Article Text

PDF
THU0422 SEL-212: enhanced serum uric acid control in hyperuricemic patients through selective mitigation of anti-drug antibodies against pegsiticase
  1. E Sands1,
  2. A Kivitz2,
  3. L Johnston1,
  4. TK Kishimoto1
  1. 1Selecta Biosciences, Watertown
  2. 2Altoona Center for Clinical Research, Duncansville, United States

Abstract

Background Recent 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.

Objectives To 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.

Methods Cohorts 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.

Results Sixty-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.

Conclusions Data 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

  1. Richette P, et al., 2017, 76:29–42.

  2. Lipsky PE, et al., Arthritis Res Ther. 2014, 16:R60.

  3. Kishimoto, TK, et al., Nat Nanotechnol. 2016, 11:890–899.

References

Disclosure of Interest E. Sands Employee of: CMO for Selecta Biosciences, A. Kivitz: None declared, L. Johnston Employee of: COO for Selecta Biosciences, T. K. Kishimoto Employee of: CSO for Selecta Biosciences

Statistics from Altmetric.com

Request permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.