Efficacy of Avacopan in ANCA associated vasculitis: A meta-analysis of randomized controlled trials

Efficacy of Avacopan in ANCA associated vasculitis: A meta-analysis of randomized controlled trials | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Efficacy of Avacopan in ANCA associated vasculitis: A meta-analysis of randomized controlled trials Veronica Manchanda, Suchith Boodegere Suresh, Anastasiia Babintseva This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7199300/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Avacopan is a novel C5a inhibitor that has shown promise in treating ANCA-associated vasculitis. We aimed to compare its therapeutic effects and efficacy with the current standard of care, which typically includes high-dose steroids and other immunosuppressive agents, such as cyclophosphamide, rituximab, and azathioprine. Methods We conducted a meta-analysis of randomized controlled trials that compared the therapeutic effects of avacopan with those of the standard of care. We selected three trials from five databases, including Cochrane, PubMed, Science Direct, Google Scholar, and ClinicalTrials.gov as of February 15, 2025. The primary outcomes were change in GFR, percent change in Urine Albumin Creatinine Ratio (UACR), and proportion of subjects achieving disease remission. The secondary outcome was the percent change in the Monocyte Chemoattractant Protein(MCP1)/creatinine ratio. The results are presented as mean differences for continuous variables or odds ratios for dichotomous variables. Results Three trials including 404 patients (204 avacopan, 200 standard care) were analyzed. Avacopan was associated with a significantly smaller reduction in proteinuria (mean difference in UACR change: 7; 95% CI: 5.75–8.25; p<0.00001) and a greater reduction in MCP-1/creatinine ratio (mean difference: -3; 95% CI: -3.81 to -2.19; p<0.00001). Differences in GFR change and remission rates were not statistically significant. Conclusion In conclusion, avacopan has beneficial steroid-sparing effects, but it may not be a viable alternative on its own. Further long-term studies are needed to better evaluate the efficacy and the risk of adverse effects associated with the use of avacopan in conjunction with low-dose steroid use. Urology & Nephrology Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Key points This is the first meta-analysis of avacopan use for ANCA-associated vasculitis. Our findings showed that avacopan was associated with a lower reduction in proteinuria than the standard of care. However, it was equally effective in achieving disease remission and preserving the Glomerular Filtration Rate (GFR). Our results suggest that avacopan may be more beneficial when used in addition to steroids rather than as a replacement. Introduction ANCA-associated vasculitis is a type of small vessel vasculitis characterized by neutrophil activation and degranulation on the surface of small vessel endothelial cells leading to end organ damage. It includes granulomatosis with polyangiitis(GPA), microscopic polyangiitis(MPA), renal-limited vasculitis, and eosinophilic granulomatosis with polyangiitis. Although AAV can involve any organ system, the upper and lower respiratory tracts and kidneys are most commonly involved. Untreated GPA and MPA can rapidly progress and be fatal. Pulmonary capillaritis with alveolar hemorrhage is a severe complication.[4] Kidney involvement is common in ANCA(Anti-Neutrophil cytoplasmic antibodies) vasculitis. The typical presentation is rapidly progressive glomerulonephritis. The most common causes of mortality in ANCA-associated vasculitis are cardiovascular diseases, infections, malignancies, and renal death [1]. The pathophysiology of ANCA vasculitis involves an initial trigger, such as an infection that causes naïve T helper cells to differentiate into Th 17 cells. This leads to the release of pro-inflammatory cytokines from macrophages, which activates neutrophils. Concurrently, the alternative complement pathway also releases C5a which activates neutrophils by interacting with the C5a receptor. Furthermore, neutrophils activated by C5a, release reactive oxygen species, properdin, and other molecules that stimulate the complement pathway, leading to the production of more C5a in a vicious cycle.[9] Before the use of immunosuppressive agents, survival was approximately five months[6]. Indeed, the use of steroids and other immunosuppressive agents, such as rituximab, cyclophosphamide, and azathioprine has reversed this poor prognosis. The current standard of care involves the induction of remission with rituximab or cyclophosphamide plus glucocorticoids, followed by maintenance therapy primarily with rituximab, with alternatives including azathioprine, methotrexate, or mycophenolate mofetil.[7] However, these medications are not without their list of adverse effects, which has led to the search for steroid-sparing agents. The adverse effects of steroids include osteoporosis, glucocorticoid-induced myopathy, coronary artery disease, hypertension, heart failure, skin atrophy, striae, cataracts, glaucoma, cognitive impairment, psychosis, and also metabolic complications such as, hyperglycemia, dyslipidemia, cushingoid facies, and, adrenal suppression. [17] Avacopan a first-in-class oral C5a inhibitor was approved by the FDA for use in ANCA vasculitis in 2021[2]. Avacopan is a C5a receptor antagonist that blocks C5a-induced upregulation of C11b (integrin alpha M) in neutrophils and inhibits C5a-mediated neutrophil activation and migration.[8] Avacopan is largely protein-bound (99%) but has a large distribution volume of 345L.[11] Avacopan is primarily excreted in feces but a small amount ( approximately 10%) can also be eliminated in the urine. Hence, it should be effective for patients with decreased renal function. In this meta-analysis, we aimed to evaluate the efficacy of avacopan compared to the standard of care. Methods This meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. Search strategy We performed a comprehensive search from inception through February 15, 2025, using Cochrane, PubMed, ScienceDirect, Google Scholar, and ClinicalTrials.gov. The search strategy included relevant keywords, such as avacopan and ANCA vasculitis. Study selection and data extraction The eligibility criteria were randomized controlled trials in English irrespective of geographical location. We included RCTs that compared avacopan to the current standard of care in patients aged ≥ 18 who were diagnosed with ANCA vasculitis. Articles were retrieved from the above-mentioned sources and imported into Rayyan. Owing to import limitations, Cochrane records were manually extracted into an Excel spreadsheet. Duplicate records were removed using Rayyan Automated Software. Two investigators (Veronica Manchanda and Suchith B S) independently screened the titles and abstracts, followed by a full-text review. Discrepancies were resolved by a third reviewer (Anastasiia Babintseva). Please refer to the supplementary material (Supplementary Table1) for further information on the search strategy. Data extracted included baseline characteristics, such as race, age, sex, and four outcomes. Change in GFR Percent change in MCP1/creatinine ratio Percent change in UACR Percent of patients achieving disease remission. Inclusion and exclusion criteria Inclusion criteria Patients 18 years of age and above with ANCA-associated vasculitis Intervention: Avacopan Control: Placebo or standard of care Articles in English Human studies Outcomes assessed were: change in Glomerular Filtration Rate(GFR), percent change in Urinary Albumin Creatinine Ratio (UACR), percent change in urinary Monocyte Chemoattractant Protein 1(MCP1)/creatinine ratio, and proportion of patients achieving disease remission. Exclusion criteria Observational studies Animal studies Articles not in English Clinical trials in healthy volunteers Outcome The primary outcomes included changes in GFR, percentage change in UACR, and the proportion of patients achieving disease remission. In the Advocate trial, disease remission was defined as a Birmingham Vasculitis Activity score (BVAS) of 0 and no steroid administration for 4 weeks. In the Clear Trial, disease remission was defined as a BVAS of 0 to 1 with no worsening in estimated Glomerular Filtration Rate (eGFR) and urinary Red Blood Cell (RBC) count less than 10/high-power field. In the Classic trial, disease remission was defined as a BVAS of 0. The secondary outcome was a percentage change in MCP1/creatinine ratio. Data on the outcomes were extracted using an Excel sheet. Data analysis and quality assessment Study quality was assessed using the Cochrane Risk of Bias tool (ROB 2). Each domain was judged as low, high, or some concerns. Two investigators (Veronica Manchanda and Suchith BS) independently performed these assessments. The data were then analyzed using the Review Manager (RevMan) version 5.4 software. Statistical significance was set at p<0.05. Continuous outcomes were reported as standardized mean differences with 95% confidence intervals. Dichotomous outcomes were expressed as odds ratios (OR) with a 95% confidence interval. Between trial heterogeneity was determined using the I2 statistic, and a value of more than 50% was considered significant. I2 less than 30%: Fixed effects model I2 more than 30-75%: Moderate to high heterogeneity- Random effects model I2 more than 75%: High heterogeneity- Random Effects model Results were visualized using a forest plot. Results Three trials including 404 patients (204 avacopan, 200 standard care) were analyzed. Avacopan was associated with a significantly smaller reduction in proteinuria (mean difference in UACR change: 7; 95% CI: 5.75–8.25; p < 0.00001) and a greater reduction in MCP-1/creatinine ratio (mean difference: -3; 95% CI: -3.81 to -2.19; p < 0.00001). Differences in GFR change and remission rates were not statistically significant. Quality assessment was performed using the Cochrane Risk of Bias tool (ROB2), and all three studies were determined to be low risk, as shown in (Figure 1) The baseline characteristics of the included studies are shown in the table below (Table 1). The three RCTs included 404 participants, 204 receiving avacopan and 200 receiving standard of care. The majority of patients were middle-aged Caucasians. Table 1 Baseline characteristics Classic trial Clear trial Advocate trial Mean age (SD) 57.7(13.18) 57.4 66.5 Sex (Male%) 45.2 72.7 56.4 Ethnicity (% Caucasians) 90.5 100 84.2 % patients receiving rituximab 92.9 22.7 64.8 % patients receiving cyclophosphamide 7.2 77.3 35.2 BVAS score 15.3 13.8 16.2 Mean GFR in ml/min/1.73m2 59.4 54.7 45.1 Mean UACR 104.7 283.4 372.5 Mean MCP1/creat ratio(pg/mg) 522.6 846.4 965.8 The endpoints were recorded as a Forest Plot. The mean change in GFR was 0.50 which was not statistically significant with a p-value of 0.87 (CI -5.31 to 6.30). I2 was 70% indicating significant heterogeneity. The mean percent change in the MCP 1/creatinine ratio was -3.00 which was statistically significant with a p-value of <0.00001 (CI -3.81 to -2.19) and favored the avacopan arm. I2 was 0 indicating negligible heterogeneity between the trials. The percent change in UACR was 7.00 which was statistically significant with a P value of <0.00001 (CI: 5.75 to 8.25) favoring the control arm. An I2 value of 0 implied negligible heterogeneity between trials. The percentage of patients achieving disease remission was analyzed in terms of the odds ratio which was 0.98, and was not statistically significant with a p-value of 0.94 (CI: 0.64 to 1.51). I2 was 0, implying negligible heterogeneity. Discussion According to our meta-analysis, avacopan was associated with a greater reduction in the MCP 1/creatinine ratio but a lesser reduction in UACR than the standard of care. MCP 1 is one of the first chemokines involved in renal inflammatory diseases.[3] It has direct signaling effects on monocytes and influences the migration, proliferation, and differentiation of leukocytes. Hence, it is not surprising that the levels of MCP decrease with disease remission and elevate with relapse. [18] A greater reduction in MCP 1/creatinine ratio implies a better clinical outcome. Similarly, UACR, with its increased sensitivity and specificity plays a crucial role in the early diagnosis of CKD and is associated with an increase in all-cause mortality, especially in patients with poor cardiovascular health.[19]. A decreased reduction in the UACR in the avacopan arm raises the question of its ability to completely replace steroids. The change in GFR was not statistically significant between the two arms. However, due to increased heterogeneity, these results must be interpreted with caution. In addition, the proportion of patients achieving disease remission was not statistically significant between the two arms, which implies that it was as successful as steroids in achieving disease remission and hence can decrease our reliance on steroids in the future. While the trials were designed, the patients were not supposed to receive steroids; however, they ended up receiving steroids. In the Classic trial, the avacopan arm was associated with a low dose of prednisone, whereas in the Clear trial, the avacopan arm did not receive any steroids. This inconsistent use of steroids across the three arms could partially explain some of the heterogeneity. In a post hoc analysis of the advocate trial, the avacopan arm was associated with a lower glucocorticoid toxicity index, which was measured using the cumulative worsening score (CWS) and Aggregate Improvement score (AIS), both of which favored the avacopan arm.[15]. In a post-marketing retrospective cohort analysis of 92 patients[10], it was found to be associated with higher rates of clinical remission. This study also included a subset of the population that was not included in the aforementioned trials. Nine patients who were on renal replacement therapy were included, of which five were able to discontinue renal replacement therapy. This study included patients with a GFR of less than 15ml/min/1.73 m2 and avacopan was also effective in this population group. However, based on this study, the avacopan arm was associated with a cumulative dose of 2212 mg prednisone compared to 1676 mg in the ADVOCATE trial. The low-dose prednisone arm also received a mean cumulative dose of 2.3g compared with 3847mg in the ADVOCATE trial. This was most likely related to a delay in initiating avacopan induction therapy. Further long-term studies are needed to evaluate the role of avacopan in reducing reliance on steroids for the management of ANCA vasculitis. Most patients in the trials were Caucasians, which is the population with a predilection for ANCA vasculitis. The overall prevalence of ANCA vasculitis is two times higher in people of European descent than those of non-European descent.[5] Advocate trial included 330 patients who carried the most weight in our analysis. Kidney Diseases Improving Global Outcomes (KDIGO) guidelines were revised in 2024 to include avacopan as the agent of choice for inducing remission as an alternative to glucocorticoid taper in addition to cyclophosphamide/rituximab/combination of cyclophosphamide and rituximab. [7] However, it has not been included as a maintenance therapy as of, yet which only includes rituximab or azathioprine. Our study has several strengths. To the best of our knowledge, this is the first meta-analysis to date. We included 404 patients making this the largest study to date. Second, in this meta-analysis, the avacopan arm was associated with a lower cumulative dose of steroids or no steroids, and our results support an acceptable efficacy of avacopan with a decreased reliance on steroids. This answers a clinically relevant question: “Can avacopan decrease our reliance on steroids for the treatment of ANCA-associated vasculitis?” In addition, the incorporation of MCP1/ creatinine ratio and UACR provides more insight into the effect of our intervention on renal inflammation and injury. Nevertheless, our study had several important limitations that warrant careful consideration. The most significant limitation relates to the substantial discordance between clinical trial protocols and real-world practice patterns, where avacopan utilization in clinical practice can extend to more severely ill patients with advanced renal dysfunction,- who are largely excluded from clinical trials[10]. Additionally, real-world steroid use patterns differ markedly from trial protocols, with patients receiving comparable glucocorticoid doses in both treatment arms despite the intended steroid-sparing design, although the avacopan arm demonstrated higher rates of clinical remission even when compared to the Advocate trial. In this retrospective cohort study, clinical remission was achieved in 90% of patients at week 26 receiving avacopan compared to 70% of patients at week 26 in the Advocate trial. This was largely due to differences in the definition of remission. Furthermore, the relatively short follow-up periods across the included trials (84 days to 26 weeks) represent another critical limitation, as these durations are insufficient to assess long-term outcomes, including sustained remission, relapse rates, progressive renal dysfunction, and, the durability of steroid-sparing effects. This temporal limitation is particularly concerning given the chronic, relapsing nature of ANCA-associated vasculitis where long-term disease control and organ preservation are primary therapeutic goals. Future Directions: Future research should focus on addressing several critical knowledge gaps to optimize the clinical utility of avacopan. Randomized controlled trials are urgently needed in previously understudied populations, including patients with renal replacement therapy and those with GFR less than 15ml/min/1.73m2. Patients receiving Plasma Exchange (PLEX) are another key population that needs to be studied since avacopan is about 99% protein bound and PLEX would render it ineffective by removing the proteins. However, given that it has a large volume of distribution of approximately 3.45L if administered after PLEX therapy, it may continue to be effective. Further studies are needed to compare avacopan in addition to combination therapy with rituximab and cyclophosphamide, which has been proven to be more effective than monotherapy,- along with investigations of the optimal timing for avacopan initiation.[16]. This may reduce reliance on steroids in the future. Further trials are needed to evaluate the role of avacopan in maintenance therapy, whether used alone or in combination with rituximab or azathioprine given the oral administration and good tolerability of the drug. The incorporation of glucocorticoid toxicity index in future trials would provide quantifiable data regarding the toxicity benefits of steroid-sparing therapies. The utilization of biomarkers such as the MCP-1/creatinine ratio, ANCA titers, MPO and PR3 positivity, UACR, ESR [20], and CRP in future clinical trials holds significant potential for identifying prognostic indicators in ANCA-associated vasculitis. Incorporating these tools could help stratify patients based on disease activity or risk of relapse and, over time, may allow for more individualized and biomarker-guided therapeutic strategies. This approach can ultimately enhance treatment precision and improve patient outcomes. Given the cost of this drug, future trials should also assess the cost-effectiveness and the impact on healthcare resource utilization. Conclusion In conclusion, our meta-analysis shows that avacopan has no significant effect on changes in GFR or the proportion of subjects achieving disease remission, indicating that it is at least similar to steroids in this regard. A larger reduction in the MCP1/creatinine ratio was observed, indicating a better role in decreasing disease activity. It also showed a lesser reduction in the UACR, which is associated with worse renal outcomes and an increase in all-cause mortality. Thus, its renal benefits remain uncertain and warrant further investigation. Our meta-analysis is the first and largest to date on avacopan use in ANCA-associated vasculitis. It highlights its potential for steroid-sparing effects, but is limited by short follow-up periods and discrepancies between the trial design and real-world steroid use. Declarations Funding Statement: No funding was received for the conduct of this study. This meta-analysis was carried out independently without external financial support. Ethical Compliance: This study is a meta-analysis of previously published randomized controlled trials. No new research involving human participants was conducted by the authors. Data Access Statement: All data used in this meta-analysis were obtained from publicly available published studies. Conflict of Interest: The authors declare no conflicts of interest. References Wallace ZS, Fu X, Harkness T, Stone JH, Zhang Y, Choi H. All-cause and cause-specific mortality in ANCA-associated vasculitis: overall and according to ANCA type. Rheumatology (Oxford) . 2020;59(9):2308–2315. doi:10.1093/rheumatology/kez589. Thorley J. FDA approves avacopan for ANCA-associated vasculitis. Lancet Rheumatol . 2022;4(1):e21. doi:10.1016/S2665-9913(21)00391-X. Kronbichler A, Kerschbaum J, Gründlinger G, Leierer J, Mayer G, Rudnicki M. Evaluation and validation of biomarkers in granulomatosis with polyangiitis and microscopic polyangiitis. Nephrol Dial Transplant . 2016;31(6):930–936. doi:10.1093/ndt/gfv336. Gómez-Puerta JA, Hernández-Rodríguez J, López-Soto A, Bosch X. Antineutrophil cytoplasmic antibody-associated vasculitides and respiratory disease. Chest . 2009;136(4):1101–1111. doi:10.1378/chest.08-3043. Mahr A, Guillevin L, Poissonnet M, Aymé S. Prevalences of polyarteritis nodosa, microscopic polyangiitis, Wegener's granulomatosis, and Churg-Strauss syndrome in a French urban multiethnic population in 2000: a capture-recapture estimate. Arthritis Rheum . 2004;51(1):92–99. doi:10.1002/art.20077. Chung SA, Langford CA, Maz M, Abril A, Gorelik M, Guyatt G, et al. 2021 American College of Rheumatology/Vasculitis Foundation Guideline for the Management of Antineutrophil Cytoplasmic Antibody–Associated Vasculitis. Arthritis Care Res (Hoboken) . 2021;73(8):1088–1105. doi:10.1002/acr.24634. KDIGO ANCA Vasculitis Work Group. KDIGO 2024 Clinical Practice Guideline for the Management of Antineutrophil Cytoplasmic Antibody (ANCA)-Associated Vasculitis. Kidney Int . 2024;105(3S):S71–S116. doi:10.1016/j.kint.2023.10.008. Bekker P, Dairaghi D, Seitz L, Leleti M, Wang Y, Ertl L, et al. Characterization of pharmacologic and pharmacokinetic properties of CCX168, a potent and selective orally administered complement 5a receptor inhibitor, based on preclinical evaluation and randomized phase 1 clinical study. PLoS One . 2016;11(10):e0164646. doi:10.1371/journal.pone.0164646. Xiao H, Dairaghi DJ, Powers JP, Ertl LS, Baumgart T, Wang Y, et al. C5a receptor (CD88) blockade protects against MPO-ANCA GN. J Am Soc Nephrol . 2014;25(2):225–231. doi:10.1681/ASN.2013020143. Zonozi R, Aqeel F, Le D, Cortazar FB, Thaker J, Zabala Ramirez MJ, et al. Real-world experience with avacopan in antineutrophil cytoplasmic autoantibody-associated vasculitis. Kidney Int Rep . 2024;9(6):1783–1791. doi:10.1016/j.ekir.2024.03.022. National Center for Biotechnology Information. PubChem Compound Summary for CID 49841217, Avacopan. PubChem . https://pubchem.ncbi.nlm.nih.gov/compound/Avacopan. Accessed April 6, 2025. Jayne DRW, Merkel PA, Schall TJ, Bekker P; ADVOCATE Study Group. Avacopan for the treatment of ANCA-associated vasculitis. N Engl J Med . 2021;384(7):599–609. doi:10.1056/NEJMoa2023386. Jayne DRW, Bruchfeld AN, Harper L, Schaier M, Venning MC, Hamilton P, et al. Randomized trial of C5a receptor inhibitor avacopan in ANCA-associated vasculitis. J Am Soc Nephrol . 2017;28(9):2756–2767. doi:10.1681/ASN.2016111179. Merkel PA, Niles J, Jimenez R, Spiera RF, Rovin BH, Bomback A, et al. Adjunctive treatment with avacopan, an oral C5a receptor inhibitor, in patients with antineutrophil cytoplasmic antibody-associated vasculitis. ACR Open Rheumatol . 2020;2(11):662–671. doi:10.1002/acr2.11185. Patel NJ, Jayne DRW, Merkel PA, Bekker P, Zhang Y, Yue H, et al. Glucocorticoid toxicity index scores by domain in patients with antineutrophil cytoplasmic antibody-associated vasculitis treated with avacopan versus standard prednisone taper: post-hoc analysis of data from the ADVOCATE trial. Lancet Rheumatol . 2023;5(3):e130–e138. doi:10.1016/S2665-9913(23)00030-9. Gulati K, Edwards H, Prendecki M, Cairns TD, Condon M, Galliford J, et al. Combination treatment with rituximab, low-dose cyclophosphamide and plasma exchange for severe antineutrophil cytoplasmic antibody-associated vasculitis. Kidney Int . 2021;100(6):1316–1324. doi:10.1016/j.kint.2021.08.025. Oray M, Abu Samra K, Ebrahimiadib N, Meese H, Foster CS. Long-term side effects of glucocorticoids. Expert Opin Drug Saf . 2016;15(4):457–465. doi:10.1517/14740338.2016.1140743. Haller H, Bertram A, Nadrowitz F, Menne J. Monocyte chemoattractant protein-1 and the kidney. Curr Opin Nephrol Hypertens . 2016;25(1):42–49. doi:10.1097/MNH.0000000000000186. Mahemuti N, Zou J, Liu C, Xiao Z, Liang F, Yang X. Urinary albumin-to-creatinine ratio in normal range, cardiovascular health, and all-cause mortality. JAMA Netw Open . 2023;6(12):e2348333. doi:10.1001/jamanetworkopen.2023.48333. Ivković V, Windpessl M, Berke I, Geetha D, Callemeyn J, Norouzi S, Bajema IM, Kronbichler A. ANCA-Associated Glomerulonephritis: Diagnosis and Therapy Proceedings of the Henry Shavelle Lectureship. Glomerular Dis. 2024 Dec 2;5(1):26-47. doi: 10.1159/000542925. PMID: 39991195; PMCID: PMC11842095. Additional Declarations The authors declare no competing interests. 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legend\u003c/p\u003e","description":"","filename":"3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7199300/v1/058e4466782184f42bf3f081.jpg"},{"id":87577414,"identity":"09e3e7c3-e7f6-4c79-8e32-2984964179f4","added_by":"auto","created_at":"2025-07-25 11:53:28","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":54119,"visible":true,"origin":"","legend":"\u003cp\u003eSee image above for figure legend\u003c/p\u003e","description":"","filename":"4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7199300/v1/a158781e4bec7c9c1a07f1d1.jpg"},{"id":87576775,"identity":"50520d1c-81b7-48f8-8df4-f6da4b214ce9","added_by":"auto","created_at":"2025-07-25 11:45:28","extension":"jpg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":59120,"visible":true,"origin":"","legend":"\u003cp\u003eSee image above for figure legend\u003c/p\u003e","description":"","filename":"5.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7199300/v1/75a2bb430a999028f80346fc.jpg"},{"id":87576786,"identity":"95b22c79-c05f-47f5-b211-b5d5defaa9c9","added_by":"auto","created_at":"2025-07-25 11:45:28","extension":"jpg","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":99026,"visible":true,"origin":"","legend":"\u003cp\u003eUnnumbered image in the Result section.\u003c/p\u003e","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7199300/v1/305b258dd24584d55d4c6b5f.jpg"},{"id":87578301,"identity":"f8aaef8c-2238-4e09-bb28-28c4ab40b76b","added_by":"auto","created_at":"2025-07-25 12:01:33","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":834040,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7199300/v1/850c0146-ada4-4613-a7d1-58d7a5976a54.pdf"},{"id":87576767,"identity":"d06fbad1-3c5c-4d30-bd75-fbde293792d3","added_by":"auto","created_at":"2025-07-25 11:45:28","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":13492,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementarymaterial.docx","url":"https://assets-eu.researchsquare.com/files/rs-7199300/v1/f641add8cc946171b1e02cc6.docx"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"\u003cp\u003e\u003cstrong\u003eEfficacy of Avacopan in ANCA associated vasculitis: A meta-analysis of randomized controlled trials\u003c/strong\u003e\u003c/p\u003e","fulltext":[{"header":"Key points","content":"\u003col\u003e\n \u003cli\u003eThis is the first meta-analysis of avacopan use for ANCA-associated vasculitis.\u003c/li\u003e\n \u003cli\u003eOur findings showed that avacopan was associated with a lower reduction in proteinuria than the standard of care. However, it was equally effective in achieving disease remission and preserving the Glomerular Filtration Rate (GFR).\u003c/li\u003e\n \u003cli\u003eOur results suggest that avacopan may be more beneficial when used in addition to steroids rather than as a replacement.\u0026nbsp;\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Introduction","content":"\u003cp\u003eANCA-associated vasculitis is a type of small vessel vasculitis characterized by neutrophil activation and degranulation on the surface of small vessel endothelial cells leading to end organ damage. It includes granulomatosis with polyangiitis(GPA), microscopic polyangiitis(MPA), renal-limited vasculitis, and eosinophilic granulomatosis with polyangiitis. Although AAV can involve any organ system, the upper and lower respiratory tracts and kidneys are most commonly involved. Untreated GPA and MPA can rapidly progress and be fatal. Pulmonary capillaritis with alveolar hemorrhage is a severe complication.[4] Kidney involvement is common in ANCA(Anti-Neutrophil cytoplasmic antibodies) vasculitis. The typical presentation is rapidly progressive glomerulonephritis.\u003c/p\u003e\n\u003cp\u003eThe most common causes of mortality in ANCA-associated vasculitis are cardiovascular diseases, infections, malignancies, and renal death [1]. The pathophysiology of ANCA vasculitis involves an initial trigger, such as an infection that causes naïve T helper cells to differentiate into Th 17 cells. This leads to the release of pro-inflammatory cytokines from macrophages, which activates neutrophils. Concurrently, the alternative complement pathway also releases C5a which activates neutrophils by interacting with the C5a receptor. Furthermore, neutrophils activated by C5a, release reactive oxygen species, properdin, and other molecules that stimulate the complement pathway, leading to the production of more C5a in a vicious cycle.[9]\u003c/p\u003e\n\u003cp\u003eBefore the use of immunosuppressive agents, survival was approximately five months[6]. Indeed, the use of steroids and other immunosuppressive agents, such as rituximab, cyclophosphamide, and azathioprine has reversed this poor prognosis. The current standard of care involves the induction of remission with rituximab or cyclophosphamide plus glucocorticoids, followed by maintenance therapy primarily with rituximab, with alternatives including azathioprine, methotrexate, or mycophenolate mofetil.[7] However, these medications are not without their list of adverse effects, which has led to the search for steroid-sparing agents. The adverse effects of steroids include osteoporosis, glucocorticoid-induced myopathy, coronary artery disease, hypertension, heart failure, skin atrophy, striae, cataracts, glaucoma, cognitive impairment, psychosis, and also metabolic complications such as, hyperglycemia, dyslipidemia, cushingoid facies, and, adrenal suppression. [17]\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Avacopan a first-in-class oral C5a inhibitor was approved by the FDA for use in ANCA vasculitis in 2021[2]. Avacopan is a C5a receptor antagonist that blocks C5a-induced upregulation of C11b (integrin alpha M) in neutrophils and inhibits C5a-mediated neutrophil activation and migration.[8] Avacopan is largely protein-bound (99%) but has a large distribution volume of 345L.[11] Avacopan is primarily excreted in feces but a small amount ( approximately 10%) can also be eliminated in the urine. Hence, it should be effective for patients with decreased renal function.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn this meta-analysis, we aimed to evaluate the efficacy of avacopan compared to the standard of care.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eThis meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSearch strategy\u003c/p\u003e\n\u003cp\u003eWe performed a comprehensive search from inception through February 15, 2025, using Cochrane, PubMed, ScienceDirect, Google Scholar, and ClinicalTrials.gov. The search strategy included relevant keywords, such as avacopan and ANCA vasculitis.\u003c/p\u003e\n\u003cp\u003eStudy selection and data extraction\u003c/p\u003e\n\u003cp\u003eThe eligibility criteria were randomized controlled trials in English irrespective of geographical location. We included RCTs that compared avacopan to the current standard of care in patients aged \u0026ge; 18 who were diagnosed with ANCA vasculitis. Articles were retrieved from the above-mentioned sources and imported into Rayyan. Owing to import limitations, Cochrane records were manually extracted into an Excel spreadsheet. Duplicate records were removed using Rayyan Automated Software. Two investigators (Veronica Manchanda and Suchith B S) independently screened the titles and abstracts, followed by a full-text review. Discrepancies were resolved by a third reviewer (Anastasiia Babintseva). Please refer to the supplementary material (Supplementary Table1) for further information on the search strategy. Data extracted included baseline characteristics, such as race, age, sex, and four outcomes.\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003eChange in GFR\u003c/li\u003e\n \u003cli\u003ePercent change in MCP1/creatinine ratio\u003c/li\u003e\n \u003cli\u003ePercent change in UACR\u0026nbsp;\u003c/li\u003e\n \u003cli\u003ePercent of patients achieving disease remission.\u0026nbsp;\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003e\u003cstrong\u003eInclusion and exclusion criteria\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInclusion criteria\u003c/strong\u003e\u003c/p\u003e\n\u003col\u003e\n \u003cli\u003ePatients 18 years of age and above with ANCA-associated vasculitis\u003c/li\u003e\n \u003cli\u003eIntervention: Avacopan\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eControl: Placebo or standard of care\u003c/li\u003e\n \u003cli\u003eArticles in English\u003c/li\u003e\n \u003cli\u003eHuman studies\u003c/li\u003e\n \u003cli\u003eOutcomes assessed were: change in Glomerular Filtration Rate(GFR), percent change in Urinary Albumin Creatinine Ratio (UACR), percent change in urinary Monocyte Chemoattractant Protein 1(MCP1)/creatinine ratio, and proportion of patients achieving disease remission.\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003e\u003cstrong\u003eExclusion criteria\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003col\u003e\n \u003cli\u003eObservational studies\u003c/li\u003e\n \u003cli\u003eAnimal studies\u003c/li\u003e\n \u003cli\u003eArticles not in English\u003c/li\u003e\n \u003cli\u003eClinical trials in healthy volunteers\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003eOutcome\u003c/p\u003e\n\u003cp\u003eThe primary outcomes included changes in GFR, percentage change in UACR, and the proportion of patients achieving disease remission. In the Advocate trial, disease remission was defined as a Birmingham Vasculitis Activity score (BVAS) of 0 and no steroid administration for 4 weeks. In the Clear Trial, disease remission was defined as a BVAS of 0 to 1 with no worsening in estimated Glomerular Filtration Rate (eGFR) and urinary Red Blood Cell (RBC) count less than 10/high-power field. In the Classic trial, disease remission was defined as a BVAS of 0. The secondary outcome was a percentage change in MCP1/creatinine ratio. Data on the outcomes were extracted using an Excel sheet.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eData analysis and quality assessment\u003c/p\u003e\n\u003cp\u003eStudy quality was assessed using the Cochrane Risk of Bias tool (ROB 2). Each domain was judged as low, high, or some concerns. Two investigators (Veronica Manchanda and Suchith BS) independently performed these assessments.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe data were then analyzed using the Review Manager (RevMan) version 5.4 software. Statistical significance was set at p\u0026lt;0.05. Continuous outcomes were reported as standardized mean differences with 95% confidence intervals. Dichotomous outcomes were expressed as odds ratios (OR) with a 95% confidence interval.\u003c/p\u003e\n\u003cp\u003eBetween trial heterogeneity was determined using the I2 statistic, and a value of more than 50% was considered significant.\u003c/p\u003e\n\u003cp\u003eI2 less than 30%: Fixed effects model\u003c/p\u003e\n\u003cp\u003eI2 more than 30-75%: Moderate to high heterogeneity- Random effects model\u003c/p\u003e\n\u003cp\u003eI2 more than 75%: High heterogeneity- Random Effects model\u003c/p\u003e\n\u003cp\u003eResults were visualized using a forest plot.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eThree trials including 404 patients (204 avacopan, 200 standard care) were analyzed. Avacopan was associated with a significantly smaller reduction in proteinuria (mean difference in UACR change: 7; 95% CI: 5.75\u0026ndash;8.25; p\u0026thinsp;\u0026lt;\u0026thinsp;0.00001) and a greater reduction in MCP-1/creatinine ratio (mean difference: -3; 95% CI: -3.81 to -2.19; p\u0026thinsp;\u0026lt;\u0026thinsp;0.00001). Differences in GFR change and remission rates were not statistically significant.\u003c/p\u003e\u003cp\u003eQuality assessment was performed using the Cochrane Risk of Bias tool (ROB2), and all three studies were determined to be low risk, as shown in (Figure 1)\u003c/p\u003e\n\u003cp\u003eThe baseline characteristics of the included studies are shown in the table below (Table 1). The three RCTs included 404 participants, 204 receiving avacopan and 200 receiving standard of care. The majority of patients were middle-aged Caucasians.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTable 1\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 129px;\"\u003e\n \u003cp\u003eBaseline characteristics\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 148px;\"\u003e\n \u003cp\u003eClassic trial\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 152px;\"\u003e\n \u003cp\u003eClear trial\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 172px;\"\u003e\n \u003cp\u003eAdvocate trial\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 129px;\"\u003e\n \u003cp\u003eMean age (SD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 148px;\"\u003e\n \u003cp\u003e57.7(13.18)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 152px;\"\u003e\n \u003cp\u003e57.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 172px;\"\u003e\n \u003cp\u003e66.5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 129px;\"\u003e\n \u003cp\u003eSex (Male%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 148px;\"\u003e\n \u003cp\u003e45.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 152px;\"\u003e\n \u003cp\u003e72.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 172px;\"\u003e\n \u003cp\u003e56.4\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 129px;\"\u003e\n \u003cp\u003eEthnicity (% Caucasians)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 148px;\"\u003e\n \u003cp\u003e90.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 152px;\"\u003e\n \u003cp\u003e100\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 172px;\"\u003e\n \u003cp\u003e84.2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 129px;\"\u003e\n \u003cp\u003e% patients receiving rituximab\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 148px;\"\u003e\n \u003cp\u003e92.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 152px;\"\u003e\n \u003cp\u003e22.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 172px;\"\u003e\n \u003cp\u003e64.8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 129px;\"\u003e\n \u003cp\u003e% patients receiving cyclophosphamide\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 148px;\"\u003e\n \u003cp\u003e7.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 152px;\"\u003e\n \u003cp\u003e77.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 172px;\"\u003e\n \u003cp\u003e35.2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 129px;\"\u003e\n \u003cp\u003eBVAS score\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 148px;\"\u003e\n \u003cp\u003e15.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 152px;\"\u003e\n \u003cp\u003e13.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 172px;\"\u003e\n \u003cp\u003e16.2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 129px;\"\u003e\n \u003cp\u003eMean GFR in ml/min/1.73m2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 148px;\"\u003e\n \u003cp\u003e59.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 152px;\"\u003e\n \u003cp\u003e54.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 172px;\"\u003e\n \u003cp\u003e45.1\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 129px;\"\u003e\n \u003cp\u003eMean UACR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 148px;\"\u003e\n \u003cp\u003e104.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 152px;\"\u003e\n \u003cp\u003e283.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 172px;\"\u003e\n \u003cp\u003e372.5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 129px;\"\u003e\n \u003cp\u003eMean MCP1/creat ratio(pg/mg)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 148px;\"\u003e\n \u003cp\u003e522.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 152px;\"\u003e\n \u003cp\u003e846.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 172px;\"\u003e\n \u003cp\u003e965.8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eThe endpoints were recorded as a Forest Plot. The mean change in GFR was 0.50 which was not statistically significant with a p-value of 0.87 (CI -5.31 to 6.30). I2 was 70% indicating significant heterogeneity.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe mean percent change in the MCP 1/creatinine ratio was -3.00 which was statistically significant with a p-value of \u0026lt;0.00001 (CI -3.81 to -2.19) and favored the avacopan arm. I2 was 0 indicating negligible heterogeneity between the trials.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe percent change in UACR was 7.00 which was statistically significant with a P value of \u0026lt;0.00001 (CI: 5.75 to 8.25) favoring the control arm. An I2 value of 0 implied negligible heterogeneity between trials.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe percentage of patients achieving disease remission was analyzed in terms of the odds ratio which was 0.98, and was not statistically significant with a p-value of 0.94 (CI: 0.64 to 1.51). I2 was 0, implying negligible heterogeneity.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eAccording to our meta-analysis, avacopan was associated with a greater reduction in the MCP 1/creatinine ratio but a lesser reduction in UACR than the standard of care. MCP 1 is one of the first chemokines involved in renal inflammatory diseases.[3] It has direct signaling effects on monocytes and influences the migration, proliferation, and differentiation of leukocytes. Hence, it is not surprising that the levels of MCP decrease with disease remission and elevate with relapse. [18] A greater reduction in MCP 1/creatinine ratio implies a better clinical outcome. Similarly, UACR, with its increased sensitivity and specificity plays a crucial role in the early diagnosis of CKD and is associated with an increase in all-cause mortality, especially in patients with poor cardiovascular health.[19]. A decreased reduction in the UACR in the avacopan arm raises the question of its ability to completely replace steroids.\u003c/p\u003e\n\u003cp\u003eThe change in GFR was not statistically significant between the two arms. However, due to increased heterogeneity, these results must be interpreted with caution. In addition, the proportion of patients achieving disease remission was not statistically significant between the two arms, which implies that it was as successful as steroids in achieving disease remission and hence can decrease our reliance on steroids in the future. While the trials were designed, the patients were not supposed to receive steroids; however, they ended up receiving steroids. In the Classic trial, the avacopan arm was associated with a low dose of prednisone, whereas in the Clear trial, the avacopan arm did not receive any steroids. This inconsistent use of steroids across the three arms could partially explain some of the heterogeneity.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn a post hoc analysis of the advocate trial, the avacopan arm was associated with a lower glucocorticoid toxicity index, which was measured using the cumulative worsening score (CWS) and Aggregate Improvement score (AIS), both of which favored the avacopan arm.[15]. In a post-marketing retrospective cohort analysis of 92 patients[10], it was found to be associated with higher rates of clinical remission. This study also included a subset of the population that was not included in the aforementioned trials. Nine patients who were on renal replacement therapy were included, of which five were able to discontinue renal replacement therapy. This study included patients with a GFR of less than 15ml/min/1.73 m2 and avacopan was also effective in this population group. However, based on this study, the avacopan arm was associated with a cumulative dose of 2212 mg prednisone compared to 1676 mg in the ADVOCATE trial. The low-dose prednisone arm also received a mean cumulative dose of 2.3g compared with 3847mg in the ADVOCATE trial. This was most likely related to a delay in initiating avacopan induction therapy. Further long-term studies are needed to evaluate the role of avacopan in reducing reliance on steroids for the management of ANCA vasculitis.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eMost patients in the trials were Caucasians, which is the population with a predilection for ANCA vasculitis. The overall prevalence of ANCA vasculitis is two times higher in people of European descent than those of non-European descent.[5] Advocate trial included 330 patients who carried the most weight in our analysis.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eKidney Diseases Improving Global Outcomes (KDIGO) guidelines were revised in 2024 to include avacopan as the agent of choice for inducing remission as an alternative to glucocorticoid taper in addition to cyclophosphamide/rituximab/combination of cyclophosphamide and rituximab. [7] However, it has not been included as a maintenance therapy as of, yet which only includes rituximab or azathioprine.\u003c/p\u003e\n\u003cp\u003eOur study has several strengths. To the best of our knowledge, this is the first meta-analysis to date. We included 404 patients making this the largest study to date. Second, in this meta-analysis, the avacopan arm was associated with a lower cumulative dose of steroids or no steroids, and our results support an acceptable efficacy of avacopan with a decreased reliance on steroids. This answers a clinically relevant question: “Can avacopan decrease our reliance on steroids for the treatment of ANCA-associated vasculitis?” In addition, the incorporation of MCP1/ creatinine ratio and UACR provides more insight into the effect of our intervention on renal inflammation and injury.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eNevertheless, our study had several important limitations that warrant careful consideration. The most significant limitation relates to the substantial discordance between clinical trial protocols and real-world practice patterns, where avacopan utilization in clinical practice can extend to more severely ill patients with advanced renal dysfunction,- who are largely excluded from clinical trials[10]. Additionally, real-world steroid use patterns differ markedly from trial protocols, with patients receiving comparable glucocorticoid doses in both treatment arms despite the intended steroid-sparing design, although the avacopan arm demonstrated higher rates of clinical remission even when compared to the Advocate trial. In this retrospective cohort study, clinical remission was achieved in 90% of patients at week 26 receiving avacopan compared to 70% of patients at week 26 in the Advocate trial. This was largely due to differences in the definition of remission. Furthermore, the relatively short follow-up periods across the included trials (84 days to 26 weeks) represent another critical limitation, as these durations are insufficient to assess long-term outcomes, including sustained remission, relapse rates, progressive renal dysfunction, and, the durability of steroid-sparing effects. This temporal limitation is particularly concerning given the chronic, relapsing nature of ANCA-associated vasculitis where long-term disease control and organ preservation are primary therapeutic goals.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFuture Directions:\u003c/p\u003e\n\u003cp\u003eFuture research should focus on addressing several critical knowledge gaps to optimize the clinical utility of avacopan. Randomized controlled trials are urgently needed in previously understudied populations, including patients with renal replacement therapy and those with GFR less than 15ml/min/1.73m2. Patients receiving Plasma Exchange (PLEX) are another key population that needs to be studied since avacopan is about 99% protein bound and PLEX would render it ineffective by removing the proteins. However, given that it has a large volume of distribution of approximately 3.45L if administered after PLEX therapy, it may continue to be effective. Further studies are needed to compare avacopan in addition to combination therapy with rituximab and cyclophosphamide, which has been proven to be more effective than monotherapy,- along with investigations of the optimal timing for avacopan initiation.[16]. This may reduce reliance on steroids in the future. Further trials are needed to evaluate the role of avacopan in maintenance therapy, whether used alone or in combination with rituximab or azathioprine given the oral administration and good tolerability of the drug.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe incorporation of glucocorticoid toxicity index in future trials would provide quantifiable data regarding the toxicity benefits of steroid-sparing therapies. The utilization of biomarkers such as the MCP-1/creatinine ratio, ANCA titers, MPO and PR3 positivity, UACR, ESR [20], and CRP in future clinical trials holds significant potential for identifying prognostic indicators in ANCA-associated vasculitis. Incorporating these tools could help stratify patients based on disease activity or risk of relapse and, over time, may allow for more individualized and biomarker-guided therapeutic strategies. This approach can ultimately enhance treatment precision and improve patient outcomes. Given the cost of this drug, future trials should also assess the cost-effectiveness and the impact on healthcare resource utilization.\u0026nbsp;\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn conclusion, our meta-analysis shows that avacopan has no significant effect on changes in GFR or the proportion of subjects achieving disease remission, indicating that it is at least similar to steroids in this regard. A larger reduction in the MCP1/creatinine ratio was observed, indicating a better role in decreasing disease activity. It also showed a lesser reduction in the UACR, which is associated with worse renal outcomes and an increase in all-cause mortality. Thus, its renal benefits remain uncertain and warrant further investigation. Our meta-analysis is the first and largest to date on avacopan use in ANCA-associated vasculitis. It highlights its potential for steroid-sparing effects, but is limited by short follow-up periods and discrepancies between the trial design and real-world steroid use.\u0026nbsp;\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding Statement:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo funding was received for the conduct of this study. This meta-analysis was carried out independently without external financial support.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical Compliance:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study is a meta-analysis of previously published randomized controlled trials. No new research involving human participants was conducted by the authors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Access Statement:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data used in this meta-analysis were obtained from publicly available published studies.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of Interest:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no conflicts of interest.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eWallace ZS, Fu X, Harkness T, Stone JH, Zhang Y, Choi H. All-cause and cause-specific mortality in ANCA-associated vasculitis: overall and according to ANCA type. \u003cem\u003eRheumatology (Oxford)\u003c/em\u003e. 2020;59(9):2308\u0026ndash;2315. doi:10.1093/rheumatology/kez589.\u003c/li\u003e\n\u003cli\u003eThorley J. FDA approves avacopan for ANCA-associated vasculitis. \u003cem\u003eLancet Rheumatol\u003c/em\u003e. 2022;4(1):e21. doi:10.1016/S2665-9913(21)00391-X.\u003c/li\u003e\n\u003cli\u003eKronbichler A, Kerschbaum J, Gr\u0026uuml;ndlinger G, Leierer J, Mayer G, Rudnicki M. Evaluation and validation of biomarkers in granulomatosis with polyangiitis and microscopic polyangiitis. \u003cem\u003eNephrol Dial Transplant\u003c/em\u003e. 2016;31(6):930\u0026ndash;936. doi:10.1093/ndt/gfv336.\u003c/li\u003e\n\u003cli\u003eG\u0026oacute;mez-Puerta JA, Hern\u0026aacute;ndez-Rodr\u0026iacute;guez J, L\u0026oacute;pez-Soto A, Bosch X. Antineutrophil cytoplasmic antibody-associated vasculitides and respiratory disease. \u003cem\u003eChest\u003c/em\u003e. 2009;136(4):1101\u0026ndash;1111. doi:10.1378/chest.08-3043.\u003c/li\u003e\n\u003cli\u003eMahr A, Guillevin L, Poissonnet M, Aym\u0026eacute; S. Prevalences of polyarteritis nodosa, microscopic polyangiitis, Wegener\u0026apos;s granulomatosis, and Churg-Strauss syndrome in a French urban multiethnic population in 2000: a capture-recapture estimate. \u003cem\u003eArthritis Rheum\u003c/em\u003e. 2004;51(1):92\u0026ndash;99. doi:10.1002/art.20077.\u003c/li\u003e\n\u003cli\u003eChung SA, Langford CA, Maz M, Abril A, Gorelik M, Guyatt G, et al. 2021 American College of Rheumatology/Vasculitis Foundation Guideline for the Management of Antineutrophil Cytoplasmic Antibody\u0026ndash;Associated Vasculitis. \u003cem\u003eArthritis Care Res (Hoboken)\u003c/em\u003e. 2021;73(8):1088\u0026ndash;1105. doi:10.1002/acr.24634.\u003c/li\u003e\n\u003cli\u003eKDIGO ANCA Vasculitis Work Group. KDIGO 2024 Clinical Practice Guideline for the Management of Antineutrophil Cytoplasmic Antibody (ANCA)-Associated Vasculitis. \u003cem\u003eKidney Int\u003c/em\u003e. 2024;105(3S):S71\u0026ndash;S116. doi:10.1016/j.kint.2023.10.008.\u003c/li\u003e\n\u003cli\u003eBekker P, Dairaghi D, Seitz L, Leleti M, Wang Y, Ertl L, et al. Characterization of pharmacologic and pharmacokinetic properties of CCX168, a potent and selective orally administered complement 5a receptor inhibitor, based on preclinical evaluation and randomized phase 1 clinical study. \u003cem\u003ePLoS One\u003c/em\u003e. 2016;11(10):e0164646. doi:10.1371/journal.pone.0164646.\u003c/li\u003e\n\u003cli\u003eXiao H, Dairaghi DJ, Powers JP, Ertl LS, Baumgart T, Wang Y, et al. C5a receptor (CD88) blockade protects against MPO-ANCA GN. \u003cem\u003eJ Am Soc Nephrol\u003c/em\u003e. 2014;25(2):225\u0026ndash;231. doi:10.1681/ASN.2013020143.\u003c/li\u003e\n\u003cli\u003eZonozi R, Aqeel F, Le D, Cortazar FB, Thaker J, Zabala Ramirez MJ, et al. Real-world experience with avacopan in antineutrophil cytoplasmic autoantibody-associated vasculitis. \u003cem\u003eKidney Int Rep\u003c/em\u003e. 2024;9(6):1783\u0026ndash;1791. doi:10.1016/j.ekir.2024.03.022.\u003c/li\u003e\n\u003cli\u003eNational Center for Biotechnology Information. PubChem Compound Summary for CID 49841217, Avacopan. \u003cem\u003ePubChem\u003c/em\u003e. https://pubchem.ncbi.nlm.nih.gov/compound/Avacopan. Accessed April 6, 2025.\u003c/li\u003e\n\u003cli\u003eJayne DRW, Merkel PA, Schall TJ, Bekker P; ADVOCATE Study Group. Avacopan for the treatment of ANCA-associated vasculitis. \u003cem\u003eN Engl J Med\u003c/em\u003e. 2021;384(7):599\u0026ndash;609. doi:10.1056/NEJMoa2023386.\u003c/li\u003e\n\u003cli\u003eJayne DRW, Bruchfeld AN, Harper L, Schaier M, Venning MC, Hamilton P, et al. Randomized trial of C5a receptor inhibitor avacopan in ANCA-associated vasculitis. \u003cem\u003eJ Am Soc Nephrol\u003c/em\u003e. 2017;28(9):2756\u0026ndash;2767. doi:10.1681/ASN.2016111179.\u003c/li\u003e\n\u003cli\u003eMerkel PA, Niles J, Jimenez R, Spiera RF, Rovin BH, Bomback A, et al. Adjunctive treatment with avacopan, an oral C5a receptor inhibitor, in patients with antineutrophil cytoplasmic antibody-associated vasculitis. \u003cem\u003eACR Open Rheumatol\u003c/em\u003e. 2020;2(11):662\u0026ndash;671. doi:10.1002/acr2.11185.\u003c/li\u003e\n\u003cli\u003ePatel NJ, Jayne DRW, Merkel PA, Bekker P, Zhang Y, Yue H, et al. Glucocorticoid toxicity index scores by domain in patients with antineutrophil cytoplasmic antibody-associated vasculitis treated with avacopan versus standard prednisone taper: post-hoc analysis of data from the ADVOCATE trial. \u003cem\u003eLancet Rheumatol\u003c/em\u003e. 2023;5(3):e130\u0026ndash;e138. doi:10.1016/S2665-9913(23)00030-9.\u003c/li\u003e\n\u003cli\u003eGulati K, Edwards H, Prendecki M, Cairns TD, Condon M, Galliford J, et al. Combination treatment with rituximab, low-dose cyclophosphamide and plasma exchange for severe antineutrophil cytoplasmic antibody-associated vasculitis. \u003cem\u003eKidney Int\u003c/em\u003e. 2021;100(6):1316\u0026ndash;1324. doi:10.1016/j.kint.2021.08.025.\u003c/li\u003e\n\u003cli\u003eOray M, Abu Samra K, Ebrahimiadib N, Meese H, Foster CS. Long-term side effects of glucocorticoids. \u003cem\u003eExpert Opin Drug Saf\u003c/em\u003e. 2016;15(4):457\u0026ndash;465. doi:10.1517/14740338.2016.1140743.\u003c/li\u003e\n\u003cli\u003eHaller H, Bertram A, Nadrowitz F, Menne J. Monocyte chemoattractant protein-1 and the kidney. \u003cem\u003eCurr Opin Nephrol Hypertens\u003c/em\u003e. 2016;25(1):42\u0026ndash;49. doi:10.1097/MNH.0000000000000186.\u003c/li\u003e\n\u003cli\u003eMahemuti N, Zou J, Liu C, Xiao Z, Liang F, Yang X. Urinary albumin-to-creatinine ratio in normal range, cardiovascular health, and all-cause mortality. \u003cem\u003eJAMA Netw Open\u003c/em\u003e. 2023;6(12):e2348333. doi:10.1001/jamanetworkopen.2023.48333.\u003c/li\u003e\n\u003cli\u003eIvković V, Windpessl M, Berke I, Geetha D, Callemeyn J, Norouzi S, Bajema IM, Kronbichler A. ANCA-Associated Glomerulonephritis: Diagnosis and Therapy Proceedings of the Henry Shavelle Lectureship. Glomerular Dis. 2024 Dec 2;5(1):26-47. doi: 10.1159/000542925. PMID: 39991195; PMCID: PMC11842095.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"Montefiore Health System","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-7199300/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7199300/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAvacopan is a novel C5a inhibitor that has shown promise in treating ANCA-associated vasculitis. We aimed to compare its therapeutic effects and efficacy with the current standard of care, which typically includes high-dose steroids and other immunosuppressive agents, such as cyclophosphamide, rituximab, and azathioprine.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe conducted a meta-analysis of randomized controlled trials that compared the therapeutic effects of avacopan with those of the standard of care. We selected three trials from five databases, including Cochrane, PubMed, Science Direct, Google Scholar, and ClinicalTrials.gov as of February 15, 2025. The primary outcomes were change in GFR, percent change in Urine Albumin Creatinine Ratio (UACR), and proportion of subjects achieving disease remission. The secondary outcome was the percent change in the Monocyte Chemoattractant Protein(MCP1)/creatinine ratio. The results are presented as mean differences for continuous variables or odds ratios for dichotomous variables.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThree trials including 404 patients (204 avacopan, 200 standard care) were analyzed. Avacopan was associated with a significantly smaller reduction in proteinuria (mean difference in UACR change: 7; 95% CI: 5.75–8.25; p\u0026lt;0.00001) and a greater reduction in MCP-1/creatinine ratio (mean difference: -3; 95% CI: -3.81 to -2.19; p\u0026lt;0.00001). Differences in GFR change and remission rates were not statistically significant.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn conclusion, avacopan has beneficial steroid-sparing effects, but it may not be a viable alternative on its own. Further long-term studies are needed to better evaluate the efficacy and the risk of adverse effects associated with the use of avacopan in conjunction with low-dose steroid use.\u003c/p\u003e","manuscriptTitle":"Efficacy of Avacopan in ANCA associated vasculitis: A meta-analysis of randomized controlled trials","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-07-25 11:45:23","doi":"10.21203/rs.3.rs-7199300/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"a56535b7-1862-4583-a563-9cf607b9da12","owner":[],"postedDate":"July 25th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":52069536,"name":"Urology \u0026 Nephrology"}],"tags":[],"updatedAt":"2025-07-25T11:45:23+00:00","versionOfRecord":[],"versionCreatedAt":"2025-07-25 11:45:23","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7199300","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7199300","identity":"rs-7199300","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}