Background:Immunoglobulin A nephropathy (IgAN) is a leading cause of chronic kidney disease (CKD) worldwide. While racial and ethnic differences in disease progression are well documented, the Hispanic/Latinx populations remain understudied despite their elevated risk of kidney failure among other CKD populations. Objective:This study aimed to evaluate the kidney function decline and progression in Hispanic/Latinx patients with biopsy-proven IgAN within a large, integrated healthcare system and to contextualize to other racial/ethnic groups. Methods:We conducted a retrospective case series study of 259 Hispanic/Latinx adults with biopsy-proven IgAN from the Kaiser Permanente Southern California (KPSC) health system. Patients were followed from biopsy to ≥50% decline in the estimated glomerular filtration rate (eGFR), kidney failure, mortality, the study end date of November 30, 2022, or disenrollment. Annualized eGFR decline and the incidence of composite kidney outcomes were assessed. Results:At diagnosis, Hispanic/Latinx patients had significant CKD and a high risk of progression to kidney failure, indicated by a median eGFR of 56 ml min-1 1.73 m-2 and a median urine protein/creatinine ratio of 1.8 g/g. Common treatments included immunosuppressive agents (41%), angiotensin-converting enzyme (ACE) inhibitors (48%), and angiotensin receptor blockers (ARBs; 20%). The mean annual eGFR decline was -4.5 ml min-1 1.73 m-2, and 30.9% experienced rapid decline (>5 ml min-1 1.73 m-2 per year). The composite kidney outcome occurred at 73.3 events per 1,000 patient-years, with a median time to event of 2.8 years and a median age at event of 46 years. Conclusion:Hispanic/Latinx patients with IgAN demonstrate rapid kidney function decline and early-onset kidney failure. These findings underscore the need for earlier detection and targeted management in this underserved group.

KEY POINTS:The phase 2 ENVISION trial evaluated efficacy and safety of intravenous sibeprenlimab, a selective A PRoliferation-Inducing Ligand inhibitor. Because the trial was conducted during the coronavirus disease 2019 pandemic, we assessed if sibeprenlimab affected humoral responses to coronavirus disease 2019 infection or vaccine. Sibeprenlimab treatment resulted in reduced pathogenic IgA and preserved protective humoral response to coronavirus disease 2019 vaccine and infection. BACKGROUND:In phase 2 ENVISION trial, sibeprenlimab, a selective A PRoliferation-Inducing Ligand inhibitor, significantly decreased proteinuria and stabilized eGFR in adults with IgA nephropathy. This exploratory substudy evaluated coronavirus disease 2019 (COVID-19) severity, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific antibody responses to vaccine and infection, and circulating B-cell populations in patients with IgA nephropathy treated with sibeprenlimab or placebo. METHODS:Participants enrolled in ENVISION ( NCT04287985 ) received 12 monthly intravenous infusions of sibeprenlimab (2, 4, or 8 mg/kg) or placebo. COVID-19 infection and vaccination data were recorded for all participants. In a substudy, serum IgG responses to SARS-CoV-2 spike protein, its receptor binding domain (RBD), and nucleocapsid antigen were assessed, with further analysis of serum IgM and IgA and salivary IgA against RBD in a subset of participants. Circulating T cells and B-cell subsets were analyzed by flow cytometry. RESULTS:Overall, symptomatic COVID-19 incidence was comparable between groups (33.3% sibeprenlimab versus 44.7% placebo), indicating no observable excess risk of COVID-19 infection with sibeprenlimab. Of 155 participants, 72 (sibeprenlimab n =52; placebo n =20) consented to the substudy. Within the substudy, COVID-19 seroconversion rates were 100% for IgG against SARS-CoV-2 RBD (IgG-RBD) after vaccination or infection. Peak IgG-RBD titers after mRNA vaccination exceeded protective thresholds in all COVID-19-naive sibeprenlimab recipients, and IgG-RBD durability was comparable between sibeprenlimab and placebo. COVID-19-specific IgG, IgA, and IgM antibody responses to infection were preserved, and IgA-RBD responses detected in saliva suggested preservation of mucosal immunity with sibeprenlimab. No meaningful perturbations in B or T cells were observed. CONCLUSIONS:A PRoliferation-Inducing Ligand inhibition with sibeprenlimab reduced pathogenic IgA while preserving mucosal immunity and systemic antibody responses to COVID-19 vaccination and infection. The absence of B-cell perturbations and the apparent absence of an increased risk of impaired vaccine response suggest that sibeprenlimab may not confer clinically significant immunosuppressive risks; the substudy's size and exploratory design preclude definitive conclusions, warranting further evaluation. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER:ClinicalTrials.gov, NCT04287985 .

# Background Progression rates in immunoglobulin A nephropathy (IgAN) are variable, making future healthcare needs in this patient population difficult to anticipate. # Objectives We sought to determine whether baseline patient characteristics at biopsy diagnosis are predictive of subsequent healthcare resource utilization (HCRU) in individuals affected by IgAN. # Methods This was a longitudinal, retrospective cohort study of members enrolled in Kaiser Permanente Southern California, a racially, ethnically, and socioeconomically diverse population. We extracted data on members diagnosed with primary IgAN based on kidney biopsies performed from 2000 to 2021. Statistical associations between indicators of disease severity at baseline and subsequent HCRU were evaluated. The baseline variables assessed were chronic kidney disease (CKD) stage, urine protein creatinine ratio (UPCR), and the individual burden of comorbidities expressed as Elixhauser Comorbidity Index. The HCRU outcomes were emergency department visits, inpatient visits, outpatient visits, radiology, laboratory, and medication dispensations within 2 years after biopsy, all expressed as utilization per patient per month (PPPM). # Results A total of 612 adults with primary IgAN were identified. Worse baseline CKD stage and UPCR exhibited statistically significant positive correlations with the PPPM for aggregate HCRU. Patients in CKD stage G4 had an overall PPPM of 2.94, which was significantly (P < .01) greater than for each milder CKD category (1.56-2.04). Patients with UPCR >2 g/g had an overall PPPM (2.38), which was significantly (P < .01) greater than each milder UPCR category (1.70-1.84). Aggregate PPPM showed a numerically increasing trend from the least (<0.5 g/g) to most severe UPCR category (>2 g/g). CKD stage, UPCR, and comorbidity score all correlated significantly with individual HCRU outcomes. # Discussion Easily assessed patient baseline variables including CKD stage, proteinuria, and comorbidities are predictive of HCRU in primary IgAN. Our findings are consistent with recent IgAN management guidelines designating proteinuria ≥0.5 g/g as indicative of elevated progression risk. # Conclusions Patient clinical characteristics can be used to estimate future HCRU in IgAN, facilitating cost-benefit analysis. The accurate estimation of anticipated HCRU is becoming increasingly important in IgAN as new, disease-specific therapies become available for this long-term, progressive condition.

Background In phase 2 ENVISION trial, sibeprenlimab, a selective A PRoliferation-Inducing Ligand inhibitor, significantly decreased proteinuria and stabilized eGFR in adults with IgA nephropathy. This exploratory substudy evaluated coronavirus disease 2019 (COVID-19) severity, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific antibody responses to vaccine and infection, and circulating B-cell populations in patients with IgA nephropathy treated with sibeprenlimab or placebo.Methods Participants enrolled in ENVISION () received 12 monthly intravenous infusions of sibeprenlimab (2, 4, or 8 mg/kg) or placebo. COVID-19 infection and vaccination data were recorded for all participants. In a substudy, serum IgG responses to SARS-CoV-2 spike protein, its receptor binding domain (RBD), and nucleocapsid antigen were assessed, with further analysis of serum IgM and IgA and salivary IgA against RBD in a subset of participants. Circulating T cells and B-cell subsets were analyzed by flow cytometry.Results Overall, symptomatic COVID-19 incidence was comparable between groups (33.3% sibeprenlimab versus 44.7% placebo), indicating no observable excess risk of COVID-19 infection with sibeprenlimab. Of 155 participants, 72 (sibeprenlimab n=52; placebo n=20) consented to the substudy. Within the substudy, COVID-19 seroconversion rates were 100% for IgG against SARS-CoV-2 RBD (IgG-RBD) after vaccination or infection. Peak IgG-RBD titers after mRNA vaccination exceeded protective thresholds in all COVID-19-naive sibeprenlimab recipients, and IgG-RBD durability was comparable between sibeprenlimab and placebo. COVID-19-specific IgG, IgA, and IgM antibody responses to infection were preserved, and IgA-RBD responses detected in saliva suggested preservation of mucosal immunity with sibeprenlimab. No meaningful perturbations in B or T cells were observed.Conclusions A PRoliferation-Inducing Ligand inhibition with sibeprenlimab reduced pathogenic IgA while preserving mucosal immunity and systemic antibody responses to COVID-19 vaccination and infection. The absence of B-cell perturbations and the apparent absence of an increased risk of impaired vaccine response suggest that sibeprenlimab may not confer clinically significant immunosuppressive risks; the substudy's size and exploratory design preclude definitive conclusions, warranting further evaluation.Clinical Trial registry name and registration number: ClinicalTrials.gov, .

Immunoglobulin A nephropathy (IgAN) is one of the most common forms of primary glomerulonephritis (GN) worldwide. While specific treatment differs regionally, treatment usually focuses on background therapy, with short-term (≤ 6 months) corticosteroids recommended as an add-on treatment for patients at high risk of progressive chronic kidney disease. Although corticosteroids can help to manage IgAN, treatment with corticosteroids may lead to undesirable adverse outcomes. To highlight corticosteroid treatment burden in patients with IgAN globally. Embase, MEDLINE, and Cochrane CENTRAL were searched for articles published in any language from January 1, 2013 to August 24, 2023. Eligible studies reported ≥ 1 outcome related to the clinical, humanistic, or economic burden of corticosteroids in patients with IgAN. Articles were independently screened by 2 reviewers. Data extraction and quality assessment were completed by 1 researcher and validated by a second. Results are reported among the number of studies with data on each outcome. Of 1,024 records screened, 64 studies were included. Of 37 studies reporting treatment duration, 68

BACKGROUND AND HYPOTHESIS:We assessed disease progression among patients with immunoglobulin A nephropathy (IgAN) and characterized factors associated with risk for adverse outcomes. METHODS:A retrospective longitudinal cohort (2000-2022) study of adults with biopsy-confirmed IgAN within Kaiser Permanente Southern California was performed. The outcome of interest was a composite of ≥50% estimated glomerular filtration rate (eGFR) decline, kidney failure, or mortality. Cox proportional hazards regression modeling was used to estimate hazard ratios (HR) for the eGFR decline/kidney failure with adjustment for potential confounders. RESULTS:Among 655 patients with primary IgAN (31% Asian/Pacific Islander, 3% Black, 40% Hispanic/Latino, 24% White), 234 (36%) reached the composite outcome of ≥50% eGFR decline (17%), kidney failure (16%), or mortality (3%). The composite outcome occurred at a rate of 79.4 events (95% confidence intervals (CI) 69.6, 90.7) per 1000 patient-years, with a median time to event of 2.7 years. Compared to urine protein creatinine ratio (UPCR) <0.5 vs 0.5-<1 g/g, 1-2, and >2 g/g, the HR (95% CI) for ≥50% eGFR decline/kidney failure were 2.4 (1.1, 5.1), 3.2 (1.5, 6.6), and 5.1 (2.5, 10.4) for baseline UPCR and 5.4 (2.3, 13.0), 14.4 (16.5, 32.2), and 41.2 (17.9, 94.5) for time-averaged UPCR. Lower baseline eGFR and diabetes were also associated with higher risk, while age ≥30 years was associated with lower risk for ≥50% eGFR decline/kidney failure. There were no clear trends differentiating risk by race/ethnicity. CONCLUSION:In this large, diverse cohort, high rates of kidney outcomes occurred within a relatively short follow-up duration. Our findings suggest that IgAN carries elevated risk for kidney outcomes starting at proteinuria levels ≥0.5 g/g, in contrast to earlier perceptions that levels below 1 g/g are associated with low risk.

INTRODUCTION:At least 50% of patients with immunoglobulin A nephropathy (IgAN) reach kidney failure within 12 years of diagnosis. Delayed progression to kidney failure remains the gold standard treatment endpoint in IgAN, but the prolonged time course limits feasibility as a primary endpoint in clinical trials. Earlier measurable endpoints may serve as surrogate endpoints for clinically important long-term kidney outcomes. Regulatory bodies recognize surrogate endpoints like proteinuria reduction. However, other stakeholders, like payers, health technology assessment agencies, and policymakers, may require additional evidence. This literature review assessed data on associations between surrogate endpoints, including proteinuria and estimated glomerular filtration rate (eGFR), and long-term kidney outcomes in IgAN. METHODS:A systematic search of IgAN studies conducted in any country was performed in MEDLINE, Embase, and CENTRAL via Ovid (January 1, 2006-September 1, 2023), supplemented by conference abstracts (2019-2023) and relevant literature reviews and meta-analyses. Eligible studies evaluated the association of surrogate endpoints of kidney disease progression with long-term outcomes in IgAN. RESULTS:Among 1833 unique citations screened, 23 publications met inclusion criteria. Proteinuria was associated with progression to kidney failure (p < 0.001-0.021; n = 5 studies), reaching a composite kidney event (p < 0.001-0.02; n = 6), doubling of serum creatinine (p = 0.009; n = 1), and long-term eGFR decline (p < 0.001-0.910; n = 5); absolute eGFR at months 3 and 6 was associated with composite kidney events (p ≤ 0.001-0.03; n = 2); and eGFR slope was associated with kidney failure (p < 0.001; n = 1) and doubling of serum creatinine (p < 0.001-0.007; n = 1). CONCLUSION:The literature supports associations of proteinuria and eGFR with long-term clinical outcomes in IgAN across multiple studies and geographic regions. Despite regional variability in standard of care, which introduces heterogeneity in the strength of associations, the consistency of findings across regions supports the utility of proteinuria and eGFR as surrogate endpoints for clinically important long-term kidney outcomes.

IgAN is the most common primary glomerulonephritis worldwide with up to 40% of IgAN patients progressing to kidney failure within 20 years following diagnosis. Almost all patients with IgAN are expected to progress to kidney failure during their lifetime, regardless of age or estimated glomerular filtration rate (eGFR) at diagnosis. IgAN is characterized by race/ethnic predilection, heterogeneity in disease progression, and potential race/ethnic variations in treatment response. Previous studies have assessed disease progression in Asian and non-Hispanic white patients; however, there remains a lack of understanding of IgAN disease progression in Hispanic/Latino patients.

Abstract Background and Aims In the Phase 2 placebo-controlled ENVISION trial, the APRIL (A Proliferation Inducing Ligand) inhibitor sibeprenlimab significantly decreased proteinuria and stabilized estimated glomerular filtration rate decline in patients with immunoglobulin A nephropathy (IgAN) [1]. A substudy was conducted to evaluate the humoral response to SARS-CoV-2 mRNA vaccination and infection. Here, we report the unblinded analysis of COVID outcomes in the overall and substudy populations of ENVISION. Method Patients enrolled in ENVISION (NCT04287985) received 12 monthly intravenous infusions of sibeprenlimab (2, 4, or 8 mg/kg) or placebo and were followed for 16 months after the first dose of study drug. Recognized COVID infection (reported as an adverse event [AE]) and vaccination data were recorded for all patients. For patients in the substudy, serum antibody responses to SARS-CoV-2 spike and nucleocapsid proteins were measured monthly using a validated Meso Scale Discovery V-PLEX SARS-CoV-2 Panel 24 multiplex assay. Vaccine responses among those who received a primary two-dose mRNA COVID vaccine series, with no recent or concurrent COVID infection, were evaluated. Peak post-vaccine serum SARS-CoV-2 receptor-binding domain (RBD) immunoglobulin G (IgG) titers were reported in World Health Organization binding antibody units (BAU)/mL. Slopes of RBD IgG decline curves were used to generate estimates of time above a protective threshold of 300 BAU/mL. Welch's two-sample t-test was applied to log-transformed peak RBD titers for significance testing. COVID infection–induced antibody responses and severity of COVID symptoms were also assessed. In substudy patients, retrospective serologic diagnosis of COVID infection was established when simultaneous elevation of nucleocapsid and spike antibody titers, unexplained by vaccine history, was observed. Results Among 155 patients who received sibeprenlimab (n = 117) or placebo (n = 38), 56 (36.1%) had COVID infection reported as an AE during the study (Table 1). Overall, proportionally fewer sibeprenlimab recipients (33.3%) had a reported COVID AE compared with placebo recipients (44.7%). Two patients (one each in the sibeprenlimab and placebo groups) were hospitalized with serious COVID AEs in accordance with local management protocols; none were admitted to intensive care or mechanically ventilated and there were no COVID-related deaths. The majority of COVID AEs were of mild severity, regardless of treatment/dosing arm. In the serology substudy (n = 74), symptomatic COVID (reported as an AE) occurred in 47.3% of all patients. With the addition of serologic diagnoses (in the absence of AEs), the overall rate of COVID infection increased to 68.9%. Asymptomatic COVID was identified in 1 of 15 (6.7%) placebo recipients versus 15 of 36 (41.7%) sibeprenlimab recipients, raising the possibility that patients treated with sibeprenlimab may have had attenuated symptom presentation compared with patients who received placebo. COVID seroconversion rates were 100% and peak RBD IgG antibody titers following primary mRNA vaccination exceeded the protective threshold of 300 BAU/mL in all patients (Fig. 1a), with higher geometric mean peak titers in placebo (4670 BAU/mL) compared with sibeprenlimab (1700 BAU/mL) recipients (p = 0.005). The rate of decline of peak RBD IgG titers after mRNA vaccination (in patients with ≥1 dose without confounding subsequent vaccination or infection) was similar between groups (Fig. 1b), with modeled time above the 300 BAU/mL threshold of 192 and 174 days in the sibeprenlimab and placebo groups, respectively. Conclusion COVID-specific antibody responses to vaccination or infection were preserved in patients with IgAN treated with sibeprenlimab. The possibility that COVID symptom presentation may have been modulated by sibeprenlimab warrants further investigation.

INTRODUCTION:IgA nephropathy (IgAN), a leading cause of kidney failure worldwide, is one of the most common forms of primary glomerulonephropathy with variability by race and ethnicity. Using a diverse cohort within a large integrated health system in the United States (US), we identified and characterized patients with biopsy-proven IgAN and report annual incidence rates across racial/ethnic groups and standardized to the US nationally. METHODS:A cross-sectional study between January 1, 2010, and December 31, 2021 within Kaiser Permanente Southern California was performed. Patients (age >/=18 years) who underwent a native kidney biopsy and identified as having primary IgAN comprised the study population. Laboratory, demographic, and comorbidity information were obtained from the electronic health records. Annual incidence rates were calculated for biopsy-proven IgAN (per 100,000 person-years) and standardized to 2020 US Census. RESULTS:Of 9,392 individuals who underwent kidney biopsy, 606 adult patients were identified with primary IgAN. Crude annual IgAN incidence rates ranged from 1.3 to 2.2 (per 100,000 person-years). US census standardized incidence rate (CI) of IgAN was 1.4 (0.8, 2.0) per 100,000 person-years in the 12-year period. Incidence rate (per 100,000 person-years) was highest among Asian/Pacific Islander (4.5) and Hispanic (1.7) patients and lowest among White (1.2) and Black (0.6) patients. Median estimated glomerular filtration rate (eGFR) was 51 mL/min with median urine protein creatinine ratio (uPCR) 1.8 g/g. CONCLUSION:Among a large diverse US population within Southern California, we observed an IgAN incidence rate of 1.7 which estimated to a standardized US incidence of 1.4 (per 100,000 person-years) within a 12-year period. Patients appear to be diagnosed at more advanced disease given kidney function and proteinuria at biopsy.

BACKGROUND:A proliferation-inducing ligand (APRIL) is implicated in the pathogenesis of IgA nephropathy. Sibeprenlimab is a humanized IgG2 monoclonal antibody that binds to and neutralizes APRIL. METHODS:In this phase 2, multicenter, double-blind, randomized, placebo-controlled, parallel-group trial, we randomly assigned adults with biopsy-confirmed IgA nephropathy who were at high risk for disease progression, despite having received standard-care treatment, in a 1:1:1:1 ratio to receive intravenous sibeprenlimab at a dose of 2, 4, or 8 mg per kilogram of body weight or placebo once monthly for 12 months. The primary end point was the change from baseline in the log-transformed 24-hour urinary protein-to-creatinine ratio at month 12. Secondary end points included the change from baseline in the estimated glomerular filtration rate (eGFR) at month 12. Safety was also assessed. RESULTS:Among 155 patients who underwent randomization, 38 received sibeprenlimab at a dose of 2 mg per kilogram, 41 received sibeprenlimab at a dose of 4 mg per kilogram, 38 received sibeprenlimab at a dose of 8 mg per kilogram, and 38 received placebo. At 12 months, the geometric mean ratio reduction (±SE) from baseline in the 24-hour urinary protein-to-creatinine ratio was 47.2±8.2%, 58.8±6.1%, 62.0±5.7%, and 20.0±12.6% in the sibeprenlimab 2-mg, 4-mg, and 8-mg groups and the placebo group, respectively. At 12 months, the least-squares mean (±SE) change from baseline in eGFR was -2.7±1.8, 0.2±1.7, -1.5±1.8, and -7.4±1.8 ml per minute per 1.73 m2 in the sibeprenlimab 2-mg, 4-mg, and 8-mg groups and the placebo group, respectively. The incidence of adverse events that occurred after the start of administration of sibeprenlimab or placebo was 78.6% in the pooled sibeprenlimab groups and 71.1% in the placebo group. CONCLUSIONS:In patients with IgA nephropathy, 12 months of treatment with sibeprenlimab resulted in a significantly greater decrease in proteinuria than placebo. (Funded by Visterra; ENVISION ClinicalTrials.gov number, NCT04287985; EudraCT number, 2019-002531-29.).

A PRoliferation-Inducing Ligand (APRIL) is a key driver in the immune-related pathogenesis of immunoglobulin A nephropathy (IgAN). Sibeprenlimab, a humanized IgG2 monoclonal antibody that blocks APRIL, demonstrated acceptable safety with robust urine protein creatinine ratio (uPCR) reduction and eGFR stability at 12 months in a Phase 2 study of patients with IgAN.1 Defined criteria for remission in IgAN are varied and include reduction of proteinuria below certain thresholds (<1.0 g/d, <500 mg/d and <300 mg/day) as well as remission in hematuria (reduction in red blood cell [RBC] count to <5 RBC/high power field [HPF]).2–4 We report the effect of sibeprenlimab on hematuria resolution and remission of proteinuria.

Immunoglobulin-A nephropathy (IgAN) is the most common primary glomerulonephritis in the world, with up to 40% of patients progressing to end-stage kidney disease (ESKD) within 30 years of diagnosis. IgAN is characterized by elevated serum levels of galactose-deficient IgA1 (Gd-IgA1), which leads to immune complex formation and deposition in the glomerular mesangium, causing kidney injury. A diverse disease course and the long-term follow-up required for clinically relevant endpoints (e.g., ESKD) have been barriers to the development of novel therapies in IgAN. Disease management has focused on supportive care with inhibitors of the renin–angiotensin system and, more recently, sodium–glucose transporter inhibitors to control proteinuria. The recent acceptance of proteinuria as a surrogate endpoint by regulatory bodies and a better understanding of disease pathology have helped to initiate the development of several novel treatments. Subsequently, a targeted-release formulation of budesonide and a dual endothelin/angiotensin inhibitor (sparsentan) have received accelerated approval for patients with IgAN. However, additional therapies are needed to target the different pathogenic mechanisms and individualize patient care. Several compounds currently under investigation target various effectors of pathology. There are promising clinical results from emerging compounds that target the generation of Gd-IgA1 by B cells, including inhibitors of A PRoliferation-Inducing Ligand (APRIL) and dual inhibitors of APRIL and B-cell activating factor (BAFF). Other investigational therapies target the complement cascade by inhibiting proteins of the lectin or alternative pathways. As the therapeutic landscape evolves, it will be important to revise treatment guidelines and develop updated standards of care.

Randomized clinical trials are underway to evaluate the efficacy of novel agents targeting the alternative complement pathway in patients with C3 glomerulopathy (C3G), a rare glomerular disease. The Kidney Health Initiative convened a panel of experts in C3G to ( 1 ) assess the data supporting the use of the prespecified trial end points as measures of clinical benefit and ( 2 ) opine on efficacy findings they would consider compelling as treatment(s) of C3G in native kidneys. Two subpanels of the C3G Trial Endpoints Work Group reviewed the available evidence and uncertainties for the association between the three prespecified end points-( 1 ) proteinuria, ( 2 ) eGFR, and ( 3 ) histopathology-and anticipated outcomes. The full work group provided feedback on the summaries provided by the subpanels and on what potential treatment effects on the proposed end points they would consider compelling to support evidence of an investigational product's effectiveness for treating C3G. Members of the full work group agreed with the characterization of the data, evidence, and uncertainties, supporting the end points. Given the limitations of the available data, the work group was unable to define a minimum threshold for change in any of the end points that might be considered clinically meaningful. The work group concluded that a favorable treatment effect on all three end points would provide convincing evidence of efficacy in the setting of a therapy that targeted the complement pathway. A therapy might be considered effective in the absence of complete alignment in all three end points if there was meaningful lowering of proteinuria and stabilization or improvement in eGFR. The panel unanimously supported efforts to foster data sharing between academic and industry partners to address the gaps in the current knowledge identified by the review of the end points in the aforementioned trials.

Sibeprenlimab blocks the cytokine "A Proliferation-Inducing Ligand" (APRIL), which may play a key role in immunoglobulin A nephropathy pathogenesis. A phase 1 study of subcutaneous (SC) sibeprenlimab evaluated preliminary safety, tolerability, pharmacokinetics, and pharmacodynamics in healthy participants. This was an open-label, single-ascending-dose study. Twelve participants in each of 4 sequential dosing cohorts received 1 SC dose of sibeprenlimab (200 mg [1x1 mL injection], 400 mg [2x1 mL injections], 400 mg [1x2 mL injection], or 600 mg [1 mL+2 mL injections]) and underwent 16-week follow-up for adverse events, pharmacokinetics, and pharmacodynamics (serum APRIL, immunoglobulin [Ig] levels). Sibeprenlimab in single SC doses of 200-600 mg was slowly absorbed into the systemic circulation, with a median time to maximum serum concentration of approximately 6-10.5 days, and a mean elimination half-life of approximately 8-10 days. Serum APRIL, IgA, IgM, and, to a lesser extent, IgG decreased in a dose-dependent and reversible manner. Maximal reduction in serum IgA was approximately 60% at the 400- and 600-mg doses and 40% at 200 mg. Serum APRIL rapidly decreased to near the lower limit of quantification, and duration of suppression was dose-dependent, with near complete suppression until weeks 4-6 at the 400-mg dose and week 8 at the 600-mg dose. Adverse events occurred in 30/48 (62.5%) participants; none were serious or led to study discontinuation. Sibeprenlimab rapidly and sustainably reduced target APRIL and Ig biomarkers in a dose-dependent and reversible manner, with acceptable preliminary safety and pharmacokinetics.

Single cell sequencing technologies have rapidly advanced in the last decade and are increasingly applied to gain unprecedented insights by deconstructing complex biology to its fundamental unit, the individual cell. First developed for measurement of gene expression, single cell sequencing approaches have evolved to allow simultaneous profiling of multiple additional features, including chromatin accessibility within the nucleus and protein expression at the cell surface. These multi-omic approaches can now further be applied to cells in situ, capturing the spatial context within which their biology occurs. To extract insights from these complex datasets, new computational tools have facilitated the integration of information across different data types and the use of machine learning approaches. Here, we summarize current experimental and computational methods for generation and integration of single cell multi-omic datasets. We focus on opportunities for multi-omic single cell sequencing to augment therapeutic development for kidney disease, including applications for biomarkers, disease stratification and target identification.