Novel Gout Treatment

About

Hyperuricemia (HA), elevated serum urate levels, is a major risk factor for gout, the major form of arthritis globally. It is estimated to affect approximately 3.9% of adults in the United States (8.3 million). Old drugs are current gold standards (colchicine, allopurinol) and many have adverse side effects with black-box warning labels - drug compliance is poor. There are two main classes of drugs: urate synthesis inhibitors (USI) - drugs that prevent uric acid production by xanthine oxidase (XO); or drugs that enhance renal excretion by inhibiting reabsorption (uricosurics). Uricosurics in particular have safety issues. Chronic gout guidelines recommend lowering UA levels by the use of USI, such as allopurinol or Uloric (febuxostat), as the first-line treatment. However, inability to achieve target UA levels with USI has led to co-treatment or combination drug development with uricosurics. Finally, for the treatment of refractory gout an injectable drug, Kytrexxa (pegylated uricase) is used to actively transform uric acid into a more readily excretable form, allantoin. Kytrexxa use is limited by severe safety limitations: black box warning for anaphylaxis and infusion reactions (up to 90% patients have antibody response) and is contraindicated in patients with G6PD deficiency. Thus there remains a significant unmet need for safe and efficacious treatments in both hyperuricemia and gout. HA has unique biophysical properties making it valuable in a number of existing products. However a major limitation in vivo is that HMW HA degrades into LMW forms which are proinflammatory by activating Toll-like Receptor-4 (TLR4). Researchers at Queen’s University have now identified novel N-acyl analogs of HA, in particular N-butyl HA (BHA), which prevent LMW HA from activating TLR4 and the inflammasome – a key mechanism involved in the pathogenesis of hyperuricemia and gout. Hyperuricemia is also associated with oxidative stress due to production of reactive oxygen species (ROS) from increased XO expression and activity. Such species result in degradation of HMW HA producing LMW HA and further activating TLR4 and inflammasome. Finally, urate itself is an activator of the inflammasome via TLR4 further supporting the potential benefit of this novel HA analogs in treating hyperuricemia. The potential benefit of BHA in treating hyperuricemia and gout has been borne out in preclinical models. TLR4 has be demonstrated to be essential for the mouse gout model induced by urate monohydrate injection into joints. Thus the researchers chose this model as a first test for in vivo activity of BHA. In this model, a single 10 µg or 50 µg injection of BHA was given into joints of mice concomitantly with the monosodium urate. These treatments were compared to a current standard clinical treatment, colchicine, which was given prior to inducing the gout as well as after. In this model, BHA significantly reduced inflammation-induced swelling to control levels (controls received saline injection) and BHA reduced swelling more quickly and to a larger extent than colchicine. Concurrent with these benefits significant beneficial changes were seen in serums levels of Il-1β, IL-8, Il-10, MCP-1 and IFNγ. Furthermore, in a hyperuricemia rat model a short term treatment of BHA given intraperitoneally significantly reduced serum uric acid as did oral allopurinol. Similarly BHA significantly reduced creatinine and urea nitrogen in liver and serum, significantly reduced XO activity in liver, and significantly reduced ROS levels in serum and liver.