With complements: C3 inhibition in the clinic.

C3 is a key complement protein, located at the nexus of all complement activation pathways. Extracellular, tissue, cell-derived, and intracellular C3 plays critical roles in the immune response that is dysregulated in many diseases, making it an attractive therapeutic target. However, challenges such as very high concentration in blood, increased acute expression, and the elevated risk of infections have historically posed significant challenges in the development of C3-targeted therapeutics. This is further complicated because C3 activation fragments and their receptors trigger a complex network of downstream effects; therefore, a clear understanding of these is needed to provide context for a better understanding of the mechanism of action (MoA) of C3 inhibitors, such as pegcetacoplan. Because of C3's differential upstream position to C5 in the complement cascade, there are mechanistic differences between pegcetacoplan and eculizumab that determine their efficacy in patients with paroxysmal nocturnal hemoglobinuria. In this review, we compare the MoA of pegcetacoplan and eculizumab in paroxysmal nocturnal hemoglobinuria and discuss the complement-mediated disease that might be amenable to C3 inhibition. We further discuss the current state and outlook for C3-targeted therapeutics and provide our perspective on which diseases might be the next success stories in the C3 therapeutics journey.

Discovering C3 targeting therapies for paroxysmal nocturnal hemoglobinuria: Achievements and pitfalls.

The treatment of paroxysmal nocturnal hemoglobinuria (PNH) was revolutionized by the introduction of the anti-C5 agent eculizumab, which resulted in sustained control of intravascular hemolysis, leading to transfusion avoidance and hemoglobin stabilization in at least half of all patients. Nevertheless, extravascular hemolysis mediated by C3 has emerged as inescapable phenomenon in PNH patients on anti-C5 treatment, frequently limiting its hematological benefit. More than 10 years ago we postulated that therapeutic interception of the complement cascade at the level of C3 should improve the clinical response in PNH. Compstatin is a 13-residue disulfide-bridged peptide binding to both human C3 and C3b, eventually disabling the formation of C3 convertases and thereby preventing complement activation via all three of its activating pathways. Several generations of compstatin analogs have been tested in vitro, and their clinical evaluation has begun in PNH and other complement-mediated diseases. Pegcetacoplan, a pegylated form of the compstatin analog POT-4, has been investigated in two phase I/II and one phase III study in PNH patients. In the phase III study, PNH patients with residual anemia already on eculizumab were randomized to receive either pegcetacoplan or eculizumab in a head-to-head comparison. At week 16, pegcetacoplan was superior to eculizumab in terms of hemoglobin change from baseline (the primary endpoint), as well as in other secondary endpoints tracking intravascular and extravascular hemolysis. Pegcetacoplan showed a good safety profile, even though breakthrough hemolysis emerged as a possible risk requiring additional attention. Here we review all the available data regarding this innovative treatment that has recently been approved for the treatment of PNH.

The complement model disease paroxysmal nocturnal hemoglobinuria.

We describe initial, current, and future aspects of complement activation and inhibition in the rare hematological disease paroxysmal nocturnal hemoglobinuria (PNH). PNH is a rare but severe hematological disorder characterized by complement-mediated intravascular hemolysis resulting in anemia and severe thrombosis. Insights into the complement-mediated pathophysiology ultimately led to regulatory approval of the first-in-class complement inhibitor, eculizumab, in 2007. This anti-complement C5 therapy resulted in the stabilization of many hematologic parameters and dramatically reduced the often fatal, coagulant-resistant thrombotic events. Despite the remarkable clinical success, a substantial proportion of PNH patients experience suboptimal clinical responses during anti-C5 therapy. We describe the identification and mechanistic dissection of four unexpected processes responsible for such suboptimal clinical responses: (1) pharmacokinetic and (2) pharmacodynamic intravascular breakthrough hemolysis, (3) continuing low-level residual intravascular hemolysis, and (4) extravascular hemolysis. Novel complement therapeutics mainly targeting different complement proteins proximal in the cascade attempt to address these remaining problems. With five approved complement inhibitors in the clinic and many more being evaluated in clinical trials, PNH remains one of the complement diseases with the highest intensity of clinical research. Mechanistically unexpected breakthrough events occur not only with C5 inhibitors but also with proximal pathway inhibitors, which require further mechanistic elaboration.

Disease Activity and Therapeutic Response to Pegcetacoplan for Geographic Atrophy Identified by Deep Learning-Based Analysis of OCT.

PURPOSE: To quantify morphological changes of the photoreceptors (PRs) and retinal pigment epithelium (RPE) layers under pegcetacoplan therapy in geographic atrophy (GA) using deep learning-based analysis of OCT images. DESIGN: Post hoc longitudinal image analysis. PARTICIPANTS: Patients with GA due to age-related macular degeneration from 2 prospective randomized phase III clinical trials (OAKS and DERBY). METHODS: Deep learning-based segmentation of RPE loss and PR degeneration, defined as loss of the ellipsoid zone (EZ) layer on OCT, over 24 months. MAIN OUTCOME MEASURES: Change in the mean area of RPE loss and EZ loss over time in the pooled sham arms and the pegcetacoplan monthly (PM)/pegcetacoplan every other month (PEOM) treatment arms. RESULTS: A total of 897 eyes of 897 patients were included. There was a therapeutic reduction of RPE loss growth by 22% and 20% in OAKS and 27% and 21% in DERBY for PM and PEOM compared with sham, respectively, at 24 months. The reduction on the EZ level was significantly higher with 53% and 46% in OAKS and 47% and 46% in DERBY for PM and PEOM compared with sham at 24 months. The baseline EZ-RPE difference had an impact on disease activity and therapeutic response. The therapeutic benefit for RPE loss increased with larger EZ-RPE difference quartiles from 21.9%, 23.1%, and 23.9% to 33.6% for PM versus sham (all P < 0.01) and from 13.6% (P = 0.11), 23.8%, and 23.8% to 20.0% for PEOM versus sham (P < 0.01) in quartiles 1, 2, 3, and 4, respectively, at 24 months. The therapeutic reduction of EZ loss increased from 14.8% (P = 0.09), 33.3%, and 46.6% to 77.8% (P < 0.0001) between PM and sham and from 15.9% (P = 0.08), 33.8%, and 52.0% to 64.9% (P < 0.0001) between PEOM and sham for quartiles 1 to 4 at 24 months. CONCLUSIONS: Deep learning-based OCT analysis objectively identifies and quantifies PR and RPE degeneration in GA. Reductions in further EZ loss on OCT are even higher than the effect on RPE loss in phase 3 trials of pegcetacoplan treatment. The EZ-RPE difference has a strong impact on disease progression and therapeutic response. Identification of patients with higher EZ-RPE loss difference may become an important criterion for the management of GA secondary to AMD. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Development of a target concentration intervention to individualize paroxysmal nocturnal hemoglobinuria treatment with pegcetacoplan.

Pegcetacoplan (Aspaveli®/Empaveli™) is a factor C3 inhibitor that is approved for the treatment of paroxysmal nocturnal hemoglobinuria. An individualized dosing strategy might be useful to improve patient-friendliness and cost-effectiveness of this very expensive drug. Therefore, the aim of this study was to develop an individualized treatment regimen for pegcetacoplan based on the pharmacokinetic-pharmacodynamic data of the manufacturer. We conducted a clinical trial simulation with the approved dosing regimen of 1080 mg twice-weekly and a target concentration intervention-based dosing regimen in patients with and without prior eculizumab use. For eculizumab-naïve patients, the target concentration intervention-based dosing regimen resulted in a comparable fraction of patients with LDH normalization (LDH < 226 U/L) and hemoglobulin normalization (> 12 g/dL) compared to the approved regimen (LDH 50.2% and 50.0% respectively and hemoglobulin 45.6% and 44.4%). A modest dose reduction of ~ 5% was possible with target concentration intervention-based dosing. An intensified dosing interval was necessary in 2.3% of the patients however an interval prolongation was possible in 28.2% of the patients. Similar results were obtained for patients prior treated with eculizumab. In this study we show the potential of an individualized dosing regimen of pegcetacoplan with can improve patient friendliness in approximately 30% of the patients and improve therapy in approximately 2% of the patients at slightly reduced costs.

Pegcetacoplan in paroxysmal nocturnal haemoglobinuria: Its use, its clinical effectiveness, and its influence on health-related quality of life and productivity.

OBJECTIVES: To describe real-world use/effectiveness of pegcetacoplan (PEG) in paroxysmal nocturnal haemoglobinuria (PNH). METHODS: Data were drawn from the Adelphi PNH Disease Specific Programme™, a cross-sectional survey conducted in France, Italy, Germany, Spain and the United States from January to November 2022. Patients had a confirmed PNH diagnosis and received PEG for ≥1 month. Physicians reported patient characteristics, treatment use/satisfaction and their perception of patients' fatigue and health-related quality of life (HRQoL). Patients reported treatment satisfaction and completed questionnaires assessing fatigue, HRQoL and productivity. Descriptive statistics were reported. RESULTS: Overall, 14 physicians provided data for 61 patients who had received 1080 mg/dose PEG for 1.3-14.8 months. At data collection compared to PEG initiation: haemoglobin was 2.5 g/dL higher on average; proportion of patients with lactate dehydrogenase (LDH) ≥1.5 × upper limit of normal was reduced by 27.4%; physician-perceived fatigue was lower and HRQoL better. Physician- and patient-reported treatment satisfaction was high for >90% of patients. Physicians and patients were more satisfied with PEG than previously prescribed C5 complement inhibitors. Mean work impairment and activity impairment in the 7 days prior to data collection were 32.9% and 22.4%, respectively. CONCLUSIONS: These real-world data support the effectiveness of PEG through positive effects on haemoglobin, LDH, fatigue and HRQoL.

Moving toward Individual Treatment Goals with Pegcetacoplan in Patients with PNH and Impaired Bone Marrow Function.

Paroxysmal nocturnal haemoglobinuria (PNH) is a rare, potentially life-threatening haematological disease characterised by chronic complement-mediated haemolysis with multiple clinical consequences that impair quality of life. This post hoc analysis assessed haematological and clinical responses to the first targeted complement C3 inhibitor pegcetacoplan in patients with PNH and impaired bone marrow function in the PEGASUS (NCT03500549) and PRINCE (NCT04085601) studies. For patients with impaired bone marrow function, defined herein as haemoglobin <10 g/dL and absolute neutrophil count <1.5 × 109 cells/L, normalisation of the parameters may be difficult. Indeed, 20% and 43% had normalised haemoglobin in PEGASUS and PRINCE, respectively; 60% and 57% had normalised LDH, and 40% and 29% had normalised fatigue scores. A new set of parameters was applied using changes associated with clinically meaningful improvements, namely an increase in haemoglobin to ≥2 g/dL above baseline, decrease in LDH to ≤1.5× the upper limit of normal, and an increase in fatigue scores to ≥5 points above baseline. With these new parameters, 40% and 71% of PEGASUS and PRINCE patients had improved haemoglobin; 60% and 71% had an improvement in LDH, and 60% and 43% had an improvement in fatigue scores. Thus, even patients with impaired bone marrow function may achieve clinically meaningful improvements with pegcetacoplan.

Three Years On: The Role of Pegcetacoplan in Paroxysmal Nocturnal Hemoglobinuria (PNH) since Its Initial Approval.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare disease characterized by complement-mediated hemolysis and potentially life-threatening complications. Pegcetacoplan, an inhibitor of complement components C3 and C3b, was approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) in 2021. A recent expansion to its indication by the EMA has made pegcetacoplan available for the treatment of both complement inhibitor-naïve and -experienced patients with PNH who have hemolytic anemia, a similarly broad patient population as in the US. This approval was based on results from the Phase 3 PEGASUS study, where pegcetacoplan showed superiority over the C5 inhibitor eculizumab with regard to improving the hemoglobin level in patients with anemia despite eculizumab treatment, and the Phase 3 PRINCE study, where pegcetacoplan showed superiority over supportive care with regard to hemoglobin stabilization and improving the lactate dehydrogenase level in complement inhibitor-naïve patients. In light of this recent indication expansion by the EMA, this article describes how the strong efficacy of pegcetacoplan is linked to its mechanism of action, which provides broad hemolysis control over both intravascular and extravascular hemolysis to improve a range of disease markers and enhance patients' quality of life. Furthermore, additional data and learnings obtained from over 3 years of experience with pegcetacoplan are summarized, including long-term efficacy and safety results, real-world clinical experiences, pharmacokinetic characteristics, and extensive practical guidance for the first-to-market proximal complement inhibitor for PNH.

Navigating the Complement Pathway to Optimize PNH Treatment with Pegcetacoplan and Other Currently Approved Complement Inhibitors.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare and potentially life-threatening hematologic disorder caused by a somatic mutation in a relevant portion of hematopoietic stem cells. Mutation of the phosphatidylinositol glycan biosynthesis class A (PIGA) gene prevents the expression of cell-surface proteins, including the complement regulatory proteins CD55 and CD59. With decreased or a lack of CD55 and CD59 expression on their membranes, PNH red blood cells become susceptible to complement-mediated hemolysis (symptoms of which include anemia, dysphagia, abdominal pain, and fatigue), leading to thrombosis. State-of-the-art PNH treatments act by inhibiting the dysregulated complement at distinct points in the activation pathway: late at the C5 level (C5 inhibitors, eculizumab, ravulizumab, and crovalimab), centrally at the C3 level (C3/C3b inhibitors and pegcetacoplan), and early at the initiation and amplification of the alternative pathway (factor B inhibitor, iptacopan; factor D inhibitor, danicopan). Through their differing mechanisms of action, these treatments elicit varying profiles of disease control and offer valuable insights into the molecular underpinnings of PNH. This narrative review provides an overview of the mechanisms of action of the six complement inhibitors currently approved for PNH, with a focus on the C3/C3b-targeted therapy, pegcetacoplan.

Novel approach to antiangiogenic factors in age-related macular degeneration therapy.

Age-related macular degeneration (AMD) is a leading cause of irreversible vision loss among the population above 85 worldwide. There are two main types of AMD: neovascular and dry AMD. Neovascular AMD leads to macular changes resulting from abnormal choroidal neovascularization. Untreated neovascular AMD leads to scar formation and irreversible sight deterioration. Dry AMD in consequence leads to atrophic changes of the macula. The last decades brought a breakthrough in the therapy of neovascular age-related macular degeneration by introduction of, firstly, photodynamic therapy and, later, anti-VEGF agents administered intravitreally in order to stop neoangiogenesis. However, the treatment of dry AMD is still challenging. Among the directions in dry AMD treatment, the most promising are complement cascade inhibitors and complement cascade targeted gene therapy. In the article we outline the main directions in up-to-date experimental and practical approaches to wet and dry AMD therapy with the emphasis on antiangiogenic factors and gene therapy focused on the inhibition of pathological angiogenesis.

Occlusive Retinal Vasculitis After a Single Injection of Pegcetacoplan.

Purpose: To describe a patient with retinal vasculitis after a single intravitreal injection (IVI) of pegcetacoplan. Methods: A case and its findings were analyzed. Results: An 80-year-old woman was treated with pegcetacoplan for subfoveal geographic atrophy. Ten days later, the patient noted "purple iridescent waves" but did not immediately report it. On day 18, she presented with pain and decreased visual acuity from 20/80 (pinhole) preinjection to 20/150 postinjection. No signs of inflammation were observed, and she was treated for high intraocular pressure (30 mm Hg). On day 23, iritis was noted. The fluorescein angiogram showed severe occlusive vasculitis involving all quadrants and the macula. The vasculitis/neuroretinitis laboratory panels were negative, and no contributing systemic features were identified other than well-controlled diabetes. Conclusions: In this patient, occlusive retinal vasculitis occurred shortly after a single IVI of pegcetacoplan.

A case report of pegcetacoplan use for a pregnant woman with paroxysmal nocturnal hemoglobinuria.

Background: Paroxysmal nocturnal hemoglobinuria (PNH), a rare hematologic disease, is associated with high maternal and fetal mortality rates. Only 1 medication approved for PNH, the complement component 5 inhibitor eculizumab, has published evidence of use during pregnancy. Key Clinical Question: What were the circumstances and outcomes of the first use of pegcetacoplan, a complement component 3 inhibitor, by a pregnant woman with PNH? Clinical Approach: The patient, with a history of 2 miscarriages and a suboptimal response to eculizumab, had hematologic improvement after switching to pegcetacoplan. She continued pegcetacoplan throughout her pregnancy. At gestational week 30, she developed abruptio placentae and breakthrough hemolysis. She delivered a normal-appearing male infant via emergency cesarean section. The breakthrough hemolysis resolved quickly with short-term intensive pegcetacoplan dosing and add-on eculizumab. To date, her laboratory values remain normal, and she has had no thromboembolic events; her son has not demonstrated growth defects. Conclusion: This is the first report of pegcetacoplan treatment for PNH throughout pregnancy. The mother recovered promptly from breakthrough hemolysis that prompted an emergency delivery. Her son, who was born prematurely but healthy, has developed normally.

Anti-complement drugs for the treatment of geographic atrophy and the release of silicone oil.

Intravitreal injections are a common procedure in ophthalmology, often using syringes coated with silicone to aid piston movement and needles coated with silicone oil to facilitate penetration of the sclera. Pegcetacoplan and avacincaptad pegol, recently approved for clinical use by the US Food and Drug Administration, have higher viscosity and seem more susceptible to entrap air bubbles compared to anti-VEGF drugs.It is plausible that both anti-complement drugs could be associated with a higher likelihood of introducing silicone oil in the vitreous because of higher viscosity, with potentially higher friction at the inner surface of syringe barrel, in the vicinity of silicone oil. In addition to this, undesirable agitation might be inadvertently promoted by some retina specialists to remove air bubbles from the drug solution.In conclusion, recent reports of silicone oil droplets in the vitreous of patients receiving pegcetacoplan injection might be related to both its viscosity and to agitation of the syringe to remove air bubbles. Since avacincaptad pegol also is viscous, though with different pH, syringe and filter needle, we might expect similar reports for this agent soon. We also recommend further studies be carried not only to clarify the current matter but also the potential association between the combination of agitation, silicone oil and inflammation or any immune response.

Cost-Utility Analysis Comparing Pegcetacoplan to Anti-C5 Monoclonal Antibodies in the Treatment of Paroxysmal Nocturnal Hemoglobinuria.

Background: Paroxysmal nocturnal hemoglobinuria is a rare, acquired disease characterized by hemolytic episodes and associated with significant clinical burden. The introduction of C5 inhibitory monoclonal antibodies (C5i) represented a major breakthrough in PNH treatment, effectively reducing intravascular hemolysis (IVH) but showing limited impact on extravascular hemolysis (EVH). In 2021, the C3 inhibitor pegcetacoplan was approved by EMA and recently reimbursed in Italy, which also has the advantages in the reduction of both IVH and EVH, increasing hemoglobin values and simultaneously improving the quality of life and fatigue of patients. A cost-utility analysis was developed to compare pegcetacoplan to C5i (eculizumab and ravulizumab) in the PNH population who remain anemic after treatment with C5i for at least 3 months. Materials and Methods: The analysis employed a Markov model with a 5-year time horizon whereby patients can transition among 3 PNH health states, adopting the perspective of the Italian NHS. Efficacy data were sourced from the PEGASUS study, with drug prices reflecting ex-factory costs. Additionally, costs associated with resource utilization, adverse events, and complications were estimated based on outpatient and hospital care rates, excluding indirect expenses. Utility and disutility values related to transfusions were also considered, with pegcetacoplan allowing for dose escalation. Results: The cumulative cost of treatment per individual patient at 5 years was estimated to be €1,483,454 for pegcetacoplan, €1,585,763 for eculizumab, and €1,574,826 for ravulizumab. Pegcetacoplan demonstrated a superior increase in quality-adjusted life years (QALYs) compared to both eculizumab (0.51 increase) and ravulizumab (0.27 increase). Furthermore, pegcetacoplan showed a reduction in complication management costs (€22,891 less compared to eculizumab and €22,611 less compared to ravulizumab) and lower transfusion-related expenses (€14,147 less than both C5i treatments). Conclusion: Pegcetacoplan emerged as the dominant strategy in this analysis, being more effective, less expensive and improves quality of life in the analyzed population affected by PNH.

Exploring treatment strategies for paroxysmal nocturnal hemoglobinuria: an overview of registered clinical trials.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired disease in which blood cells lack anchored proteins that regulate the complement system. The erythrocytes are then destroyed because of uncontrolled complement activity, leading to intravascular hemolysis (IVH) and a high risk of thrombosis outcome. A huge alteration in the treatment of the disease was the development of terminal complement inhibitors, with the achievement of IVH blockade, reduction or abolishment of red blood cell (RBC) transfusions, and thromboembolic events prevention. However, patients treated with these inhibitors can still present extravascular hemolysis (EVH) caused by C3 activation and residual IVH or clinically relevant levels of breakthrough hemolysis (BTH). Proximal complement inhibitors turned out to be the key to the solution of this problem by targeting components of the proximal complement pathway, avoiding intra and extravascular hemolysis. FDA approved eculizumab, ravulizumab (terminal inhibitors), pegcetacoplan, iptacopan, and danicopan (proximal inhibitors) as a treatment for PNH so far. Various clinical trials are underway to find the most effective method to treat patients with PNH. This review aimed to summarize 71 registered clinical trials in the ClinicalTrials.gov database with the various treatment drugs, possible mechanisms, and novel findings related to PNH treatment.

Thrombosis and meningococcal infection rates in pegcetacoplan-treated patients with paroxysmal nocturnal hemoglobinuria in the clinical trial and postmarketing settings.

Background: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired hematologic disease characterized by complement-mediated hemolysis and thrombosis. Complement component 5 (C5) inhibitors have decreased PNH-related thrombosis rates and reduced mortality compared with those of age-matched controls. A small but significantly increased risk of life-threatening Neisseria infections, especially N meningitidis, represents a long-term safety risk of complement inhibition. Objectives: To evaluate the rates of thrombosis and meningococcal infections in patients with PNH treated with the complement component 3-targeted therapy pegcetacoplan. Methods: Cumulative patient-year exposure to pegcetacoplan was calculated, and thrombotic events and meningococcal infections were reviewed in 7 clinical trials and in the postmarketing setting. The clinical trial protocols and pegcetacoplan labeling required vaccination against Streptococcus pneumoniae, N meningitidis, and Haemophilus influenzae before pegcetacoplan use; the label allowed for prophylactic antibiotic use if pegcetacoplan must be administered before vaccination. Results: As of November 13, 2022, 464 patients with PNH had 619.4 patient-years of pegcetacoplan exposure in completed/ongoing clinical trials and the postmarketing setting. Seven thrombotic events were reported: 5 in clinical trials (2 in the same patient) and 2 in the postmarketing setting. The overall thrombosis rate was 1.13 events per 100 patient-years (clinical trials: 1.22 events/100 patient-years in 409.4 years; postmarketing: 0.95 events/100 patient-years in 210.0 years). No infections with meningococcal bacteria were reported. Conclusion: Event rates for thrombosis were comparable between pegcetacoplan and previously reported rates of C5 inhibitors in patients with PNH, and no cases of meningococcal infection were reported with pegcetacoplan. Continued follow-up is required.

Retinal Vasculitis After Intravitreal Pegcetacoplan: Report From the ASRS Research and Safety in Therapeutics (ReST) Committee.

Purpose: To analyze post-marketing cases of retinal vasculitis after intravitreal pegcetacoplan. Methods: The American Society of Retina Specialists (ASRS) Research and Safety in Therapeutics (ReST) Committee as well as an expert panel performed a retrospective review of cases of retinal vasculitis reported to the ASRS. Clinical and imaging characteristics were reviewed for evidence of retinal vasculitis and analyzed. Results: Fourteen eyes of 13 patients were confirmed to have retinal vasculitis by review of imaging studies. All cases occurred after the first pegcetacoplan injection. Occlusive retinal vasculopathy was confirmed in 11 eyes (79%). Patients presented a median of 10.5 days (range, 8-23 days) after pegcetacoplan injection. All eyes had anterior chamber inflammation, and 12 eyes (86%) had vitritis. Vasculopathy involved retinal veins (100%) more than arteries (73%), and 12 eyes (86%) had retinal hemorrhages. The median visual acuity (VA) was 20/60 (range, 20/30-5/200) at baseline, 20/300 (range, 20/100-no light perception [NLP]) at vasculitis presentation, and 20/200 (range 20/70-NLP) at the last follow-up. Eight eyes (57%) had more than a 3-line decrease in VA, and 6 eyes (43%) had more than a 6-line decrease in VA from baseline to the final follow-up, including 2 eyes that were enucleated. Six eyes (43%) developed signs of anterior segment neovascularization. Conclusions: There is currently no known etiology for vasculitis in this series. Optimum treatment strategies remain unknown. Infectious etiologies should be considered, and corticosteroid treatments may hasten resolution of inflammatory findings. Continued treatment of affected patients with pegcetacoplan should be avoided.

Retinal vasculitis following intravitreal pegcetacoplan administration.

Purpose: To describe a case of retinal vaso-occlusive vasculitis with associated lid edema and conjunctivitis following intravitreal pegcetacoplan administration in a patient with geographic atrophy (GA). Observation: A 78 year old Caucasian woman presented with complaints of lid edema, conjunctival injection, loss of vision, and mild ocular discomfort eleven days after receiving an intravitreal pegcetacoplan injection in the left eye for geographic atrophy. Visual acuity on presentation was decreased to 20/400 from 20/200 previously in that eye. Eyelid edema and conjunctival injection were present with minimal anterior chamber reaction. Dilated fundus examination revealed hemorrhages throughout the retina and signs of retinal vasculitis. The patient subsequently developed hyphema and vitreous hemorrhage. Laboratory evaluations for common infectious and inflammatory causes including aqueous and vitreous cultures for bacteria and Herpes simplex PCR were normal or negative. A delayed hypersensitivity to pegcetacoplan was suspected and was treated with topical, oral subconjunctival and intravitreal steroids. Conclusion: This index report illustrates a case of retinal vaso-occlusive vasculitis associated with intravitreal pegcetacoplan associated with lid edema and conjunctival injection and subsequent hyphema and vitreous hemorrhage. Therapy with steroids topically, systemically, periocularly and intravitreally were used to treat the inflammatory process and prevent further visual loss.

Complement Inhibitors for Geographic Atrophy in Age-Related Macular Degeneration-A Systematic Review.

BACKGROUND/OBJECTIVES: Age-related macular degeneration (AMD) is one of the main causes of blindness and visual impairment worldwide. Intravitreal complement inhibitors are an emergent approach in the treatment of AMD, which have had encouraging results. This systematic review analyzes the outcomes and safety of complement inhibitor therapies for GA in AMD cases. METHODS: A comprehensive search on the PubMed and Web of Science databases returned 18 studies involving various complement inhibitor agents, with a total of 4272 patients and a mean follow-up of 68.2 ± 20.4 weeks. RESULTS: Most treated patients were white (96.8%) and female (55.8%), with a mean age of 78.3 ± 7.8 years and a mean GA area of 8.0 ± 3.9 mm2. There were no differences in visual function change between treated and control participants. The mean GA area change was 2.4 ± 0.7 mm2 in treated participants vs. 2.7 ± 0.8 mm2 in control groups (p < 0.001). The ocular and systemic side effects were similar to those of intravitreal anti-VEGF. A less-understood effect was that of the onset of choroidal neovascularization (CNV) in 1.1-13% of patients; this effect was found to be more frequent in patients with neovascular AMD in the fellow eye or nonexudative CNV in the study eye at baseline. CONCLUSIONS: Complement inhibitors may represent a useful therapy for GA in AMD, but a personalized approach to patient selection is necessary to optimize the outcomes.