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ABS0329 (2025)

SAFETY PROFILE OF AVACOPAN IN ANCA-ASSOCIATED VASCULITIS: INSIGHTS FROM THE JAPANESE MULTICENTER J-CANVAS STUDY

Keywords: Safety, Observational studies/registry, Infection, Real-world evidence

T. Uchida¹, S. Fukui¹, K. Ichinose^1,2, H. Ide³, Y. Tsuji¹, T. Shimizu¹, M. Umeda¹, R. Sumiyoshi¹, T. Igawa¹, T. Koga¹, S. Y. Kawashiri¹, N. Iwamoto¹, M. Tamai¹, T. Origuchi¹, S. Omura⁴, D. Nakagomi⁵, Y. Abe⁶, M. Wada⁷, N. Takizawa⁸, A. Nomura⁹, Y. Kukida¹⁰, N. Kondo¹¹, Y. Yasuhiko¹², H. Takagi¹³, K. Endo^14,15, S. Hirata¹⁶, N. Azuma¹⁷, T. Takeuchi¹⁸, K. Kamada¹⁹, R. Yanai²⁰, Y. Matsuo^21,22, Y. Shimojima²³, R. Nishioka²⁴, R. Okazaki²⁵, T. Takata²⁶, M. Moriyama², A. Takatani²⁷, Y. Miyawaki²⁸, T. Shirai²⁹, H. Dobashi³⁰, T. Ito³¹, I. Matsumoto³², T. Takada³³, T. Ito-Ihara³⁴, T. Kida⁴, N. Yajima²⁰, T. Kawaguchi³⁵, Y. Kawahito⁴, A. Kawakami

¹Graduate School of Biomedical Sciences, Nagasaki University, Department of Immunology and Rheumatology, Nagasaki, Japan
²Shimane University Faculty of Medicine, Department of Rheumatology, Izumo, Japan
³Komachi Clinic for Rheumatology, Osaka, Japan
⁴Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Inflammation and Immunology, Kyoto, Japan
⁵University of Yamanashi Hospital, Department of Rheumatology, Chuo, Japan
⁶Juntendo University, Department of Internal Medicine and Rheumatology, Bunkyo, Japan
⁷Japanese Red Cross Society Kyoto Daiichi Hospital, Center for Rheumatic Disease, Kyoto, Japan
⁸Chubu Rosai Hospital, Department of Rheumatology, Nagoya, Japan
⁹St. Luke’s International Hospital, Immuno-Rheumatology Center, Chuo, Japan
¹⁰Japanese Red Cross Society Kyoto Daini Hospital, Department of Rheumatology, Kyoto, Japan
¹¹Kyoto Katsura Hospital, Department of Nephrology, Kyoto, Japan
¹²Tosei General Hospital, Department of Respiratory Medicine and Allergy, Seto, Japan
¹³Kagoshima University Hospital, Department of Hematology and Rheumatology, Kagoshima, Japan
¹⁴Tottori Prefectural Central Hospital, Department of General Internal Medicine, Tottori, Japan
¹⁵Graduate School of Medicine and Public Health, Kyoto University, Department of Pharmacoepidemiology, Kyoto, Japan
¹⁶Hiroshima University Hospital, Department of Clinical Immunology and Rheumatology, Hiroshima, Japan
¹⁷Hyogo Medical University School of Medicine, Department of Diabetes, Endocrinology and Clinical Immunology, Nishinomiya, Japan
¹⁸Osaka Medical and Pharmaceutical University, Department of Internal Medicine (IV), Takatsuki, Japan
¹⁹Graduate School of Medicine, Hokkaido University, Division of Rheumatology, Endocrinology and Nephrology, Sapporo, Japan
²⁰Showa University School of Medicine, Division of Rheumatology, Department of Medicine, Shinagawa, Japan
²¹Tokyo Kyosai Hospital, Department of Rheumatology, Meguro, Japan
²²Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Department of Rheumatology, Bunkyo, Japan
²³Shinshu University School of Medicine, Department of Medicine (Neurology and Rheumatology), Matsumoto, Japan
²⁴Graduate School of Medical Science, Kanazawa University, Department of Rheumatology, Kanazawa, Japan
²⁵Faculty of Medicine, Tottori University, Division of Respiratory Medicine and Rheumatology, Department of Multidisciplinary Internal Medicine, Yonago, Japan
²⁶Tottori University, Division of Gastroenterology and Nephrology, Yonago, Japan
²⁷Sasebo Chuo Hospital, Rheumatic Disease Center, Sasebo, Japan
²⁸Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama, Japan
²⁹Tohoku University Graduate School of Medicine, Department of Hematology and Rheumatology, Sendai, Japan
³⁰Faculty of Medicine, Kagawa University, Division of Hematology, Rheumatology and Respiratory Medicine, Department of Internal Medicine, Kida-gun, Japan
³¹Teikyo University Chiba Medical Center, Division of Nephrology, Department of Internal Medicine, Ichihara, Japan
³²Faculty of Medicine, University of Tsukuba, Department of Rheumatology, Tsukuba, Japan
³³Shirakawa Satellite for Teaching And Research (STAR) Fukushima Medical University, Department of General Medicine, Shirakawa, Japan
³⁴University Hospital, Kyoto Prefectural University of Medicine, The Clinical and Translational Research Center, kyoto, Japan
³⁵Tokyo University of Pharmacy and Life Sciences, Department of Clinical Assessment, Hachioji, Japan

Background: Avacopan, the first orally active complement 5a receptor (C5aR) inhibitor, has emerged as a promising therapeutic option for ANCA-associated vasculitis (AAV). By selectively targeting C5aR, avacopan reduces neutrophil activation and vascular inflammation. ADVOCATE study have demonstrated that avacopan effectively induces and sustains remission in AAV while minimizing glucocorticoid-related toxicities [1]. Despite these promising results, the efficacy and safety of avacopan in real-world clinical settings remain unclear. Recent studies and case reports, have raised concerns regarding avacopan-induced severe liver injury, such as vanishing bile duct syndrome, particularly in Japan [2, 3].

Objectives: To assess the safety profile and incidence of adverse events associated with avacopan in AAV using data from a nationwide registry in Japan.

Methods: This multicenter retrospective cohort study analyzed data from the Japan Collaborative Registry of ANCA-Associated Vasculitis (J-CANVAS) between January 2017 and March 2023. Patients with granulomatosis with polyangiitis and microscopic polyangiitis (MPA), newly diagnosed or with severe relapse, were included. Disease classification followed the 2012 International Chapel Hill Consensus Conference definitions and the European Medicines Agency algorithm. Baseline clinical characteristics, including the Birmingham Vasculitis Activity Score (BVAS) 3.0, treatments, and prognoses (serious adverse events [SAEs], serious infections), were documented. The follow-up period ranged from the disease onset to death, loss to follow-up, severe relapse, or March 2024. Weighted Cox proportional hazard models were used to compare the risk of serious infections between the avacopan-treated and the non-avacopan-treated groups. The imbalance of clinical characteristics between the two groups was adjusted by overlap weighting with propensity scores calculated from age, sex, diagnosis, diabetes mellitus, smoking, pulmonary involvement, renal involvement, BVAS, C-reactive protein, intravenous cyclophosphamide use, rituximab use, methylprednisolone pulse use, the initial dose of prednisolone, and use of trimethoprim-sulfamethoxazole. The analysis employed the average treatment effect in the overlap population to estimate treatment effects and minimize comparison bias. After weighting, the balance in these variables was assessed by the standardized mean differences. We also collected data on SAEs associated with avacopan and analyzed the risk factors for avacopan-induced liver dysfunction in the avacopan-treated group. SAEs were defined as events leading to avacopan discontinuation, and serious infections were defined as those requiring or prolonging hospitalization. Baseline characteristics were compared using Wilcoxon’s rank-sum test for continuous variables and Fisher’s exact test for categorical variables between patients with and without SAEs. Kaplan-Meier analysis was performed to estimate SAE-free survival.

Results: Among 792 AAV patients, 67 received avacopan, including 18 as induction therapy. Other reasons for initiating avacopan included persistence or worsening of disease activity (27 cases) and elevated ANCA titers (12 cases). The baseline characteristics were summarized in Table 1. The avacopan-treated group had younger age (median: 71 vs. 75 years, p < 0.01), a higher proportion of relapse cases (15 [22.4%] vs. 85 [11.7%] cases, p = 0.019), less MPA cases (41 [61.2%] vs. 532 [73.4%] cases, p = 0.045), higher eGFR (67.31 vs. 53.42 mL/min/1.73 m², p = 0.012), higher BVAS (14.0 vs. 12.0, p = 0.041), and more rituximab use (31 [46.3%] vs. 215 [29.7%] cases, p = 0.008) than those of the non-avacopan-treated group. There were no significant differences in MPO-ANCA positivity (53 vs. 622 cases, p = 0.15). Serious infections occurred in 2 patients in the avacopan-treated group and 123 patients in the non-avacopan-treated group. The adjusted hazard ratio for the incidence of serious infections was comparable between the two groups (HR: 0.44, 95% CI: 0.11–1.76; Figure 1a). Twelve SAEs were identified in the avacopan-treated group, with liver dysfunction being the most common (8 cases). Kaplan-Meier analysis of SAE-free survival is shown in Figure 1b. Patients who developed avacopan-induced liver dysfunction were significantly older than those without avacopan-induced liver dysfunction (median: 75.5 vs. 69.0 years, p = 0.037).

Conclusion: This study provides real-world data on the safety profile of avacopan in Japanese patients with AAV. The risk of serious infections in the avacopan-treated patients was comparable to non-avacopan-treated patients. However, liver dysfunction emerged as the most frequent SAE of avacopan. Patients with liver dysfunction were older than patients without liver dysfunction. These findings highlight the importance of careful monitoring of liver function, especially in older patients receiving avacopan.

REFERENCES: [1] N Engl J Med. 2021;384:599-609.

[2] J Rheumatol. 2024;51:1146-1148.

[3] Rheumatology (Oxford). 2024:keae689.

Acknowledgements: NIL.

Disclosure of Interests: Tomohisa Uchida Asahi Kasei Pharma Co., Ltd., Chugai Pharmaceutical Co., Ltd, Mitsubishi-Tanabe Pharma Co., Shoichi Fukui: None declared , Kunihiro Ichinose Chugai, Nihon-Shinyaku, AbbVie, Asahi-Kasei Pharma, Astellas, AstraZeneca, Ayumi, Bristol Myers Squibb, Boehringer Ingelheim, Chugai, Eisai, Eli Lilly, Glaxo SmithKline, Nihon-Shinyaku, Otsuka Pharmaceutical, Pfizer, Taisho, Tanabe-Mitsubishi, UCB, Otsuka Pharmaceutical, Asahi-Kasei Pharma, Asahi-Kasei Pharma, Chugai, Otsuka, Japan Blood Products Organization, Hiroyuki Ide Eisai, Yoshika Tsuji: None declared , Toshimasa Shimizu: None declared , Masataka Umeda Otsuka Pharmaceutical Co., Ltd., AstraZeneca plc, AbbVie GK, Asahi Kasei Pharma Corporation, GlaxoSmithKline plc., Remi Sumiyoshi: None declared , Takashi Igawa: None declared , Tomohiro Koga: None declared , Shin-ya Kawashiri: None declared , Naoki Iwamoto: None declared , Mami Tamai: None declared , Tomoki Origuchi: None declared , Satoshi Omura Asahi Kasei, UCB Japan, Janssen, Daiki Nakagomi AbbVie, Asahi-Kasei Pharma, AstraZeneca, Chugai, Eisai, Novartis, Taisho, Taisho, Asahi-Kasei Pharma, Chugai, Yoshiyuki Abe Asahi-Kasei Pharma, Chugai, Eisai, Glaxo SmithKline, Kissei, Makoto Wada: None declared , Naoho Takizawa Chugai, AbbVie, Asahi-Kasei Pharma, Astellas, AstraZeneca, Boehringer Ingelheim, Chugai, Eisai, Eli Lilly, Glaxo SmithKline, Janssen, Pfizer, Taisho, Tanabe-Mitsubishi, UCB, Atsushi Nomura: None declared , Yuji Kukida AbbVie, Asahi Kasei Pharma, Boehringer Ingelheim, Chugai, Daiichi-Sankyo, Eisai, Mitsubishi Tanabe and Taisho, Naoya Kondo: None declared , Yamano Yasuhiko Boehringer Ingelheim、Bristol Myers Squibb、GlaxoSmithKline, Hirosuke Takagi Janssen, Kissei, Taisho, AbbVie, Asahi-Kasei Pharma, Astellas, Eli Lilly, Kissei, Tanabe-Mitsubishi, UCB, Koji Endo: None declared , Shintaro Hirata AbbVie, Asahi-Kasei Pharma, Astellas, AstraZeneca, Ayumi, Bristol Myers Squibb, Boehringer Ingelheim, Chugai, Daiichi-Sankyo, Eisai, Eli Lilly, Gilead Sciences, Glaxo SmithKline, Janssen, Nihon-Shinyaku, Novartis, Otsuka Pharmaceutical, Pfizer, Taisho, Tanabe-Mitsubishi, UCB, Eisai, Asahi-Kasei Pharma, Chugai, Otsuka, Taisho, Naoto Azuma: None declared , Tohru Takeuchi AbbVie, Asahi-Kasei Pharma, AstraZeneca, Boehringer Ingelheim, Chugai, Eisai, Eli Lilly, Glaxo SmithKline, Janssen, Nihon-Shinyaku, Otsuka Pharmaceutical, Taisho, Tanabe-Mitsubishi, Taisho, Asahi-Kasei Pharma, Chugai, Boehringer Ingelheim, Kazuro Kamada: None declared , Ryo Yanai: None declared , Yusuke Matsuo: None declared , Yasuhiro Shimojima: None declared , Ryo Nishioka Kissei Pharmaceutical Co., Ltd, Ryota Okazaki Eli Lilly, Asahi-Kasei Pharma, Tomoaki Takata Kyowa Kirin, Kyowa Kirin, Chugai Pharmaceutical, Mitsubishi Tanabe Pharma, Mayuko Moriyama Eisai, Eisai, Eli Lilly, Taisho, Tanabe-Mitsubishi, Ayuko Takatani: None declared , Yoshia Miyawaki: None declared , Tsuyoshi Shirai: None declared , Hiroaki Dobashi Abbvie, Eli Lilly, Astellas, Ayumi Pharmaceutical, Chugai Pharmaceutical, Eisai Pharmaceutical, Asahi Kasei Pharma, UCB Pharmaceutical, and KISSEI Pharmaceutical, Asahi Kasei Pharma, Chugai Pharmaceutical, and AbbVie Japan, Takafumi Ito: None declared , Isao Matsumoto: None declared , Toshihiko Takada: None declared , Toshiko Ito-Ihara: None declared , Takashi Kida: None declared , Nobuyuki Yajima: None declared , Takashi Kawaguchi: None declared , Yutaka Kawahito Pfizer Japan Inc., Asahi Kasei Pharma Co., Ltd., AbbVie Japan GK, Astellas Pharma Inc., AstraZeneca plc., Ayumi Pharmaceutical Co., Boehringer Ingelheim Japan, Inc., Bristol Myers Squibb Co., Ltd., Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., Daiichi Sankyo., GlaxoSmithKline K.K., Janssen Pharmaceutical K.K., Kissei Pharmaceutical Co., Ltd., Mitsubishi-Tanabe Pharma Co., Nippon Kayaku Co., Ltd., Novartis Pharma K.K., Pfizer Japan Inc., Taisho Toyama Pharmaceutical Co., Ltd., UCB Japan Co. Ltd. and Viatris Pharmaceuticals Japan Inc., Asahi KASEI Pharma Co., Ltd., Boehringer Ingelheim Japan, Inc., Chugai Pharmaceutical Co., and Eisai Co., Ltd., Atsushi Kawakami AbbVie, Asahi Kasei, Chugai, Eisai, Eli Lilly, ONO, Taisho, Boehringer Ingelheim, Pfizer, AbbVie, Asahi Kasei, AYUMI, Boehringer Ingelheim, Bristol-Myers Squibb, Celltrion, Chugai, Daiichi Sankyo, Gilead, Neopharma, ONO, Taisho.

© The Authors 2025. This abstract is an open access article published in Annals of Rheumatic Diseases under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ). Neither EULAR nor the publisher make any representation as to the accuracy of the content. The authors are solely responsible for the content in their abstract including accuracy of the facts, statements, results, conclusion, citing resources etc.

DOI: annrheumdis-2025-eular.B1196

Keywords: Safety, Observational studies/registry, Infection, Real-world evidence

Citation: , volume 84, supplement 1, year 2025, page 2361

Session: Vasculitis, small and medium size vessels (Publication Only)

version:	1.02