P160 The first phase 2A proof-of-concept study of a selective NLRP3 inflammasome inhibitor, dapansutrile™ (OLT1177™), in acute gout
Authors: TL Jansen, V Klück, M Janssen, A Comarniceanu, M Efdé, CL Scribner, RB Barrow, DB Skouras, CA Dinarello, LA Joosten
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Career situation of first and presenting author</h3> Young investigator. <h3>Introduction</h3> Acute gout is a severe debilitating type of arthritis that is treated in the acute phase with potent anti-inflammatory drugs. To date, prednisolone, colchicine and/or non-steroidal anti-inflammatory drugs are the standard of care despite serious side effects of chronic use, especially in the older population most often presenting with an acute gout attack. In addition, interleukin-1 (IL-1) biologics (e.g., canakinumab/rilonacept/ anakinra) have proven efficacy in RCTs, however, these biologics have not been broadly adopted due to barriers such as the requirement of parenteral administration, cost and risk of infection. There is an unmet need for a safe, oral, cost effective IL-1 inhibitor targeting the NLRP3 inflammasome pathway. Dapansutrile™ (OLT1177™) has been shown to inhibit IL-1β and IL-18 release in human macrophages and to prevent NLRP3 inflammasome activation, with no effect on the priming phase of the NLRP3 inflammasome formation or on TNF-alpha. Dapansutrile™ has no effect on the AIM2 or NLRC4 inflammasomes. In addition to acute gout, dapansutrile™ is under clinical development in heart failure and it has demonstrated positive results in numerous preclinical models. Dapansutrile's™ Phase 1 dose escalation clinical trial demonstrated safety at doses up to 1000 mg/day for 8 days. <h3>Objectives</h3> The Phase 2a study is a dose ranging, proof-of-concept trial to demonstrate the clinical effectiveness, pharmacodynamics (e.g., cytokine levels and other relevant biomarkers), safety/tolerability and pharmacokinetics of dapansutrile™ in four cohorts at doses of 100 mg QD, 300 mg QD, 500 mg BID or 500 mg QID. <h3>Methods</h3> An adaptive dose design was used with planned enrollment of 8 patients per cohort to assess the efficacy of dapansutrile™ in treating the clinical signs and symptoms of acute gout over an 8 day treatment period. Clinical effect was targeted to be greater than 50% pain reduction from baseline at approximately 72 hours after the first dose. Cohorts 1, 2 and 3 were administered dapansutrile™ doses of 500 mg BID, 500 mg QID and 300 mg dapansutrile™ (200 mg at 08.00 hour and 100 mg at 20.00 hour), respectively. Cohort 4 is currently enrolling subjects given 100 mg dapansutrile™ QD. VAS pain, general disability and walking disability scores were measured by daily diary and blood sampling was conducted on study days 0 (baseline), 3, 7 and 14 to assess PK and PD (including plasma cytokine levels, hsCRP, inflammasome activity, etc). Safety was measured over the duration of the study with clinic visits on study days 0 (baseline), 3, 7, 14 and a follow-up telephonic visit on day 35. <h3>Results</h3> A significant clinical and inflammatory cytokine response at Day 3 was seen in all dose groups and will be elaborated upon once the final datasets become available. There were no metabolic, physiological or hematological changes and all doses were well tolerated. <h3>Conclusions</h3> On the basis of both the clinical response and the biomarkers, dapansutrile™ is a safe and effective anti-inflammatory oral NLRP3 inhibitor in the treatment of acute gout with a broad therapeutic range and promise for further clinical development in this indication. <h3>Acknowledgements</h3> We wish to acknowledge the gout patients willing to participate as well as Daniëlle Poeth and Dorine Baselmans for their commitment to the conduct of this study. <h3>Potential investigators conflicts of interest</h3> DS is founder and CEO of Olatec, CS is CMO of Olatec, RB is COO of Olatec, CD is CSO and SAB member of Olatec, LJ is SAB member of Olatec. <h3>Disclosure of Interest</h3> None declared.