Iptacopan (LNP023) is a highly selective small-molecule inhibitor of factor B (FB) with an IC₅₀ of 10nM and a KD of 7.9nM. Iptacopan competitively binds to FB, thereby inhibiting the formation and activation of the alternative pathway C3 convertase (C3bBb). Iptacopan has been approved by the FDA, NMPA, and other regulatory agencies for the treatment of paroxysmal nocturnal hemoglobinuria (PNH), for reducing proteinuria in adult patients with C3 glomerulopathy (C3G), and for reducing proteinuria in primary IgA nephropathy (IgAN), as well as being studied in other complement-mediated diseases[1-4].
In vivo, Iptacopan (20, 60, or 180mg/kg; twice daily) was administered via oral gavage to C57BL/6 mice in an arthritis model for 6 consecutive days. Iptacopan significantly reduced the overall clinical scores for joint swelling, suppressed the levels of complement activation products Ba, C3d, and C5a in joint tissue, and blocked joint inflammatory cell infiltration, bone erosion, and proteoglycan loss[5]. From gestation days 6 to 17, Iptacopan (100–1000mg/kg/day) was administered via oral gavage to pregnant rats. Iptacopan caused no maternal adverse effects. At 1000mg/kg/day, Iptacopan resulted in one fetus (out of 22 newborn fetuses) developing a benign cyst in the left parietal region of the scalp, but there was no effect on the skeleton (skull), central nervous system (brain), or any other head structure[6].
References:
[1] Syed YY. Iptacopan: First Approval. Drugs. 2024 May;84(5):599-606.
[2] de Castro CM, Patel BJ. Iptacopan for the treatment of paroxysmal nocturnal hemoglobinuria. Expert Opin Pharmacother. 2024 Dec;25(18):2331-2339.
[3] Mainolfi N, Ehara T, Karki RG, et al. Discovery of 4-((2S,4S)-4-Ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)benzoic Acid (LNP023), a Factor B Inhibitor Specifically Designed To Be Applicable to Treating a Diverse Array of Complement Mediated Diseases. J Med Chem. 2020 Jun 11;63(11):5697-5722.
[4] Mastellos DC, Reis ES, Yancopoulou D, et al. Expanding Complement Therapeutics for the Treatment of Paroxysmal Nocturnal Hemoglobinuria. Semin Hematol. 2018 Jul;55(3):167-175.
[5] Schubart A, Anderson K, Mainolfi N, et al. Small-molecule factor B inhibitor for the treatment of complement-mediated diseases. Proc Natl Acad Sci U S A. 2019 Apr 16;116(16):7926-7931.
[6] Anthony DeLise, Natasa Zamurovic, Regine Hansen, et al. Results of Preclinical Animal Studies to Evaluate the Effect of Iptacopan on Pregnancy-Related Outcomes. Blood. 2023 Nov 142(1):4094.