european crystal network workshop

    Olt1177™, an oral nlrp3 inflammasome inhibitor, inhibits acute joint inflammation and circulating il-1β during gout flares in humans


    V. Klück 1, T. Jansen 2, M. Janssen 2, I. W. Tengesdal 1,4, K. Schraa 1, D. B. Skouras 3, C. Marchetti 4, C. A. Dinarello 1,4 and L. A.B. Joosten 1,5

    ¹ Department of Internal Medicine, Radboudumc, Nijmegen, Nl, ² Department of Rheumatology, Viecuri Mc, Venlo, Nl, ³ Olatec Therapeutics Llc, New York, Ny, Usa, 4 Department of Medicine, University of Colorado, Aurora, Co, Usa 5 Department of Medical Genetics, “Iuliu Haţieganu” University of Medicine and Pharmacy, Cluj Napoca, Romania.


    Background: Gout flares are characteristically mediated by the pro-inflammatory cytokine interleukin
    (IL)-1β [1]. Uptake of monosodium urate (MSU) crystals by macrophages activates the nucleotide-binding domain and leucine-rich repeat containing family, pyrin domain containing 3 (NLRP3) inflammasome, which converts intracellular pro-interleukin-1β (pro-IL-1β) to mature bioactive IL-1β by proteolytic cleavage. Deposition of MSU crystals alone is not sufficient to trigger a gout flare. In the presence of concomitant pro-inflammatory stimuli, i.e., Toll-Like Receptor (TLR) agonists, transcription of IL-1β gene is induced and pro-IL-1β is rapidly converted into its active form.  IL-1β binds to its receptor (IL-1R1) and induces a cascade of secondary inflammatory mediators including prostaglandins, cytokines and chemokines. Recently, OLT1177™, a β-sulfonyl nitrile compound, safe in humans, was shown to inhibit the NLRP3 inflammasome, reverse the metabolic cost of inflammation and inhibit joint inflammation in murine models of acute
    arthritis [2, 3].

    Objectives: To explore the mechanism by which oral OLT1177™ inhibits joint inflammation in humans with gout flares.

    Methods: 26 patients with a gout flare were treated within 4 days after the start of the symptoms with three different doses of OLT1177™ for 7 days (EudraCT: 2016-000943-14; study ongoing). Blood was drawn at baseline, days 3, 7 and 14 (7 days after finishing treatment). Haematology, hsCRP and SAA were measured as markers for systemic inflammation. Plasma was collected for assessment of circulating cytokines. Peripheral blood mononuclear cells (PBMCs) were isolated and cultured under unstimulated or stimulated conditions with a TLR ligands (Pam3Cys and LPS) in combination with MSU crystals after which intra- and extracellular cytokine production was assessed.

    Results: Plasma IL-1β and IL-6 levels are increased in samples from intercritical gout patients and individuals with gout flares when compared to healthy controls (healthy controls < intercritical gout < gout flares). Haematology, hsCRP and SAA of individuals treated with OLT1177™ during a gout flare show a dose-dependent reduction during course of treatment. Circulating IL-1β and IL-6, but not TNF-a were reduced and stimulated cytokine production of PBMCs declined during treatment. In unstimulated PBMCs on day 3, ratio of intracellular pro-IL-1β and IL-1β revealed inhibition of the NLRP3 inflammasome by oral OLT1177™ treatment.

    Discussion: Oral OLT1177™, safe in humans, inhibits IL-1β production and inflammation in patients with an acute gout flare by inhibiting the NLRP3 inflammasome. OLT1177™ has great therapeutic potential in a broad range of IL-1β mediated diseases.

    Keywords: gout flare, therapeutics, NLRP3 inflammasome

    References: 1. Dinarello, C.A. How interleukin-1β induces gouty arthritis. Arthritis Rheum 2010. 62(11):3140-4.  2. Marchetti, C., et al., OLT1177, a β-sulfonyl nitrile compound, safe in humans, inhibits the NLRP3 inflammasome and reverses the metabolic cost of inflammation. Proc Natl Acad Sci USA 2018. 115(7):E1530-E1539.   3. Marchetti, C., et al., NLRP3 inflammasome inhibitor OLT1177 suppresses joint inflammation in murine models of acute arthritis. Arthritis Res Ther 2018. 20(1):169.