Pegloticase (trade name Krystexxa) is a medication for the treatment of severe, treatment-refractory, chronic

gout Gout ( ) is a form of inflammatory arthritis characterized by recurrent attacks of a red, tender, hot and swollen joint, caused by deposition of monosodium urate monohydrate crystals. Pain typically comes on rapidly, reaching maximal intensit ...

. It is a third line treatment in those in whom other treatments are not tolerated. The drug is administered by infusion

intravenous Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutrie ...

ly. It was developed by

Savient Pharmaceuticals Savient Pharmaceuticals was a New Jersey-based biopharmaceutical company. Its lead product, pegloticase, was a biologic drug for treatment resistant chronic gout, which it marketed beginning in 2011. It also marketed oxandrolone beginning in ...

. It was approved in the United States in 2010, after two clinical trials found it lowered uric acid levels and reduced deposits of uric acid crystals in joints and soft tissue. The

European Medicines Agency The European Medicines Agency (EMA) is an agency of the European Union (EU) in charge of the evaluation and supervision of medicinal products. Prior to 2004, it was known as the European Agency for the Evaluation of Medicinal Products or Euro ...

(EMA) granted marketing authorization in 2013 for treatment of disabling tophaceous gout. In 2016 this authorization was ended in Europe.

Medical uses

It is an option for the 3% of people with gout who are intolerant to other medications. Pegloticase is given as an intravenous infusion every two weeks, and has been found to reduce uric acid levels in this population. There is moderate quality evidence that It is useful for

tophi A tophus (Latin: "stone", plural tophi) is a deposit of monosodium urate crystals, in people with longstanding high levels of uric acid in the blood, a condition known as hyperuricemia. Tophi are pathognomonic for the disease gout. Most people wit ...

but has a high rate of side effects and withdrawals due to adverse events. About 40% of people develop resistance to the medication over time.

Side effects

In individuals with

glucose-6-phosphate dehydrogenase deficiency Glucose-6-phosphate dehydrogenase deficiency (G6PDD), which is the most common enzyme deficiency worldwide, is an inborn error of metabolism that predisposes to red blood cell breakdown. Most of the time, those who are affected have no symptoms. ...

, pegloticase may precipitate a severe, life-threatening

hemolysis Hemolysis or haemolysis (), also known by several other names, is the rupturing (lysis) of red blood cells (erythrocytes) and the release of their contents (cytoplasm) into surrounding fluid (e.g. blood plasma). Hemolysis may occur in vivo o ...

with methemoglobinemia; it is therefore contraindicated in such individuals. Pegloticase may also show

immunogenicity Immunogenicity is the ability of a foreign substance, such as an antigen, to provoke an immune response in the body of a human or other animal. It may be wanted or unwanted: * Wanted immunogenicity typically relates to vaccines, where the injectio ...

Mechanism of action

Pegloticase is a recombinant

porcine The pig (''Sus domesticus''), often called swine, hog, or domestic pig when distinguishing from other members of the genus '' Sus'', is an omnivorous, domesticated, even-toed, hoofed mammal. It is variously considered a subspecies of ''Sus ...

-like

uricase The enzyme urate oxidase (UO), uricase or factor-independent urate hydroxylase, absent in humans, catalyzes the oxidation of uric acid to 5-hydroxyisourate: :Uric acid + O2 + H2O → 5-hydroxyisourate + H2O2 :5-hydroxyisourate + H2O → allan ...

. Similarly to

rasburicase Rasburicase (trade names Elitek in the US and Fasturtec in the EU) is a medication that helps to clear uric acid from the blood. It is a recombinant version of urate oxidase, an enzyme that metabolizes uric acid to allantoin. Urate oxidase is kn ...

, it metabolises

uric acid Uric acid is a heterocyclic compound of carbon, nitrogen, oxygen, and hydrogen with the formula C5H4N4O3. It forms ions and salts known as urates and acid urates, such as ammonium acid urate. Uric acid is a product of the metabolic breakdown of ...

allantoin Allantoin is a chemical compound with formula C4H6N4O3. It is also called 5-ureidohydantoin or glyoxyldiureide. It is a diureide of glyoxylic acid. Allantoin is a major metabolic intermediate in most organisms including animals, plants and bacter ...

. This reduces the risk of precipitates, since allantoin is five to ten times more soluble than uric acid. In contrast to

, pegloticase is

pegylated PEGylation (or pegylation) is the process of both covalent and non-covalent attachment or amalgamation of polyethylene glycol (PEG, in pharmacy called macrogol) polymer chains to molecules and macrostructures, such as a drug, therapeutic protein ...

to increase its elimination half-life from about eight hours to ten or twelve days, and to decrease the immunogenicity of the foreign uricase protein. This modification allows for a dosing interval of two to four weeks, increasing its suitability for long-term treatment.

Chemistry

Pegloticase is a

tetramer A tetramer () (''tetra-'', "four" + '' -mer'', "parts") is an oligomer formed from four monomers or subunits. The associated property is called ''tetramery''. An example from inorganic chemistry is titanium methoxide with the empirical formula Ti ...

ic protein composed of four identical chains of about 300

amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...

s each. Approximately nine of the 30

lysine Lysine (symbol Lys or K) is an α-amino acid that is a precursor to many proteins. It contains an α-amino group (which is in the protonated form under biological conditions), an α-carboxylic acid group (which is in the deprotonated −C ...

residues in each chain are pegylated. These PEG chains consist of about 225

ethylene glycol Ethylene glycol (IUPAC name: ethane-1,2-diol) is an organic compound (a vicinal diol) with the formula . It is mainly used for two purposes, as a raw material in the manufacture of polyester fibers and for antifreeze formulations. It is an odo ...

units each (10 kg/mol PEG).

References

External links

DailyMed
{{Antigout preparations Antigout agents