Potential Markets for Pegsitacase
Uric acid is a poorly soluble end product of purine nucleotide metabolism. In all mammals except humans and some New World monkeys, the enzyme uricase breaks down uric acid into the highly soluble allantoin; the absence of uricase in humans results in relatively high uric acid levels that can sometimes result in the formation of urate crystals. Urate crystals can be deposited in a variety of soft tissues, leading to intensely painful joint inflammation, the formation of tophi and renal calculi, and if in the case of acute elevations of uric acid seen in tumor lysis syndrome, can cause renal failure.
Target Market: Gout
Gout is an intermittent inflammatory arthritis caused by the formation of urate crystals in joint fluid. It is a common disease with increasing incidence, driven mainly by an aging population (the likelihood of having elevated levels of uric acid increases sharply with age over 65). Although the majority of those with elevated uric acid do not have symptoms of gout, over time, a substantial portion will experience one or more attacks of acute gout. In addition to increasing the propensity for gout flares, chronically elevated uric acid can result in deposition of urate crystals and associated inflammatory cells in joints and soft tissue, forming masses called tophi, and can lead to the development of kidney stones.
An acute gout flare may last for several days and is managed mainly by treating pain and inflammation. For patients with more than three attacks per year, treatment with uric acid-lowering drugs is warranted. The majority of patients requiring chronic therapy are treated with the xanthine oxidase inhibitors allopurinol or fubuxostat (Uloric), which inhibit the synthesis of uric acid. While many gout patients have a great benefit from these drugs, some cannot tolerate the drugs or do not have an adequate response. These gout patients may continue to have gout flares, experience a destructive arthritis and develop uric acid deposits called tophi. These patients have few therapeutic options.
Targeted Market: Tumor Lysis Syndrome
Tumor lysis syndrome is an oncologic emergency characterized by severe electrolyte abnormalities, high uric acid levels, and commonly results in acute renal failure. It typically occurs in patients with certain kinds of leukemias or lymphomas upon administration of chemotherapy. Treatment of the cancer rapidly kills large numbers of tumor cells, resulting in the release of potassium, phosphate, and DNA from the dying tumor cells. The purines in the DNA are metabolized into uric acid, and the resulting rapid increas in uric acid levels can lead to deposition of urate and calcium phosphate crystals in the kidneys. Although tumor lysis syndrome is most commonly observed in pediatric patients with high-grade tumors, for example acute lymphocytic leukemia and Burkitt’s lymphoma, it has also been reported to occur in adults and in many solid tumors, including lung and breast cancer. The hyperuricemia associated with tumor lysis syndrome tends to develop around two to three days after the initiation of chemotherapy, although some patients with very high tumor loads can present with elevated uric acid and signs of renal failure before treatment has even been initiated. Currently, treatment of tumor lysis syndrome consists of administration of allopurinol and, in some cases, use of an unpegylated uricase, rasburicase (Elitek®). Because rasburicase is unmodified, it must be administered repeatedly and can only be administered for short periods of time before antibodies against it develop.