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

Current and Emerging Therapies for C3 Glomerulopathy and Primary (Idiopathic) Immune Complex Membranoproliferative Glomerulonephritis. (PubMed, Kidney Int Rep) - "However, recent advances in targeted complement inhibitor therapy have been made in these diseases with positive results from phase 3 clinical trials of both the factor B inhibitor, iptacopan (in adults with native kidney C3G) and the C3/C3b inhibitor, pegcetacoplan (in adults and adolescents with native or posttransplant C3G or primary IC-MPGN). In this review, we summarize what is known and what questions still remain regarding the effect of complement inhibitors on widely accepted surrogate end points for efficacy in C3G/primary IC-MPGN (proteinuria, estimated glomerular filtration rate [eGFR], and kidney biopsy histology). Additional controversies, including candidate patient populations, optimal treatment duration, and how best to monitor patients on complement inhibitor therapy are also discussed, in an effort to prepare the nephrology community for innovative therapeutic options for patients whose long-term prognosis has generally been dismal."

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

Sobi Receives European Commission Approval for Aspaveli (pegcetacoplan) for the Treatment of C3G and Primary IC-MPGN (Yahoo Finance) - "This approval is based on positive results from the Phase 3 VALIANT study, in which Aspaveli demonstrated benefits across the three key markers of disease, including significant reduction in proteinuria, stabilisation of kidney function, and substantial clearance of C3 deposits."

EMA approval • Glomerulonephritis • Renal Disease

EMPAVELI: Approximately $35 million and $102 million in preliminary U.S. net product revenues in the fourth quarter and full year 2025, respectively. (Apellis Press Release)

Sales • Focal Segmental Glomerulosclerosis • Glomerulonephritis • Paroxysmal Nocturnal Hemoglobinuria

Pegcetacoplan in Combination With Modified FOLFIRINOX for the Treatment of Metastatic Pancreatic Ductal Adenocarcinoma (clinicaltrials.gov) - P1/2 | N=35 | Not yet recruiting | Sponsor: Roswell Park Cancer Institute | Initiation date: Dec 2025 ➔ Mar 2026

Trial initiation date • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor

Advancing treatment goals for paroxysmal nocturnal hemoglobinuria to align with quality of life improvements in the era of anti-complement therapy (PubMed, Rinsho Ketsueki) - "Eculizumab, a C5 inhibitor introduced in 2010, directly inhibits intravascular hemolysis, and thus not only resolves hemolysis-related symptoms but also prevents organ damage and improves survival...Various drugs have been developed to address these issues, including long-acting C5 inhibitors (ravulizumab and crovalimab) and proximal complement inhibitors capable of blocking extravascular hemolysis, such as a C3 inhibitor (pegcetacoplan), a factor B inhibitor (iptacopan), and a factor D inhibitor (danicopan). In particular, proximal complement inhibitors further enhance QOL because they inhibit both intravascular and extravascular hemolysis, resulting in greater improvement of hemoglobin levels and transfusion independence, and thereby further enhancing of QOL. Today, it is possible to achieve optimal improvement in QOL by appropriately selecting one of the three C5 inhibitors as first-line therapy or one of the three proximal complement inhibitors as second-line..."

HEOR • Journal • Cardiovascular • Chronic Kidney Disease • Complement-mediated Rare Disorders • Hematological Disorders • Nephrology • Paroxysmal Nocturnal Hemoglobinuria • Rare Diseases • Renal Disease • Thrombosis

Recurrence of C3 Glomerulopathy and Immune Complex-Mediated Membranoproliferative Glomerulonephritis After Kidney Transplantation: Challenges and Opportunities. (PubMed, Kidney Int Rep) - "Conventional treatments, including intensified immunosuppression, rituximab, and plasma exchange, have shown limited and inconsistent efficacy...Although eculizumab remains the most extensively studied agent, emerging proximal complement inhibitors such as iptacopan and pegcetacoplan have shown encouraging efficacy in both native and recurrent disease. However, optimal timing, prophylactic use, and long-term safety in transplant recipients remain uncertain. In this review, we outline the clinical spectrum, key diagnostic and therapeutic challenges, and emerging treatment strategies for recurrent C3G and IC-MPGN, highlighting advances that may ultimately improve graft survival and patient outcomes."

Journal • Review • Chronic Kidney Disease • Complement-mediated Rare Disorders • Glomerulonephritis • Lupus Nephritis • Monoclonal Gammopathy • Nephrology • Renal Disease • Transplantation

Laboratory findings in patients treated with complement factor C3 inhibitor pegcetacoplan. (PubMed, Clin Chem Lab Med) - "Because of the increasing use of pegcetacoplan in routine clinical practice, it is important that both clinicians and laboratory specialists are aware of these unexpected therapy-induced laboratory findings."

Journal • Complement-mediated Rare Disorders • Glomerulonephritis • Hematological Disorders • Paroxysmal Nocturnal Hemoglobinuria • Rare Diseases

Real-world clinical outcomes and treatment response in complement inhibitor experienced and naïve PNH patients prescribed pegcetacoplan in Europe and Canada. (PubMed, Hematology) - "At pegcetacoplan initiation, 4.4% of patients met criteria of good-to-complete response versus 79.5% at survey. Pegcetacoplan proved effective for CInaïve and CIexp patients in a real-world setting, with numerically improved clinical outcomes and high response rate."

Clinical data • Journal • Real-world evidence • Complement-mediated Rare Disorders • Paroxysmal Nocturnal Hemoglobinuria

Enable Injections Announces Regulatory Approval in Saudi Arabia for the EMPAVELI Injector based on enFuse Technology (The Manila Times)

Approval • Paroxysmal Nocturnal Hemoglobinuria

Ravulizumab demonstrates real-world effectiveness in patients with paroxysmal nocturnal hemoglobinuria: A US chart review study (ASH 2025) - "Complement inhibitor (Ci)-experienced patients had previous eculizumab or pegcetacoplan use pre-index; Ci-naive patients had no previous use of any Ci pre-index. (2025), which reported BT-IVH in 14.8% of C5i-naive (event rate: 1.0 per 10 PY) and 7.8% of eculizumab-experienced patients (event rate: 0.33 per 10 PY) with PNH over a follow-up period of up to 6 years (median: 3.9 and 2.7 years, respectively). Overall, this analysis supports the use of ravulizumab, with only 6–7 infusions per year, as an effective treatment for patients with PNH in the real-world setting."

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

Real-world effectiveness of pegcetacoplan in paroxysmal nocturnal hemoglobinuria: A systematic review of clinical and patient-reported outcomes (ASH 2025) - "Conclusions RWE indicates PEG is associated with improved hematological parameters, reduced RBCt dependence and fatigue, and enhanced HRQoL. These findings from studies with diverse cohorts support generalizability and are broadly comparable with clinical trial evidence."

Clinical • Patient reported outcomes • Real-world • Real-world effectiveness • Real-world evidence • Review • Complement-mediated Rare Disorders • Hematological Malignancies • Paroxysmal Nocturnal Hemoglobinuria • Rare Diseases

Optimizing PNH treatment with the complement inhibitor pegcetacoplan: A case report (ASH 2025) - "The current treatment landscape includes 6 approved complement cascade inhibitors: 3 C5 inhibitors (eculizumab, ravulizumab, crovalimab), 1 C3/C3b inhibitor (pegcetacoplan), 1 factor B inhibitor (iptacopan), and 1 factor D inhibitor used as add-on treatment (danicopan)...Concomitant medications included apixaban, penicillin, and folic acid. In November 2020, her platelets count declined, and a bone marrow evaluation was diagnostic for moderate aplastic anemia (55-65% cellularity for age) and she was started on eltrombopag and cyclosporin. Despite ravulizumab and eltrombopag treatments, the patient developed significant anemia related to extravascular hemolysis (hemoglobin, 5.7 g/dL; LDH, 495 U/L; C5, 26.1 mg/dL [high]; complement hemolytic activity 50 [CH50], 7 U/mL [low])...After receiving both pegcetacoplan and iptacopan for 1 week and rivaroxaban 10 mg once daily for 48 hours, pegcetacoplan treatment ended on May 16, 2024... For this patient with PNH, the..."

Case report • Clinical • Anorexia • Aplastic Anemia • Complement-mediated Rare Disorders • Hematological Disorders • Infectious Disease • Meningococcal Infections • Paroxysmal Nocturnal Hemoglobinuria • Rare Diseases

Successful retreatment of PNH with switch to ravulizumab and add-on danicopan after experiencing breakthrough hemolysis on pegcetacoplan: A case report (ASH 2025) - "Terminal complement inhibition with C5 inhibitors ravulizumab (Rav), the standard of care for PNH treatment, and eculizumab (Ecu) have provided effective control of terminal complement activity and IVH and decreased rates of thrombosis...The patient was treated intermittently with antithymocyte globulin and/or cyclosporine for ~5 years while receiving red blood cell transfusions... Hb, 11.8 g/dL; LDH, 351 U/L). The patient restarted Rav with 2 loading doses 2 weeks apart. The patient experienced 1 mild episode of BTH ~4 months after restarting Rav (Hb, 9.9 g/dL; LDH, 382 U/L), resolving rapidly with her scheduled dose of Rav."

Case report • Clinical • Cardiovascular • Complement-mediated Rare Disorders • Hematological Disorders • Paroxysmal Nocturnal Hemoglobinuria • Rare Diseases • Thrombosis

Overview of treatment advances with complement inhibitors in patients with paroxysmal nocturnal hemoglobinuria (ASH 2025) - P3 | "The success of terminal C5 inhibitors emboldened researchers to investigate proximal complement inhibitors that have the potential to control both IVH and EVH, such as pegcetacoplan (C3/C3b inhibitor) and iptacopan (factor B inhibitor), as well as danicopan (factor D inhibitor) used as an add-on to C5 inhibitors...In the most recent analysis of the phase 3 ALPHA trial (NCT04469465), 57 patients (mean age 53 years) with PNH and residual clinically significant EVH (Hb ≤9.5 g/dL with ARC ≥120 × 10 9 /L) while receiving ravulizumab (63%) or eculizumab (37%) for a mean of 5 years were given danicopan in addition to their current C5 inhibitor for 12 weeks.[Kulasekararaj A, et al... Across clinical studies that included patients with PNH and Hb ≥10 g/dL after C5 inhibition, proximal complement inhibitors improved measures of residual anemia and quality of life to clinically significant degrees (increases of ≥2 g/dL in Hb levels and ≥3–5 points in FACIT-Fatigue..."

Clinical • Aplastic Anemia • Cardiovascular • Complement-mediated Rare Disorders • Hematological Disorders • Infectious Disease • Meningococcal Infections • Otorhinolaryngology • Paroxysmal Nocturnal Hemoglobinuria • Pneumonia • Rare Diseases • Respiratory Diseases • Thrombosis

User experience with pegcetacoplan on-body injector in patients with paroxysmal nocturnal hemoglobinuria (ASH 2025) - " Twelve patients with PNH (mean age, 46 years) previously treated with C5is (eculizumab, n=5; ravulizumab, n=7) and on pegcetacoplan for a mean of 18.2 months were recruited; 1 patient who had limited experience with the injector did not complete the interview. Most patients with PNH were satisfied with multiple aspects of their experience with the pegcetacoplan injector. Patients perceived the injector positively as it provides significant benefits, improving their quality of life and reducing treatment burden. Similar on-body delivery systems used by patients with relapsed/refractory multiple myeloma (phase 2 IZALCO and phase 3 IRAKLIA trials) were associated with low infusion-reaction rates, potentially leading to improved long-term adherence, patient quality of life, and practice efficiency [Parmar G, et al."

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

Low risk for meningococcal and other encapsulated bacteria infections with systemically administered pegcetacoplan in paroxysmal nocturnal hemoglobinuria and C3 glomerulopathies (ASH 2025) - P3 | "Clinical benefits of the initially available C5 inhibitors that blocked terminal complement activation (eculizumab, ravulizumab, crovalimab) paved the way for the development of proximal inhibitors, including the C3/C3b inhibitor pegcetacoplan, the factor B inhibitor iptacopan, and the add-on (to C5 inhibitors) factor D inhibitor danicopan. Understanding the safety profile of pegcetacoplan and other complement-targeted therapies, especially the risk for meningococcal and other encapsulated bacteria infections, will help physicians and patients make informed treatment decisions for individuals with complement-mediated conditions. For nearly over 7 years, systemically administered pegcetacoplan has had a consistently low rate of encapsulated bacteria infections in patients with PNH, C3G, or primary IC-MPGN. These findings may reflect effective risk mitigation strategies."

CNS Disorders • Complement-mediated Rare Disorders • Glomerulonephritis • Hematological Disorders • Immunology • Infectious Disease • Influenza • Lupus Nephritis • Meningococcal Infections • Nephrology • Paroxysmal Nocturnal Hemoglobinuria • Pneumococcal Infections • Pneumonia • Primary Immunodeficiency • Rare Diseases • Respiratory Diseases • Septic Shock

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