Intravenous Forodesine (BCX-1777), a Novel Purine Nucleoside Phosphorylase (PNP) Inhibitor, Demonstrates Clinical Activity in Patients with Refractory Cutaneous T-Cell Lymphoma.

The profound suppression of T-cell immunity seen in patients with an inherited PNP deficiency supports the potential application of inhibitors of this purine salvage enzyme in the therapy of T-cell malignancies. Forodesine is an especially promising candidate for such a use since it is a potent and selective transition-state analog inhibitor of human PNP that has demonstrated clinical activity and a good safety profile in patients with advanced T-cell malignancies. A multi-center phase I/II dose-escalation study was conducted in which 9 doses of forodesine were administered to patients with refractory cutaneous T-cell lymphoma (CTCL) via a 30-minute intravenous infusion (day 1) followed 24 hours later by doses every 12 hours (days 2–5); three courses were given at 16-day intervals. To-date 13 patients with CTCL or Sezary syndrome, a prototype of CTCL, have been enrolled and treated with at least one course of forodesine. 9/13 patients had an improvement in skin and/or a pharmacodynamic response as measured by a decrease in the absolute Sezary cell numbers and/or the CD4/CD8 ratio (Table 1), although the percentage of Sezary cells did not change except for patient 03 (eg, 63.4% pre-course 3 diminished to 17.6% post-course 3). There was one complete response and two partial responses. The plasma 2′-deoxyguanosine (dGuo) concentration was elevated in all 13 patients (range: 1.7 – 12.8 μM) (Table 1). Forodesine was generally safe and well tolerated in this population; hyperuricemia was considered dose-limiting in only one patient.

Table 1. Clinical and pharmacodynamic activity of forodesine in CTCL/Sezary patients

2/4 patients (patients 06 and 09), who received further treatment with forodesine on compassionate use, continue to show evidence of clinical activity after 7–9 courses administered over 4–6 months. Additional clinical and pharmacodynamic data will be presented. These encouraging findings have led to the initiation of a phase I/II study of an oral formulation of forodesine in CTCL/Sezary patients.