Dose Intensive Administration of PR-047, a Novel Orally Bioavailable Inhibitor of the 20S Proteasome, Is Well Tolerated in Experimental Animals.
Authors: Muchamuel Tony , Kapur Shirin , Kirk Christopher J , Jiang Jing , Lee Susan , Bennett Mark K , Lewis Evan , Yang Jinfu , Jumaa Mouhannad , Ring Eileen , Phiasivongsa Pasit , Zhou Han-Jie , Wang Zhengping 
Published: October 2019

Abstract
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 5th dose that was equivalent to or greater than inhibition seen after the 1st 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.

Disclosures
Muchamuel: Proteolix Inc.: Employment. Kapur:Proteolix, Inc.: Employment. Kirk:Proteolix, Inc: Employment. Jiang:Proteolix, Inc.: Employment. Lee:Proteolix, Inc.: Employment. Bennett:Proteolix: Employment. Lewis:Proteolix, Inc.: Employment. Yang:Proteolix, Inc.: Employment. Jumaa:Proteolix, Inc.: Employment. Ring:Proteolix Inc.: Employment. Phiasivongsa:Proteolix Inc.: Employment. Zhou:Proteolix Inc.: Employment. Wang:Proteolix, Inc.: Employment.