medwireNews: Findings from a proof-of-concept phase 2a trial provide preliminary evidence to suggest that dapansutrile, an inhibitor of the NLRP3 inflammasome, may be a promising therapeutic option for gout flares.
“Gout flares are driven by uptake of deposited monosodium urate crystals by macrophages and consequent activation of the NLRP3 inflammasome,” leading to “maturation of interleukin (IL)-1β, which causes fulminant joint inflammation,” explain the study authors.
They add that previous studies have demonstrated “that dapansutrile is an NLRP3 inhibitor that reduces IL-1β generation, and that it has pre-clinical and early clinical promise as an oral treatment for gout flares.”
The current open-label phase 2a trial included 29 adults with monosodium urate crystal-proven monoarticular gout flare who were given once-daily oral dapansutrile at a dose of 100 mg, 300 mg, 1000 mg, or 2000 mg.
Tim Jansen (VieCuri Medical Center, Venlo, the Netherlands) and co-investigators report in The Lancet Rheumatology that target joint pain “markedly decreased” from baseline to days 3 and 7 in all four dose groups, with no significant between-group differences.
Specifically, patient-reported pain as measured on a visual analog scale was reduced by an average of 52.4% from baseline to day 3 for participants given the 100 mg dose, and by 68.4%, 55.8%, and 57.6% for those in the 300 mg, 1000 mg, and 2000 mg groups, respectively. The corresponding pain reductions from baseline to day 7 were 82.1%, 84.2%, 68.9%, and 83.9%.
While these results were similar across the dose groups, Jansen and colleagues note that only half of the eight patients in the lowest dose group achieved a 50% or greater reduction in pain by day 3, compared with 67–75% of patients in the other dose groups. Moreover, they point out that people in the three higher-dose groups, but not those in the 100 mg group, experienced “a rapid reduction in target joint pain,” in the first day after treatment, indicating reduced efficacy with the lowest dose.
The team says that dapansutrile was well tolerated, and “no pathological changes were reported in metabolic, physiological, or haematological measurements for any dose group.” A total of 73.5% of participants experienced adverse events, most frequently metabolism and nutrition-related events (37.8%) and gastrointestinal disorders (22.2%).
Together, these findings indicate that “[t]his novel NLRP3 inflammasome inhibitor has substantial potential for further development for the treatment of gout flares and other NLRP3-mediated diseases,” conclude Jansen and team.
Discussing the trial results in an accompanying comment, Michael Toprover (New York University, USA) and Michael Pillinger (Department of Veterans Affairs, New York) say that “[t]he potential benefits of [dapansutrile] include oral administration, and a mechanism of action directed at hindering the generation of IL-1β rather than neutralising it after it is already generated (as with current biologics).”
They urge caution “when interpreting a very small, uncontrolled study,” but believe that if efficacy is confirmed in phase 2b and 3 trials, then “dapansutrile could prove to be a novel, rapidly-acting anti-inflammatory agent – perhaps allowing clinicians to send more patients with gout flare home from the emergency room.”
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