POS0260 ONCE-MONTHLY SEL-212 DEMONSTRATES EFFICACY AND SAFETY FOR UP TO 6-MONTHS IN GOUT REFRACTORY TO CONVENTIONAL THERAPY: COMBINED DATA FROM THE DISSOLVE I &amp; II PHASE 3, DOUBLE-BLIND, PLACEBO-CONTROLLED CLINICAL TRIALS
Authors: H. S. B. Baraf, P. Khanna, A. Patel, A. Singhal, J. Sobierska, H. Santin-Janin, R. Azeem, W. Dehaan, P. Traber, A. Kivitz
Journal: Annals of the Rheumatic Diseases (2024)

<h3>Background:</h3> In gout refractory (RG) to conventional uric acid lowering therapy (ULT), sustained hyperuricemia increases the risk of painful flares, chronic gouty arthropathy, and tophi. Uricase-based therapy can effectively reverse these outcomes but is limited by immunogenicity, which impairs efficacy and compounds the risk of infusion reactions. SEL-212 is a novel, once-monthly therapeutic platform that consists of sequential infusions of immune-tolerising nanoparticles containing sirolimus (SEL-110), followed by a pegylated uricase (pegadricase, SEL-037). DISSOLVE I &amp; II were US and global clinical trials, respectively, that evaluated efficacy and safety of SEL-212 in adults with RG.Individual study data from DISSOLVE I &amp; II have been presented previously.[1,2] <h3>Objectives:</h3> To describe the combined efficacy and safety data for SEL-212 from the 6-month DISSOLVE studies. <h3>Methods:</h3> DISSOLVE I &amp; II were placebo-controlled, double-blind, randomised clinical trials that evaluated once-monthly sequential administration of SEL-110 at either 0.15 mg/kg [high-dose, HD] or 0.1 mg/kg [low-dose, LD] with SEL-037 (0.2 mg/kg) for 6 treatment periods (TP). RG was defined as failure to normalise serum uric acid (sUA) and inadequate control of signs or symptoms with medically appropriate doses of an oral ULT. Investigational treatment was withdrawn based on a stopping rule: sUA &lt;2.0 mg/dL (1-hr following the study treatment in TP1), and sUA &gt;1.0 mg/dL (Day 21, TP1), or sUA &gt;6.0 mg/dL (Day 21, TP2, 3, 4, or 5). Pre-specified analyses of combined outcomes included sUA responses, sUA reduction, and safety. <h3>Results:</h3> The combined ITT population included 87, 88, and 90 patients in the HD, LD, and placebo arms, respectively. Sixty (40 on treatment, OT), 60 (39 OT) and 70 (68 OT), respectively, completed the double-blind treatment phase. Forty-six percent (122/265) of the pooled analysis patients discontinued treatment; 23.0% (20/87) and 43.2% (38/88) in the HD and LD arms, respectively, met the stopping rule. Other key reasons for discontinuation in the HD, LD and placebo arms, respectively, were withdrawal of consent (10.3%, 8.0%, and 8.9%) and adverse events (13.8%, 6.8%, and 2.2%). Baseline characteristics were largely similar across arms (<b>Table 1</b>). The primary endpoint (response rate, RR), defined as sUA levels &lt;6mg/dL for ≥80% of the time during TP6, was higher with HD and LD (51% and 43%) than placebo (8%; p&lt;0.0001 for HD and LD vs placebo, <b>Figure 1</b>). In those with tophi at baseline, SEL-212 RRs (HD: 41%; LD 43%) were significantly different from placebo (9%; p=0.0003 and 0.0002, respectively; <b>Figure 1</b>). Mean absolute (percentage) sUA reductions from baseline were 5.3 mg/dL (60.8%) for HD, 4.5 mg/dL (52.2%) for LD, and 0.3 mg/dL (2.1%) for placebo (p&lt;0.001 for SEL-212 vs placebo). Most patients (72.4%, 70.5%, and 63.3% in the HD, LD, and placebo arms) experienced ≥1 treatment emergent adverse event (TEAE); with most being mild/moderate in severity. Only gout flares, infusion-related reactions, COVID-19 infections, and rash TEAEs affected ≥5% in SEL-212 arms. The most common TEAE was gout flare with 37 (42.5%) in the HD, 39 (44.3%) in the LD, and 39 (43.3%) in the placebo arm affected. Infusion-related reactions (≤1h) were reported in 3 (3.4%) in HD, 4 (4.5%) in LD, and 0 (0.0%) in the placebo arms. Mild to moderate combined adverse events of stomatitis, oral ulcer and aphthous ulcers were reported in 8 (9.2%) in the HD and 3 (3.4%) in the LD arms but did not cause any withdrawals. COVID-19 infections affected 5 (5.7%) with HD and LD and 6 (6.7%) with placebo. No TEAEs resulted in death. <h3>Conclusion:</h3> Combined DISSOLVE I &amp; II data confirm the results from the individual studies. Both SEL-212 doses demonstrated clinical efficacy and safety. The lower proportion of patients meeting the stopping rule with HD vs LD SEL-212 suggests that HD SEL-212 may be more efficacious. Overall, investigational once-monthly SEL-212 could be a well-tolerated and effective uricase-based urate-lowering therapy in patients with RG. <h3>REFERENCES:</h3> [1] Baraf HSB, et al. Annals of the Rheumatic Diseases 2023;82(suppl 1):200-201 (abstract LB0002). [2] Baraf HSB, et al. Arthritis Rheumatol. 2023;75(suppl 9): abstract number 0246. <h3>Acknowledgements:</h3> The DISSOLVE I &amp; II (NCT04513366 and NCT04596540) studies were jointly funded by Sobi and Selecta BioSciences, Inc and this publication was funded by Sobi. <h3>Disclosure of Interests:</h3> Herbert S.B. Baraf Horizon Pharmaceuticals, Fresenius Kabi, Grunenthal, Olatec, SElecta BioSciences and Sobi, Horizon Pharmaceuticals, Sobi, Puja Khanna Horizon Pharmaceuticals, Sobi, Dyve Biosciences, Selecta Biosciences, Anand Patel Lexicon Pharmaceuticals, Atul Singhal: None declared, Joanna Sobierska Sobi, Hugues Santin-Janin Sobi, Rehan Azeem Selecta Biosciences, Sobi, Wesley DeHaan Selecta Biosciences, Sobi, Peter Traber Selecta Biosciences, Sobi, Alan Kivitz AbbVie, Eli Lilly, Flexion, GSK, Sanofi-Regeneron, Amgen, GKS, Gilead, Novartis, Pfizer, AbbVie, Chemocentryx, Coval, ECOR1, Fresenius Kabi, Genzyme, Gilead, Grunenthal, GSK, HOrizon Pharmaceuticals, Janssen, Prime, Prometheus, Selecta, Synact, Takeda-Nimbus, UCF, XBiotech.