OVERVIEW

PRODUCT INFORMATION

REPRESENTATIVE TRADE NAMES

Avacopan – Tavneos®

DRUG CLASS

Immunosuppressive Agents

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

CHEMICAL FORMULA AND STRUCTURE

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DRUG	CAS REGISTRY NUMBER	MOLECULAR FORMULA	STRUCTURE
Avacopan	1346623-17-3	C33-H35-F4-N3-O2

ANNOTATED BIBLIOGRAPHY

References updated: 15 October 2024

Abbreviations: ANCA, Antineutrophil cytoplasmic autoantibody; C5aR, complement factor 5a receptor.

• Zimmerman HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott, 1999.

  (Review of hepatotoxicity published in 1999 before the availability of complement receptor antagonists).
• FDA. Multidiscipline Review. 2021.
• https://www​.accessdata​.fda.gov/drugsatfda_docs​/nda/2021/214487Orig1s000MultidisciplineR.pdf

  (FDA website with product label and clinical review of data on avacopan provided by the sponsor in support of its approval as therapy of ANCA-associated vasculitis, mentions that in a pooled analysis of safety in 237 patients, hepatobiliary adverse events arose in 6% vs 1.8%, which were severe in 3.6% vs 0.6% and led to early discontinuation in 3% vs 0.6%. Of 9 hepatic severe adverse events analyzed in detail, 4 were considered drug induced liver injury, but none resulted in death or liver transplantation).
• Jayne DRW, Bruchfeld AN, Harper L, Schaier M, Venning MC, Hamilton P, Burst V, Get al.; CLEAR Study Group. Randomized trial of C5a receptor inhibitor avacopan in ANCA-associated vasculitis. J Am Soc Nephrol. 2017;28:2756-2767. [PMC free article: PMC5576933] [PubMed: 28400446]

  (Among 67 patients with newly diagnosed or relapsed ANCA-associated vasculitis treated with avacopan alone, avacopan with prednisone [20 mg], or placebo with prednisone [60 mg] daily for 12 weeks, clinical responses were higher with avacopan [81% and 86% vs 70%], while total adverse event rates were similar, and ALT elevations above 3 times ULN occurred in 5% of all three groups, one patient on avacopan alone developed marked liver and pancreatic enzyme elevations requiring discontinuation).
• Merkel PA, Niles J, Jimenez R, Spiera RF, Rovin BH, Bomback A, Pagnoux C, et al.; CLASSIC Investigators. Adjunctive treatment with avacopan, an oral C5a receptor inhibitor, in patients with antineutrophil cytoplasmic antibody-associated vasculitis. ACR Open Rheumatol. 2020;2:662-671. [PMC free article: PMC7672305] [PubMed: 33128347]

  (Among 42 patients with ANCA-associated vasculitis treated with standard of care [rituximab or cyclophosphamide] and avacopan [10 or 30 mg] or placebo twice daily for 12 weeks, response rates were high in all three groups [92% and 80% vs 85%], and adverse event rates were similar in the avacopan and placebo groups, including infections [24% vs 15%], severe adverse events [17% vs 15%], and discontinuations because of adverse events [14% vs 15%]; no mention of ALT elevations or hepatotoxicity).
• Jayne DRW, Merkel PA, Schall TJ, Bekker P; ADVOCATE Study Group. Avacopan for the treatment of ANCA-associated vasculitis. N Engl J Med. 2021;384:599-609. [PubMed: 33596356]

  (Among 331 adults with ANCA-associated vasculitis treated with avacopan [30 mg] twice daily vs a tapering dose regimen of prednisone [both groups also received rituximab or cyclophosphamide], the sustained remission rate at 52 weeks was 66% vs 55%, with serious adverse event rates of 37% vs 39%, including serious infections in 13% vs 15% [including a case of reactivation of hepatitis B], and serious liver related adverse events in 5.4% vs 3.7%, all of which resolved upon stopping).
• Lee A. Avacopan: first approval. Drugs. 2022;82:79-85. [PubMed: 34826105]

  (Review of the mechanism of action, history of development, pharmacology, clinical efficacy, and safety of avacopan shortly after its initial approval as therapy of ANCA-associated vasculitis mentions that serious cases of hepatotoxicity have been reported, although in preregistration clinical trials hepatic adverse events occurred in 13% on avacopan vs 12% on corticosteroids which were considered severe in 5.4% vs 3.7%; at least two cases of reactivation of hepatitis B has been reported in treated patients, although both had received other agents known to be associated with reactivation [cyclophosphamide and rituximab as well as corticosteroids]).
• van Leeuwen JR, Popov T, Obergfell A, Rabelink TJ, Teng YKO. Preliminary assessment of safety and tolerability of avacopan during the early access program for ANCA-associated vasculitis. Biologics. 2023;17:11-14. [PMC free article: PMC9884459] [PubMed: 36721867]

  (Among 30 patients with ANCA-associated vasculitis treated with avacopan [30 mg twice daily] in a European early access program for an average of 12 months, 24 adverse events were reported occurring in 8 patients including 15 serious adverse events in 5 patients, the events were largely renal dysfunction and infections, and none were hepatic).
• Kojima K, Fukui S, Tanigawa M, Sumiyoshi R, Koga T, Shimakura A, Okano S, Kawakami A. Severe prolonged liver abnormality with jaundice during treatment for granulomatosis with polyangiitis with rituximab and avacopan. Rheumatology (Oxford). 2024;63:e101-e103. [PubMed: 37740250]

  (76 year old Japanese woman with ANCA-associated granulomatosis with polyangiitis treated with rituximab and avacopan for 4 weeks developed jaundice [bilirubin 2.2 rising to 14 mg/dL, ALT to 395 U/L, Alk P to 686 U/L], with biopsy showing bland cholestasis with focal necrosis and with prolonged jaundice and persistent Alk P elevations).
• Yamaguchi S, Yamazaki M, Kido T, Hounoki H, Muraishi N, Tajiri K, Tanaka S, et al. A case of vanishing bile duct syndrome during treatment of microscopic polyangiitis with avacopan. Rheumatology (Oxford). 2024;63:e120-e122. [PubMed: 37307092]

  (75 year old Japanese woman with ANCA-associated microscopic polyangiitis developed jaundice 45 days after starting avacopan [bilirubin 7.7 rising to 26.0 mg/dL, ALT 565 U/L, GGT 654 U/L], improving gradually after stopping, liver biopsy showing bile duct paucity, remaining jaundiced with GGT elevations for more than 5 months).
• Zonozi R, Aqeel F, Le D, Cortazar FB, Thaker J, Zabala Ramirez MJ, Sattui Cortes SE, et al. Real-world experience with avacopan in antineutrophil cytoplasmic autoantibody-associated vasculitis. Kidney Int Rep. 2024;9:1783-1791. [PMC free article: PMC11184253] [PubMed: 38899183]

  (Among 92 patients with ANCA-associated vasculitis treated with avacopan for 52 weeks in 12 US medical centers, clinical responses were achieved in 84%, and 18 patients (20%) discontinued therapy early because of adverse events including 4 for elevations in serum aminotransferase levels which were above 3 times ULN in 2, all of which resolved after stopping).
• Miao S, Suso P, Furst JA, Hudson MG, Trivedi A. Effect of mild or moderate hepatic impairment on the pharmacokinetics of avacopan, a small-molecule complement C5a receptor antagonist, for the treatment of antineutrophil cytoplasmic autoantibody-associated vasculitis. Clin Pharmacol Drug Dev. 2024;13:1000-1010. [PubMed: 38993026]

  (Among 24 volunteers undergoing a single dose pharmacokinetic study of avacopan [30 mg], peak plasma levels and area under the curve of plasma levels were similar in 8 healthy controls, 8 persons with mild [Child-Pugh Class A] and 8 with moderate [Class B] hepatic dysfunction suggesting that dose adjustment is not necessary for mild-to-moderate hepatic dysfunction).
• Uchida T, Fukui S, Iwamoto N, Umetsu A, Okamoto M, Fujikawa K, Mizokami A, et al. Absence of glucocorticoids concomitant with avacopan and subsequent liver injury in antineutrophil cytoplasmic antibody-associated vasculitis. 2024;51:1146-1148. [PubMed: 39147418]

  (Among 36 Japanese adults with ANCA-associated polyangiitis treated with avacopan, 6 developed aminotransferase elevations [peak values 149 to 624 U/L], 2 with concurrent bilirubin elevations [peak levels 14.1 and 14.9 mg/dL] which resolved after stopping therapy; corticosteroid therapy was less frequent in those with liver injury [50% vs 90%] and none had received intravenous steroids [0% vs 43%], suggesting that concurrent corticosteroid therapy may ameliorate or prevent avacopan hepatic injury).
• Nishino T, Tomori S, Haruyama M, Takahashi K, Mimaki M. A case of rapid avacopan-induced liver injury in pediatric granulomatosis with polyangiitis. Pediatr Nephrol. 2024;39:2919-2922. [PubMed: 38619581]

  (A 10 year old Japanese boy with granulomatosis and polyangiitis developed liver test abnormalities 31 days after starting rituximab [375 mg/m² every 7 days] and avacopan [30 mg twice daily] that followed methylprednisolone pulse therapy [bilirubin 0.6 mg/dL, ALT 1145 U/L, GGT 616 U/L, INR 0.9], which resolved after stopping therapy and with prednisone and ursodiol therapy).
• Bomback AS, Herlitz LC, Kedia PP, Petersen J, Yue H, Lafayette RA. Safety and efficacy of avacopan in patients with C3 glomerulopathy: randomized, double-blind clinical trial. J Am Soc Nephrol. 2024 Oct 11. Epub ahead of print. [PubMed: 39392695]

  (Among 57 patients with complement 3 [C3] glomerulopathy treated with avacopan [30 mg] or placebo twice daily for 52 weeks, there were no differences between the 2 groups in renal function or histologic outcomes, total adverse event rates [93% vs 86%], liver related events, and changes in chemistry laboratory values).