Empaveli (pegcetacoplan SC) / Apellis, SOBI - LARVOL DELTA

Novel treatment strategies for C3 glomerulopathy: complement blockade. (PubMed, Int Urol Nephrol) - "Successful use of eculizumab has been reported in aggressive disease forms...New agents such as iptacopan and pegcetacoplan look very promising. Notably, use of both agents was recently approved by the United States Food and Drug Administration. Herein we review novel treatment strategies for patients suffering from C3G with a focus on agents targeting complement system."

Journal • Review • Complement-mediated Rare Disorders • Glomerulonephritis • Nephrology • Renal Disease • Transplantation

Trial of Pegcetacoplan in C3 Glomerulopathy and Immune-Complex MPGN. (PubMed, N Engl J Med) - P3 | "Pegcetacoplan resulted in a significantly greater reduction in proteinuria than placebo among patients with C3 glomerulopathy or primary immune-complex MPGN. (Funded by Apellis Pharmaceuticals and Sobi [Swedish Orphan Biovitrum]; VALIANT ClinicalTrials.gov number, NCT05067127.)."

Journal • Complement-mediated Rare Disorders • Glomerulonephritis • Infectious Disease • Lupus Nephritis • Nephrology • Novel Coronavirus Disease • Pneumonia • Respiratory Diseases • Transplant Rejection • Transplantation

Pegcetacoplan for Treatment of C3 Glomerulopathy and Immune-Complex MPGN. (PubMed, N Engl J Med) - No abstract available

Journal • Complement-mediated Rare Disorders • Glomerulonephritis

Real-world data on breakthrough hemolysis in patients with paroxysmal nocturnal hemoglobinuria treated with proximal and terminal complement inhibitors. (ASH 2025) - "Four patients were treated with factor D inhibitor danicopan(n=3) or iptacopan (n=1) concurrently with ravulizumab.A total of 49 BTH events were identified; while on eculizumab (26 events, 12 patients), ravulizumab (14events, 7 patients), ravulizumab and danicopan (6 events, 3 patients), pegcetacoplan (1 event, 1 patient),zilucoplan (2 events, 2 patients), and no events while on iptacopan. Twelve BTH events were incidentally detected during routine CIadministration; more frequent lab draws may be beneficial for patients with chronic hemolysis. Moredata is needed to understand the BTH rates of different CIs and guide clinicians in BTH management."

Clinical • Real-world • Real-world evidence • Anemia • Aplastic Anemia • Breast Cancer • Complement-mediated Rare Disorders • Infectious Disease • Paroxysmal Nocturnal Hemoglobinuria • Rare Diseases • Solid Tumor • CD55 • CD59 • HP

Factor bb as a biomarker during breakthrough hemolysis in paroxysmal nocturnal hemoglobinuria (ASH 2025) - "Patients were grouped according to CI at sampling; untreated [n=16],eculizumab [n=8], ravulizumab [n=21], pegcetacoplan [n=16], iptacopan [n=16]). Its consistent rise during BTH, followed by return tobaseline within days, supports its use as a sensitive biomarker. This may help assess ongoing BTHseverity and guide clinical decisions."

Biomarker • Complement-mediated Rare Disorders • Hepatology • Liver Failure • Paroxysmal Nocturnal Hemoglobinuria • Rare Diseases

Real-world clinical characteristics and treatment outcomes in PNH patients prescribed pegcetacoplan across europe, the United States and Canada (ASH 2025) - P3 | "These data suggest thatpegcetacoplan has positive outcomes regardless of prior CI exposure. These findings indicate that theefficacy of pegcetacoplan in a real-world clinical practice is consistent with results from clinical trials andother real-world evidence for both CIexp and CInaive patients."

Clinical • Real-world • Real-world evidence • Complement-mediated Rare Disorders • Hematological Disorders • Paroxysmal Nocturnal Hemoglobinuria • Rare Diseases

Pegcetacoplan for patients with transplant-associated thrombotic microangiopathy treatment: A real-world report of six cases (ASH 2025) - "This cohort included one patient refractory to plasmaexchange and another who had failed both eculizumab and ravulizumab. This case series provides the first real-world evidence suggesting that proximal C3 inhibitionwith pegcetacoplan may be an effective and safe therapeutic option for pediatric TA-TMA. Treatment wasassociated with rapid and complete remissions, including in patients refractory to C5 inhibitors and otherconventional therapies. These encouraging findings support the investigation of pegcetacoplan inprospective clinical trials to formally establish its role in the management of this severe HSCTcomplication."

Clinical • Real-world • Real-world evidence • Acute Lymphocytic Leukemia • Beta-Thalassemia • Bone Marrow Transplantation • Genetic Disorders • Graft versus Host Disease • Hematological Disorders • Hematological Malignancies • Hepatology • Hypertension • Immunology • Infectious Disease • Leukemia • Nephrology • Primary Immunodeficiency • Sickle Cell Disease • Transplantation

Real-world breakthrough hemolysis patterns across 1,723 patient-years of complement inhibition in paroxysmal nocturnal hemoglobinuria (ASH 2025) - "Clinical BTH episodes were more common in non-responders than responders in eculizumab(OR 2.32; p = .003), ravulizumab (OR 2.32; p = .a044), iptacopan (OR 10; p = 0.18) and pegcetacoplan (OR2.5; p = 0.21). These findings support prospective multicenter validation and thatiptacopan could maintain long-term disease stability. Current complement sequencing analysis is ongoingto classify patients with hemolysis."

Clinical • Real-world • Real-world evidence • Complement-mediated Rare Disorders • Hematological Disorders • Paroxysmal Nocturnal Hemoglobinuria • Rare Diseases

Iptacopan monotherapy demonstrated improved clinical outcomes in a real-world cohort with paroxysmal nocturnal hemoglobinuria: Evidence from a managed access program (ASH 2025) - "The proportion of pts previously treated witheculizumab, ravulizumab, pegcetacoplan, and danicopan was 71.6%, 37.9%, 13.7%, and 6.3%,respectively. The updated data from this MAP confirm hematological and clinical improvements withiptacopan in Ci-naive and Ci-experienced pts with PNH, with approximately 6 months of iptacopantherapy. Oral iptacopan monotherapy led to normalization of Hb and LDH level, and RLC, along with ahigher proportion of pts achieving transfusion avoidance at retreatment visits compared to BL. Pts alsoreported notable improvements in fatigue and tx satisfaction."

Clinical • Clinical data • Monotherapy • Real-world • Real-world evidence • Complement-mediated Rare Disorders • Hematological Disorders • Infectious Disease • Paroxysmal Nocturnal Hemoglobinuria • Rare Diseases • CFB

Maternal and fetal pharmacokinetics (PK) of pegcetacoplan in paroxysmal nocturnal hemoglobinuria (PNH): A case report of use in pregnancy (ASH 2025) - "Aftertrials of vemircopan and iptacopan, she was transitioned to pegcetacoplan 1080 mg subcutaneous2x/week and achieved transfusion independence (hemoglobin ~110 g/L)...Thesefindings are consistent with preclinical non-human animal data and pegcetacoplan's physicochemicalproperties—a large, pegylated, and hydrophilic cyclic peptide, expected to have limited membranepermeability.In a patient with hemolytic PNH and inadequate hematologic response to eculizumab, conception onpegcetacoplan was not associated with adverse fetal/pregnancy outcomes, and third-trimesterreinitiation resulted in rapid hematologic improvement, transfusion independence, and anuncomplicated peripartum course.In conclusion, this report provides the first clinical and PK evidence suggesting that third-trimester use ofpegcetacoplan may be a viable treatment option in select pregnant patients with PNH with suboptimalresponse to C5 inhibitors. Following reinitiation of pegcetacoplan at 28 weeks GA,..."

Case report • Clinical • PK/PD data • Cardiovascular • Complement-mediated Rare Disorders • Diabetes • Genetic Disorders • Gestational Diabetes • Obesity • Paroxysmal Nocturnal Hemoglobinuria • Rare Diseases • Thrombosis

The effect of breakthrough hemolysis on complement factor h and factor I levels in paroxysmal nocturnal hemoglobinuria (ASH 2025) - "Patients were grouped according to CI at sampling; untreated [n=16],eculizumab [n=10], ravulizumab [n=15], pegcetacoplan [n=16], iptacopan [n=15]). CFI is dependent on the presence of cofactors, such as CFH, to regulatecomplement which may explain why upstream CFH levels and not CFI levels rise in BTH. These findingssupport the concept that dynamic changes in CFH may play an active role in the acute regulation ofcomplement during BTH."

Complement-mediated Rare Disorders • Hematological Disorders • Paroxysmal Nocturnal Hemoglobinuria • Rare Diseases • CD55 • CD59

Early results from the ongoing pegcetacoplan silo of the international paroxysmal nocturnal hemoglobinuria interest group registry (ASH 2025) - "Of the 24 enrolled patients, 23had prior experience with anti-complement therapies, most commonly eculizumab (66.7%) and/orravulizumab (62.5%) in the clinical setting. As of data cut-off, 24 patients were enrolled in the pegcetacoplan silo of the IPIG PNHRegistry. In this first interim report, safety results with pegcetacoplan were consistent with previouslyreported clinical trial data and no new safety signals were detected."

Cardiovascular • Chronic Kidney Disease • Complement-mediated Rare Disorders • Immunology • Infectious Disease • Nephrology • Novel Coronavirus Disease • Paroxysmal Nocturnal Hemoglobinuria • Pneumonia • Rare Diseases • Respiratory Diseases • Septic Shock • Thrombosis

Paroxysmal Nocturnal Hemoglobinuria in Pregnancy Treated With Pegcetacoplan: Case Report and Pharmacokinetic Analysis. (PubMed, EJHaem) - "In a patient with transfusion-dependent anemia on eculizumab, third-trimester initiation of pegcetacoplan led to hematological stabilization, transfusion independence, and an uncomplicated term cesarean delivery of a healthy infant. Pegcetacoplan was undetectable in cord blood and breast milk despite therapeutic maternal levels, suggesting fetal and neonatal safety due to lack of significant placental and lactational transfer, and advancing evidence for pegcetacoplan use in pregnancy. Trial Registration: The authors have confirmed clinical trial registration is not needed for this submission."

Journal • PK/PD data • Complement-mediated Rare Disorders • Hematological Disorders • Paroxysmal Nocturnal Hemoglobinuria • Rare Diseases

Navigating the complement cascade: A multicenter journey from pegcetacoplan to iptacopan in paroxysmal nocturnal hemoglobinuria (ASH 2025) - "This first multicenter real-world analysis demonstrates that the pegcetacoplan-to-iptacopantransition provides clinical benefit in the majority of this initial set of patients with PNH, with significantimprovements in hemoglobin and an excellent safety profile while maintaining clone stability. The highacceptance rate suggests that patients prefer oral therapy over subcutaneous administration. Thesefindings address a critical knowledge gap in proximal complement inhibitor sequencing, suggesting thatiptacopan is an effective therapeutic option for patients with inadequate pegcetacoplan response andsupporting the development of evidence-based treatment algorithms for optimal PNH care in the era ofmultiple complement inhibitor options."

Clinical • Anemia • Aplastic Anemia • Complement-mediated Rare Disorders • Hematological Malignancies • Multiple Myeloma • Myelofibrosis • Paroxysmal Nocturnal Hemoglobinuria • Rare Diseases • Thrombosis

Management of a real-world cohort of patients with paroxysmal nocturnal hemoglobinuria treated with iptacopan: A multi-institutional analysis (ASH 2025) - "In the 50 patients who switched, 60%transitioned from ravulizumab, 30% from pegcetacoplan, 8% from eculizumab, and 2% fromravulizumab and danicopan. In this real-world cohort, iptacopan provided substantial and durable hemoglobinimprovement across naive and previously treated patients with PNH, with meaningful reduction inhemolytic parameters, absence of thrombosis, and low BTH rate predominantly linked to infection.Patients with previous satisfactory responses also showed improved Hgb levels. The favorable safetyprofile and high treatment persistence underscore iptacopan's role as an effective first-line or switchtherapy and support its incorporation into evidence-based sequencing algorithms in the evolving PNHtreatment landscape."

Clinical • Real-world • Real-world evidence • Cardiovascular • CNS Disorders • Complement-mediated Rare Disorders • Congestive Heart Failure • Heart Failure • Hematological Disorders • Infectious Disease • Pancreatitis • Paroxysmal Nocturnal Hemoglobinuria • Rare Diseases • Thrombosis • Vascular Neurology

Real-world treatment patterns and clinical outcomes among patients with paroxysmal nocturnal hemoglobinuria treated with iptacopan in the United States (ASH 2025) - "Overall, 25% of patients (n=13) were complementinhibitor (CI) naive at the time of iptacopan initiation, while 75% (n=39) were treatment experienced andhad received ≥1 prior CI therapy for PNH (77% ravulizumab, 46% eculizumab, 26% pegcetacoplan). These data represent early insights into the real-world use of iptacopan and related Hbresponse in US patients with PNH. Adherence to iptacopan was high, and iptacopan treatment improvedHb and LDH parameters, providing comprehensive hemolysis control. Enrollment is currently ongoing; data on additional patients with longer follow-up are forthcoming."

Clinical • Clinical data • HEOR • Real-world • Real-world evidence • Anemia • Aplastic Anemia • Cardiovascular • Complement-mediated Rare Disorders • Hematological Disorders • Hematological Malignancies • Myelodysplastic Syndrome • Paroxysmal Nocturnal Hemoglobinuria • Rare Diseases • Thrombosis

Real-world use of oral iptacopan monotherapy in paroxysmal nocturnal hemoglobinuria (ASH 2025) - "Therapy received immediately prior to iptacopan included C5i (n=105),pegcetacoplan (n=27), dual proximal and terminal inhibition (n=7) and clinical trial (n=7)...3 patients received additional doses of eculizumab, and 3 patients were permanently switched toalternative CI.Infections requiring antibiotics occurred in 21 patients (14.1%), most commonly respiratory source (9/21).8 patients required hospitalization (urinary tract infection (n=2), chest infection (n=4), cellulitis (n=1)unknown (n=1)), 3 with BTH...No thrombotic eventsoccurred. These findings support the effectiveness of iptacopan in the treatment of PNH."

Clinical • Monotherapy • Real-world • Real-world evidence • Anemia • Aplastic Anemia • Bone Marrow Transplantation • Complement-mediated Rare Disorders • Dermatology • Infectious Disease • Meningococcal Infections • Nephrology • Paroxysmal Nocturnal Hemoglobinuria • Rare Diseases • Thrombosis

Iron overload and iron chelation therapy in PNH patients on complement inhibitors: A single centre experience. (ASH 2025) - "We collecteddata on which complement inhibitor were the patients recieving, if they needed iron chelation therapyand which drug was used, serum ferritin, liver iron overload measured by MRi (LIC) and duration ofchelation therapy.Our goal is to define our population's characteristics in relation to iron overload so as to serve as aplatform for future studdies. We currently treat 12 PNH patients, 5 of which recieve proximal complement inhibitors(iptacopan) and 7 recieve terminal complement inhibitors, including ravulizumab, eculizumab andcrovalimab...After 2 years of follow-up of chelation therapy, median LIC was 2.11mg/g,which correlates to a minimal liver iron overload.3 of the 4 patients on iron chelation therapy have been able to discontinue treatment after switchingfrom iC5 to proximal complement inhibition (iptacopan and 1 case pegcetacoplan), due to said treatmentbeing able to control both IVH and EVH...Iron overload in PNH patients is a long-term rising..."

Clinical • Hematological Disorders

Complement inhibitor use is not a significant predictor of cancer incidence: A real-world study of patients requiring chronic complement blockade. (ASH 2025) - "Sixwere treated with eculizumab and ravulizumab, 4 with eculizumab alone, 1 with ravulizumab alone, and 1with eculizumab, ravulizumab, pegcetacoplan, and iptacopan at various points...Factors such asfamily history, smoking/alcohol use, and past medical history of HPV, hepatitis B, hepatitis C, and HIVremain established predictors for cancer incidence. Further analysis in a larger cohort is needed tovalidate these initial results."

Clinical • Real-world • Real-world evidence • Age-related Macular Degeneration • Atypical Hemolytic Uremic Syndrome • Bladder Cancer • Breast Cancer • CNS Disorders • Complement-mediated Rare Disorders • Endocrine Cancer • Hepatitis B • Hepatitis C • Hepatology • Human Immunodeficiency Virus • Immunology • Infectious Disease • Kaposi Sarcoma • Macular Degeneration • Myasthenia Gravis • Nephrology • Neuroendocrine Tumor • Neuromyelitis Optica Spectrum Disorder • Oncology • Ophthalmology • Paroxysmal Nocturnal Hemoglobinuria • Rare Diseases • Renal Disease • Retinal Disorders • Sarcoma • Solid Tumor

Switching between complement inhibitors in patients with PNH: A real-world analysis of strategy, efficacy, and safety. (ASH 2025) - "In 2025, 3 C5 inhibitors (C5i) are approved (eculizumab (ECU), ravulizumab (RAV), crovalimab) & 3proximal inhibitors (PI) (pegcetacoplan (PEG), ipatacopan (IPTA), danicopan (DAN) plus C5i). Some clinicaltrial therapies have not continued development (vermicopan (VERM), BCX9930 (BCX), other C5i).PI clinical trials have protocols for changing from terminal to PI, based on drug half-life... Sixty-two pts from 8 countries were included with mean age at diagnosis 38.4 years (range 16-79)& mean Hb 87.8 g/L (missing data, n=17). Where reported indications for CI were hemolysis (49/62),hemolysis and thrombosis (5/62), thrombosis (3/62). Mean time on CI was 103.6 months (range 23-276; missing n=3) & mean granulocyte clone 86% (range 31-99; missing n=9).First-line CI were ECU/RAV (50/62), VERM (9/62) & investigational C5i (3/62)."

Clinical • Real-world • Real-world evidence • Cardiovascular • Complement-mediated Rare Disorders • Hematological Disorders • Paroxysmal Nocturnal Hemoglobinuria • Rare Diseases • Thrombosis

Consistent benefits of pegcetacoplan treatment in PNH patients with and without a history of aplastic anemia in real world: Analysis of the ongoing COMPLETE Phase IV observational study (ASH 2025) - P, P3 | "The safety profile was consistent with previous findings, with SAEs being infrequent and largelyunrelated to PEG. These findings confirm the meaningful clinical benefits of PEG in managing PNH anddemonstrate its effectiveness across diverse patient populations."

Clinical • Observational data • P4 data • Real-world • Real-world evidence • Anemia • Aplastic Anemia • Hematological Disorders • Rare Diseases

Comparative efficacy of complement inhibitors in complement Inhibitor–Naïve PNH: A network meta-analysis of randomized trials (ASH 2025) - "A frequentist model network meta-analyses were conducted in RStudio (v5.4.1) using acommon-effects model. A total of 4 randomized controlled trials evaluating 4 complement inhibitor agents (Ravulizumab,Crovalimab, Eculizumab & Pegcetacoplan) were included in this meta-analysis, involving 589 complementinhibitor–naïve adults with PNH. We found no single agent being consistently superior to others across all clinically relevantoutcomes. Notably, the treatment of choice should be individualized based on the goals of care andpriorities of the patients such as transfusion independence or quality of life. Post-market real-worldanalysis and comparison of these agents may guide optimal sequencing or cost-effective strategies in themanagement of PNH."

Retrospective data • Anemia • Aplastic Anemia • Complement-mediated Rare Disorders • Hematological Disorders • Hematological Malignancies • Myelodysplastic Syndrome • Paroxysmal Nocturnal Hemoglobinuria • Rare Diseases

Evaluating the Value Elements Considered in Health Technology Assessments of Paroxysmal Nocturnal Hemoglobinuria Treatments: A Targeted Review (ISPOR-EU 2025) - "This analysis assessed how value elements were considered in HTAs for PNH treatments and their impact on HTA decision-making. A targeted search was conducted in June 2025 for PNH treatments approved since 2020 (iptacopan, pegcetacoplan, danicopan, crovalimab) across five HTA body websites (NICE, GBA, HAS, TLV, Medicinrådet). Novel ISPOR value elements were included in CSs and CRs with qualitative supporting data, however costs and QALYs remained the primary focus. Research and efforts from companies/HTA bodies are needed to generate supporting data and facilitate adoption of broader value elements in decision-making, particularly in rare diseases."

Review • Complement-mediated Rare Disorders • Hematological Disorders • Paroxysmal Nocturnal Hemoglobinuria • Rare Diseases

Real-World Adherence with Pegcetacoplan in Paroxysmal Nocturnal Hemoglobinuria Compared with Previously Reported Oral Medication Adherence Rates (ASH 2024) - "Several complement inhibitors are approved for PNH, including the intravenous or subcutaneous C5 inhibitors (C5is) eculizumab, ravulizumab, and crovalimab; the subcutaneous self-administered C3 inhibitor pegcetacoplan; and the oral factor B inhibitor iptacopan and factor D inhibitor danicopan (as add-on therapy to a C5i)...OAC adherence rates in AF range widely (~40% to ~90%), differing across countries, patient populations (incident AF vs. post cardiovascular event), OAC types (warfarin, direct OACs), and follow-up period lengths...2020; 26 : 186].Pegcetacoplan adherence for PNH in the US postmarketing setting from launch (2021) to date (2024) was estimated at 97%, well above the 80% threshold defining medication adherence in the literature.Conclusions : Real-world patients with PNH who self-administer pegcetacoplan subcutaneously have adherence rates exceeding the reported real-world adherence rates for oral medications in chronic conditions, especially those with high..."

Adherence • Clinical • HEOR • Real-world • Real-world evidence • Atrial Fibrillation • Cardiovascular • Complement-mediated Rare Disorders • Diabetes • Hematological Malignancies • Metabolic Disorders • Oncology • Paroxysmal Nocturnal Hemoglobinuria • Rare Diseases • Thrombosis • Type 2 Diabetes Mellitus

Current Real-World Treatment Landscape for Patients with Paroxysmal Nocturnal Hemoglobinuria in the United States (ASH 2024) - "CI therapies included eculizumab, ravulizumab, pegcetacoplan, iptacopan, danicopan, and crovalimab. Following its approval, uptake of iptacopan among patients with PNH has been rapid in US real-world clinical practice, with 14% of CI-treated patients currently receiving iptacopan as their most recent therapy. Nonetheless, the majority of included patients with PNH did not have a claim for a CI therapy during the study period, despite the availability of six approved CI therapies."

Clinical • HEOR • Real-world • Real-world evidence • Complement-mediated Rare Disorders • Hematological Disorders • Paroxysmal Nocturnal Hemoglobinuria • Rare Diseases