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Design and Rationale of the APPELHUS Phase 3 Open-Label Study of Factor B Inhibitor Iptacopan for Atypical Hemolytic Uremic Syndrome

Lookup NU author(s): Professor David KavanaghORCiD

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

Introduction: Atypical hemolytic uremic syndrome (aHUS) is a rare, progressive, and life-threatening form of thrombotic microangiopathy (TMA) which is caused by dysregulation of the alternative complement pathway (AP). Complement inhibition is an effective therapeutic strategy in aHUS, though current therapies require intravenous administration and increase the risk of infection by encapsulated organisms, including meningococcal infection. Further studies are required to define the optimal duration of existing therapies, and to identify new agents that are convenient for long-term administration. Iptacopan (LNP023) is an oral, first-in-class, highly potent, proximal AP inhibitor that specifically binds factor B (FB). In phase 2 studies of IgA nephropathy, paroxysmal nocturnal hemoglobinuria, and C3 glomerulopathy, iptacopan inhibited the AP, showed clinically relevant benefits, and was well tolerated. Iptacopan thus has the potential to become an effective and safe treatment for aHUS, with the convenience of oral administration. Methods: Alternative Pathway Phase III to Evaluate LNP023 in aHUS (APPELHUS; NCT04889430) is a multicenter, single-arm, open-label, phase 3 study to evaluate the efficacy and safety of iptacopan in patients (N ¼ 50) with primary complement-mediated aHUS naïve to complement inhibitor therapy (including anti-C5). Eligible patients must have evidence of TMA (platelet count <150  109 /l, lactate dehydrogenase $1.5  upper limit of normal, hemoglobin # lower limit of normal, serum creatinine $ upper limit of normal) and will receive iptacopan 200 mg twice daily. The primary objective is to assess the proportion of patients achieving complete TMA response without the use of plasma exchange or infusion or anti-C5 antibody during 26 weeks of iptacopan treatment. Conclusion: APPELHUS will determine if iptacopan is safe and efficacious in patients with aHUS


Publication metadata

Author(s): Kavanagh D, Greenbaum LA, Bagga A, Karki RJ, Chen CW, Vasudevan S, Charney A, Dahlke M, Fakhouri F

Publication type: Article

Publication status: Published

Journal: Kidney International Reports

Year: 2023

Volume: 8

Issue: 7

Pages: 1332-1341

Print publication date: 01/07/2024

Online publication date: 29/04/2023

Acceptance date: 24/04/2023

Date deposited: 04/06/2023

ISSN (electronic): 2468-0249

Publisher: Elsevier Inc.

URL: https://doi.org/10.1016/j.ekir.2023.04.029

DOI: 10.1016/j.ekir.2023.04.029


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Funding

Funder referenceFunder name
Novartis Pharma AG

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