Introduction

Descriptions of gout, in its many clinical presentations, go back many centuries, e.g., in the Greek and Roman literature. Gout has been disproportionately represented in prominent authority figures, including members of the French, Spanish, and British aristocracy. In fact, gout has been called the “disease of kings”. It is of interest that the chemical identity of uric acid was first established as a constituent of a renal calculus in 1776 and in a tophus in 1797. Half a century later, the so-called “thread test”, a semiquantitative method for the measurement of uric acid, was described as a diagnostic test for gout and hyperuricemia (1).

Drug Approvals

There have been a total of 8 new molecule approvals for gout and hyperuricemia, in 4 pharmacologic classes. The first pharmacologic class, microtubule polymerization inhibitors (exact mechanism in gout still unknown), has only 1 drug, colchicine, which has been in clinical use for several decades as colchicine preparations, and for centuries as its precursor Colchicum extract. The next two pharmacologic classes, uricosuric agents, which inhibit proximal tubular reabsorption of uric acid,  and xanthine oxidase inhibitors, which inhibit the conversion of uric acid from xanthine and hypoxanthine, had their beginnings with probenecid and allopurinol in 1951 and 1966, respectively. The most recent pharmacologic class involves urate oxidase or uricase, an enzyme that catalyzes the degradation of uric acid to a more soluble allantoin, with its first approval in 2002.

Refer to the accompanying chart below (click for a larger chart). In keeping with our convention, new formulations of approved drugs and new combinations of previously approved drugs are not included. The new molecule drug approvals are listed below:

• Microtubule Polymerization Inhibitors: 1 new molecule; Colcrys (colchicine, 2009, official FDA approval of colchicine occurred as part of the 2006 FDA safety program on Unapproved Drug Initiative).
• Uricosuric Agents: 3 new molecules; Benemid (probenecid, 1951), Anturane (sulfinpyrazone, 1953), and Zurampic (lesinurad, 2015).
• Xanthine Oxidase Inhibitors: 2 new molecules; Zyloprim (allopurinol, 1966) and Uloric (febuxostat, 2009).
• Uricase Preparations: 2 molecules; Elitek (rasburicase, recombinant uricase, 2002) and Krystexxa (pegloticase, pegylated uricase, 2010).

Comments

A few things stand out regarding gout and hyperuricemia therapeutics, as follows:

• The long and remarkable history of the alkaloid colchicine, perhaps the oldest drug still used today, traces its start to ancient times, including the first description of Colchicum extract from the plant autumn crocus (Colchicum autumnale) as a treatment of gout in the first century AD. Colchicine was first isolated in 1820, and first synthesized in 1959. Benjamin Franklin, a gout sufferer, is said to have used Colchicum extract while serving as the Ambassador to France, and to have brought Colchicum plants to North America.
• Numerous unapproved colchicine preparations had been in clinical use for several decades, until colchicine was officially approved by FDA in 2009, under the trade name Colcrys, as part of the 2006 FDA safety program on Unapproved Drug Initiative; shortly thereafter, all unapproved colchicine preparations were removed from the market.
• The long hiatus in new drug approvals for gout and hyperuricemia since the approval of allopurinol in 1966 until the approval of the recombinant uricase preparation rasburicase (Elitek) in 2002 – almost 36 years; eigth years later a pegylated uricase preparation was approved.
• The 2 other new drug approvals since 2009 involve the two other old pharmacologic classes, xanthine oxidase inhibitors and uricosuric agents, with the approvals of Uloric (febuxostat, 2009) and Zurampic (lesinurad, 2015), respectively.

Conclusions

Mechanistically, three of the four current pharmacologic classes for the treament of gout and hyperuricemia involve reducing uric acid levels, one class by reducing its production, i.e., xanthine oxidase inhibitors, which inhibit the conversion of uric acid from xanthine and hypoxanthine, and two classes by increasing its elimination, i.e., uricosuric agents by increasing the renal elimination of uric acid, and uricase preparations by increasing the conversion of uric acid to a more soluble and more readily eliminated allantoin. The fourth pharmacologic class represented by one drug, colchicine, works through multiple mechanisms of action affecting inflammatory processes, accounting for its efficacy in acute gout flare (2). Apart from possible new xanthine oxidase inhibitors and uricosuric agents, it would seem more plausible that new therapeutics for the treatment of acute gout would involve one or more of the anti-inflammatory mechanisms of colchicine.

References

1. Nuki G, Simkin PA. A concise history of gout and hyperuricemia and their treatment. Arthritis Research & Therapy, 8(Suppl 1):S1, 2006.
2. Dalbeth N, Lauterio TJ, Wolfe HR. Mechanism of action of colchicine in the treatment of gout. Clinical Therapeutics, 36 (10), 1465-1479, 2014.

Refer to Progression of Modern Therapeutics (2015 Report) available under Reports on this website, which includes the methodology used. Note the 2 uricase preparations have been added in this commentary.