Dapansutrile (lab code: OLT1177®) exhibits exceptional attributes as a pharmaceutical product, most notably: compelling nonclinical efficacy and clinical benefit, no observed human toxicity, an attractive pharmacokinetic profile and cost of goods.
Dapansutrile's Clean Safety Profile
In all six completed clinical trials to date, Olatec has demonstrated a remarkably clean safety profile.
Dapansutrile's Clinical Experience to date
Acute Gouty Arthritis
Acute Gout Flares is a prototypical NLRP3 mediated disease, therefore it was chosen as the first Phase 2 proof of concept, proof of mechanism trial.
It is widely understood that Interleukin (IL)-1β is the pivotal cytokine in gouty inflammation and that NLRP3-dependent IL-1β release is the causative agent mediating the symptoms of acute gout flares. Recurrent autoinflammatory episodes are driven by a hyperuricemia-associated activation of the NLRP3 inflammasome due to deposited monosodium urate (MSU) crystals. In an acute gout flare, MSU crystals induce a variety of inflammatory cytokines and chemokines, including IL-1β and IL-6. For prompt and effective control of the clinical signs and symptoms in subjects with an acute gout flare, therapeutic agents are required to rapidly and significantly reduce or eliminate the acute inflammatory response. Furthermore, gouty arthritis flares contribute to increased synovial fluid neutrophils in affected joints – a process that is mediated by the NLRP3 inflammasome and pro-inflammatory cytokines, primarily IL-1 (Martinon 2006; Pope and Tschopp 2007; Hoffman and Wanderer 2010).
In a Phase 2a trial (Study OLT1177-05), in which oral dapansutrile was tested in patients with acute gout flares, the study met its primary and secondary endpoints. The trial represents the first known selective NLRP3 inhibitor to demonstrate clinical benefit, safety and a reduction in systemic inflammation. See publication "Dapansutrile, an oral selective NLRP3 inflammasome inhibitor, for treatment of gout flares: an open-label, dose-adaptive, proof-of-concept, phase 2a trial" in The Lancet Rheumatology which presents the results of the trial.
Based on the positive results from this study, the Company is preparing to launch its next Phase 2 trial.
Subjects with heart failure (HF), as well as those with gout and many other diseases, have a persistent underlying pro-inflammatory pathology that both derives from and perpetuates enhanced IL-1β activity, a result mediated by the NLRP3 inflammasome. Specifically, in cardiovascular disease, IL-1β has been identified as a cause of reversible cardiac dysfunction in HF, and processing of IL-1β via the NLRP3 inflammasome and the downstream signaling via IL‑1R are associated with the development of coronary heart disease, myocardial remodeling and HF. After IL-1β blockade, subjects with ST-segment elevation AMI have shown a signal for reduced incidence of HF (Abbate 2010) and subjects with symptomatic heart failure have demonstrated signals of improved exercise capacity (Van Tassell 2016).
In a Phase 1b trial (Study OLT1177-06) in patients with clinically stable systolic HF, the safety and tolerability of dapansutrile was established in subjects with stable systolic HF symptomatic for NYHA functional classification II-III and left ventricular ejection fraction (LVEF) ≤40% in Study OLT1177-06. The outcomes of the trial showed dapansutrile had no safety concerns or adverse consequences on any of the cardiac parameters tested, including no adverse clinically significant alterations were noted for blood pressure, heart rate, body weight, creatinine clearance or peak oxygen uptake during exercise testing. In the high dose cohort, several indicators of improved cardiovascular function were observed; a significant improvement in both LVEF and cardiopulmonary exercise time were observed. Moreover, in the pooled group of subjects with a medical history of diabetes, a statistically significant decrease in mean fasting glucose was observed after the 14-day Treatment Period.
Rare Disease (program ongoing)
Olatec has completed two placebo-controlled Phase 2 studies with the topical formulation of dapansutrile in patients with osteoarthritis (OA). In two Phase 2 studies, topically applied dapansutrile demonstrated a reduction of pain associated with inflammation that significantly exceeded the Minimal Clinically Important Improvement (MCII) as established in the literature (Tubach 2012). In both studies, the reduction of pain was most pronounced in the subset of subjects with more severe and advanced OA. In all three studies, dapansutrile exhibited a remarkably clean safety profile.
Other Disease Indications Currently in Preclinical Development for Dapansutrile
Several preclinical studies are ongoing in translational animal models to establish the disease-modifying activity of dapansutrile in a number of other conditions that have been established as IL-1β mediated diseases