Treatment Of Geographic Atrophy Research Articles

Use of artificial intelligence in geographic atrophy in age-related macular degeneration

The first regulatory approval of treatment for geographic atrophy (GA) secondary to age-related macular degeneration in the USA constitutes an important milestone; however, due to the nature of GA as anon-acute, insidiously progressing pathology, the ophthalmologist faces specific challenges concerning risk stratification, making treatment decisions, monitoring of treatment and patient education. Innovative retinal imaging modalities, such as fundus autofluorescence (FAF) and optical coherence tomography (OCT) have enabled identification of typical morphological alterations in relation to GA, which are also suitable for the quantitative characterization of GA. Solutions based on artificial intelligence (AI) enable automated detection and quantification of GA-specific biomarkers on retinal imaging data, also retrospectively and over time. Moreover, AI solutions can be used for the diagnosis and segmentation of GA as well as the prediction of structure and function without and under GA treatment, thereby making a valuable contribution to treatment monitoring and the identification of high-risk patients and patient education. The integration of AI solutions into existing clinical processes and software systems enables the broad implementation of informed and personalized treatment of GA secondary to AMD.

C5 inhibitor avacincaptad pegol treatment for geographic atrophy: A comprehensive review.

Geographic atrophy (GA) remains a leading cause of central vision loss with no known cure. Until recently, there were no approved treatments for GA, often resulting in poor quality of life for affected patients. GA is characterized by atrophic lesions on the retina that may eventually threaten the fovea. Emerging treatments have demonstrated the ability to reduce the rate of lesion growth, potentially preserving visual function. Avacincaptad pegol (ACP; Astellas Pharma Inc), a complement component 5 inhibitor, is an FDA-approved treatment for GA that has been evaluated in numerous clinical trials. Here we review the current clinical trial landscape of ACP, including critical post hoc analyses that suggest ACP may reduce the risk of severe loss among patients with GA.

Advancements in Imaging and Therapeutic Options for Dry Age-Related Macular Degeneration and Geographic Atrophy.

Age-related macular degeneration (AMD) is a leading cause of vision loss in the elderly, with dry AMD (d-AMD) leading to geographic atrophy (GA) and significant visual impairment. Multimodal imaging plays a crucial role in d-AMD diagnosis and management, allowing for detailed classification of patient phenotypes and aiding in treatment planning and prognosis determination. Treatment approaches for d-AMD have recently witnessed profound change with the development of specific drugs targeting the complement cascade, with the first anticomplement agents recently approved for GA treatment. Additionally, emerging strategies such as gene therapy and laser treatments may offer potential benefits, though further research is needed to fully establish their efficacy. However, the lack of effective therapies capable of restoring damaged retinal cells remains a major challenge. In the future, genetic treatments aimed at preventing the progression of d-AMD may emerge as a powerful approach. Currently, however, their development is still in the early stages.

Phase 1 Study of JNJ-81201887 Gene Therapy in Geographic Atrophy Secondary to Age-Related Macular Degeneration

ObjectiveTo evaluate the safety and tolerability of a single intravitreal injection of JNJ-81201887 (JNJ-1887) in patients with geographic atrophy (GA) secondary to advanced dry age-related macular degeneration (AMD). DesignPhase 1, open-label, single-center, first-in-human clinical study. SubjectsAdult patients (aged ≥50 years) with GA secondary to AMD in the study-treated eye (treated eye) with a best corrected visual acuity (BCVA) Snellen equivalent of 20/200 or worse in the treated eye (20/80 or worse after the first 3 patients), a total GA lesion size between 5 and 20 mm2 (2-8 disc area), and BCVA of 20/800 or better in fellow, non-treated eye were included. MethodsPatients (N=17) were sequentially enrolled into low (3.56×1010 viral genome [vg]/eye; n=3), intermediate (1.07×1011 vg/eye; n=3), and high (3.56×1011 vg/eye; n=11) dose cohorts without steroid prophylaxis and assessed for safety and tolerability over 24 months. Main Outcome MeasuresSafety and tolerability outcomes included assessment of ocular and non-ocular treatment-emergent adverse events (AEs) over 24 months. Secondary outcomes included GA lesion size and growth rate. ResultsBaseline patient characteristics were consistent with the disease under study, and all enrolled patients had foveal center–involved GA. JNJ-1887 was well tolerated across all cohorts, with no dose-limiting AEs. There were no serious or systemic AEs related to study intervention. Overall, 5/17 (29%) patients experienced 6 events of mild ocular inflammation related to study treatment; exam findings in all resolved, and AEs resolved in 4 of 5 patients following topical steroids or observation. One unresolved vitritis event, managed with observation, occurred in a patient with an unrelated fatal AE. No endophthalmitis or new-onset choroidal neovascularization was reported. GA lesion growth rate was similar among all cohorts over 24 months. For treated eyes in the high-dose cohort, GA lesion growth rate showed continued decline through 24 months, with a reduction in mean square root lesion growth from 0.211 mm at months 0-6 to 0.056 mm at months 18-24. ConclusionsAll 3 studied doses of JNJ-1887 had a manageable safety profile through 24 months of follow-up. Further investigation of JNJ-1887 for the treatment of GA is warranted.

Correlation Between Blue Fundus Autofluorescence and SD-OCT Measurements of Geographic Atrophy in Dry Age-Related Macular Degeneration

To compare fundus autofluorescence (FAF) and spectral domain optical coherence tomography (OCT) measurements of geographic atrophy (GA) area and to analyze lesion area changes measured by spectral domain OCT in GATHER1. An assessment reliability analysis using prospective, randomized, double-masked phase 2/3 clinical trial data. GATHER1 examined the efficacy and safety of avacincaptad pegol (ACP) for GA treatment. A post hoc analysis was performed to identify correlations between FAF- and OCT-based measurements of GA. GA area was measured on blue-light FAF images using semiautomatic segmentation software with support from OCT and near-infrared imaging. Machine-learning enhanced, multilayer segmentation of OCT scans were reviewed by human readers, and segmentation errors were corrected as needed. GA area was defined as total RPE loss on cross-sectional B scans. Time points included Months 0, 6, 12, and 18. Additionally, OCT-based GA-area changes between ACP and sham were analyzed. There was a strong correlation (r = 0.93) between FAF and OCT GA area measurements that persisted through 18 months. Mean (SD) differences between OCT and FAF GA measurements were negligible: 0.11 mm2 (1.42) at Month 0, 0.03 mm2 (1.62) at Month 6, -0.17 mm2 (1.81) at Month 12, and -0.07 mm2 (1.78) at Month 18. OCT assessments of GA growth revealed a 30% and 27% reduction at Months 12 and 18, respectively, between ACP and sham, replicating FAF measurements from GATHER1. The strong correlation between blue FAF and OCT measurements of GA area supports OCT as a reliable method to measure GA lesion area in clinical trials.

Phase 2 Trial Evaluating Minocycline for Geographic Atrophy in Age-Related Macular Degeneration

Existing therapies to slow geographic atrophy (GA) enlargement in age-related macular degeneration (AMD) have relatively modest anatomic efficacy, require intravitreal administration, and increase the risk of neovascular AMD. Additional therapeutic approaches are desirable. To evaluate the safety and possible anatomic efficacy of oral minocycline, a microglial inhibitor, for the treatment of GA in AMD. This was a phase 2, prospective, single-arm, 45-month, nonrandomized controlled trial conducted from December 2016 to April 2023. Patients with GA from AMD in 1 or both eyes were recruited from the National Institutes of Health (Bethesda, Maryland) and Bristol Eye Hospital (Bristol, UK). Study data were analyzed from September 2022 to May 2023. After a 9-month run-in phase, participants began oral minocycline, 100 mg, twice daily for 3 years. The primary outcome measure was the difference in rate of change of square root GA area on fundus autofluorescence between the 24-month treatment phase and 9-month run-in phase. Of the 37 participants enrolled (mean [SD] age, 74.3 [7.6] years; 21 female [57%]), 36 initiated the treatment phase. Of these participants, 21 (58%) completed at least 33 months, whereas 15 discontinued treatment (8 by request, 6 for adverse events/illness, and 1 death). Mean (SE) square root GA enlargement rate in study eyes was 0.31 (0.03) mm per year during the run-in phase and 0.28 (0.02) mm per year during the treatment phase. The primary outcome measure of mean (SE) difference in enlargement rates between the 2 phases was -0.03 (0.03) mm per year (P = .39). Similarly, secondary outcome measures of GA enlargement rate showed no differences between the 2 phases. The secondary outcome measures of mean difference in rate of change between 2 phases were 0.2 letter score per month (95% CI, -0.4 to 0.9; P = .44) for visual acuity and 0.7 μm per month (-0.4 to 1.8; P = .20) for subfoveal retinal thickness. Of the 129 treatment-emergent adverse events among 32 participants, 49 (38%) were related to minocycline (with no severe or ocular events), including elevated thyrotropin level (15 participants) and skin hyperpigmentation/discoloration (8 participants). In this phase 2 nonrandomized controlled trial, oral minocycline was not associated with a decrease in GA enlargement over 24 months, compared with the run-in phase. This observation was consistent across primary and secondary outcome measures. Oral minocycline at this dose is likely not associated with slower rate of enlargement of GA in AMD.

Drug Approval for the Treatment of Geographic Atrophy: How We Got Here and Where We Need to Go

PurposeTo discuss the clinical trial results leading to the FDA approval of anti-complement therapies for geographic atrophy (GA), perspectives on functional data from the GA clinical trials, and how lessons from the FDA approval may guide future directions for basic and clinical research in AMD. DesignSelected literature review with analysis and perspective MethodsWe performed a targeted review of publicly available data from the clinical trials of pegcetacoplan and avacincaptad for the treatment of GA as well as scientific literature on the natural history of GA and the genetics and basic science of complement in AMD. ResultsThe approval of pegcetacoplan and avacincaptad was based on an anatomic endpoint of a reduction in the rate of GA expansion over time. However, functional data from two phase 3 clinical trials for each drug demonstrated no visual benefit to patients in the treatment groups. Review of the genetics of AMD and the basic science of the role for complement in AMD provides only modest support for targeting complement as treatment for GA expansion, and alternative molecular targets for GA treatment are therefore discussed. Reasons for the disconnect between anatomic and functional outcomes in the clinical trials of anti-complement therapies are discussed, providing insight to guide the configuration of future clinical studies for GA. ConclusionWhile avacincaptad and pegcetacoplan are our first FDA-approved treatments for GA, results from the clinical trials failed to show any functional improvement after one and two years, respectively, calling into question whether the drugs represent a “clinically relevant outcome.” To improve the chances of more impactful therapies in the future, we: i) provide basic-science rationale for pursuing non-complement targets, ii) emphasize the importance of ongoing clinical research that more closely pins anatomic features of GA to functional outcomes, and iii) provide suggestions for clinical endpoints for future clinical trials on GA.

Safety Results for Geographic Atrophy Associated with Age-Related Macular Degeneration Using Subretinal Cord Blood Platelet-Rich Plasma

PurposeTo evaluate the safety of subretinal injection of cord blood platelet-rich plasma (CB-PRP) and its possible effect in eyes affected by geographic atrophy (GA) associated with dry age-related macular degeneration (d-AMD). DesignInterventional, open-label study started in January 2021 with at 12 months of follow-up (the Si.Cord Study). This study was a single-center, nonrandomized, sequential-assigned clinical trial conducted in Rome, Italy, at Fondazione Policlinico Universitario Agostino Gemelli IRCCS (ClinicalTrials.gov_NCT04636853). Subjects, Participants, and ControlsThirteen patients (26 eyes) with bilateral d-AMD-related GA were enrolled. One eye from each patient (with more advanced GA) underwent CB-PRP treatment, and the fellow eye was considered the control. All patients participated in follow-up at 12 months. InterventionAll 13 eyes received 23-gauge (G) vitrectomy and subretinal injection of CB-PRP using a 41-G needle. Main Outcomes and MeasuresBest corrected visual acuity (BCVA) with Early Treatment Diabetic Retinopathy Study (ETDRS) letters, central macular thickness using optical coherence tomography (OCT) and atrophic area measured on en-face OCT images were assessed at baseline, 1, 3, 6 and 12 months. ResultsThe BCVA in the treated group was 34.46 ± 20.8 ETDRS at baseline; 40.84 ± 20.52 at 1 month; 40.07 ± 20.34 at 3 months; 39.38 ± 19.84 at 6 months and 35.84 ± 18.38 at 12 months. In the untreated group, the BCVA was 53 ± 21.1 ETDRS letters at baseline; 51.54 ± 20.99 at 1 month; 46.62 ± 19.47 at 3 months; 46.85 ± 18.58 at 6 months and 43.92 ± 17.97 at 12 months (two-way ANOVA: interaction of treatment by eye or time, p= -0.084). Central macular thickness (CMT) did not show a significant inter-eye difference at 12 months (p=0.97). The atrophic geographic areas tended to increase in both treated and fellow eyes at 12 months (p<0.0001). No inflammatory reaction, endophthalmitis, retinal detachment, uveitis, or other complications due to the subretinal injection of CB-PRP were observed during the follow-up. ConclusionsSubretinal injection of CB-PRP could be safely used for d-AMD in its GA form. Despite its safety, a larger cohort of patients, and probably a new way of administration, will be needed in order to understand whether the CB-PRP could have a role in the GA treatment.

Long-term Follow-up of a Phase 1/2a Clinical Trial of a Stem Cell-Derived Bioengineered Retinal Pigment Epithelium Implant for Geographic Atrophy

PurposeTo report long-term results from a Phase 1/2a clinical trial assessment of a scaffold-based human embryonic stem cell-derived retinal pigmented epithelium (RPE) implant in subjects with advanced geographic atrophy (GA). DesignThe study was a US Food and Drug Administration (FDA)-approved single-arm, open-label Phase 1/2a clinical trial. SubjectsSubjects were between the ages of 69 and 85 at the time of enrollment and were legally blind in the treated eye (best corrected visual acuity (BCVA) of ≤ 20/200) as a result of GA involving the fovea. InterventionThe clinical trial enrolled 16 subjects, 15 of whom were successfully implanted. The implant was administered to the worse-seeing eye with the use of a custom subretinal insertion device. The companion non-implanted eye served as the control. The primary endpoint was at 1 year; thereafter subjects were followed at least yearly. Main Outcome MeasuresSafety was the primary endpoint of the study. The occurrence and frequency of adverse events were determined by scheduled eye exams, including measurement of BCVA, intraocular pressure, and multimodal imaging (fundus photography, optical coherence tomography, and fluorescein angiography). In addition, serum antibody titers were collected to monitor systemic humoral immune responses to the implant cells. ResultsAt a median follow-up of three years, fundus photography revealed no migration of the implant. There were no unanticipated, severe, implant-related adverse events throughout the follow-up period, and the most common anticipated severe adverse event (severe retinal hemorrhage) was eliminated in the second cohort (9 subjects) through the use of improved intraoperative hemostasis. Non-severe, transient retinal hemorrhages were noted either intra-op or post-op in all subjects as anticipated for a subretinal surgical procedure. Throughout the median 3-year follow-up, the results show that implanted eyes were more likely to improve by >5 letters BCVA, and less likely to decrease by >5 letters compared to non-implanted eyes. ConclusionsThis report details the long-term follow-up of the largest study of subjects with GA to receive a scaffold-based stem cell-derived bioengineered RPE implant. Results show that the implant, at a median 3-year follow-up, is safe and well-tolerated in subjects with advanced dry AMD. The safety profile, along with the early indication of efficacy, warrants further clinical evaluation of this novel approach for the treatment of GA.

Geographic atrophy: pathophysiology and current therapeutic strategies.

Geographic atrophy (GA) is an advanced stage of age-related macular degeneration (AMD) that leads to gradual and permanent vision loss. GA is characterized by the loss of photoreceptor cells and retinal pigment epithelium (RPE), leading to distinct atrophic patches in the macula, which tends to increase with time. Patients with geographic atrophy often experience a gradual and painless loss of central vision, resulting in difficulty reading, recognizing faces, or performing activities that require detailed vision. The primary risk factor for the development of geographic atrophy is advanced age; however, other risk factors, such as family history, smoking, and certain genetic variations, are also associated with AMD. Diagnosis is usually based on a comprehensive eye examination, including imaging tests such as fundus photography, optical coherence tomography (OCT), and fluorescein angiography. Numerous clinical trials are underway, targeting identified molecular pathways associated with GA that are promising. Recent approvals of Syfovre and Izervay by the FDA for the treatment of GA provide hope to affected patients. Administration of these drugs resulted in slowing the rate of progression of the disease. Though these products provide treatment benefits to the patients, they do not offer a cure for geographic atrophy and are limited in efficacy. Considering these safety concerns and limited treatment benefits, there is still a significant need for therapeutics with improved efficacy, safety profiles, and better patient compliance. This comprehensive review discusses pathophysiology, currently approved products, their limitations, and potential future treatment strategies for GA.

Advancements in the treatment of geographic atrophy: focus on pegcetacoplan in age-related macular degeneration

Geographic atrophy (GA) is a progressive form of age-related macular degeneration characterized by the degeneration of retinal pigment epithelial cells and photoreceptor death. The dysregulation of the complement cascade has been implicated in GA progression. This review provides a comprehensive overview of the pathophysiology of age-related macular degeneration and GA, discusses current therapeutic options, and focuses on the recent breakthrough drug, pegcetacoplan (SYFOVRE). Pegcetacoplan is a complement inhibitor that selectively targets the C3 complement protein, effectively modulating complement activation. Clinical trials, including the OAKS and DERBY studies, have demonstrated the efficacy of SYFOVRE in reducing the growth of GA lesions compared to placebo. The FDA approval of SYFOVRE as the first and only definitive therapy for GA marks a significant milestone in the management of this debilitating condition. The review also explores potential future treatment strategies, including immune-modulating agents and ocular gene therapy. While SYFOVRE offers new hope for GA patients, further research is needed to evaluate its long-term benefits, safety profile, and optimal treatment regimens.

WITHDRAWN: Pegcetacoplan in the treatment of geographic atrophy.

Ahead of Print article withdrawn by publisher.

Exploring patient acceptability of emerging intravitreal therapies for geographic atrophy: A mixed-methods study.

The acceptability of emerging intravitreal therapies for patients with Geographic Atrophy (GA) is currently unknown. This study therefore aimed to investigate the extent to which regular intravitreal injections may be acceptable to GA patients. Thirty UK-based individuals with GA secondary to age-related macular degeneration (AMD), recruited from two London-based hospitals, were interviewed in April-October 2021 regarding acceptability of new GA treatments. Participants responded to a structured questionnaire, as well as open-ended questions in a semi-structured interview.The Theoretical Framework of Acceptability (TFA) informed frameworkanalysis of the qualitative data. Twenty participants (67%) were female, and median (interquartile range (IQR)) age was 83 (78, 87) years. 37% of participants had foveal centre-involving GA, and better eye median (IQR) logMAR visual acuity was 0.30 (0.17, 0.58). Data suggested that 18 participants (60% (95% CI: 41-79%)) would accept the treatment, despite awareness of potential drawbacks. Eight participants (27% (95% CI: 10-43%) were ambivalent or undecided about treatment, and four (13%) (95% CI: 0-26%) would be unlikely to accept treatment. Reducing the frequency of injections from monthly to every other month increased the proportion of participants who considered the treatments acceptable. Conversely, factors limiting acceptability clustered around: the limited magnitude of treatment efficacy; concerns about side effects or the increased risk of neovascular AMD; and the logistical burden of regular clinic visits for intravitreal injections. Misunderstandings of potential benefits indicate the need for appropriately-designed patient education tools to support decision-making. Our study suggests a majority of participants would be positive about intravitreal treatment for GA, in spite of potential burdens.

Geographic atrophy: Mechanism of disease, pathophysiology, and role of the complement system.

Geographic atrophy (GA) is an advanced form of age-related macular degeneration (AMD), characterized by atrophic lesions that first start in the outer retina and progressively expand to cover the macula and the fovea, the center of the macula, leading to irreversible loss of vision over time. GA is distinct from wet or neovascular AMD (nAMD), the other form of advanced AMD. Neovascular AMD is characterized by new invading leaky blood vessels in the macula that can lead to acute vision loss. GA and nAMD may coexist in the same eye. The underlying pathophysiology of GA is complex and thought to involve chronic inflammation due to overactivation of the complement system that leads to the loss of photoreceptors, retinal pigment epithelium (RPE), and the underlying choriocapillaris. The disappearance of these structures appears as sharply demarcated atrophic lesions that are typical of GA. Researchers have reported about 1 million reported cases of GA in the United States, and about 160,000 cases occur per year. The most important risk factors for GA are increasing age and family history. Diagnosis of GA is usually made by using multimodal imaging techniques. Lesions associated with GA are highly heterogeneous, and the growth rate may differ from patient to patient. Despite the progressive nature of GA, the fovea may be spared until much later in the disease, thereby retaining central vision in patients. With time, atrophic lesions may progressively grow to involve the fovea, thereby severely impairing central vision. Vision loss can happen rapidly once the lesions reach the fovea. However, even without the involvement of the fovea, ongoing vision impairment impacting daily life may be present. Median time from GA not involving the center of the fovea (without subfoveal involvement) to GA with lesion boundary affecting the foveal center (subfoveal involvement) ranges from 1.4 to 2.5 years. GA can greatly impact patients' functioning and quality of life and limit their independence by interfering with activities of daily living, including difficulties with reading, driving, watching television, recognizing faces, and being unable to do household chores. No treatments have been available until intravitreal pegcetacoplan was recently approved by the US Food and Drug Administration for GA secondary to AMD. DISCLOSURES: Dr Bakri serves as a consultant to Apellis Pharmaceuticals, as well as AbbVie, Adverum, Eyepoint, iLumen, Iveric Bio, Genentech, Novartis, Outlook Therapeutics, Pixium, Regeneron, Roche, and Regenxbio. Drs Sharp, Luo, and Sarda are employees of Apellis Pharmaceuticals. Dr Bektas and Ms Khan are employees of RTI Health Solutions. Apellis developed and led the concept design of this publication, review and interpretation, approval, and decision to publish. This research was developed under a research contract between RTI Health Solutions and Apellis Pharmaceuticals and was funded by Apellis Pharmaceuticals. This supplement is to describe the disease of geographic atrophy and was funded by Apellis. Apellis Pharmaceuticals has developed Syfovre (pegcetacoplan), the first and only treatment for geographic atrophy.

Avacincaptad pegol for geographic atrophy secondary to age-related macular degeneration: 18-month findings from the GATHER1 trial

Background/ObjectivesTo assess the safety and efficacy of avacincaptad pegol (ACP), a C5 inhibitor, for geographic atrophy (GA) secondary to age-related macular degeneration (AMD) over an 18-month treatment course.Subjects/MethodsThis study was an international, prospective, randomized, double-masked, sham-controlled, phase 2/3 clinical trial that consisted of 2 parts. In part 1, 77 participants were randomized 1:1:1 to receive monthly intravitreal injections of ACP 1 mg, ACP 2 mg, or sham. In part 2, 209 participants were randomized 1:2:2 to receive monthly ACP 2 mg, ACP 4 mg, or sham. The mean rate of change of GA over 18 months was measured by fundus autofluorescence.ResultsCompared with their respective sham cohorts, monthly ACP treatment reduced the mean GA growth (square root transformation) over 18 months by 28.1% (0.168 mm, 95% CI [0.066, 0.271]) for the 2 mg cohort and 30.0% (0.167 mm, 95% CI [0.062, 0.273]) for the 4 mg cohort. ACP treatment was generally well tolerated over 18 months, with most ocular adverse events (AEs) related to the injection procedure. Macular neovascularization (MNV) was more frequent in both 2 mg (11.9%) and 4 mg (15.7%) cohorts than their respective sham control groups (2.7% and 2.4%).ConclusionsOver this 18-month study, ACP 2 mg and 4 mg showed continued reductions in the progression of GA growth compared to sham and continued to be generally well tolerated. A pivotal phase 3 GATHER2 trial is currently underway to support the efficacy and safety of ACP as a potential treatment for GA.

Identifying geographic atrophy.

Age-related macular degeneration (AMD) is one of the leading causes of blindness and can progress to geographic atrophy (GA) in late stages of disease. This review article highlights recent literature which assists in the accurate and timely identification of GA, and monitoring of GA progression. Technology for diagnosing and monitoring GA has made significant advances in recent years, particularly regarding the use of optical coherence tomography (OCT). Identification of imaging features which may herald the development of GA or its progression is critical. Deep learning applications for OCT in AMD have shown promising growth over the past several years, but more prospective studies are needed to demonstrate generalizability and clinical utility. Identification of GA and of risk factors for GA development or progression is essential when counseling AMD patients and discussing prognosis. With new therapies on the horizon for the treatment of GA, identification of risk factors for the development and progression of GA will become critical in determining the patients who would be appropriate candidates for new targeted therapies.

Allosteric inhibition of HTRA1 activity by a conformational lock mechanism to treat age-related macular degeneration

The trimeric serine protease HTRA1 is a genetic risk factor associated with geographic atrophy (GA), a currently untreatable form of age-related macular degeneration. Here, we describe the allosteric inhibition mechanism of HTRA1 by a clinical Fab fragment, currently being evaluated for GA treatment. Using cryo-EM, X-ray crystallography and biochemical assays we identify the exposed LoopA of HTRA1 as the sole Fab epitope, which is approximately 30 Å away from the active site. The cryo-EM structure of the HTRA1:Fab complex in combination with molecular dynamics simulations revealed that Fab binding to LoopA locks HTRA1 in a non-competent conformational state, incapable of supporting catalysis. Moreover, grafting the HTRA1-LoopA epitope onto HTRA2 and HTRA3 transferred the allosteric inhibition mechanism. This suggests a conserved conformational lock mechanism across the HTRA family and a critical role of LoopA for catalysis, which was supported by the reduced activity of HTRA1-3 upon LoopA deletion or perturbation. This study reveals the long-range inhibition mechanism of the clinical Fab and identifies an essential function of the exposed LoopA for activity of HTRA family proteases.

The Effect of Pegcetacoplan Treatment on Photoreceptor Maintenance in Geographic Atrophy Monitored by Artificial Intelligence–Based OCT Analysis

To investigate the therapeutic effect of intravitreal pegcetacoplan on the inhibition of photoreceptor (PR) loss and thinning in geographic atrophy (GA) on conventional spectral-domain OCT (SD-OCT) imaging by deep learning-based automated PR quantification. Post hoc analysis of a prospective, multicenter, randomized, sham (SM)-controlled, masked phase II trial investigating the safety and efficacy of pegcetacoplan for the treatment of GA because of age-related macular degeneration. Study eyes of 246 patients, randomized 1:1:1 to monthly (AM), bimonthly (AEOM), and SM treatment. We performed fully automated, deep learning-based segmentation of retinal pigment epithelium (RPE) loss and PR thickness on SD-OCT volumes acquired at baseline and months 2, 6, and 12. The difference in the change of PR loss area was compared among the treatment arms. Change in PR thickness adjacent to the GA borders and the entire 20° scanning area was compared between treatment arms. Square-root transformed PR loss area in μm or mm, PR thickness in μm, and PR loss/RPE loss ratio. A total of 31 556 B-scans of 644 SD-OCT volumes of 161 study eyes (AM 52, AEOM 54, SM 56) were evaluated from baseline to month 12. Comparison of the mean change in PR loss area revealed statistically significantly less growth in the AM group at months 2, 6, and 12 than in the SM group (-41 μm ± 219 vs. 77 μm ± 126; P= 0.0004; -5 μm ± 221 vs. 156 μm ± 139; P < 0.0001; 106 μm ± 400 vs. 283 μm ± 226; P= 0.0014). Photoreceptor thinning was significantly reduced under AM treatment compared with SM within the GA junctional zone, as well as throughout the 20° area. A trend toward greater inhibition of PR loss than RPE loss was observed under therapy. Distinct and reliable quantification of PR loss using deep learning-based algorithms offers an essential tool to evaluate therapeutic efficacy in slowing disease progression. Photoreceptor loss and thinning are reduced by intravitreal complement C3 inhibition. Automated quantification of PR loss/maintenance based on OCT images is an ideal approach to reliably monitor disease activity and therapeutic efficacy in GA management in clinical routine and regulatory trials.

Update on Avacincaptad Pegol for Geographic Atrophy

Geographic atrophy (GA) secondary to age-related macular degeneration is the leading cause of permanent vision loss in patients over the age of 50 in developed countries. GA is characterized by the atrophy of retinal pigment epithelium and photoreceptors and can lead to central or peripheral vision loss, depending on the location of the atrophy. Currently, there are no US Food and Drug Administration-approved treatments for GA. Avacincaptad pegol (Zimura®; IVERIC Bio Inc, New York, NY, USA) is a C5-specific inhibitor that is being investigated as a potential treatment for GA. C5 is a key protein within the complement system, which maintains retina integrity and health under normal conditions. It is hypothesized that unregulated activation of the complement system (indicated by elevated levels of active proteins such as the membrane attack complex) can exacerbate the progression of GA. This article reviews the latest data regarding avacincaptad pegol as an investigational therapeutic for GA.

Investigational Agents in Development for the Treatment of Geographic Atrophy Secondary to Age-Related Macular Degeneration.

Geographic atrophy (GA) is an advanced form of age-related macular degeneration, a late-onset, complex, genetic degenerative disease of the retina. Multiple environmental and genetic factors have been implicated in the development of GA, a pathology ultimately defined by loss of photoreceptors and the underlying retinal pigment epithelium and choriocapillaris. The personal burden of GA has been documented to have a substantial negative impact on quality of life, with progressive and cumulative loss of visual function each year. Currently, there are no treatments to prevent or slow the development or progression of GA. Multiple genetic and histopathologic studies have implicated dysregulation of the complement cascade in GA pathogenesis, leading to the development of several investigational pharmaceuticals targeting key factors in this inflammatory pathway. Several other biochemical pathways have also been implicated in GA development and progression, such as mitochondrial components, mediators of apoptosis and molecules involved in extracellular matrix remodeling, many of which are also being investigated for their potential value as therapeutic targets for GA treatment. Recent advancements in our understanding of GA pathogenesis and the progression of multiple potential therapeutics into later-stage human clinical trials hold great promise for a clinically effective therapeutic for patients with GA to emerge within the near future.