BACKGROUND:Overactivation of the alternative complement pathway contributes to IgA nephropathy and glomerular inflammation. In the 9-month interim analysis of this phase 3 trial, iptacopan, a complement factor B inhibitor, led to a significant reduction of 38.3% in the 24-hour urinary protein-to-creatinine ratio as compared with placebo and had an acceptable safety profile. METHODS:In this phase 3 trial, we enrolled adults who had IgA nephropathy, an estimated glomerular filtration rate (eGFR) of at least 30 ml per minute per 1.73 m2 of body-surface area, and a 24-hour urinary protein-to-creatinine ratio of 1 or higher (with protein and creatinine both measured in grams) despite supportive care. Patients were randomly assigned, in a 1:1 ratio, to receive oral iptacopan (200 mg) or placebo twice daily. The primary end point for the final analysis was the annualized total eGFR slope as estimated over a 24-month period. Secondary end points included a composite kidney-failure end point (i.e., a sustained decline in eGFR of ≥30%, a sustained eGFR of <15 ml per minute per 1.73 m2, the initiation of maintenance dialysis, receipt of kidney transplant, or death from kidney failure), assessed in a time-to-event analysis. Safety was also assessed. RESULTS:Among 477 patients included in the final analysis, 238 had been randomly assigned to iptacopan and 239 to placebo. The annualized total eGFR slope was -3.10 ml per minute per 1.73 m2 per year with iptacopan, as compared with -6.12 ml per minute per 1.73 m2 per year with placebo (difference, 3.02 ml per minute per 1.73 m2 per year; 95% confidence interval [CI], 2.02 to 4.01; adjusted P<0.001). A composite kidney-failure end-point event occurred in 21.4% of the patients in the iptacopan group, as compared with 33.5% of those in the placebo group (hazard ratio, 0.57; 95% CI, 0.40 to 0.81; adjusted P = 0.003). The incidence of adverse events was 87.0% in the iptacopan group and 89.1% in the placebo group. Serious adverse events occurred in 12.2% of the patients who received iptacopan and in 11.7% of those who received placebo, and serious infections in 6.7% and 2.1%, respectively. No deaths occurred. CONCLUSIONS:Iptacopan therapy led to a significantly slower decline in kidney function than placebo. (Funded by Novartis; APPLAUSE-IgAN ClinicalTrials.gov number, NCT04578834.).

Studies have shown involvement of the alternative complement pathway (AP) in glomerular inflammation and tubulointerstitial damage in IgAN. AP inhibition with iptacopan, a potent oral complement factor B inhibitor, demonstrated a significant reduction in proteinuria, leading to its accelerated approval by the US FDA. The effect of iptacopan discontinuation on relevant IgAN characteristics are of clinical interest. Herein, we report proteinuria and AP biomarker data from a Phase II (PhII) study that included an observational period after iptacopan discontinuation, and preliminary data from the ongoing open-label extension study (OLE; NCT04557462), in which iptacopan was reinitiated. The PhII randomized, double-blind, placebo (pbo)-controlled study recruited adults with confirmed IgAN and urine protein–creatinine ratio (UPCR) ≥0.8 g/g or urine protein ≥0.75 g/day on stable renin–angiotensin system inhibitors to receive pbo or iptacopan (10, 50, 100 [in Part 2 only] or 200 mg twice daily [bid]) for 90 days in Part 1 or 180 days in Part 2 (Fig. 1). After stopping iptacopan treatment in either part, patients (pts) were followed for a 90-day off-iptacopan phase. Eligible pts could restart iptacopan 200 mg bid in the OLE (time from PhII study end [EoS] to OLE start varied). In this post hoc analysis, data were pooled in the iptacopan dose arms >10 mg bid (which showed effective AP inhibition) to compare the change from baseline (BL) in proteinuria between the on- and off-iptacopan phases. Data from the approved iptacopan dose 200 mg bid arms were also pooled from both parts. OLE data were pooled in all analyses up to Month (M) 12 (cut-off date: 15 August 2023). Mixed models for repeated measures were used to assess UPCR (from first morning void) during the PhII study and OLE. Descriptive analyses were conducted for AP biomarkers (urine soluble C5b-9 [sC5b-9], serum Wieslab and plasma Bb) in pts who received iptacopan 200 mg bid during the PhII study; AP biomarker data were not collected in the OLE. The PhII BL was considered the BL for all analyses. PhII data were used from 67 pts (Part 1: n = 23; Part 2: n = 44), 40 of which joined the OLE. In the pooled PhII study cohorts, the relative reduction in UPCR (95% CI) from BL in Part 1 was 30.0% (13.5, 43.4%) at Day (D) 90 (Fig. 2A) and in Part 2 was 35.4% (17.5, 49.5%) at D180 (Fig. 2B). In pts from Part 1 who had a shorter duration of iptacopan treatment relative to pts in Part 2, UPCR returned to BL levels within 30 days of iptacopan discontinuation (Fig. 2A). In pts from Part 2, UPCR remained below BL 30 days after iptacopan discontinuation but was higher compared with the end of treatment (EoT) visit (Fig. 2B). Upon iptacopan reinitiation in the OLE, UPCR decreased again for pts entering from Parts 1 and 2 (Fig. 2A and B). Similar trends were seen in the iptacopan 200 mg bid arms (n = 26); there was a relative reduction in UPCR (95% CI) of 27.0% (10.8, 40.3%) at D90 and 23.2% (−0.8, 41.5%) at EoT (D180). In the first off-iptacopan visit, UPCR increased to near PhII BL values, before decreasing after treatment reinitiation in the OLE. Iptacopan 200 mg bid inhibited the AP in pts pooled from both parts of the PhII trial (n = 26), as shown by a decrease in AP biomarkers (median [interquartile range (IQR)] reduction from BL to D90 in urinary sC5b-9: 97.2% [89.3, 98.4%]; serum Wieslab: 81.4% [72.9, 92.5%]; plasma Bb: 24.5% [13.6, 40.6%]). AP biomarkers increased at the first off-iptacopan visit, with a median (IQR) increase from BL of 18.3% (−77.8, 168.8%) for urinary sC5b-9 and 3.3% (−12.7, 11.2%) for plasma Bb, and a serum Wieslab reduction from BL of only 10.3% (0, 19.7%). The data indicate that iptacopan discontinuation leads to quick reactivation of systemic and renal complement to near BL levels. Renal complement reactivation is associated with an increase in proteinuria. Notably, proteinuria decreased again after reinitiation of iptacopan, indicating continued sensitivity to complement inhibition. Limitations of this analysis include the short duration of PhII treatment, low pt numbers, and varying duration and lack of knowledge of other treatments or disease progression between the PhII EoS and the OLE.

Key PointsAcute effects impact the clinical endpoint independently of treatment effects on the chronic slope.Our findings support the 3-year total slope as the primary slope-based outcome in randomized trials.BackgroundSlope of the GFR is considered a validated surrogate endpoint for CKD trials. However, differing short-term and long-term treatment effects on GFR slope can create ambiguities concerning the appropriate period for evaluating slope, in part because current methods cannot separate the distinct contributions of the acute (before 3 months) and chronic (after 3 months) slopes for treatment effects on clinical endpoints (CEs).MethodsWe estimated treatment effects on the acute and chronic GFR slopes and on the established CE of kidney failure or serum creatinine doubling for 66 randomized treatment comparisons from previous CKD clinical trials. We used a novel Bayesian meta-regression framework to relate treatment effects on the established CE to both the acute and chronic slopes in a single multivariable model to determine the independent contributions of the acute and chronic slopes.ResultsTreatment effects on both the acute and chronic slopes independently predicted the treatment effect on the established CE with a high median R2 (95% credible interval) of 0.95 (0.79 to 1.00). For a fixed treatment effect on the chronic slope, each 1 ml/min per 1.73 m2 greater acute GFR decline for the treatment versus control increased the hazard ratio for the established CE by 11.4% (7.9%-15.0%), against the treatment. The optimal weights for the acute and chronic slopes were consistent with the 3-year total slope defined as the average slope extending from baseline to 3 years.ConclusionsTreatment effects on both the acute and chronic GFR slopes are independent determinants of the effects on the established CE, with variation in acute effects accounting for much of the observed variation in treatment effects on the CE across previous trials. Our results establish that acute effects affect the CE independently of treatment effects on the chronic slope and support the 3-year total slope as the primary slope-based outcome in randomized trials.

IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide, with up to 50% of patients progressing to ESKD or death within 20 years. The cytokines B-cell Activating Factor (BAFF) and A Proliferation-Inducing Ligand (APRIL) play key roles in IgAN pathophysiology by binding to the TACI receptor on B cells and fueling production of galactose-deficient IgA1 (Gd-IgA1) and anti-Gd-IgA1 autoantibodies. Gd-IgA1 is recognized as an autoantigen by anti-Gd-IgA1 autoantibodies, forming the immune complexes which drive kidney pathology and clinical disease. Atacicept is a fully humanized TACI-Fc fusion protein that inhibits both BAFF and APRIL with nanomolar binding affinity, interrupting the immunopathogenesis of IgAN. Atacicept is self-administered at home by subcutaneous injection once weekly (QW). The ORIGIN 2b study evaluated the safety and efficacy of atacicept in IgAN and met the primary endpoint with a statistically significant and clinically meaningful UPCR reduction at 24 wk, with deepening efficacy through 36 wk as compared to placebo. In the open-label extension (OLE), atacicept demonstrated further Gd-IgA1 reductions, hematuria improvements, and UPCR reductions with eGFR stabilization at a rate of decline similar to the general population without kidney disease through 96 wk, suggesting atacicept offers a potentially safe, long-term, disease-modifying treatment for IgAN. Herein, we report the changes in Gd-IgA1 and eGFR during the 26-wk follow-up period after atacicept discontinuation. The randomized, double-blind, placebo-controlled Phase 2b ORIGIN study included 116 participants with biopsy-proven IgAN, 24 h urine protein >0.75 g/day or UPCR >0.75 g/g, and eGFR ≥30 mL/min/1.73 m2 despite optimized renin–angiotensin system blockade. Participants were randomized to atacicept or placebo QW for up to 36 wk. The double-blind, randomized treatment period was followed by an OLE in which participants received atacicept 150 mg QW for up to 60 wk, for a total of up to 96 wk of treatment. Participants were subsequently followed for a 26-wk follow-up period after completing atacicept treatment, with evaluations at 12 and 26 wk post-treatment. During this follow-up period, routine hematology, chemistry, and Gd-IgA1 levels were collected and analyzed; no urine samples were collected. This analysis includes participants treated with atacicept who had a last on-treatment Gd-IgA1 or eGFR value in the study wk 96 analysis window and ≥1 measure in the follow-up period, with the study wk 96 values reset as the new baseline and analyzed along with the follow-up 12 and 26 wk data. Gd-IgA1 and eGFR changes were analyzed using a MMRM model. There were 103 participants who received ≥1 atacicept dose for ≥60 wk and remained in the follow-up study period. Following completion of atacicept treatment, increases in serum Gd-IgA1 were observed at wk 12 and 26 of +90% and +117% respectively. In addition, changes in eGFR at wk 12 and 26 were −1.6 and −3.9 ml/min/1.73 m2, respectively. (Fig. 1) IgAN is a chronic and progressive disease of B-cell origin, in which cytokines BAFF and APRIL are sustaining factors in its pathophysiology. Treatment with atacicept, a precision B-cell modulator inhibiting both BAFF and APRIL, demonstrated significant and sustained reductions in Gd-IgA1, improvements in hematuria, and reductions in UPCR, along with stabilization of eGFR over 96 wk. Following discontinuation of atacicept, an increase in Gd-IgA1 and decline in eGFR were observed, consistent with the typical clinical progression of IgAN in high-risk patients despite standard-of-care treatments. In light of these findings, participants may enroll in a new OLE study (ORIGIN Extend), which will provide insights into the effects of atacicept treatment reinitiation. The rapid impact on key markers of kidney function decline and disease progression after atacicept discontinuation underscores the potential therapeutic benefit of atacicept and supports the paradigm of sustained treatment with atacicept in IgAN patients.

Background:Immunoglobulin A nephropathy (IgAN) is the most common type of primary glomerulonephritis, requiring a kidney biopsy for diagnosis. This study aimed to estimate the prevalence of primary IgAN within the European Union (EU) and investigate the potential impact of the coronavirus disease 2019 (COVID-19) pandemic on kidney biopsy rates and IgAN diagnosis frequency. Methods:We conducted four comprehensive literature searches to identify data on the IgAN prevalence and incidence, native kidney biopsy rates and COVID-19 impact on these metrics. We calculated country-specific prevalence estimates based on a combination of published and modeled data, incorporating biopsy frequency and the Healthcare Access and Quality Index (HAQI). The EU IgAN prevalence was derived from country-specific prevalence estimates weighted by population size. Results:The estimated prevalence of IgAN in the EU was 4.31 per 10 000 population, with large geographic variation among countries, ranging from 0.16 to 14.4 per 10 000 population. A strong correlation was observed between the IgAN incidence and biopsy rate (R2 = 0.96). Countries with a higher HAQI mostly exhibited higher biopsy rates and IgAN incidences. The COVID-19 pandemic resulted in a notable decrease in kidney biopsy rates for most European countries with available information in 2020 compared with both pre- and post-pandemic periods. However, the long-term implications of this reduction on biopsy rates and subsequent IgAN incidence remain to be determined. Conclusion:Our findings confirm the rarity of IgAN, albeit the most common type of glomerulonephritis. They underscore a robust correlation between biopsy rates and IgAN incidence, influenced by healthcare access and quality. The COVID-19 pandemic's temporary suppression of biopsy rates in 2020 suggests potential delays in IgAN diagnosis, warranting further investigation into the long-term effects.

Background: Slope of the glomerular filtration rate (GFR) is considered a validated surrogate endpoint for chronic kidney disease (CKD) trials. However, differing short and long-term treatment effects on GFR slope can create ambiguities concerning the appropriate time period for evaluating slope, in part because current methods cannot separate the distinct contributions of the acute (before three months) and chronic (after three months) slopes for treatment effects on clinical endpoints. Methods: We estimated treatment effects on the acute and chronic GFR slopes and on the established clinical endpoint (CE) of kidney failure or serum creatinine doubling for 66 randomized treatment comparisons from previous CKD clinical trials. We used a novel Bayesian meta-regression framework to relate treatment effects on the established CE to both the acute and chronic slopes in a single multivariable model to determine the independent contributions of the acute and chronic slopes. Results: Treatment effects on both the acute and chronic slopes independently predicted the treatment effect on the established CE with a high median R 2 (95% credible interval) of 0.95 (0.79,1.00). For a fixed treatment effect on the chronic slope, each 1 mL/min/1.73m 2 greater acute GFR decline for the treatment vs. control increased the HR for the established CE by 11.4% (7.9%, 15.0%), against the treatment. The optimal weights for the acute and chronic slopes were consistent with the three-year total slope defined as the average slope extending from baseline to three years. Conclusion: Treatment effects on both the acute and chronic GFR slopes are independent determinants of the effects on the established CE, with variation in acute effects accounting for much of the observed variation in treatment effects on the CE across previous trials. Our results establish that acute effects impact the CE independently of treatment effects on the chronic slope, and support the three-year total slope as the primary slope-based outcome in randomized trials.

Introduction:IgA nephropathy (IgAN) has a high risk of progression to kidney failure in East Asia. At the month 9 interim analysis (IA) of the APPLAUSE-IgAN trial, iptacopan, a complement factor B inhibitor, demonstrated a -38.3% change from baseline in 24-hour urine protein-to-creatinine ratio (UPCR) versus placebo and had a favorable safety profile. Considering the IgAN clinical burden in East Asia, we report APPLAUSE-IgAN IA findings from East Asian patients. Methods:APPLAUSE-IgAN was a phase 3 trial (NCT04578834) in adults with biopsy-confirmed IgAN and 24-hour UPCR ≥ 1 g/g despite optimized supportive care. Patients were randomized to iptacopan 200 mg or placebo twice daily. Interim efficacy was assessed in the first 250 patients who remained in or discontinued the trial by month 9; safety was assessed in 443 patients. In these exploratory analyses, efficacy was analyzed in 102 patients (51 per group) and safety in 177 patients (iptacopan: n = 88; placebo: n = 89) from East Asia. Results:In patients from East Asia, iptacopan led to adjusted geometric mean changes from baseline of -38.0% in 24-hour UPCR (95% confidence interval [CI]: -18.9% to -52.6%) and -36.4% in UPCR from first morning void (FMV) (95% CI: -17.1% to -51.3%) versus placebo at month 9. Iptacopan led to a greater improvement in hematuria than placebo. Treatment-emergent adverse events (TEAEs) occurred in a similar proportion of patients in both groups. Conclusions:In patients from East Asia in the APPLAUSE-IgAN main study population, iptacopan led to clinically meaningful proteinuria reductions and had a favorable safety profile, consistent with results from the global main study population.

BACKGROUND:IgA nephropathy, the most common primary glomerulopathy worldwide, is a kidney disorder of B-cell origin characterized by mesangial accumulation of IgA-containing immune complexes. In at least 50% of patients, IgA nephropathy leads to kidney failure or death within 10 to 20 years after diagnosis. Atacicept is a native human transmembrane activator and calcium-modulator and cyclophilin-ligand interactor (TACI)-Fc fusion protein that inhibits two key immunoregulatory cytokines - B-cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL) - that are thought to be central to the pathophysiology of IgA nephropathy. METHODS:In this ongoing, phase 3, multicenter, double-blind, randomized, placebo-controlled trial, we assigned patients with IgA nephropathy in a 1:1 ratio to receive atacicept at a dose of 150 mg once weekly, administered subcutaneously by patients at home, or matching placebo. The primary end point was the percentage change from baseline in the 24-hour urinary protein-to-creatinine ratio at week 36. Safety was also evaluated. RESULTS:A total of 203 patients were included in the prespecified interim analysis: 106 patients in the atacicept group and 97 in the placebo group. At week 36, the percentage reduction from baseline in the urinary protein-to-creatinine ratio was 45.7% in the atacicept group and 6.8% in the placebo group, with a geometric mean between-group difference of 41.8 percentage points (95% confidence interval, 28.9 to 52.3; P<0.001). Adverse events were observed in 59.3% of the patients in the atacicept group and in 50.0% in the placebo group; most were mild or moderate in severity. CONCLUSIONS:In this prespecified interim analysis, treatment with atacicept resulted in a significantly greater reduction in proteinuria than placebo at week 36 in patients with IgA nephropathy. (Funded by Vera Therapeutics; ORIGIN 3 ClinicalTrials.gov number, NCT04716231.).

Overactivation of the complement system via the alternative pathway (AP) is a key driver of immunoglobulin A nephropathy (IgAN) pathophysiology. This mechanistic study aims to evaluate the effects of iptacopan, a selective oral complement factor B inhibitor, on the underlying immunopathology in patients with IgAN. This Phase IIa multicenter, single-arm, open-label, repeat-biopsy study will enroll up to 20 adult patients with biopsy-proven IgAN, estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2, proteinuria ≥0.8 g/g or 1 g/day, and receiving a maximally tolerated and/or stable dose of supportive care treatment (angiotensin converting enzyme inhibitor or angiotensin receptor blocker and sodium-glucose co-transporter 2 inhibitors) for ≥90 days before baseline (Fig. 1). Patients will receive iptacopan 200 mg bid for 9 months, with kidney biopsies at baseline and study end. The primary objective is to quantify changes in mesangial complement 3c (C3c) and its C3c-containing fragment deposition from baseline to 9 months. The secondary objectives are to describe the histopathological changes after iptacopan treatment, changes in CD68+ cells and immunoglobulins from baseline at 9 months. The exploratory objectives include evaluating the histopathological changes in complement biomarkers after iptacopan treatment, changes in the MEST-C scores from baseline at 9 months; describing changes in urine protein–creatinine ratio (UPCR; log-transformed ratio to baseline of UPCR), hematuria (change from baseline in dipstick and red blood cell per high power field [RBC/HPF] at 9 months), and eGFR (change from baseline at 9 months); and exploring the correlation of histopathological changes with UPCR and eGFR changes. Results This study will explore the impact of iptacopan on IgAN immunopathology by assessing glomerular complement activation together with renal histopathology, kidney function, and key biomarkers. The findings will enhance understanding of iptacopan's mechanistic effects on IgAN and potential kidney protective benefits.

IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide, with up to 50% of patients progressing to end-stage kidney disease or death within 20 years [1, 2]. B-cell Activating Factor (BAFF) and A PRoliferation-Inducing Ligand (APRIL) bind to the TACI receptor on B cells and play key roles in IgAN pathophysiology by fueling B cells to produce both galactose-deficient IgA1 (Gd-IgA1) and anti-Gd-IgA1 autoantibodies. Gd-IgA1 is recognized as an autoantigen by anti-Gd-IgA1 autoantibodies, forming the immune complexes which drive kidney pathology and clinical disease. Atacicept is a fully humanized TACI-Fc fusion protein that binds BAFF and APRIL with nanomolar binding affinity to modulate the activity of dysregulated B cells and has been shown to reduce circulating levels of Gd-IgA1, anti-Gd-IgA1, and immune complexes. The ORIGIN 2b study evaluated the safety and efficacy of atacicept in patients with biopsy-proven IgAN and met the primary endpoint with a statistically significant and clinically meaningful UPCR reduction at 24 weeks, with deepening efficacy through 36 weeks as compared to placebo. In the open-label extension, atacicept demonstrated further Gd-IgA1 reductions, hematuria improvement, and UPCR reduction with eGFR stabilization at a rate of decline similar to the general population without kidney disease through 96 weeks, suggesting atacicept offers a potentially safe, long-term, disease-modifying treatment for IgAN [3]. ORIGIN 3 is a global, randomized, double-blind, placebo-controlled Phase 3 study evaluating safety and efficacy of atacicept 150 mg for treatment of IgAN (Fig. 1). Eligible patients are adults with biopsy-proven IgAN and persistent proteinuria despite stable and maximum-tolerated RASi regimen for ≥12 weeks (see Fig. 1 for key entry criteria). 376 patients globally will be randomized 1:1 to at-home self-administered weekly subcutaneous atacicept 150 mg or placebo for a 104-week double-blind treatment period, followed by a 52-week open-label extension. The primary endpoint is UPCR % change from baseline at 36 weeks analyzed using a mixed-effects model with repeated measurement. The key secondary endpoint is eGFR annualized rate of change through 104 weeks. This pivotal Phase 3 study has a consistent design, patient population and atacicept dose and subcutaneous formulation with that of the completed ORIGIN Phase 2b study, which demonstrated the efficacy of atacicept in reducing Gd-IgA1, improving hematuria, reducing proteinuria, and stabilizing eGFR. This Phase 3 study will further evaluate atacicept's disease-modifying potential as a treatment for IgAN.

BACKGROUND:The alternative complement pathway plays a key role in the pathogenesis of IgA nephropathy. Iptacopan specifically binds to factor B and inhibits the alternative pathway. METHODS:In this phase 3, double-blind, randomized, placebo-controlled trial, we enrolled adults with biopsy-confirmed IgA nephropathy and proteinuria with a 24-hour urinary protein-to-creatinine ratio of 1 or higher (with protein and creatinine both measured in grams) despite optimized supportive therapy. Patients were randomly assigned, in a 1:1 ratio, to receive oral iptacopan (200 mg) or placebo twice daily for 24 months while continuing to receive supportive therapy. The primary objective of this prespecified interim analysis was to assess the efficacy of iptacopan as compared with that of placebo in reducing proteinuria at month 9; the primary end point was the change from baseline in the 24-hour urinary protein-to-creatinine ratio at month 9. The proportion of patients who had a 24-hour urinary protein-to-creatinine ratio of less than 1 at month 9 without receiving rescue or alternative medication or undergoing kidney-replacement therapy (dialysis or transplantation) was a secondary end point. Safety was also assessed. The effect of iptacopan on kidney function will be assessed at the end of the 2-year double-blind treatment period. RESULTS:The main trial population included 222 patients in the iptacopan group and 221 in the placebo group. The interim efficacy analysis included the first 250 patients who underwent randomization in the main trial population (125 patients in each group) and who remained in the trial until month 9 or discontinued the trial by month 9. Safety was assessed in all the patients in the main trial population. At month 9, the adjusted geometric mean 24-hour urinary protein-to-creatinine ratio was 38.3% (95% confidence interval, 26.0 to 48.6; two-sided P<0.001) lower with iptacopan than with placebo. The reduction in proteinuria was supported by consistent results in secondary end point analyses. There were no unexpected safety findings with iptacopan. The incidence of adverse events that occurred during the treatment period was similar in the two groups; most events were mild to moderate in severity and reversible. No increased risk of infection was observed. CONCLUSIONS:Among patients with IgA nephropathy, treatment with iptacopan resulted in a significant and clinically meaningful reduction in proteinuria as compared with placebo. (Funded by Novartis; APPLAUSE-IgAN ClinicalTrials.gov number, NCT04578834.).

Key PointsParticipants who completed a 36-week double-blind study of atacicept were eligible for a 60-week, open-label extension study.Atacicept 96-week treatment resulted in sustained reductions in galactose-deficient IgA1, hematuria, and urine protein-creatinine ratio.The slope of the eGFR was similar to that observed in the general population without kidney disease.BackgroundB-cell activating factor (BAFF) and A proliferation-inducing ligand (APRIL) play key roles in the pathogenesis of IgA nephropathy. Atacicept is a novel fully humanized fusion protein, self-administered at home by subcutaneous injection, that binds and inhibits BAFF and APRIL. By inhibiting BAFF and APRIL, atacicept targets the underlying B-cell-mediated pathogenesis driving disease progression. This study evaluated the long-term efficacy and safety of atacicept in patients with IgA nephropathy over 96 weeks.MethodsParticipants with IgA nephropathy who received atacicept (25, 75, or 150 mg) or placebo in a 36-week phase 2b, randomized, blinded trial were enrolled in an open-label extension study and received atacicept 150 mg for an additional 60 weeks. Key efficacy outcomes were changes in galactose-deficient IgA1 (Gd-IgA1), percentage of participants with hematuria, urine protein-creatinine ratio (UPCR), and eGFR over 96 weeks. Long-term safety data were also evaluated.ResultsThere were 113 participants (67 [59%] male; 46 [41%] female) who ranged in age from 18 to 67 years who received >= 1 atacicept dose. Over 96 weeks, safety data demonstrated that atacicept was generally well tolerated. There were also sustained reductions (mean +/- SEM) in Gd-IgA1 (-66%+/- 2%), percentage of participants with hematuria (-75%; 95% confidence intervals, -87 to -59; in participants with baseline hematuria), and UPCR (-52%+/- 5%). The mean annualized slope of eGFR was -0.6 +/- 0.5 ml/min per 1.73 m2 through 96 weeks.ConclusionsAtacicept was also well tolerated over the duration of the study. Atacicept treatment reduced Gd-IgA1, hematuria, and UPCR with stabilization of eGFR through 96 weeks.Clinical Trial registry name and registration number:Atacicept in Subjects with IgA Nephropathy (ORIGIN 3), NCT04716231.

Atacicept is a first-in-class, dual anti-B-cell Activation Factor-A Proliferation-Inducing Ligand fusion protein in clinical evaluation for treatment of IgA nephropathy. To compare efficacy and safety of atacicept versus placebo in patients with IgAN, this randomized, double-blind, placebo-controlled phase 2b clinical trial ORIGIN enrolled 116 individuals with biopsy-proven IgA nephropathy. Participants were randomized to atacicept 150, 75, or 25 mg versus placebo once weekly for up to 36 weeks. Primary and key secondary endpoints were changes in urine protein creatinine ratio based on 24-hour urine collection at weeks 24 and 36, respectively, in the combined atacicept 150 mg and 75 mg group versus placebo. The primary endpoint was met at week 24 as the mean urine protein creatinine ratio was reduced from baseline by 31% in the combined atacicept group versus 8% with placebo, resulting in a significant 25% reduction with atacicept versus placebo. At week 36, the key secondary endpoint was met as the mean urine protein creatinine ratio reduced from baseline by 34% in the combined atacicept group versus a 2% increase with placebo, resulting in a significant 35% reduction with atacicept versus placebo. The reduction in proteinuria was accompanied by stabilization in endpoint eGFR with atacicept compared to a decline with placebo at week 36, resulting in significant between-group geometric mean difference of 11%, approximating an absolute difference of 5.7 mL/min/1.73m2. Endpoint galactose deficient IgA1 levels significantly decreased from baseline by 60% versus placebo. The safety profile of atacicept was like placebo. Thus, our results provide evidence to support a pivotal, phase 3 study of atacicept in IgA nephropathy.

IgA nephropathy (IgAN) is the most common primary glomerulopathy worldwide, with up to 50% of patients progressing to ESKD or death within 20 years.(1,2) B-cell Activating Factor (BAFF) and A PRoliferation-Inducing Ligand (APRIL) play an important role in the maturation, differentiation, and effector function of B cells and plasma cells, leading to the elevated serum levels of galactose-deficient IgA1 (Gd-IgA1), anti-Gd-IgA1 autoantibodies, and immune complex formation that are central to IgAN pathogenesis.