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 Pegloticase is a bio-uricolytic agent in late-stage development for treatment-failure gout (TFG) to control hyperuricemia and to manage the signs and symptoms of gout. “Treatment-failure gout” is gout that occurs in patients who have failed to normalize serum uric acid and whose signs and symptoms are inadequately controlled with conventional urate-lowering therapy at the maximum medically appropriate dose or for whom conventional urate-lowering therapy is contraindicated.
Gout is a crystal deposition disease with primarily rheumatological and renal manifestations that results from the long-term effect of monosodium urate crystal deposition in and around joints, on extensor surfaces of tendons, and in other tissues such as the kidney. Deposition of urate crystals is thought to occur over long periods of time (decades) when uric acid levels in the blood are persistently above the limit of solubility. Acute pain and swelling of joints, or gout flare, is thought to result from the body’s immune response to these crystalline deposits.
Approximately three to five-million Americans suffer from this debilitating disease, many of whom experience only limited success in the long-term management of their painful symptoms. Within this group, we estimate that allopurinol, the mainstay of therapy for control of uric acid, is contraindicated or has failed to achieve therapeutic success at appropriate dose levels in approximately 25,000 to 100,000 patients, meaning that tens of thousands of gout patients have no effective treatment option. It is for these TFG patients that pegloticase potentially offers a unique benefit and for which the product has been granted orphan drug designation.
Over the years, most drug discovery research in gout has focused on methods to block uric acid production (xanthine oxidase inhibitors) or enhance its excretion (uricosuric agents). Despite these efforts, gout remains a problematic disease for patients and physicians. New approaches for reducing uric acid levels and thereby, eliminating urate crystals from tissues are needed.
Pegloticase is a recombinant, PEGylated formulation of a modified mammalian urate oxidase intended to lower the blood level of uric acid safely and continuously in patients who have not benefited from conventional therapeutic approaches. Urate oxidase is an enzyme present in almost all mammals – but not in humans – that lowers uric acid levels converting uric acid into allantoin, a benign end metabolite which is easily excreted in the urine.
Our six month Phase 3 program, which was conducted under the auspices of an approved (by the FDA) Special Protocol Assessment, measured the efficacy and safety of pegloticase 8mg every two weeks or every four weeks by intravenous infusion as compared to placebo. The primary efficacy endpoint was the comparison of the proportion of subjects in either pegloticase treatment arm versus placebo that attained normalization of plasma uric acid for at least 80% of the time during Months 3 and 6. The effect of pegloticase on clinical outcomes beyond the normalization of uric acid, which is a biochemical marker of disease, was also assessed rigorously and included:
- Elimination of gout tophi (as demonstrated by digital photography, image analysis, central reading)
- Reduction in frequency and incidence of gout flares
- Improvement in the number of swollen and tender joints
- Overall improvement in patient-reported outcomes
In December 2007, we announced that pegloticase met the pre-specified primary efficacy endpoint in the two replicate Phase 3 studies in treatment-failure gout patients for both pegloticase dose regimens. The Phase 3 trials consisted of two replicate protocols, each a randomized, double-blinded, placebo-controlled study of six months duration. Pegloticase (or placebo) was administered in a 2 hour intravenous infusion, similar to other biological drugs. Approximately 110 patients were randomized into each study. Each study had three arms: placebo, Puricase 8 mg every two weeks, or Puricase 8 mg every four weeks. In order to maintain the treatment blind in these studies, every patient received an infusion every two weeks, which was either a pegloticase or placebo infusion.
In follow-on to the Phase 3 studies, we established an Open Label Extension protocol in which all patients who completed the Phase 3 program could elect to participate. This protocol allows patients the opportunity to receive pegloticase in a carefully monitored environment, or to remain for observation without pegloticase treatment.
At the end of 2008, the FDA accepted for review the Company's Biologics License Application (BLA) for pegloticase and granted it with a priority review status which accelerates the review period to six months. A priority review designation is assigned to drugs that are deemed by the FDA to have the potential to provide an important advancement in treatment or provide a treatment for which there is no adequate therapy available. Under priority review, the target date for an FDA decision on the pegloticase BLA is August 1, 2009.
If approved, we would look forward to a successful entry into the rheumatology marketplace in 2009 with a uniquely innovative product that may be able to address a fundamental and elusive problem facing patients living with treatment-failure gout.
If you are a patient or a physician wishing to learn more about the Phase 3 protocols, please use the following links:
Savient has licensed worldwide rights to the technology related to Puricase from Duke University and Mountain View Pharmaceuticals, Inc. Puricase is a registered trademark of Mountain View Pharmaceuticals, Inc.
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