SAD/MAD Safety and PK Study of RBN-3143 in Healthy and Atopic Dermatitis Subjects

Summary

RBN-3143 Background: PARP proteins are members of a family of seventeen ADP-ribosyltransferase (ART) enzymes that regulate cellular processes including gene expression, protein degradation, and multiple cellular stress responses. RBN-3143 is a PARP-14 inhibitor. PARP14 is over-expressed in tissues with inflammatory diseases. RBN-3143 is a novel, orally administered PARP14 inhibitor that was developed to be evaluated as therapy for a range of inflammatory diseases, with an initial focus on Atopic Dermatitis. Study Overview: The study consists of 2 parts. Part A: This part of the study is being conducted in a clinical research unit (CRU) and is enrolling healthy adult subjects to determine the safety of RBN-3143; its absorption, metabolism, and excretion (what the body does to this drug); and will assess its potential pharmacodynamic properties (what the drug does to the body). There are 3 subsections to this part of the study. The first segment was conducted in a double-blind manner (neither the investigator nor subject knew if placebo or RBN-3143 was given) to assess dosing regimens of RBN-3143 when taken in a fasted state (before food). The last two segments are currently recruiting and are Open Label (all subjects will receive RBN-3143) and will assess RBN-3143 when taken with food, with pantoprazole, a medication that decreases the amount of acid in the stomach, and with midazolam. Part B: In early 2023 the second part of the study will be conducted in patients with moderate to severe atopic dermatitis to measure the pharmacodynamic activity of RBN-3143 and evaluate preliminary efficacy of 28 days administration of the study drug. All patients will receive the same dose of RBN-3143.

Timeline

Start

2022-03-07

Primary completion

2024-06-30

Completion

2024-09-30

Publications

• Background Caprara G, Prosperini E, Piccolo V, Sigismondo G, Melacarne A, Cuomo A, Boothby M, Rescigno M, Bonaldi T, Natoli G. PARP14 Controls the Nuclear Accumulation of a Subset of Type I IFN-Inducible Proteins. J Immunol. 2018 Apr 1;200(7):2439-2454. doi: 10.4049/jimmunol.1701117. Epub 2018 Mar 2.
• Background Cho SH, Raybuck A, Wei M, Erickson J, Nam KT, Cox RG, Trochtenberg A, Thomas JW, Williams J, Boothby M. B cell-intrinsic and -extrinsic regulation of antibody responses by PARP14, an intracellular (ADP-ribosyl)transferase. J Immunol. 2013 Sep 15;191(6):3169-78. doi: 10.4049/jimmunol.1301106. Epub 2013 Aug 16.
• Background Cohen MS, Chang P. Insights into the biogenesis, function, and regulation of ADP-ribosylation. Nat Chem Biol. 2018 Feb 14;14(3):236-243. doi: 10.1038/nchembio.2568.
• Background Goenka S, Boothby M. Selective potentiation of Stat-dependent gene expression by collaborator of Stat6 (CoaSt6), a transcriptional cofactor. Proc Natl Acad Sci U S A. 2006 Mar 14;103(11):4210-5. doi: 10.1073/pnas.0506981103. Epub 2006 Mar 6.
• Background He H, Bissonnette R, Wu J, Diaz A, Saint-Cyr Proulx E, Maari C, Jack C, Louis M, Estrada Y, Krueger JG, Zhang N, Pavel AB, Guttman-Yassky E. Tape strips detect distinct immune and barrier profiles in atopic dermatitis and psoriasis. J Allergy Clin Immunol. 2021 Jan;147(1):199-212. doi: 10.1016/j.jaci.2020.05.048. Epub 2020 Jul 21.
• Background Iwata H, Goettsch C, Sharma A, Ricchiuto P, Goh WW, Halu A, Yamada I, Yoshida H, Hara T, Wei M, Inoue N, Fukuda D, Mojcher A, Mattson PC, Barabasi AL, Boothby M, Aikawa E, Singh SA, Aikawa M. PARP9 and PARP14 cross-regulate macrophage activation via STAT1 ADP-ribosylation. Nat Commun. 2016 Oct 31;7:12849. doi: 10.1038/ncomms12849.
• Background Mehrotra P, Hollenbeck A, Riley JP, Li F, Patel RJ, Akhtar N, Goenka S. Poly (ADP-ribose) polymerase 14 and its enzyme activity regulates T(H)2 differentiation and allergic airway disease. J Allergy Clin Immunol. 2013 Feb;131(2):521-31.e1-12. doi: 10.1016/j.jaci.2012.06.015. Epub 2012 Jul 25.
• Background Mehrotra P, Krishnamurthy P, Sun J, Goenka S, Kaplan MH. Poly-ADP-ribosyl polymerase-14 promotes T helper 17 and follicular T helper development. Immunology. 2015 Dec;146(4):537-46. doi: 10.1111/imm.12515. Epub 2015 Sep 28.
• Background Vyas S, Chesarone-Cataldo M, Todorova T, Huang YH, Chang P. A systematic analysis of the PARP protein family identifies new functions critical for cell physiology. Nat Commun. 2013;4:2240. doi: 10.1038/ncomms3240.

Drugs

Indications