Dapansutrile may drive gout flares down

The novel selective NLRP3* inflammasome inhibitor dapansutrile markedly reduced joint pain in patients with monoarticular gout flares, according to a proof-of-concept study.

Gout flares, which usually manifest in the knee, ankle, and first metatarsophalangeal joints, are driven by the activation of the NLRP3 inflammasome, causing maturation of interleukin-1β and consequent fulminant joint inflammation. [J Foot Ankle Res 2011;4:13] The accompanying excruciating pain may impair quality of life. [Rheumatology (Oxford) 2013;52:2031-2040] “[Therefore,] a prompt interruption … is needed to achieve control of symptoms, which is the main goal in gout flare [management],” said the researchers.

Thirty-four adults were sequentially assigned to four daily dapansutrile regimens – 1,000 and 2,000 mg (n=10 and 8, respectively); following success with the higher doses, dose was de-escalated to 300 and 100 mg (n=8 in each arm). [Lancet Rheumatol 2020;doi.org/10.1016/S2665-9913(20)30065-5]

The efficacy of dapansutrile was initially seen at day 3 as reflected by the mean reductions in patient-reported target joint pain with all doses (52 percent; p=0.016 [100 mg], 68 percent; p=0.016 [300 mg], 56 percent; p=0.063 [1,000 mg], and 58 percent; p=0.016 [2,000 mg]). Greater reductions were observed at day 7 (82 percent; p=0.031, 84 percent; p=0.016, 69 percent; p=0.031, and 84 percent; p=0.008, respectively).

However, only half of 100-mg recipients achieved ≥50 percent pain reduction at day 3. Moreover, no changes were seen with the 100-mg dose in the first 24 hours post-treatment, as opposed to the rapid pain reduction with the three higher doses. These suggest that 100 mg was less effective in treating gout flares, said the researchers.

The pain reductions with the higher doses mirrored those found in evidence evaluating currently available regimens** for gout flares. [Lancet 2008;371:1854-1860; Ann Rheum Dis 2012;71:1839-1848; Rheumatology (Oxford) 2019;58:1344-1352] Taken together, the findings further boost the potential of dapansutrile as a promising alternative for gout flares, noted the researchers.

Nearly three-quarters (74 percent) of patients reported treatment-emergent adverse events (AEs), which were mostly metabolic/nutritional (38 percent) and gastrointestinal in nature (22 percent). Despite gout flare worsening requiring hospital admission in two patients, these were moderate in severity and unrelated to the study drug.

The available treatment options are mostly tied to serious AEs, while the biologics entail high costs and parenteral administration. [J Rheumatol Suppl 2014;92:15-25] Furthermore, intolerance or insufficient response plus comorbidities may also narrow down the use of these regimens. [Am J Med 2011;124:155-163; BMC Med 2017;15:123]

“This novel NLRP3 inflammasome inhibitor has substantial potential for further development for the treatment of gout flares and other NLRP3-mediated diseases***,” said the researchers.

The similar joint distribution, baseline pain scores, and comorbidities across all patient groups, plus the increased generalizability due to the minimal inclusion criteria, imply that the findings may extend to a larger cohort of patients, they added.

However, the effects might have been influenced by the small study sample involving different joints, acute-phase protein concentrations, and durations of flare prior to treatment, noted the researchers. The dose response could have also been impacted by the saturation of NLRP3 inhibition with higher dapansutrile doses.

Larger randomized trials with active comparators are thus warranted to ascertain the clinical potential and optimal dosing of dapansutrile in this setting, they added.