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...
99 Background: Breast cancer patients taking tamoxifen (TAM) or an aromatase inhibitor (AI) often develop severe vasomotor symptoms (VMS) yet the only FDA approved non-hormonal treatment for VMS, 7.5 mg paroxetine, has a warning against concomitant use with TAM. Q-122, an orally-available small molecule, is being developed to address this unmet medical need. Results from the Phase 1b study, Q-1001, are presented. Methods: Q-1001 was a Phase 1 open-label, two-dose, dose-escalation study of the safety and preliminary effectiveness of Q-122 in females with breast cancer currently taking TAM or an AI and experiencing an average of at least 7-8 moderate to severe hot flashes per day. Key exclusion criteria included significant renal or hepatic disease, untreated hyperthyroidism and clinically significant abnormal laboratory findings. The study period included a 2 week drug-free screening phase, 28 day treatment phase, and 2 week drug-free follow-up period. Subjects were initially enrolled into Group 1 (100 mg Q-122) followed by Group 2 (200 mg Q-122). Safety was assessed by review of adverse events (AEs), physical findings and laboratory values. The primary efficacy endpoints were mean changes in frequency and severity (hot flash severity score, HFSS) of moderate and severe hot flashes from baseline to Week 4. Menopausal symptoms were assessed using the Greene Climacteric Scale (GCS). Results: 10 and 11 subjects received 100 and 200 mg Q-122 respectively; 8 subjects in each group completed the study. At the end of treatment for groups 1 and 2 respectively, the daily average frequency of hot flashes was reduced from 9.9 to 4.1 and from 8.6 to 3.2, and the mean HFSS was reduced by 62% and 68% from baseline values. Menopausal symptoms assessed using the GCS were significantly reduced from baseline (psychological: -82%; somatic: -65%; vasomotor: -65%). All AEs (n = 29) were either mild (79%) or moderate (21%) in severity and only 3 (all in one subject) were considered possibly related to study drug. Conclusions: Treatment with Q-122 resulted in significant reduction in the frequency and severity of VMS and improvement in menopausal symptoms as assessed by the GCS. No safety issues associated with the use of Q-122 were identified in this study.
IntroductionPegylated uricases are a promising but highly immunogenic therapy for severe gout. Preclinical studies have shown the ability of synthetic vaccine particles containing rapamycin (SVP-R) to inhibit the formation of ADAs against pegsiticase, a pegylated uricase.1 Here we report initial data on the safety, immunogenicity and activity of an ongoing Phase 2 study of SEL-212, a novel combination therapy consisting of pegsiticase and SVP-R.ObjectivesEvaluate the ability of monthly doses of SEL-212 to mitigate the immunogenicity of pegsiticase and enable sustained control of sUA in gout patients.MethodsPatients with symptomatic gout and elevated sUA (≥6 mg/dL) were treated with fixed doses of pegsiticase (0.2 mg/kg or 0.4 mg/kg) alone or co-administered with SVP-R (0.05, 0.08, or 0.1 mg/kg). SEL-212 was infused in 28 day cycles x3 doses followed by challenge with pegsiticase alone on 28 day cycles x2 doses. Safety, tolerability, sUA, and ADAs were monitoredResultsIn the SEL-212 Phase 1b study, 70% of patients administered 0.4 mg/kg pegsiticase with a mid-dose of 0.1 mg/kg SVP-R showed low or no ADA formation correlating with sustained low sUA levels for at least 30 days after a single dose, compared to 20% for patients treated with pegsiticase alone. In the ongoing Phase 2 study, the majority of patients receiving 0.1 mg/kg SVP-R administered with either 0.2 or 0.4 mg/kg pegsiticase also showed low or no ADAs and maintained low sUA levels after 3 monthly doses of SEL-212, indicating sustained activity with repeated doses of SEL-212. However after 2 subsequent doses of pegsiticase alone, a drop in activity was noted. These data suggest that either a higher dose of SVP-R or the addition of SVP-R at the 4th and 5th dose may be required to sustain activity through 5 months. Currently patients are being dosed with 0.15 mg/kg SVP-R, a dose level which enabled sustained control of sUA levels in all patients in Phase 1b. SEL-212 was generally well tolerated and associated with a low rate of gout flare rates compared to those treated with pegsiticase alone.ConclusionsSVP-R showed a dose-dependent reduction in ADAs and enabled sustained control of sUA with repeated dosing of SEL-212. SVP-R is a promising approach to prevent the formation of ADAs against immunogenic biologic therapies.Reference. Kishimoto TK, et al. Nature Nanotechnol2016;11:890–899.AcknowledgementsWe thank the patients that participated in these studies, the clinical study site investigators, and the entire SEL-212 project team.Disclosure of interestE. Sands Employee of: Selecta Biosciences, A. Kivitz: None declared, W. DeHaan Employee of: Selecta Biosciences, L. Johnston Employee of: Selecta Biosciences, T. Kishimoto Employee of: Selecta Biosciences
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