Abstract Background and Aims C3 glomerulopathy (C3G) and primary immune complex membranoproliferative glomerulonephritis (IC-MPGN) are rare diseases caused by uncontrolled complement activation, resulting in excess deposition of C3 breakdown products in the kidneys, which leads to kidney damage and eventually kidney failure. Kidney transplantation is an option for end-stage kidney disease, but disease recurrence is common (up to 67% of patients), and up to 50% of transplant recipients lose renal allografts due to recurrence. Pegcetacoplan is a targeted C3 and C3b inhibitor that may prevent excess deposition of C3 and C5 breakdown products and subsequent glomerular inflammation and kidney damage in patients with C3G or IC-MPGN, potentially improving clinical outcomes. NOBLE (NCT04572854) was the first prospective randomized controlled trial of pegcetacoplan vs standard of care (SOC) in post-transplant patients with recurrent C3G or IC-MPGN. Method Adult patients were randomized 3:1 to subcutaneous pegcetacoplan 1080 mg twice weekly plus SOC (n = 10) or SOC only (n = 3) for 12 weeks followed by a 40-week non-controlled period in which all patients received pegcetacoplan. Primary and secondary endpoint results for Week-12 data have been reported. We conducted a patient-level post hoc analysis to describe key histology changes from renal biopsy (C3c staining, C3G histologic index activity score), clinical parameters (urine protein-to-creatinine ratio [uPCR; calculated from triplicate first-morning spot urine], estimated glomerular filtration rate [eGFR]), and biomarkers (serum C3, plasma sC5b-9) through Week 12. The C3G histologic index uses a semiquantitative scale of 0–3 for 7 markers of activity (mesangial hypercellularity, endocapillary proliferation, membranoproliferative morphology, leukocyte infiltration, cellular and/or microcellular crescent formation, fibrinoid necrosis, and interstitial inflammation), for a total activity score of 0–21. eGFR stability was defined as a decrease of no more than 25% versus baseline. Results Among the 10 pegcetacoplan-treated patients, 7 (70%) had 1 previous kidney transplant, 2 (20%) had 2, and 1 (10%) had 3. The mean (range) time to disease recurrence after most recent transplant was 10.8 (0.4–31.8) months and from most recent recurrence to randomization was 12.2 (2.1–37.7) months, with 60% randomized >6 months post-disease recurrence. Among the 3 SOC-only patients, 2 (66.7%) had 1 transplant and 1 (33.3%) had 2. Mean (range) time to recurrence was 32.8 (4.6–63.8) months and to randomization was 33.9 (7.0–65.4) months. At Week 12, 8 (80%) pegcetacoplan-treated patients had a reduction in C3c staining of at least 1 order of magnitude. Of these 8, 7 (70%) had a decrease in activity score, and 6 of these 7 (60%) had a decrease in proteinuria. Four (40%) patients had reduced C3c staining, decreased activity score, and cleared electron microscopy deposits at Week 12. eGFR remained stable in 9 (90%) patients. Six of 9 (67%) patients with available Week-12 data (4 of 5 patients with >1 g/g uPCR at baseline) had a reduction in uPCR with 5 of the 6 achieving ≥50% uPCR reduction (Table). All pegcetacoplan-treated patients had increased serum C3, as expected, and 9 (90%) had decreased sC5b-9. At Week 12, no TEAEs led to study discontinuation, treatment withdrawal, or death. No encapsulated bacterial infections or events of rejection/graft loss related to the study drug were reported. Conclusion As early as Week 12, more than half (6/10 [60%]) of post-transplant patients with recurrent C3G or IC-MPGN treated with pegcetacoplan achieved reductions in C3c staining, activity score of C3G histology index, and proteinuria, suggesting that pegcetacoplan targets the underlying pathophysiology of the C3G/IC-MPGN in kidney transplant recipients. The safety and efficacy of pegcetacoplan will be further evaluated at Week 52 of the NOBLE study and as part of the Phase 3 VALIANT (NCT05067127) trial, which enrolled patients with C3G or primary IC-MPGN who have native kidney or post-transplant disease.

The term atypical hemolytic uremic syndrome has been in use since the mid-1970s.It was initially used to describe the familial or sporadic form of hemolytic uremic syndrome as opposed to the epidemic, typical form of the disease.Over time, the atypical hemolytic uremic syndrome term has evolved into being used to refer to anything that is not Shiga toxin-associated hemolytic uremic syndrome.The term describes a heterogeneous group of diseases of disparate causes, a circumstance that makes defining disease-specific natural history and/or targeted treatment approaches challenging.A working group of specialty-specific experts in the thrombotic microangiopathies was convened to review the validity of this broad term in an era of swiftly advancing science and targeted therapeutics.A Delphi approach was used to define and interrogate some of the key issues related to the atypical hemolytic uremic syndrome nomenclature.

Pegcetacoplan (PEG; C3 inhibitor) may prevent C3G or IC-MPGN progression. NOBLE (NCT04572854) is the first prospective randomized controlled trial of PEG vs standard of care (SOC) in kidney transplant recipients (KTRs) with primary C3G or IC-MPGN recurrence.

In this work, we develop recombinant human cationic ferritin (rHCF) as a contrast agent to detect glomeruli in the kidney using positron emission tomography (PET). We first expressed recombinant human ferritin (rHF) in E. coli and then functionalized and radiolabeled it with Copper-64 (64Cu) to form Cu-64-rHCF. Intravenously injected Cu-64-rHCF bound to kidney glomeruli and was detected by PET. A subchronic toxicity study after an intravenous injection of rHCF revealed no significant toxicity. The development of rHCF is an important step toward the potential clinical translation of CF to detect the nephron number in humans.

The authors regret that N. Palakow was incorrectly listed as an author for this abstract. She should be removed from the author slate. The authors would like to apologise for any inconvenience caused. DOI of original article: 10.1016/j.ekir.2022.04.069 POS-047 PHASE 2 STUDY TO EVALUATE EFFICACY AND SAFETY OF PEGCETACOPLAN IN THE TREATMENT OF PATIENTS WITH POSTTRANSPLANT RECURRENCE OF C3G OR IC MPGNKidney International ReportsVol. 7Issue 6PreviewComplement 3 glomerulopathy (C3G) and immune complex membranoproliferative glomerulonephritis (IC-MPGN) are rare but devastating kidney diseases. There are no approved therapies for these diseases, and 50% of patients develop recurrence of disease and graft loss after transplant. Uncontrolled complement activation at the level of C3 leads to excessive production of C3 breakdown products and deposition in the kidney. As an investigational C3 and C3b inhibitor, pegcetacoplan has the potential to address the underlying pathophysiology of C3G and IC-MPGN. Full-Text PDF Open Access

In 2004, the nephrology community took an introspective look at the state of clinical trials for kidney disease and realized the subspecialty holds the dubious distinction of being in last place in the performance and completion of trials compared with other disciplines. 1 Strippoli G.F. Craig J.C. Schena F.P. The number, quality, and coverage of randomized controlled trials in nephrology. J Am Soc Nephrol. 2004; 15: 411-419 Crossref PubMed Scopus (277) Google Scholar However, some recent successes, including US Food and Drug Administration–approved drugs for autosomal dominant polycystic kidney disease, diabetic kidney disease, and anti–neutrophil cytoplasmic antibody–associated vasculitis and positive interventional trials in focal segmental glomerular sclerosis and lupus nephritis, provide cause for encouragement. It is critical that the community sustains and increases the momentum of bringing novel therapeutics to trial. In this regard, the treatment of glomerular diseases could lead the way. The PMDA's view on the limited pipeline of nephrology drugs in JapanKidney InternationalVol. 100Issue 1PreviewWe truly appraise the article by Barisoni et al. introducing several actions to grow clinical trial infrastructures and calling on the nephrology community to collaborate with patients, clinicians, pathologists, industries, and regulatory agencies.1 Herein, we would like to share the recent situations of nephrology drugs in Japan. Full-Text PDF

IntroductionComplement 3 glomerulopathy (C3G) and immune complex membranoproliferative glomerulonephritis (IC-MPGN) are rare diseases characterized by excessive deposition of C3 breakdown products in renal glomeruli leading to proteinuria and progressive renal disease. Pegcetacoplan is a targeted C3 investigational therapy for diseases related to complement overactivation. This is a phase 3, randomized, placebo-controlled, double-blind, multicenter study of the efficacy and safety of pegcetacoplan in individuals with C3G or IC-MPGN.MethodsApproximately 90 patients (age, ≥12 years; weight, 20-100 kg) diagnosed with C3G or IC-MPGN, either as primary disease or posttransplant disease recurrence, will be recruited. Inclusion criteria include 2+ staining for C3c, global glomerulosclerosis <50%, urine protein-to-creatinine ratio (uPCR) ≥1000 mg/g, and estimated glomerular filtration rate (eGFR) >30 mL/min/1.73 m2. Exclusion criteria include previous pegcetacoplan exposure, C3G/IC-MPGN secondary to other conditions, and significant infection/malignancy. Patients will be randomized 1:1 to receive subcutaneous infusions of pegcetacoplan (1080 mg/20 mL) or matching volume of placebo twice weekly for 26 weeks (in addition to standard care). Thereafter, in the open-label period, all participants will receive pegcetacoplan twice weekly for 26 weeks. Assessments include first-morning uPCR every 4 weeks and renal biopsies at baseline/screening and weeks 26 and 52. Primary endpoint is proportion of participants with reduction in uPCR ≥50% relative to baseline at week 26. Secondary endpoints include proportion of participants with eGFR scores that are stable or improved from baseline; change in C3G histologic index activity score; and proportion of participants with decreased C3c staining on renal biopsy from baseline at week 26. Safety outcomes will also be monitored throughout the study. Participants may enter a subsequent 8-week follow-up period or long-term extension study.ResultsThis is a study design abstract.ConclusionsC3G and IC-MPGN are rare, progressive renal diseases due to deposition in renal glomeruli. This study will evaluate the safety and efficacy of complement protein C3 inhibitor pegcetacoplan in treating C3G and IC-MPGN.Conflict of interest Corporate sponsored research or other substantive relationships:Giuseppe Remuzzi: Consultancy Agreement with Biocryst Pharmaceuticals Bradley Dixon: Consultant for Apellis, Alexion pharmaceuticals (received honoraria) Fadi Fakhouri: Consultancy and/or speaker honoraria from Roche, Alexion, Apellis, Achillion, Novartis and Alnylam Matthew Pickering: Paid Scientific Advisor: Gyroscope, Apellis, Alexion, Sobi, Silence, Gemini Pharma Terence Cook: Consultancy agreements with Alexion, Novartis and Aurinia David Kavanaugh: Consultancy with Alexion, Novartis, Gyroscope Therapeutics, Idorsia, Sarepta Patrick Walker: Consultant for Travere Pharmaceuticals for study design and histologic data analysis Christoph Licht: Scientific advisory activities for Alexion, Aurin, Catalyst Biosciences, Novartis, Johnson&Johnson Marina Vivarelli: Consulting agreements with Travere, Novartis, Roche, Apellis, Achillion and has ongoing clinical studies with Alexion and Chemocentrix Zhiqun Zhang: employee of Apellis Li Li: employee of Apellis Helen Kocinsky: employee of Apellis IntroductionComplement 3 glomerulopathy (C3G) and immune complex membranoproliferative glomerulonephritis (IC-MPGN) are rare diseases characterized by excessive deposition of C3 breakdown products in renal glomeruli leading to proteinuria and progressive renal disease. Pegcetacoplan is a targeted C3 investigational therapy for diseases related to complement overactivation. This is a phase 3, randomized, placebo-controlled, double-blind, multicenter study of the efficacy and safety of pegcetacoplan in individuals with C3G or IC-MPGN.