidal approach for most participants; however, improvement in GA area, retardation of growth, or visual acuity were not demonstrated.