FRI0234 Sel-212: selective mitigation of anti-drug antibodies against pegsiticase to control serum uric acid in hyperuricemic subjects

Abstract

BackgroundWe previously reported initial Phase 2 study results for 60 gout patients treated with SEL-212, a novel combination treatment comprised of pegsiticase (pegylated uricase) co-administered with a synthetic vaccine particle encapsulating rapamycin (SVP-R).1 SEL-212 was well-tolerated, mitigated the formation of anti-drug antibodies, and enabled sustained control of serum uric acid (sUA) levels in most subjects.1 In this ongoing study, new treatment cohorts involving higher SVP-R dose levels and extended combination regimens were introduced.ObjectivesTo assess the tolerability and impact on sUA levels and ADA formation of escalated and expanded doses of SEL-212, designed to be the first non-immunogenic uricase therapy for refractory gout.MethodsPatients with symptomatic gout (≥1 tophus, gout flare within 6 months or gouty arthropathy) and elevated sUA (≥6 mg/dL) were enrolled to SEL-212 treatment (n=6–12 pts/cohort) of fixed doses of pegsiticase (0.2 mg/kg or 0.4 mg/kg) alone or co-administered with SVP-R (0.05, 0.08, 0.1, 0.125, and 0.15 mg/kg). SEL-212 was infused in 28 day cycles x3 doses followed by challenge with pegsiticase alone on 28 day cycles x2 doses. In addition, 2 cohorts were added that extended the combination treatment with SVP-R to all five q28 doses of pegsiticase. ADAs and sUA were assessed at baseline and 7, 14, 21, and 30 days after each dose to Day 140. Safety was monitored continuously.ResultsAs previously reported, 5 of 6 patients dosed with pegsiticase alone developed ADAs after a single dose, correlating with loss of sUA control by 30 days. The addition of SVP-R to pegsiticase showed a dose-dependent inhibition of ADAs, enabling prolonged control of sUA levels. At a mid-dose of 0.1 mg/kg SVP-R, combined with either 0.2 or 0.4 mg/kg pegsiticase, the majority of patients showed sustained control of SUA through 18 weeks. However, control of ADAs and sUA tapered off in some patients by week 20, after two injections of pegsiticase alone. Preliminary results of treatment at increased SVP-R doses (0.125–0.15 mg/kg) are consistent with Phase 1b data indicating that higher doses of the SVP-R will increase the percentage of patients that remain ADA free. These results also suggest that extending treatment to 5 doses of SVP-R and pegsiticase may enable more subjects to complete the 5 month treatment with sustained reductions in sUA. In addition to mitigating immunogenicity, patients treated with SVP-R experienced a low rate of gout flares, with less than 25% of patients experiencing flares during the first month after treatment, despite profound drop in sUA level, and continued reduction was observed during months 2–5. SEL-212 has been generally well tolerated at clinically active dose levels and infusion reactions observed with repeat dosing were reduced with increasing doses of SVP-R.ConclusionsSEL-212 has been well tolerated, mitigated immunogenicity, and sustained control of sUA levels. Escalation of the SVP-R component of SEL-212 may enhance the duration of sUA and ADA suppression without...