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A Randomized Clinical Trial of Anti–IL-6 Antibody Clazakizumab in Late Antibody-Mediated Kidney Transplant Rejection

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A Randomized Clinical Trial of Anti–IL-6 Antibody Clazakizumab in Late Antibody-Mediated Kidney Transplant Rejection CLINICAL RESEARCH www.jasn.org A Randomized Clinical Trial of Anti–IL-6 Antibody Clazakizumab in Late Antibody-Mediated Kidney Transplant Rejection Konstantin Doberer ,1 Michael Duerr,2 Philip F. Halloran,3 Farsad Eskandary,1 Klemens Budde,2 Heinz Regele,4 Jeff Reeve,3 Anita Borski,1 Nicolas Kozakowski ,4 Roman Reindl-Schwaighofer ,1 Johannes Waiser ,2 Nils Lachmann,5 Sabine Schranz,6 Christa Firbas,6 Jakob Mühlbacher,7 Georg Gelbenegger,6 Thomas Perkmann ,8 Markus Wahrmann ,1 Alexander Kainz,1 Robin Ristl,9 Fabian Halleck,2 Gregor Bond,1 Edward Chong,10 Bernd Jilma,6 and Georg A. Böhmig1 Due to the number of contributing authors, the affiliations are listed at the end of this article. ABSTRACT Background Late antibody-mediated rejection (ABMR) is a leading cause of transplant failure. Blocking IL-6 has been proposed as a promising therapeutic strategy. Methods We performed a phase 2 randomized pilot trial to evaluate the safety (primary endpoint) and efficacy (secondary endpoint analysis) of the anti–IL-6 antibody clazakizumab in late ABMR. The trial included 20 kidney transplant recipients with donor-specific, antibody-positive ABMR $365 days post-transplantation. Patients were randomized 1:1 to receive 25 mg clazakizumab or placebo (4-weekly subcutaneous injections) for 12 weeks (part A), followed by a 40-week open-label extension (part B), during which time all participants received clazakizumab. Results Five (25%) patients under active treatment developed serious infectious events, and two (10%) de- veloped diverticular disease complications, leading to trial withdrawal. Those receiving clazakizumab dis- played significantly decreased donor-specific antibodies and, on prolonged treatment, modulated rejection-related gene-expression patterns. In 18 patients, allograft biopsies after 51 weeks revealed a neg- ative molecular ABMR score in seven (38.9%), disappearance of capillary C4d deposits in five (27.8%), and resolution of morphologic ABMR activity in four (22.2%). Although proteinuria remained stable, the mean eGFR decline during part A was slower with clazakizumab compared with placebo (20.96; 95% confidence interval [95% CI], 21.96 to 0.03 versus 22.43; 95% CI, 23.40 to 21.46 ml/min per 1.73 m2 per month, re- spectively, P50.04). During part B, the slope of eGFR decline for patients who were switched from placebo to clazakizumab improved and no longer differed significantly from patients initially allocated to clazakizumab. Conclusions Although safety data indicate the need for careful patient selection and monitoring, our preliminary efficacy results suggest a potentially beneficial effect of clazakizumab on ABMR activity and progression. JASN 32: 708–722, 2021. doi: https://doi.org/10.1681/ASN.2020071106 Received July 31, 2020. Accepted November 10, 2020. Late antibody-mediated rejection (ABMR) is a common cause of kidney allograft failure.1 Its mo- Published online ahead of print. Publication date available at lecular mechanisms are increasingly understood, www.jasn.org. and diagnostic criteria have been refined continu- Correspondence: Dr. Georg A. Böhmig, Division of Nephrology ously.2,3 Treating late ABMR, however, remains a and Dialysis, Department of Medicine III, Medical University of Vienna, Währinger Gürtel 18–20, A-1090 Vienna, Austria, or Dr. Bernd Jilma, fi 4,5 signi cant challenge. Systematic trials have failed Department of Clinical Pharmacology, Medical University of Vienna, to demonstrate any benefit of therapies widely Währinger Gürtel 18–20, A-1090 Vienna, Austria. E-mail: georg. used for desensitization and acute ABMR, such as [email protected] or [email protected] rituximab plus intravenous Ig6 or bortezomib.7 Copyright © 2021 by the American Society of Nephrology 708 ISSN : 1046-6673/3203-708 JASN 32: 708–722, 2021 www.jasn.org CLINICAL RESEARCH Consequently, there is a high unmet need for an effective Significance Statement treatment.4,5 One promising therapeutic target is IL-6, a cytokine that is There is no proven effective treatment for a major cause of graft critically involved in the regulation of inflammation and im- failure, late antibody-mediated rejection, but IL-6, a cytokine known mune cell differentiation.8 Over the last decade, the concept of to promote B cell immunity, may be a promising therapeutic target. The authors describe the results of a phase 2 randomized clinical targeting IL-6 or its receptor (IL-6R) has entered clinical rou- trial involving 20 patients, designed to evaluate the safety (primary – tine, and is well established in rheumatoid arthritis.9 11 More endpoint) and efficacy (secondary endpoint analysis) of an anti–IL-6 recently, IL-6/IL-6R interference has also become of interest in antibody, clazakizumab, versus placebo in late antibody-mediated organ transplantation.8 An observational study evaluating rejection. Although the occurrence of serious infections and di- anti–IL-6R antibody tocilizumab in chronic ABMR has sug- verticulitis presented important safety signals, clazakizumab was associated with an early decrease in donor-specific antibody levels, gested stabilization of allograft function, presumably resulting modulated antibody-mediated rejection activity, and slowed the from reduced levels of donor-specific antibody (DSA).12,13 decline of renal function. Preliminary efficacy results suggest a po- The occurrence of graft losses in four recipients in whom to- tentially beneficial effect of clazakizumab and may therefore sup- cilizumab was prematurely stopped,12 however, suggested a port the design of larger trials with a longer duration of follow-up. rebound effect, triggered by IL-6 accumulated on treatment.14 Thus, the use of antibodies that directly neutralize IL-6 may be inclusion, and the study was conducted in accordance with of particular interest. International Council for Harmonisation of Technical Require- Clazakizumab is a humanized monoclonal IgG1 antibody ments for Pharmaceuticals for Human Use Good Clinical Prac- fi with high af nity for IL-6 and a long t1/2 of approximately 30 tice requirements, Good Laboratory Practice, the principles of days. This antibody has been systematically evaluated in rheu- the Declaration of Helsinki 2008, and the Declaration of Istan- 10,15 matoid and psoriatic arthritis, but has not yet been ap- bul. The trial was registered on the European Union Drug Reg- proved for clinical use. We designed this phase 2 pilot trial, the ulating Authorities Clinical Trials Database (2017–001604–30) first randomized controlled trial evaluating IL-6 signaling and ClinicalTrials.gov (NCT03444103). blockade in transplantation, to assess the safety and tolerabil- ity (primary endpoint) as well as efficacy (secondary endpoint Participants analysis) of clazakizumab in late ABMR. The trial was designed to include 20 patients (Figure 1, Supplemental Figure 1). Eligible participants were adult kid- . METHODS ney transplant recipients ( 18 years) with late active or chronic active ABMR $365 days after transplantation (with or without C4d deposits along the peritubular capillaries), Trial Oversight and Design associated with a molecular pattern of ABMR in gene array This investigator-driven, randomized, double-blind, placebo- analysis, preformed or de novo HLA class I and/or II DSA, and controlled, parallel-group phase 2 pilot trial was conducted at an eGFR (CKD Epidemiology Collaboration equation) two sites (Medical University of Vienna, Austria; Charité Uni- .30 ml/min per 1.73 m2.Exclusioncriteriawereage#18 versitätsmedizin Berlin, Germany) from January 2018 to April years, participation in another clinical trial, pregnancy or 2020 (recruitment period: January 2018 to April 2019). Details – fi of the protocol have been described previously.16 We hypoth- breastfeeding, T cell mediated rejection classi ed Banff grade $ esized that clazakizumab is a safe treatment to counteract I, de novo or recurrent severe thrombotic microangiopathy, ABMR progression. The study consisted of two parts polyoma virus nephropathy, de novo or recurrent GN, acute , (Supplemental Figure 1); a 12-week randomized placebo- rejection treatment 3 months before screening, acute dete- – controlled phase to decipher the short-term effects of treat- rioration of graft function (eGFR decline within 1 3 months . ment (part A), followed by a 40-week open-label extension 25%), nephrotic range proteinuria 3500 mg/g protein/ where all participants received clazakizumab (part B). The creatinine ratio, active viral, bacterial, or fungal infection pre- fi rationale behind this design was to offer all participants the cluding intensi ed immunosuppression, active malignant fi option of a potentially effective treatment. Furthermore, two disease precluding intensi ed immunosuppressive therapy, follow-up biopsies to analyze short- and intermediate-term abnormal liver-function tests (alanine aminotransferase, treatment effects were considered unacceptable for patients aspartate aminotransferase, bilirubin .1.53 upper limit of on long-term placebo treatment. The study was approved by normal), other significant liver disease, latent or active tuber- the institutional review board of the Medical University of culosis (positive QuantiFERON-TB-Gold test, chest x-ray), Vienna (EK1428/2017), the Berlin State Ethics Committee administration of a live vaccine within 6 weeks of screening, (17/0485– EK 15), and the regulatory authorities in Austria neutropenia (,1 G/L) or thrombocytopenia (,100 G/L), his- (Federal Office for Safety in Health Care, Austrian Agency for tory of gastrointestinal
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