New Therapy For Gout: Is It Worth It?

Krystexxa (pegloticase) is a newly approved therapeutic agent indicated for the treatment of gout, specifically, treatment failure gout (TFG). In order to understand this drug's role in the treatment of gout, one must first understand what gout is and how it affects the body. It is also important to know the drugs that are currently available for treating gout, both those used in the acute setting and in the chronic setting. Knowing these two pieces of information are critical in understanding the role of pegloticase in therapy.

There are three types of gout:acute, chronic, and treatment failure gout. Acute gout, or a gout attack, is a sudden onset of pain associated with the deposition of monosodium urate crystals. These crystals are also known as tophi. These tophi can become deposited in various tissues throughout the body. The most common areas infected involve joints of the hands and feet. These tophi can be very painful and can limit the mobility of the patient. Chronic gout is not necessarily associated with chronic pain, rather, it is a chronic state of high levels of uric acid in the blood, or hyperuricemia. Hyperuricemia is associated with an increased risk of a gout attack. Uric acid levels higher than6mg/dL are considered to be high.1 Treatment failure gout occurs when the treatment of chronic gout does not reduce the frequency of gout attacks or does not lower uric acid levels in the blood.1 In all cases hyperuricemia is the underlying problem. Hyperuricemia can develop due to one of two pathways or even both. It can be caused by overproduction of uric acid or under secretion of uric acid in the kidney.1 Uric acid production is the final step to the metabolism of purines and xanthines in humans. The enzyme xanthine oxidase is responsible for its production.2 This enzyme is an important site of action for some therapeutic agents used to treat gout.

The main goal of therapy in gout is to minimize the number of gout attacks and treat the underlying cause of hyperuricemia. In an acute gout attack, pain management also plays an important role. It is important to know that when treating an acute gout attack, one is not necessarily treating the underlying cause of hyperuricemia.1 In order to achieve these goals, many therapeutic agents are available to treat gout. In an acute gout attack, non-steroidal anti-inflammatory drugs (NSAIDs) are the first line choice for therapy.3 The most commonly prescribed NSAIDs used in gout therapy are indomethacin, ibuprofen, and diclofenac.3 The NSAIDs work by reducing the amount of inflammation in the affected joints. Another commonly used drug is colchicine. Colchicine is an antimitotic agent and its role in gout therapy, in terms of its mechanism of action, still remains unclear.2 Antihyperuricemic agents are used in the treatment of chronic gout. Allopurinol, febuxostat, probenecid, and sulfinpyrazone are the only drugs approved for use in the United States. A fifth drug, benzbromarone, is used in Europe as well. It is important to include this drug because it is still used in many studies involving gout worldwide. These drugs are only indicated when a patient has recurrent gout attacks for at least two years.1 Therapy with these agents should not begin until an acute gout attack has been resolved.1 The aim of therapy with these agents is to reduce or eliminate the size and number of tophi. Complete reduction of tophi has never been observed in a randomized clinical trial with any of these agents as it may take years for tophi to dissolve, even when adequate levels of uric acid are maintained.1 These agents have also been known to cause an acute gout attack due to the mobilization of uric acid.1 Allopurinol and febuxostat both work by inhibiting xanthine oxidase, the enzyme responsible for production of uric acid. The other three agents work by inhibiting the renal tubular reabsorption of uric acid. The final class of medications used in gout therapy are urate oxidases. These drugs are enzymes which metabolize uric acid to an inactive, water-soluble product called allantoin. The newest drug in this class is Krystexxa.

Krystexxa (pegloticase) is a recombinant polyethylene glycol (PEG) conjugated mammalian enzyme. It was approved as orphan drug status in 2001but was not FDA approved for use until 2010. It is an enzyme that was isolated from pigs and then conjugated with PEG to increase its half-life dramatically.1 The half-life of this drug (14.5 days) is long enough where it does not have to be dosed every day.4Instead, it is dosed every two weeks. According to the FDA, there are three major safety concerns associated with pegloticase. Because this medication is an enzyme, the immune system can develop antibodies against pegloticase. These antibodies are called antipegloticase antibodies. They can dramatically reduce the half-life of the drug which decreases the drugs duration of action. The second major concern is an increase incidence of cardiovascular events. These events are non-specific and in clinical trials they only occurred in patients who were already predisposed to conditions such as congestive heart failure, arrhythmias, ischemia, etc.1The third major concern involves infusion reactions and allergic reactions. To reduce these events from happening, antihistamines, corticosteroids, or both may be administered prior to the infusion.3 The enzyme oxidizes uric acid to allantoin and produces hydrogen peroxide and carbon dioxide as biproducts.1 Pegloticase should be used cautiously or not used at all in patients who are glucose-6-phosphate dehydrogenase deficient because of the formation of hydrogen peroxide which can lead to complications including hypertension or even diabetes mellitus.1, 5

Three major studies were done that investigated the effectiveness of Krystexxa. The first study was a phase II randomized clinical trial that consisted of 41 patients with treatment failure gout. These patients were split into four groups based on a dosing regimen. These groups were as follows:4mg or 8mg given every 2 weeks and 8mg or 12mg given every 4 weeks. These patients were all treated for 12-14weeks. In all groups, serum uric acid levels dropped below 6mg/dL within 6 hours. It was found that patients taking 8mg every 2 weeks was superior to both4mg every 2 weeks and those taking 8mg every 4 weeks. Patients taking 12mg every 4 weeks showed no added benefit when compared to those taking 8mg every 2 weeks. By the end of the study, fifteen people had withdrawn. Twelve of these people withdrew due to infusion reactions. In31 of these patients, antipegloticase antibody had developed and reduced the half-life and duration of action in all of these patients.6

The next two studies were phase III randomized, double-blind, clinical trials. These studies followed patients for 6 months. Patients were split into 2 groups: 8mg pegloticase every 2 weeks or placebo. It was shown that pegloticase decreased uric acid levels much faster than allopurinol and benzbromarone used in combination. Tophi dissolution was seen in 40% of the patients receiving pegloticase 8mg every 2 weeks.7, 8 A limiting factor for this medication is that it is estimated to cost about $100, 000 per patient per year.9 This may limit its role in therapy; however, if no other options are available, pegloticase may be the best choice.

Since Krystexxa is still a fairly new agent used for gout, its role in therapy may still be questioned. The drug is only approved as a last line option for patients who do not respond to other therapies. It has been shown to be an excellent agent for these patients, however, there is a very small number of people who are actually affected by treatment failure gout. It is estimated that about 1% of the, roughly, five million patients with gout end up being non-responders to therapy. A cost-benefit analysis may prove to be useful when deciding on a regimen that is best for the patient, however, there is no such analysis available yet, which may further hinder the drugs role in therapy. It will be interesting to see how patients respond to pegloticase in the real world, and also how it will affect the drug market.

1) Reinders MK, Jansen TL. New advances in the treatment of gout: review of pegloticase. Ther Clin Risk Manag. 2010; 6:543-50

2) Burke A, Smith E, Fitzgerald GA. Analgesis-antipyretic and anti-inflammatory agents;pharmacotherapy for gout in: Brunton LL, Lazo JB, Parker KL. Goodman and Gilman'sThe Pharmacological basis of Therapeutics. 2006(11); 706-12

3) TauscheAK, Jansen TL, Schrder HE, Bornstein SR, Aringer M, M ller-LadnerU. Gout--current diagnosis and treatment. DtschArzbel Int. 2009 Aug; 106(34-35): 549-55

4) Krystexxa [package insert]. 2009. SavientPharmaceuticals. East Brunswick, NJ.

5) Gaskins RS, Estwick D, Peddi R. G6PDdeficiency; its role in the high prevalence of hypertension and diabetes mellitus. Ethn Dis. 2001. Fall;11(4): 749-54.

6) Sundy JS, et al. Reduction of plasma urate levels following treatment with multiple doses of pegloticase (polyethyleneglycol-conjugated uricase) in patients with treatment-failure gout: results of a phase II randomized study. Arthritis Rheum. 2008 Sep; 58(9): 2882-91

7) Sundy JS, Baraf HS, Becker MA, et al. Efficacy and safety of intravenous (IV) pegloticase (PGL) in subjects with treatment failure gout (TFG): phase 3results from GOUT1 and GOUT2 [abstract] ArthritisRheum . 2008; 58 (Suppl9):S635

8) Sundy JS, Baraf HS, Becker MA, et al. Efficacy and safety of intravenous pegloticase (PGL) in treatment failure gout (TFG): results from GOUT1 and GOUT2 [abstract] Ann Rheum Dis . 2009; 68 (Suppl3):S318

9) Deys E. (2010, September 15).Shares rally as FDA approves gout drug. Reuters.Retrieved from http://uk.reuters.com/article/2010/09/15/savient-shares-idUKSGE68E0FS20100915