arhalofenate and Gout

Despite many effective treatments for gout, its management remains a challenge internationally. Options for optimizing gout management may differ in different practice sizes and settings. Gout incidence is rising and it continues to be associated with increased mortality. Education of patients and medical providers is essential, and newer gout medications need to be used in the most appropriate ways for cost-effective therapy. Special consideration needs to be given to such populations as the elderly and those with renal and cardiovascular disease in gout management. New agents are in development, which may add to the armamentarium for gout management.

Topics: Acetamides; Allopurinol; Antibodies, Monoclonal, Humanized; Colchicine; Diet Therapy; Febuxostat; Gout; Gout Suppressants; Humans; Medication Adherence; Patient Education as Topic; Phenylacetates; Polyethylene Glycols; Quality of Health Care; Rheumatology; Thioglycolates; Triazoles; Urate Oxidase; Uric Acid

To discuss recent studies of lesinurad and arhalofenate.. Lesinurad acts by blocking urate reabsorption channels URAT-1 and OAT-4. It has urate-lowering effect when used alone and in combination with xanthine oxidase inhibitors (XOIs). Its uricosuric activity depends on glomerular filtration, and its' efficacy is impaired at eGFR less than 30 ml/min. Lesinurad monotherapy (400 mg/day) associates with serum creatinine elevations. However, this risk is substantially attenuated with coprescription of a XOI and when prescribed at a dose of 200 mg/day. Given its' modest urate-lowering effect, and the risk of serum creatinine elevation when used alone, it is licenced for use in combination with XOI for people unable to achieve target serum uric acid with XOI alone. Lesinurad does not have the drug interactions associated with probenecid, however, it is metabolized by CYP2C9, and should be used with caution if CYP2C9 inhibitors are coprescribed. Arhalofenate also acts by blocking URAT-1; however, it also blocks the NALP-3 inflammasome providing gout-specific anti-inflammatory effect. Arhalofenate has a weaker urate-lowering effect than lesinurad and further phase III evaluation is planned.. Lesinurad provides an additional option for people with gout unable to achieve target serum uric acid with XOI alone.

Topics: Acetamides; Drug Interactions; Enzyme Inhibitors; Gout; Gout Suppressants; Humans; Phenylacetates; Probenecid; Thioglycolates; Triazoles; Uric Acid; Uricosuric Agents

To update recent developments in medications targeting hyperuricemia, but not including medications recently labelled in the European Union and the United States.. A new xanthine oxidase inhibitor, Topiloric (Fujiyakuhin Co., Ltd. Japan) Uriadec (Sanwa Kagaku Kenkyusho Co., Ltd. Japan), has been developed and labelled in Japan. An inhibitor of purine nucleoside phosphorylase, Ulodesine, is in development in combination with allopurinol. The rest of the medications in the pipeline for hyperuricemia are targeting renal transporters of uric acid, mainly URAT1 and OAT4, acting as uricosuric agents. Most of them, such as lesinurad and arhalofenate, are being tested in trials in combination with allopurinol and febuxostat. The most potent RDEA3170 is being tested in monotherapy, but also associated with febuxostat. Recently, medications showing dual activity, inhibiting both xanthine oxidoreductase and URAT1, have been communicated or started exploratory clinical trials. There is no report of medications targeting other transporters such as Glut9 or ABCG2.. There are a number of medications in the pipeline targeting hyperuricemia, mostly uricosurics in combination with xanthine oxidase inhibitors, but some targeting both xanthine oxidoreductase and URAT1. Increasing the number of available medications will ensure proper control of hyperuricemia to target serum urate levels in the near future for most, if not all, patients with hyperuricemia.

Topics: Acetamides; Drug Design; Gout; Gout Suppressants; Humans; Hyperuricemia; Imino Furanoses; Molecular Targeted Therapy; Phenylacetates; Pyrimidinones; Thioglycolates; Triazoles; Uricosuric Agents

Over the past decade much has been learned about the mechanisms of crystal-induced inflammation and renal excretion of uric acid, which has led to more specific targeting of gout therapies and a more potent approach to future management of gout. This article outlines agents being developed for more aggressive lowering of urate and more specific anti-inflammatory activity. The emerging urate-lowering therapies include lesinurad, arhalofenate, ulodesine, and levotofisopam. Novel gout-specific anti-inflammatories include the interleukin-1β inhibitors anakinra, canakinumab, and rilonacept, the melanocortins, and caspase inhibitors. The historic shortcomings of current gout treatment may, in part, be overcome by these novel approaches.

Topics: Acetamides; Adrenocorticotropic Hormone; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antirheumatic Agents; Benzodiazepines; Febuxostat; Gout; Gout Suppressants; Humans; Imino Furanoses; Interleukin 1 Receptor Antagonist Protein; Interleukin-1beta; Melanocortins; Phenylacetates; Polyethylene Glycols; Pyrimidinones; Recombinant Fusion Proteins; Thiazoles; Thioglycolates; Triazoles; Urate Oxidase; Uricosuric Agents

Arhalofenate is a novel antiinflammatory uricosuric agent. The objective of this study was to evaluate its antiflare activity in patients with gout.. This was a 12-week, randomized, double-blind, controlled phase IIb study. Eligible patients had had ≥3 flares of gout during the previous year, had discontinued urate-lowering therapy and colchicine, and had a serum uric acid (UA) level of 7.5-12 mg/dl. Patients were randomly assigned at a 2:2:2:2:1 ratio to receive 600 mg arhalofenate, 800 mg arhalofenate, 300 mg allopurinol, 300 mg allopurinol plus 0.6 mg colchicine, or placebo once a day. The primary outcome measure was the flare incidence (number of flares divided by time of exposure). The serum UA level was a secondary outcome measure.. A total of 239 gout patients were randomized and took at least 1 dose of study medication. The primary outcome measure comparing flare incidence between 800 mg arhalofenate and 300 mg allopurinol was achieved, with a 46% decrease in the 800 mg arhalofenate group (0.66 versus 1.24; P = 0.0056). Treatment with 800 mg arhalofenate was also significantly better than placebo (P = 0.049) and not significantly different from treatment with 300 mg allopurinol plus 0.6 mg colchicine (P = 0.091). Mean changes in serum UA level were -12.5% with 600 mg arhalofenate and -16.5% with 800 mg arhalofenate (P = 0.001 and P = 0.0001, respectively, versus -0.9% with placebo). There were no meaningful differences in adverse events (AEs) between groups, and there were no serious AEs related to arhalofenate. Urinary calculus occurred in 1 patient receiving 300 mg allopurinol. No abnormal serum creatinine values >1.5-fold the baseline value were observed in the arhalofenate-treated groups.. Arhalofenate at a dosage of 800 mg decreased gout flares significantly compared to allopurinol at a dosage of 300 mg. Arhalofenate was well tolerated and appeared safe. Arhalofenate is the first urate-lowering antiflare therapy.

Topics: Acetamides; Allopurinol; Double-Blind Method; Female; Gout; Gout Suppressants; Humans; Male; Middle Aged; Phenylacetates; Treatment Outcome

Gout is common in the elderly, affecting an estimated 4.7 million people aged > 60 years in the USA alone. The incidence and prevalence of gout increases, and male predisposition to gout reduces, with increasing age. The elderly have more comorbidities, and gout manifests differently, with more frequent involvement of knees, ankles, and wrists at disease onset, systemic upset, and tophi. Comorbidities and polypharmacy make the management of gout flares challenging in this population. Intra-articular corticosteroid injection remains the treatment of choice for accessible joints, oral prednisolone is preferred over low-dose colchicine, and non-steroidal anti-inflammatory drugs (NSAIDs) are best avoided. Xanthine oxidase inhibitors (XOI) remain the first-line treatment for hyperuricemia in the elderly. Arhalofenate, an emerging uricosuric anti-inflammatory drug, prevents gout flares while reducing serum urate. It may be particularly relevant in the treatment of gout in the elderly as they are unable to tolerate long-term colchicine for flare prophylaxis and frequently have contraindications to corticosteroids and NSAIDs. However, given its modest urate-lowering effect, it can only be used in combination with an XOI, and the safety and efficacy of this drug has not been examined in the elderly or in those with chronic kidney disease. Diuretics and beta-blockers should be discontinued where feasible, whereas low-dose aspirin can be continued if otherwise indicated.

Topics: Acetamides; Adult; Age Factors; Aged; Aged, 80 and over; Anti-Inflammatory Agents, Non-Steroidal; Colchicine; Female; Gout; Gout Suppressants; Humans; Male; Middle Aged; Phenylacetates; Randomized Controlled Trials as Topic

Topics: Acetamides; Gout; Humans; Phenylacetates; Uricosuric Agents