Dapansutrile Appears Safe, Effective in Gout Patients

By Anne Harding

May 11, 2020

NEW YORK (Reuters Health) - A new oral drug targeting interleukin-1beta (IL-1b), dapansutrile, is safe and effective for gout flares, according to a new phase-2a trial.

"Oral small molecules inhibiting specifically the NLRP3 inflammasome pathway, important for the upregulation of IL-1b, exist, can be effective in vitro and in vivo, and now have proven efficacy clinically in gout," Dr. Tim L. Th. A. Jansen of VieCuri Medical Center in Venlo, the Netherlands, an author of the study, told Reuters Health by email.

Olatec Therapeutics, which is developing dapansutrile, was the main funder of the trial, along with the National Institutes of Health and The Interleukin Foundation.

In the open-label trial, 34 patients with monoarticular gout flares received 100 mg, 300 mg, 1,000 mg, or 2,000 mg dapansutrile daily for eight days.

Mean reduction in patient-reported joint pain from baseline to day three ranged from 52.4% to 68.4%. From baseline to day 7, mean reduction in patient-reported joint pain was between 68.9% and 83.9%. There were no significant between-group differences at either time point.

Patients in the 1,000 mg and 2,000 mg groups had significantly reduced IL-1beta and IL-6 secretion upon stimulation in their peripheral blood mononuclear cells, which was not seen in the other dose groups.

The percentage of patients with at least a 50% reduction in pain by day 3 was 50% with 100 mg, 71% with 300 mg, 67% with 1000 mg, and 75% with 3000 mg.

There were 45 treatment-emergent adverse events reported by 25 patients, including two serious events that were considered unrelated to the study drug.

The next step is a randomized controlled trial comparing two of the three effective dapansutrile doses to colchicine, Dr. Jansen said.

"Further indications could well be erosive hand OA and/or pseudogout (pyrophosphate induced arthritis/arthropathy) as well as other IL1-dependant fever syndromes, so these will have to be studied too," he added. "Currently this pathway may be important for COVID-19 so a blind placebo-controlled trial in COVID-19 is planned."

Dr. Michael H. Pillinger of NYU School of Medicine/NYU Langone Medical Center in New York City, who co-authored an editorial accompanying the study, said, "Literally for centuries, we have been treating gouty inflammation with drugs whose mechanisms we did not - and still to a significant extent do not - understand."

"Now, thanks to a decade of advances in inflammation science, we understand the central role of the NLRP3 inflammasome, and of IL-1b in particular, in the pathogenesis of gout," he told Reuters Health by email.. "This understanding has allowed the development of dapansutrile, which is likely destined to become the first agent designed specifically to treat gouty inflammation at one of the earliest stages of the process - the cellular response to monosodium urate crystals. And the study showed that - at least in this very early cohort - dapansutrile was effective, acted rapidly, and was well tolerated."

SOURCE: https://bit.ly/3cfGU2X and https://bit.ly/3cduacV The Lancet Rheumatology, online April 8, 2020