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

David Kavanagh; Larry A Greenbaum; Arvind Bagga; Rajeshri G Karki; Chien-Wei Chen; Sajita Vasudevan; Alan Charney; Marion Dahlke; Fadi Fakhouri

doi:10.1016/j.ekir.2023.04.029

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

Kidney Int Rep. 2023 Apr 29;8(7):1332-1341. doi: 10.1016/j.ekir.2023.04.029. eCollection 2023 Jul.

Authors

David Kavanagh¹, Larry A Greenbaum², Arvind Bagga³, Rajeshri G Karki⁴, Chien-Wei Chen⁴, Sajita Vasudevan⁵, Alan Charney⁴, Marion Dahlke⁶, Fadi Fakhouri⁷

Affiliations

¹ National Renal Complement Therapeutics Centre, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK, and Complement Therapeutics Research Group, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK.
² Division of Pediatric Nephrology, Emory School of Medicine and Children's Healthcare of Atlanta, Atlanta, Georgia, USA.
³ Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India.
⁴ Clinical Development and Analytics Group, Cardiovascular, Renal and Metabolism Development Unit, Novartis Pharma, East Hanover, New Jersey, USA.
⁵ Chief Medical Office and Patient Safety, Novartis Healthcare, Hyderabad, India.
⁶ Clinical Development and Analytics Group, Cardiovascular, Renal and Metabolism Development Unit, Novartis Pharma, Basel, Switzerland.
⁷ Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland.

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 = 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.

Keywords: Factor B; LNP023; aHUS; alternative pathway; atypical hemolytic uremic syndrome; iptacopan.