University of Michigan Ann Arbor, Michigan, United States
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Background/Purpose: Patients (pts) with uncontrolled gout (UG; persistent elevation in serum uric acid [sUA] levels and clinical manifestations despite oral urate-lowering therapy) have poor health-related quality-of-life (HRQOL) outcomes. The global UG disease burden is substantial and increasing. NASP (formerly SEL-212) is an investigational, novel, every 4-wk (Q4W), sequential 2-component infusion therapy consisting of targeted nanoencapsulated sirolimus (NAS, formerly SEL-110), which mitigates the formation of antipegadricase antibodies, and a uricase (pegadricase [P]; formerly SEL-037), which reduces sUA. Here, we report sUA levels, joint exam findings, and HRQOL outcomes in pts with UG who received 6 doses of NASP or placebo (PBO) in the phase 3 DISSOLVE I and II (NCT04513366, NCT04596540) studies. Methods: Eligible pts had a history of symptomatic gout (≥3 gout flares within 18 mo of screening, ≥1 tophus, or current gouty arthritis), inability to normalize sUA and control symptoms with treatment, and screening sUA ≥7 mg/dL, which aligned with ACR diagnostic criteria for gout (Neogi et al. Arthritis Rheumatol 2015). Pts were randomized 1:1:1 to receive high-dose (HD) NASP (0.15 mg/kg NAS; 0.2 mg/kg P), low-dose (LD) NASP (0.10 mg/kg NAS; 0.2 mg/kg P), or PBO Q4W; those who received 6 doses were included in this post hoc analysis. Pt-reported outcomes (PROs) included the 36-Item Short Form Health Survey (SF-36) physical component summary (PCS) score (minimal clinically important difference [MCID], 5) and Health Assessment Questionnaire-Disability Index (HAQ-DI) pain score (MCID, 16). Results: In pts receiving HD NASP (n=42), LD NASP (n=35), or PBO (n=67), mean sUA changes of −88%, −94%, and −0.3% (median: −97%, −98%, and 1.5%) were observed from baseline (mean [standard deviation (SD)]: 8.5 [1.4], 8.5 [1.3], and 8.7 [1.6] mg/dL) to wk 24 (mean [SD]: 1.1 [2.0], 0.5 [0.8], and 8.5 [2.0] mg/dL), respectively. In the NASP arms, sUA reduction was noted immediately after the first dose, and mean sUA generally remained ≤2.0 mg/dL throughout the study (Figure 1A). Pts receiving HD NASP, LD NASP, and PBO had mean reductions in the number of tender (−74%, −92%, and −40%) and swollen (−90%, −91%, and −54%) joints from baseline (mean number of tender/swollen joints: 5.8/2.9, 6.1/3.5, and 7.7/5.2) through wk 24 (mean number of tender/swollen joints: 1.5/0.3, 0.5/0.3, and 4.6/2.4). HD and LD NASP generally led to an approximately 2-fold reduction in the mean number of tender and swollen joints vs PBO (Figure 1B). NASP-treated pts showed improvement in mean SF-36 PCS scores (HD NASP: 5.9; LD NASP: 9.7) that exceeded the MCID and was >2-fold higher than the change for PBO-treated pts by wk 24 (2.8); NASP-treated mean SF-36 PCS scores (HD NASP: 45.2; LD NASP: 46.4) were comparable to the US general population (49.2; Maglinte et al. J Clin Epidemiol 2012). By wk 24, a greater mean HAQ-DI pain score reduction was seen with NASP (HD NASP: −60%; LD NASP: −80%) vs PBO (−44%; Figure 2). Conclusion: NASP-treated pts had meaningful reductions in disease burden and key clinical manifestations, as reflected by improvements in sUA levels and PROs. This therapy has a noteworthy impact on resolving acute gout symptoms over 6 treatments and shows promise for improving HRQOL.
