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 Puricase is a pegylated recombinant urate oxidase in late stage development as a treatment for patients who suffer from gout, and for whom conventional therapy is contraindicated or has been ineffective. In the current development program, it is administered by two hour intravenous infusion either every two weeks, or every four weeks. All of the gout patients that have been studied with Puricase treatment have hyperuricemia and signs or symptoms of gout, as well as a history of gout “treatment-failure” with conventional therapy, i.e. allopurinol.
Puricase has the potential to greatly improve the quality of life for people living with gout, one of the most common rheumatic illnesses. 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 treatment-failure patients that Puricase potentially offers a unique benefit and for which the compound has been granted Orphan drug designation.
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 localized immune response to these crystalline deposits, whereas the mechanism by which joint cartilage and bone slowly degrade is less well understood. Evidence suggests that the chronic elevation of uric acid associated with gout may also have systemic consequences, including an increased risk for kidney dysfunction and cardiovascular disease.
Over the years, most drug discovery research in gout has focused on methods to block uric acid production or enhance its excretion. 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 important.
Puricase is a recombinant, PEGylated formulation of a modified porcine urate oxidase intended to dramatically lower the blood level of uric acid safely and continuously in patients who have not benefited from conventional therapeutic approaches. Urate oxidase is a hepatic enzyme present in almost all mammals – but not in humans – that lowers uric acid levels in the blood by converting uric acid into allantoin, a benign substance which is then easily excreted in the urine. Our Phase 2 trial in symptomatic, hyperuricemic gout patients with a history of treatment-failure, showed that Puricase is capable of delivering rapid, substantial, and sustained reduction of plasma urate levels in most “treatment-failure” patients.
The Puricase Phase 3 program is nearing completion. The first patient dosing occurred in June 2006. Completion of patient dosing is expected in October 2007. Phase 3 consists of two replicate protocols; each a randomized, double-blinded, placebo controlled study of six months duration. Puricase (or placebo) is administered in a 2 hour intravenous infusion, similar to other biological drugs. Approximately 110 patients were randomized into each study. Each study has three arms: placebo, Puricase 8 mg given every 2 weeks, or Puricase 8 mg given every 4 weeks. In order to maintain the treatment blind in these studies, every patient receives an infusion every two weeks, which may be a placebo infusion or Puricase.
Our Phase 3 program, conducted under the auspices of an approved (by the FDA) Special Protocol Assessment, measures the key efficacy outcomes most important to gout patients. The Phase 3 studies are designed to provide detailed tolerability and safety data as well.
The most important of the efficacy outcomes will be a demonstration that Puricase can deliver normalization of the plasma uric acid level in a statistically significant proportion of patients, i.e. a responder analysis for uric acid control. The effect of the drug on clinical outcomes beyond the normalization of uric acid, which is only a biochemical marker of disease, will also be assessed rigorously and will include:
- Elimination of gout tophi (as demonstrated by digital photography, image analysis central reading)
- Reduction in frequency of gout flares
- Improvement in the number of swollen and tender joints
- Overall improvement in patient-reported outcomes.
We have created an Open Label Extension protocol in which all completed patients may elect to participate, so that these patients who have volunteered for Phase 3 study participation will have the opportunity to receive Puricase in a carefully monitored environment until marketing authorization is attained, after the Phase 3 program has concluded.
As noted above, the first patient dosing occurred in June 2006 and patient enrollment completed in March 2007. A Biologics License Application (BLA) submission is anticipated in early 2008.
We’re excited about the critical next steps in Puricase development and look forward to a successful entry into the rheumatology marketplace in 2009 with uniquely innovative product that may be able to address a fundamental and elusive problem facing patients living with treatment-failure gout.
The following abstract titles were selected for poster presentations at the European League Against Rheumatism (EULAR) 2007 Annual Meeting:
- “Pharmacokinetics and Pharmacodynamics of PEG-uricase in Patients with Hyperuricemia and Treatment-Failure Gout” (abstract #THU0358)
- “Validation of the SF-36 and HAQ-DI in Patients with Treatment-Failure Gout” (abstract #THU0359)
In addition to the two abstracts titles that were accepted for poster presentation, two additional abstracts have been accepted for publication on-line. These are:
- Weekly Flare Burden Index: A New Metric for Evaluating Gout Treatment (abstract #AB0748)
- Uric Acid Lowering Therapy for Gout: Patterns of Care (abstract #AB0745)
For information about the EULAR scientific program, please visit the Congress website at www.eular.org.
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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