Novel 2-drug combo improves treatment possibilities for patients with refractory gout

Almost half of the participants with refractory gout achieved serum uric acid levels <6 mg/dL with a novel uricase-based therapy in the DISSOLVE I and DISSOLVE II trials. The common problem of anti-drug antibody (ADA) formation was solved by a second immune-tolerising component applied 30 minutes prior to uricase.

Uricase-based therapy is recommended for gout patients who have failed to achieve uric acid-lowering targets, but ADA diminish their effectiveness, leading to treatment failure rates in up to 38% of cases [1,2]. “Pegadricase is a potent pegylated uricase that converts uric acid to soluble and readily excreted allantoin,” Prof. Herbert SB Baraf (Center for Rheumatology and Bone Research, IL, USA) explained the mode of action of 1 component during the presentation [3]. However, as most uricases, it also elicits a vigorous ADA response, limiting its use as a monotherapy. Therefore, SEL-110, the second component of the novel infusion therapy, is administered 30 minutes before pegadricase. SEL-110 is an immune-tolerising nano-encapsulated rapamycin that has demonstrated dose-dependent inhibition of anti-pegadricase antibodies in previous trials.

In the phase 3 studies DISSOLVE I (NCT04513366) and DISSOLVE II (NCT04596540), participants were enrolled if they had ≥3 gout flares within 18 months before screening, ≥1 tophus, or a current diagnosis of gouty arthritis and failed to normalise serum uric acid and control symptoms with any xanthine oxidase inhibitor. They were randomised to receive a high or a low dose of the novel 2-drug combo SEL- 212 or placebo, every 28 days for a total of 6 treatments. The primary endpoint was the percentage of participants achieving serum uric acid levels <6 mg/dL for at least 80% of the sixth 28-day treatment period. “Stringent stopping rules were implemented to minimise the risk of infusion-related adverse events,” Prof. Baraf emphasised.

Included were 265 participants whose demographic characteristics were balanced for age, BMI, and sex, but racial imbalances existed in both studies. Gout severity was numerically greater in the 153 participants included in DISSOLVE II. The primary efficacy endpoint was met for both studies and doses (see Figure). In the DISSOLVE I study, 58% of participants in the high-dose group (n=38) and 48% in the low-dose group (n=37) responded to treatment (both P<0.0001 vs placebo). The corresponding numbers in the DISSOLVE II study were 46% in the high-dose group (P=0.0002 vs placebo) and 40% in the low-dose group (P=0.0008 vs placebo). Median change in serum uric acid levels indicates large reductions in at least half of the participants. Participants older than 50 years had similar response rates.

Treatment was relatively tolerable. The infusion reaction incidence was 3.4% in the high-dose group.

Prof. Baraf concluded that SEL-212 might potentially provide a new once-monthly uricase-based treatment option for patients with refractory gout.

Figure: Primary trial endpoint: response to SEL-212 versus placebo at week 12 [3]

1. Fitzgerald JD, et Arthritis Care Res (Hoboken). 2020;72:744-60.
2. Botson J, et Arthritis Rheumatol. 2023;75:293-304.
3. Baraf HSB, et Safety and efficacy of SEL-212 in patients with gout refractory to conventional treatment: outcomes from two randomised, double-blind, placebo- controlled, multicenter phase III studies. LB0002, EULAR 2023, 31 May–3 June, Milan, Italy.

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Posted on 30 July 202331 July 2023