1998: Reduction in Tophi Observed in Patients with Uncontrolled Gout Treated with NASP: Results from Phase 3 DISSOLVE Studies

Background/Purpose: Patients (pts) with uncontrolled gout (UG) and tophi experience joint pain, impaired function and poor quality of life (Schlesinger et al. Semin Arthritis Rheum 2020; Dalbeth et al. Nat Rev Dis Primers 2019; Dalbeth et al. Lancet 2021). With oral urate-lowering therapies, tophus resolution may take several years despite optimal dosing (Laurent et al. RMD Open 2023). NASP (formerly SEL-212) is a novel, every 4-week, sequential infusion therapy consisting of targeted immunomodulating, nanoencapsulated sirolimus (NAS; formerly SEL-110) co-administered with a pegylated uricase (formerly SEL-037) designed to reduce serum uric acid (sUA) levels in pts with UG. Here, we report pooled tophus outcomes from the DISSOLVE studies.

Methods: This post hoc analysis pooled data from DISSOLVE I II ((NCT04513366, NCT04596540) in the intent-to-treat (ITT) population and in pts who received 6 doses of NASP (high-dose [HD]: sequential infusions of 0.15 mg/kg NAS and 0.2 mg/kg pegadricase; low-dose [LD]: sequential infusions of 0.10 mg/kg NAS and 0.2 mg/kg pegadricase) or placebo (PBO). Tophi response was a predefined secondary endpoint. Percent tophus response included partial response (PR), defined as ≥50% and < 100% reduction in the area of a tophus without enlargement of any existing tophus and no new tophus, and complete response (CR), defined as 100% reduction in area of or complete disappearance of a tophus without enlargement of any existing tophus and no new tophus. A triple read model of tophus evaluation was established after unblinding to improve the quality of measuring tophus size and improve data handling in instances of images with quality issues.

Results: In the ITT population (among pts with tophi at baseline (BL): n=55 [HD]; n=55 [LD]; n=57 [PBO]), tophus response of PR or better was observed in 82% in HD (p=0.0077), 88% in LD (p=0.0016), vs 51% in PBO by week 24. NASP treatment resulted in a clinically relevant response of CR in significantly more patients receiving NASP compared with PBO by week 24: HD, 31% (p=0.0044); LD, 48% (p=0.0001), vs PBO, 5%. In the subset of pts with tophi at BL who received 6 doses of treatment (n=23 [HD]; n=22 [LD]; n=42 [PBO]), a significantly greater proportion of patients on NASP experienced CR by week 24: HD, 49% (p=0.0002); LD, 70% (p< 0.0001), vs PBO, 5%. Consistent with the correlation between tophus reduction and sUA reduction, patients who received 6 doses of HD NASP had 89% lower sUA than PBO-treated patients at Day 168 (end of study) with a similar response for LD NASP (Figure 1).

Conclusion: Treatment with NASP resulted in a greater tophus response compared to PBO. In addition, a robust sUA reduction, a key factor in tophus resolution, was observed in NASP-treated pts. These results highlight the effectiveness of NASP in lowering sUA and promoting tophus resolution.