Dose Intensive Administration of PR-047, a Novel Orally Bioavailable Inhibitor of the 20S Proteasome, Is Well Tolerated in Experimental Animals.

Abstract 4910

Proteasome inhibition is a validated therapeutic strategy for the treatment of multiple myeloma. Carfilzomib (CFZ) is a selective and irreversible proteasome inhibitor that is intravenously administered and an has shown an encouraging safety and efficacy profile in myeloma patients from multiple Phase 2 studies (ASH2008:864&865). CFZ induces prolonged proteasome inhibition in vivo and can be safely administered to patients on dose intensive schedules (e.g. QDx5); however, such schedules lack patient convenience. PR-047 is a novel inhibitor in the same chemical class as carfilzomib that is orally bioavailable Similar to carfilzomib, PR-047 potently targets the chymotrypsin-like activity of the proteasome and induces anti-tumor responses in vitro and in vivo across a range of tumor cell types including myeloma cells. We describe here the proteasome selectivity of PR-047 in vitro and the pharmacodynamics and safety of repeat dose oral administration in experimental animals. We found PR-047, like CFZ, to be highly selective for proteasomal proteases as demonstrated by a lack of inhibitory activity against a panel of non-proteasomal proteases, including serine proteases targeted by dipeptide boronates such as bortezomib, (J. Med. Chem. 2008 51:1068). In rats, well tolerated oral doses resulted in rapid and potent (>80%) inhibition of proteasome activity when the compound was administered either as a solution or in a capsule formulation suitable for clinical use. Similar to carfilzomib, PR-047 was well tolerated when administered on a dose intense schedule. Oral dosing of PR-047 to mice and rats daily for 5 consecutive days resulted in proteasome inhibition following the 5^th dose that was equivalent to or greater than inhibition seen after the 1^st dose in whole blood and tissues. This suggests that PR-047 promotes prolonged proteasome inhibition in vivo. These doses were well tolerated in GLP-compliant toxicity studies in rats and dogs where PR-047 was administered for 2, 14-day cycles of QDx5 followed by nine days rest. The MTD in rats was ∼6 fold greater than the dose required for >80% proteasome inhibition, suggesting a significant therapeutic window. At the MTD, PR-047 did not affect renal or liver function and was not associated with anemia or leukopenia. In addition, PR-047 administration did not result in behavioral or histologic signs of neurotoxicity. Comparable doses were well tolerated in dogs on the same dose schedule. Similar to CFZ, PR-047 is a selective and irreversible proteasome inhibitors that has potent anti-tumor activity and is well tolerated on dose intensive schedules that result in prolonged proteasome inhibition. These studies support a safe starting dose for Phase 1 clinical trials with PR-047, a novel agent for the treatment of malignant diseases.