OBJECTIVEITCA 650 (exenatide in osmotic mini-pump) continuously delivers exenatide subcutaneously for 3-6 months. Two doses of ITCA 650 were compared with placebo in patients with uncontrolled type 2 diabetes. RESEARCH DESIGN AND METHODSThis 39-week, phase 3, double-blind, placebo-controlled trial randomized 460 patients aged 18-80 years with glycated hemoglobin (HbA 1c ) 7.5-10% [58-86 mmol/mol] 1:1:1 to placebo, ITCA 650 40 mg/day, or ITCA 650 60 mg/day. Primary end point was change in HbA 1c at 39 weeks. was attained in 37%, 44%, and 9% of ITCA 650 40 mg/day, ITCA 650 60 mg/day, and placebo groups, respectively (P < 0.001 each dose vs. placebo). LS mean change from baseline body weight was 22.3 kg and 23.0 kg for ITCA 650 40 and 60 mg/day, respectively (P £ 0.015 vs. placebo 21.0 kg). Nausea was the most common adverse event (AE) and subsided over time. Discontinuation for gastrointestinal AEs occurred in 7.2% with ITCA and 1.3% with placebo. Most AEs associated with procedures to place and remove ITCA 650 were mild and transient. RESULTS Least squares (LS) mean change from baseline CONCLUSIONSITCA 650 significantly reduced HbA 1c and weight compared with placebo and was well tolerated in patients with uncontrolled type 2 diabetes on oral antidiabetes medications.
Background:Pegylated uricases are promising therapies for the treatment of severe chronic gout, but are limited by their immunogenicity. We have previously shown that ImmTOR tolerogenic nanoparticles (formerly known as SVP-Rapamycin) encapsulating rapamycin co-administered with pegadricase prevented the formation of anti-drug antibodies (ADAs) in a dose-dependent manner. A prior Phase 1b study of SEL-212, a novel combination product candidate consisting of pegadricase and ImmTOR, demonstrated sustained control of serum uric acid (SUA) for at least 30 days after a single dose. Here we provide data from a recently completed Phase 2 multidose clinical trial.Objectives:To assess data on the safety, tolerability, and effects on SUA, ADAs, and gout flares of five monthly doses of SEL-212 in symptomatic gout patients treated with 0.1 or 0.15 mg/kg ImmTOR in combination with 0.2 mg/kg pegadricase.Methods:Patients with symptomatic gout (≥1 tophus, gout flare within 6 months, and/or gouty arthropathy) and elevated SUA (≥6 mg/dL) were enrolled in SEL-212 treatment cohorts. Patients reported here received up to five monthly doses of SEL-212 (0.2 mg/kg pegadricase combined with 0.1 or 0.15 mg/kg ImmTOR). Safety, tolerability, SUA, and ADAs were monitored, and clinical data were collected.Results:As of 17 Dec 2018, 152 patients had been dosed in the Phase 2 study. All evaluable patients receiving 0.1 or 0.15 mg/kg ImmTOR administered with 0.2 mg/kg pegadricase who achieved three months of SUA control maintained SUA control in months four and five of combination treatment. Approximately 66% of evaluable patients maintained SUA levels below 6 mg/dL at week 20 after five monthly doses of SEL-212. The sustained reduction of SUA correlated with low or no ADAs. SEL-212 was generally well tolerated and associated with a low rate of gout flare rates. Only 35% of patients treated with five doses of 0.1-0.15 mg/kg ImmTOR, and 29% of all current patients in the SEL-212 Phase 2 trial, experienced gout flares after initiation during the first month of treatment with continued reduction of gout flare rates over months two through five. This low rate of gout flares appears to be in contrast with higher incidence of gout flares reported in clinical trials involving other urate lowering therapies.Conclusion:SEL-212 has been well-tolerated, showing substantially reduced immunogenicity, sustained control of SUA, and low rate of gout flares with repeated monthly dosing. SEL-212 has a favorable product profile to address the unmet need of patients with severe, chronic gout including low immunogenicity allowing continued dosing, lower reported flare rates and convenient monthly dosing.Disclosure of Interests:Stephen Smolinski Shareholder of: Selecta Biosciences, Inc., Employee of: Selecta Biosciences, Inc., Alan Kivitz Shareholder of: Novartis, Consultant for: Abbvie, Janssen, Pfizer, UCB, Genzyme, Sanofi, Regeneron, Boehringer Ingelheim, Sun Pharma Advanced Research, Flexion., Paid instructor for: Celgene, Horizon, Merck, Novartis, Pfizer, Genzyme,...
Objectives Serum urate (SU) lowering with PEGylated uricases in gout can reduce flares and tophi. However, treatment-emergent anti-drug antibodies adversely affect safety and efficacy, and the currently-approved PEGylated uricase pegloticase requires twice-monthly infusions. Investigational SEL-212 therapy aims to promote uricase-specific tolerance, via monthly sequential-infusions of a proprietary rapamycin-containing nanoparticle (ImmTOR™) and pegadricase. Methods COMPARE was a randomised, Phase 2, open-label trial of SEL-212 vs pegloticase in adults with refractory gout. SEL-212 (ImmTOR™ [0.15 mg/kg] and pegadricase [0.2 mg/kg]) was infused monthly or pegloticase [8 mg] twice-monthly for 6 months. Primary end point: proportion of participants with SU < 6 mg/dl for ≥80% of the time during 3 and 6 months. Secondary outcomes: mean SU, gout flares, number of tender and/or swollen joints, and safety. Results During months 3/6 combined, numerically more participants achieved and maintained SU < 6 mg/dl for ≥80% of the time with SEL-212 vs pegloticase (53.0% vs 46.0%, p= 0.181). Percentage reductions in SU levels were statistically greater during months 3 and 6 with SEL-212 vs pegloticase (–73.79% and –47.96%, p= 0.0161). Reductions in gout-flare incidence and number of tender and/or swollen joints were comparable between treatments. There were numerical differences between the most common treatment-related adverse events of interest with SEL-212 and pegloticase: gout flares (60.2% vs 50.6%), infections (25.3% vs 18.4%), and infusion-related reactions (15.7% vs 11.5%), respectively. Stomatitis (and related terms) was experienced by 8 participants (9.6%) with SEL-212 and 0 with pegloticase. Stomatitis, a known event for rapamycin, was associated with ImmTOR™ only. Conclusions SEL-212 efficacy and tolerability were comparable to pegloticase in refractory gout. This was associated with substantial reduction in treatment burden with SEL-212, due to decreased infusion frequency vs pegloticase. Clinical trial registration NCT03905512
BackgroundDespite availability of effective therapies for gout, a small proportion of patients suffer from refractory gout and/or are intolerant to standard therapies [1]. In these patients, the inability to maintain serum uric acid (sUA) levels < 6 mg/dL may lead to severe clinical manifestations for which uricase-based therapies can be highly effective, though also immunogenic. SEL-212 is a once-monthly, novel 2-component, sequential uricase-based infusion therapy being investigated in patients with refractory gout. SEL-212 consists of an infusion of tolerogenic nanoparticles containing rapamycin (SEL-110) followed by pegadricase (SEL-037). The intent of this drug combination is to inhibit the formation of anti-uricase antibodies without the need for separate immunosuppressant therapies [2].ObjectivesDISSOLVE I and II (D1 and D2, respectively) evaluated the safety and efficacy of SEL-212 in adults with refractory gout.MethodsD1 (US Study, 12 months) and D2 (Global Study, 6 months), were placebo-controlled, double-blind, randomized clinical trials that evaluated two dose levels of SEL-110 (0.15 mg/kg [high-dose] or 0.1 mg/kg [low-dose]) prior to SEL-037 (0.2 mg/kg) infusion in adults (19-80 years). Participants with a history of symptomatic gout were enrolled if they had ≥ 3 gout flares within 18 months prior to screening or ≥ 1 tophus or a current diagnosis of gouty arthritis, failed to normalize sUA and control symptoms with any xanthine oxidase inhibitor, and were not previously exposed to a uricase-based therapy. Participants were randomized 1:1:1 between the two doses of SEL-212 and placebo administered intravenously every 28 days for 6 treatments. D1 participants were continued in a 6-month blinded extension phase under the initial treatment conditions (Fig. 1). The primary endpoint was defined as the percentage of participants who achieved and maintained sUA < 6 mg/dL for ≥ 80% of the sixth 28-day treatment period (TP6) in the active treatment groups versus placebo (response rate). Safety and tolerability were assessed through monitoring of adverse events (AEs) and laboratory testing.ResultsA total of 265 participants (D1, n=112 (96% male, 66% ≥ 50 years); D2, n=153 (97% male, 72% ≥ 50 years) were randomized into the three treatment arms. Response rates in all treatment groups were significantly different from placebo (p ≤ 0.0015), with 56% and 47% of participants responding in the high-dose group and 48% and 41% in the low-dose group for D1 and D2, respectively (Table 1). The response rates in participants aged ≥ 50 years were 65% and 48% in the high-dose groups and 47% and 45% in the low-dose groups for D1 and D2, respectively (p ≤ 0.0044 vs placebo). Across all participants in the treatment groups, median sUA levels were reduced by ~96% and ~75% from baseline at TP6 for D1 and D2, respectively (p<0.001 vs placebo). The safety profile of SEL-212 was favorable, with 3.4% and 4.5% of participants experiencing infusion reactions in the high and low-dose groups, respectively. Reports of gout flares were comparable between treatment groups and placebo. Six participants (3.4%) in the pooled active treatment groups experienced treatment-related serious AEs (n=4 anaphylaxis, n=2 gout flares).ConclusionIn the DISSOLVE trials, once-monthly treatment with SEL-212 demonstrated statistically significant response rates and reductions in sUA versus placebo. The safety profile of SEL-212 was consistent with that of uricase therapies. Targeted immunomodulation with SEL-212 has the potential to provide a new uricase-based treatment option for patients with gout refractory to conventional therapies without the need for traditional immunosuppressants.References[1] Edwards NL.Arthritis Rheum2008;58(9):2587-90.[2] Sands E,et al. Nat Commun2022;13:272.Figure 1.DISSOLVE I & II Study Design.Table 1.Primary Efficacy Endpoint.DISSOLVE IDISSOLVE IINHigh dose (38)Low dose (37)Placebo (37)High dose (49)Low dose (51)Placebo (53)Response rate %56484474112Risk Difference[97.5% CI]53 [32, 73]44 [23, 64]-35 [14, 56]28 [8, 48]-p-value1<0.0001<0.0001-0.00020.0015-1p-value vs placebo (Mantel-Haenszel test)AcknowledgmentsWe would like to acknowledge all participants, investigators, and study personnel involved in the DISSOLVE phase III clinical studies. Writing support provided by Micheal Wilson, PhD, of Swedish Orphan Biovitrum.Disclosure of InterestsHerbert S.B. Baraf Consultant of: Horizon Pharmaceuticals, Swedish Orphan Biovitrum, Selecta Biosciences, Speakers bureau: Horizon Pharmaceuticals, Grant/research support from: Horizon Pharmaceuticals, Swedish Orphan Biovitrum, Alan Kivitz Consultant of: AXDEV Group, Amgen, Pfizer, Janssen, Boehringer Ingelheim, AbbVie, Flexion, Gilead, Grünenthal, Orion, Regeneron, Sun Pharma Advance Research, and ECOR1, Speakers bureau: Merck & Co, Eli Lilly, Novartis, Pfizer, Flexion, AbbVie, Amgen, Genentech, Regeneron, UCB, Horizon, and GSK, Shareholder of: Pfizer, GSK, Gilead, Novartis, and Amgen, Sheri Rhodes Consultant of: Selecta Biosciences, Shareholder of: Selecta Biosciences, Employee of: Selecta Biosciences, Sheldon Leung Consultant of: Selecta Biosciences, Shareholder of: Selecta Biosciences, Employee of: Selecta Biosciences, Olu Folarin Consultant of: Selecta Biosciences, Shareholder of: Selecta Biosciences, Employee of: Selecta Biosciences, Tania Gonzalez-Rivera Consultant of: Swedish Orphan Biovitrum, Employee of: Swedish Orphan Biovitrum, Joanna Sobierska Employee of: Swedish Orphan Biovitrum, Jacquie Christie Shareholder of: GSK Pharma, Employee of: Swedish Orphan Biovitrum, Anand Patel Speakers bureau: Lexicon Pharmaceuticals, Wesley DeHaan Consultant of: Selecta Biosciences, Shareholder of: Selecta Biosciences, Employee of: Selecta Biosciences, Rehan Azeem Shareholder of: Selecta Biosciences, Employee of: Selecta Biosciences, Peter Traber Consultant of: Selecta Biosciences, Shareholder of: Selecta Biosciences, Employee of: Selecta Biosciences.
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