THU0422 SEL-212: enhanced serum uric acid control in hyperuricemic patients through selective mitigation of anti-drug antibodies against pegsiticase

Abstract

BackgroundRecent EULAR recommendations for refractory gout treatment with pegylated uricase (pegloticase) acknowledge the risk of allergic reactions related to the development of anti-drug antibodies (ADAs) [1]. ADAs also affect the efficacy of treatment [2]. As a novel approach to treatment, we demonstrated that co-administration of pegsiticase (another pegylated uricase) and a synthetic vaccine particle encapsulating rapamycin (SVP-R) showed improved control of serum uric acid (sUA) in uricase-deficient mice by inducing antigen-specific immune tolerance to pegsiticase [3]. Here we describe the impact of SEL-212, a combination product of SVP-R and pegsiticase, on ADA formation and sUA levels in hyperuricemic patients in a Phase 1 open-label multicenter clinical trial.ObjectivesTo assess the initial safety and impact on sUA levels and ADA formation of SEL-212, which is designed to be the first non-immunogenic uricase therapy for refractory gout.MethodsCohorts of hyperuricemic (sUA ≥6 mg/dL) patients consented to a single dose of 0.4 mg/kg pegsiticase alone, SVP-R alone (0.03–0.5-mg/kg), or 0.4 mg/kg pegsiticase co-administered with SVP-R (0.03–0.3-mg/kg; SEL-212). ADAs and sUA were assessed at baseline and 7, 14, 21, and 30 days after dosing.ResultsSixty-three patients were enrolled with a median age of 49.4 years. Mean baseline sUA was 7.4±1.3 mg/dL. Patients dosed with pegsiticase alone showed an immediate drop in sUA, which returned to baseline levels by 14–21 days in 4 of 5 subjects, correlating with the induction of ADA titers >1000. Patients treated with SVP-R alone showed no meaningful change in sUA.In contrast, patients treated with SEL-212 showed a dose-dependent inhibition of anti-uricase ADAs and corresponding decrease in sUA levels through at least day 30 after a single injection. Seven of 10 patients treated with SEL-212 at a SVP-R dose of 0.1 mg/kg showed no detectable sUA at day 30, and all 10 subjects dosed with SEL-212 at SVP-R doses of 0.15 or 0.3 mg/kg showed sustained control of sUA through at least day 30. There was a strong correlation between maintenance of low uric acid levels at day 30 and with low or no ADA titers.SEL-212 was generally well tolerated at effective dose levels. One SAE (grade 2 rash) was observed in the lowest of the three effective dose levels (0.1 mg/kg SVP-R). A second SAE was determined by the investigator to be not related to study drug. All SAEs fully resolved. No SAEs were observed with SEL-212 at the higher effective dose levels of SVP-R (0.15 or 0.3 mg/kg). The maximum tolerated dose was defined at 0.3 mg/kg.ConclusionsData suggest that a single dose of SEL-212 in hyperuricemic patients can tolerably, therapeutically and durably control sUA for ≥30 days, correlating with inhibition of ADAs. These results supported monthly dosing in an ongoing Phase 2 multi-dose study in symptomatic gout patients and the potential use of SVP-R to mitigate ADAs for other immunogenic biologics.References Richette P, et al., 2017, 76:29–42.Lipsky PE, et al., Arthritis Res Ther. 2014, 1...

Tolerogenic Nanoparticles Induce Antigen-Specific Regulatory T Cells and Provide Therapeutic Efficacy and Transferrable Tolerance against Experimental Autoimmune Encephalomyelitis

“…The safety and efficacy of SEL-212, a combination of NP-encapsulated rapamycin co-administered with pegylated uricase, is currently being evaluated in an ongoing multidose Phase 2 clinical study in symptomatic gout patients with hyperuricemia (NCT02959918). Initial data from the single ascending dose Phase I clinical trial of SEL-212 (NCT02648269) showed dose-dependent inhibition of anti-uricase antibodies with a corresponding sustained reduction of serum uric acid ( 54 ). The ongoing Phase 2 study will assess the ability of tNPs to induce immune tolerance in patients.…”

Nanoparticles for the Induction of Antigen-Specific Immunological Tolerance

“…A single ascending dose Phase 1 clinical trial of SEL-212 (NCT02648269) in patients with hyperuricemia showed that the pegylated uricase is highly immunogenic in humans even after a single dose of enzyme. The addition of tNPs showed a dose-dependent inhibition of anti-uricase antibody formation resulting in sustained reduction of serum uric acid levels ( 72 ). An ongoing Phase 2 study (NCT02959918) will assess the ability of multiple doses of SEL-212 to inhibit the formation of ADAs with in patients with symptomatic gout and hyperuricemia.…”

Development of ImmTOR Tolerogenic Nanoparticles for the Mitigation of Anti-drug Antibodies

“…The addition of ImmTOR showed a dose-dependent inhibition of ADA formation. Mitigation of ADAs correlated with prolonged pharmacodynamic activity of pegadricase and sustained reduction in sUA levels for at least 30 days after a single dose (89). These results suggest that combination of ImmTOR + pegadricase would support monthly dosing.…”

“…The ability of ImmTOR to mitigate the formation of ADAs in human has been evaluated in combination with pegadricase, a highly immunogenic, pegylated uricase enzyme of fungal origin, in patients with hyperuricemia. A Phase 1b single ascending dose, open-label, multi-center clinical trial (NCT02648269) conducted in the United States showed a dose-dependent inhibition of uricase-specific ADAs (89). The activity of pegadricase was monitored through the measurement of serum uric acid (SUA).…”