Puricase, first new drug treatment approach for gout in 40 years, offers solution to unmet need

A new class of drug for tophaceous gout, the first to be developed in 40 years, is generating hope for patients currently unable to tolerate or respond to standard therapies. Puricase (PEG-Uricase), currently in phase III trials is being developed by Savient Pharmaceuticals Inc. a small company based in .

Puricase is a polyethylene-glycolated recombinant version of the porcine enzyme, uricase.  All mammals except humans and primates produce the uricase enzyme which breaks down uric acid leaving very low levels in the circulation with no untoward effects. Uricase converts uric acid to the more water-soluble metabolite allantoin that can be readily excreted. The drug is administered by two-hour intravenous infusions every two or four weeks and would probably be indicated initially for patients with hyperuricaemia – excess blood levels of uric acid resulting in severe tophaceous gout, resistant to or intolerant of conventional therapy.  The fortnightly and monthly regimens are currently being compared against placebo in phase III trials among patients who have failed standard therapy.

Uric acid build-up causes gout by formation of crystals deposited in joint tissues where they accumulate as tophi causing pain and inflammation.  Often these clump together to form disfiguring nodules.  Non-steroidal anti-inflammatory drugs (NSAIDs) are often used to control inflammation while other drugs are used to try and tackle the underlying problem.  These work by either reducing the formation of uric acid with drugs that need to be taken for life or increasing its rate of renal excretion with uricosuric agents.  

In the around 3 to 5 million people suffer from gout and similar numbers are affected in . Approximately a quarter to one third of all gout sufferers – around half a million people in the -develop tophi and gout flares despite conventional therapy, according to Savient’s Chief Medical Officer Zeb Horowitz.

About half of gout patients are treated with the oral therapy allopurinol which decreases urate production by inhibiting the enzyme xanthine oxidase.  Thousands of patients are unable to tolerate allopurinol, however, because of adverse reactions.  Often these are just gastro-intestinal effects, or the development of rash, but the most serious is a potentially life-threatening hypersensitivity reaction requiring steroid therapy and intensive care. The current alternatives are uricosuric drugs but these can also cause difficulties.  Liver toxicity problems, for example, caused benzbromarone, the latest of these drugs to be withdrawn in .

Savient presented Phase II data for Puricase used in treatment of patients failing allopurinol at this year’s annual European rheumatology meeting, EULAR. The data show 8mg of PEG-uricase every two weeks achieved rapid reductions in plasma urate to below target levels which were maintained over the study duration. Pre-treatment levels of 9.1mg/dl were reduced to a mean plasma urate level of 1.4mg/dl over 12 weeks.  (A level of 6mg/dl is required to avoid flares.)  President and CEO Christopher Clement commented: “Puricase is increasingly being recognised among the rheumatological community as a potential breakthrough treatment for this orphan gout patient population.”

A further Savient poster, showing photographic and radiographic evidence of the dramatic effects that Puricase can achieve in individuals who have failed other treatments, greatly impressed rheumatologists visiting the poster session.

Poster author Dr Herbert Baraf, a rheumatologist and Puricase trialist from , described a case study where a patient treated with PEG-uricase dropped their plasma uric acid level from 7.45mg/dl at baseline to 0.1mg/dl – the limit of detectability -within 24 hours.  This level persisted throughout the period of observation.  Before and after treatment photographs show how the patient’s tophi on the fifth distal interphalangeal joint of the right hand were radically reduced.  Similar reductions of tophi affecting the feet enabled the patient to recommence wearing the shoes he had previously had to abandon.

Dr Baraf said:   “Conventional treatment, if effective, reduces uric acid levels very slowly taking up to five years to obtain complete resolution of painful tophi.   Puricase however is able to radically reduce uric acid crystal stores within three to 12 months.“

“Many physicians and patients now believe older therapies are sub optimal and want better treatments,” commented Dr Horowitz.  Savient is hoping that, ultimately, the use of Puricase could be extended to earlier intervention as an alternative to conventional treatments . Early intervention with Puricase could potentially prevent the accumulation of uric acid crystals that form tophi and keep patients from experiencing flares, Dr Horowitz suggested.  Puricase would need only to be administered over six to 12 months to be able to eradicate body stores of uric acid.

Savient hopes to complete the Phase III trials before the end of next year and to make Puricase available to clinicians by 2009.  The company will market it in the itself but is currently seeking a partnership with a European company to develop Puricase for the European gout market.

To see more features by Olwen Glynn Owen follow this link to his first feature article and scroll to the end for a list:
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