POS0135 REDUCING IMMUNOGENICITY OF PEGLOTICASE (RECIPE) WITH CONCOMITANT USE OF MYCOPHENOLATE MOFETIL IN PATIENTS WITH REFRACTORY GOUT: A PHASE II RANDOMIZED CONTROLLED TRIAL

Background:Pegloticase is a recombinant, pegylated uricase, used for treatment of gout patients who fail oral urate lowering therapy (ULT). Its use has been limited due to immunogenicity leading to infusion reactions.1Objectives:We evaluated if co-administration of an immunomodulatory agent could prolong the efficacy of pegloticase.Methods:Participants were recruited in a Phase II, double-blind, placebo-controlled trial over 18 months and randomized in a 3:1 ratio by site. Inclusion criteria were: a) Age ≥ 18 years who met 2015 ACR/EULAR gout classification criteria and b) chronic refractory gout defined as symptoms inadequately controlled with ULT or contraindications. After a 2-week run-in of mycophenolate mofetil (MMF) 1000 mg twice daily or matching placebo (PBO), they received a combination of pegloticase 8 mg biweekly with MMF or PBO for 12 weeks. Subsequent to this MMF or PBO were discontinued but pegloticase was continued for another 12 weeks. The primary endpoint was proportion of patients who sustained a serum urate (SU) level of ≤ 6 mg/dl at 12 weeks. Secondary endpoints included 24-week durability of SU ≤ 6 mg/dl and rate of adverse events (AEs). Fisher’s exact test and Wilcoxon two-sample test were used for analyses along with Kaplan-Meier estimates and log-rank tests to compare survival curves between groups. Hypothesis tests were two-tailed and p-value (p) < 0.05 indicated statistical significance.Results:Of 42 subjects screened, 35 were randomized, and 32 who received at least one dose of pegloticase were included in modified intention to treat analyses. Subjects were predominantly men (88%), mean age of 55.2 years (SD=9.7). Mean duration of gout was 13.4 years (SD=9.0), mean baseline sUA was 9.2 mg/dL (SD=1.6). Tophi were present in 88% and majority were on optimized ULT - 59% on allopurinol and 16% on febuxostat, with 63% reporting > 1 flare in the past year. At baseline both arms (MMF vs. PBO) had similar comorbidities – (82% vs 70%), diabetes mellitus/metabolic syndrome (14% vs 20%), coronary artery disease/peripheral vascular disease (41% vs.70%), BMI>30 (86% vs. 90%) and renal insufficiency (defined as eGFR < 90 mL/min; 73% vs. 70%). At 12 weeks, 19 of 22 (86%) in the MMF arm achieved SU ≤ 6 mg/dl compared to 4 of 10 (40%) in PBO arm (p-value = 0.01). At 24 weeks, the SU was ≤ 6 mg/dl in 68% of MMF arm vs. 30% in PBO (p-value = 0.06), and rates of AEs per month were similar between groups with the PBO arm having more infusion reactions (30% vs. 0%). The MMF arm had higher AEs compared to placebo: musculoskeletal (41% vs. 10%), gastrointestinal (18% vs. 10%), and infections (9% vs. 0%). Figure 1 shows that the percentage of subjects maintaining a sUA < 6 mg/dL at 12 weeks was significantly higher (p=0.02) in the MMF arm, and a significant difference (p=0.03) at 24 weeks indicates sustained benefit from MMF.Conclusion:To our knowledge this is the first randomized-controlled proof of concept trial to demonstrate the ability of an immunomodulatory agent in prolonging the efficacy of pegloticase. Short-term concomitant use of MMF therapy with pegloticase was well tolerated and showed a clinically meaningful improvement in the targeted SU ≤6 mg/dL at 12 and 24 weeks. This study suggests an innovative approach to utilize pegloticase therapy in patients with chronic gout.References:[1]Sundy et al. Efficacy and tolerability of pegloticase for the treatment of chronic gout in patients refractory to conventional treatment: two randomized controlled trials. JAMA. 2011;306(7):711-20.Figure 1.Proportion of subjects maintaining serum urate (SU) ≤ 6 mg/dL over 24 week study period in mycophenolate mofetil + pegloticase vs. placebo + pegloticaseDisclosure of Interests:Puja Khanna Consultant of: Horizon Pharmaceuticals, Swedish Orphan Biovitrum A, Grant/research support from: Selecta, 2)DYVE, Dinesh Khanna Consultant of: Horizon Pharmaceuticals, Gary Cutter: None declared, Jeff Foster: None declared, Josh Melnick: None declared, Sara Jaafar: None declared, Stephanie Biggers: None declared, Fazlur Rahman: None declared, Hui-Chen Kuo: None declared, Michelle Feese: None declared, Kenneth Saag Consultant of: AbbVie, Inc., Bayer, Daiichi Sankyo Company LTD, Gilead Services, Inc., Horizon Pharma plc, Mallinkrodt, Radius Health, Inc., Roche/Genentech, Shanton Pharma Co., LTD, Teijin, Dyve Bioscience, LG Chem, Regeneron Pharmaceuticals., Swedish Orphan Biovitrum AB, Takeda Pharmaceuticals America, Inc.,

Formulation and Characterization of Febuxostat loaded Nanostructured Lipid Carriers (NLCs) - Gel for Topical Treatment of Gout

Background: The aim of present study was to formulate and characterize Nano Structured lipid carriers (NLCs) of Febuxostat (FB) incorporated in gel for the treatment of Gout. FB is a Xanthine Oxidase (XO) inhibitor drug used for chronic Gout and hyperuricemia. FB is BCS class II drug so water solubility is very poor and due to its poor solubility and wettability, it leads to poor dissolution. The hot high pressure homogenization technique was used in this study to improve physicochemical property of FB. Method: The carbopol 934 was used to prepare NLCs Gel of FB. The NLCs of FB was prepared in different drug: polymer ratios w/w (2:1), (1:1), (1:2), (1:3) and (1:4) with solid lipid (Stearic Acid) and liquid lipid (Oleic acid). The preformulation study of FB included FTIR study melting point, standard calibration curves and drug polymer interaction study. Result: The NLCs (1:3) showed high entrapment and drug content. The NLCs gel formulation had 87% release within 6 hours in controlled manner. Conclusion: NLCs gel modifies the drug release, increases the bioavailability and reduces side effects of FB. The prepared gel is the efficient formulation for the better treatment of chronic Gout and hyperuricemia. The research findings have shown the undesirable side effects associated with the oral route can be reduced by use of NLCs formulation through transdermal route in an effective manner.

Interdisciplinary approach to the management of patients with chronic gout

Gout, one of the most common forms of inflammatory arthritis, is characterized by severe joint pain, which often interferes with daily activities. In recent years, further research on its causes and on improving diagnosis, treatment and prevention has been ongoing. It is known that gout usually occurs due to the accumulation of sodium monourate crystals in joints due to high levels of serum uric acid. In 2019, the Annals of the Rheumatic Diseases journal published new data on imaging and clinical diagnostics methods based on the principles of evidence-based medicine. Formulated by experts, they were adopted as a consensus of the European League Against Rheumatism (EULAR). The American College of Rheumatology (ACR) has now developed new strategies to treat and prevent gout. On May 11, 2020, the Arthritis & Rheumatology Journal presented guidelines for the management of gout patients, including the treatment of acute gout attack, indications for urate-lowering therapy and instructions for its optimal use, as well as recommendations on lifestyle and drugs that are often prescribed to patients with comorbidity. The purpose of this review is to summarize current knowledge with a focus on recent advances in the algorithm for managing acute and chronic gout patients.

Interdisciplinary approach to the management of patients with chronic gout

Gout, one of the most common forms of inflammatory arthritis, is characterized by severe joint pain, which often interferes with daily activities. In recent years, further research on its causes and on improving diagnosis, treatment and prevention has been ongoing. It is known that gout usually occurs due to the accumulation of sodium monourate crystals in joints due to high levels of serum uric acid. In 2019, the Annals of the Rheumatic Diseases journal published new data on imaging and clinical diagnostics methods based on the principles of evidence-based medicine. Formulated by experts, they were adopted as a consensus of the European League Against Rheumatism (EULAR). The American College of Rheumatology (ACR) has now developed new strategies to treat and prevent gout. On May 11, 2020, the Arthritis & Rheumatology Journal presented guidelines for the management of gout patients, including the treatment of acute gout attack, indications for urate-lowering therapy and instructions for its optimal use, as well as recommendations on lifestyle and drugs that are often prescribed to patients with comorbidity. The purpose of this review is to summarize current knowledge with a focus on recent advances in the algorithm for managing acute and chronic gout patients.

Die Gichtarthritis: Pathogenese, Diagnostik und Behandlung

The initial presentation of gouty arthritis can be a dramatic event. Chronic gout may lead to the destruction of joints, invalidity and increased mortality. The incidence of this disorder is high, despite effective therapeutic measures. The treatment of refractory cases may be a challenge to the general practitioner and the specialist alike. The article presented here summarizes the current state of diagnostics and treatment of acute and chronic gout.

Risk for death increasing with cardiovascular chronic gout patients associated with febuxostat

Febuxostat used for the treatment of patients with arthritis littered with Hyperuricemia and is utilized in its Chronic Management. a number of the internal organ adverse effects have diode to the employment of febuxostat replaced with with allopurinol drug. Febuxostat, associate degree compound accelerator matter, achieves its therapeutic result by decreasing humour acid. At therapeutic concentrations it is not expected that Febuxostat will inhibit different enzymes which are involved in purine and pyrimidine synthesis and their metabolism. Metabolism of Febuxostat is done by conjugation via uridine diphosphate glucuronosyltransferase (UGT) enzymes and also by UGT1A1, UGT1A3, UGT1A9, and UGT2B7 and reaction via hemoprotein P450 (CYP) enzymes as well as CYP1A2, 2C8 and 2C9 and non-P450 enzymes. Febuxostat is eliminated primarily through each viscus and excretory organ pathways. Febuxostat could cause heart issues that may result in coronary failure, could cause issues within the blood vessels that visit your brain. this could conjointly result in stroke, urarthritis flare-ups and Liver injury. Some facet effects of febuxostat could occur that sometimes don't would like medical attention. We conclude from our review, vessel Death urarthritis patients with established vessel (CV) illness treated with febuxostat had a better rate of CV death compared to those treated with allopurinol drug in a very CV outcomes study.