KPT-8602 is a second-generation SINE™ compound that, like selinexor, selectively blocks the nuclear export protein XPO1. Most of the key tumor suppressor proteins, or TSPs, are cargos of XPO1 and inhibition of XPO1 by KPT-8602 sequesters TSPs in the nucleus where they can carry out their normal functions. As KPT-8602 acts through induction of TSPs, it is selectively cytotoxic for cells with genomic damage, i.e., for tumor cells, both in vitro and in vivo. KPT-8602 and other SINE™ compounds are not intrinsically cytotoxic. Rather, they can restore the highly effective tumor suppressing pathways that lead to selective elimination of genomically damaged, or neoplastic, cells. Cancer cells with damaged genomes are induced to undergo apoptosis. Normal cells, with an intact genome, remain in a transient, reversible cell cycle arrest until the export block is relieved. Tumors of hematopoietic lineage are particularly susceptible to apoptosis induction by XPO1 inhibition; normal hematopoietic cells and their functions are largely spared.
In preclinical models, KPT-8602 has a broad therapeutic window with minimal penetration of the blood brain barrier and, therefore, has the potential to serve as a second generation SINE™ compound for cancer indications. Following oral administration, animals treated with KPT-8602 show lower percentage of body weight loss and improved food consumption than animals similarly treated with selinexor. This allows more frequent dosing of KPT-8602, enabling a longer period of exposure at higher levels than is possible with selinexor. As a result, we believe that KPT-8602 represents a second generation SINE™ compound and are evaluating safety, tolerability and efficacy in humans.
Following the completion of toxicology studies, we filed an investigational new drug, or IND, application for KPT-8602 with the FDA in November 2015. Our first-in-humans clinical trial for KPT-8602 is a Phase 1/2 study in patients with relapsed/refractory multiple myeloma. The first patient in the Phase 1 dose escalation portion of the study was dosed in January 2016.