Current development phase: Phase II/III

preclinical

phase i

phase ii

phase iii

preregistration

Febuxostat (Adenuric®) is a potent, non-purine selective inhibitor of xanthine oxidase (XO), approved in EU through a centralized procedure in April 2008 with the following indication: “treatment of chronic hyperuricaemia in conditions where urate deposition has already occurred (including history, or presence of tophus and/or gouty arthritis)”.

After completing the development in adults as preventive treatment of the Tumour Lysis Syndrome, in 2015 Febuxostat obtained the approval in Europe for the “prevention/treatment of the Tumour Lysis Syndrome in adult patients with haematological neoplasia treated with chemotherapy”.

In order to verify the efficacy in comparison to the current standard therapy of allopurinol, the phase III study FLORENCE has been conducted enrolling 347 patients with lymphoma and leukemia, in 79 highly specialized centers for the treatment of haematological tumours.

Febuxostat, compared to the standard of care, has shown in adult patients a significant superiority in the control of uricaemia in intermediate/high risk patients with tumor lysis syndrome.

Currently the fase I/II study FLORET is ongoing in the pediatric population for the same indication.

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Tumor Lysis Syndrome (TLS)

TLS is a critical and possibly fatal complication resulting from the rapid lysis of large numbers of tumor cells, observed most often after initial treatment with chemotherapy particularly in patients with haematological malignancies.
In this condition, the rapid release of intracellular metabolites can alter the normal homeostatic and electrolyte balances, potentially leading to severe hyperuricemia, hyperkalemia, hyperphosphatemia and hypocalcemia. The precipitation/crystallization of uric acid or calcium phosphate in renal tubules may then lead to impaired renal function/failure. In addition to acute renal failure, other important clinical manifestations of TLS, commonly observed within 12 to 72 hours after the initiation of cytoreductive therapy, may include: nausea, vomiting, diarrhea, anorexia, lethargy, edema, haematuria, heart failure, cardiac arrhythmias, seizures, muscle cramps, tetany and possibly death.
The risk of developing TLS or more simply the risk of developing acute renal impairment is significantly increased in patients with higher levels of uric acid versus those with lower levels. In light of this the “Guidelines for the management of paediatric and adult Tumor Lysis Syndrome” strongly recommend pharmacological prevention in addition to hydration prior to start chemotherapy in patients with haematological malignancies.
In general, the standard of care in prevention of TLS associated hyperuricemia is allopurinol which is considered an effective and well tolerated treatment. However, similarly to gout, there may be some limitations with the use of allopurinol in this indication, including:
1. need of careful dose-adjustment in patients with hepatic or renal impairment (the latter being a frequent condition in this patient population);
2. rare occurrence of serious drug-related hypersensitivity reactions;
3. inability to reach/maintain the recommended uric acid target levels in all the patients with TLS
To date, the only alternative treatment to allopurinol in TLS prevention is rasburicase a recombinant form of urate-oxidase that catalyzes the oxidation of uric acid into an inactive and soluble metabolite, allantoin. The use of rasburicase in clinical practice is up to now limited (where available) to the prevention of TLS in high risk patients or in the treatment of TLS.
In light of this, Febuxostat, which has already demonstrated its efficacy in decreasing serum urate levels in gout subjects and a good safety profile, may be an important addition in the armamentarium of TLS prevention.