Karyopharm Therapeutics Inc. announced the initiation of a Phase 1/2 study of oral KPT-8602, a novel, second generation, small-molecule selective inhibitor of nuclear export (SINE) protein XPO1, in patients with relapsed/refractory multiple myeloma (MM). This first-in-human study is designed to evaluate the safety, tolerability and activity of approximately eight dose levels of KPT-8602 in up to 116 patients in multiple centers in the United States and Canada. This dosing schedule and tolerability profile, if translated to the clinic, has the potential to yield a drug profile distinct from selinexor, Karyopharm's first-in-class, oral SINE compound.

More frequent dosing provides continuous XPO1 inhibition and the potential for differentiated tolerability, efficacy, and combinability with available oncology treatments and targeted therapies. This first-in-human study represents a key expansion of the clinical pipeline and a new avenue for exploring and leveraging the mechanism for XPO1 inhibition in hematologic malignancies. Data from several preclinical studies of KPT-8602 presented at the 2015 American Society of Hematology (ASH) annual meeting demonstrated that the compound had single-agent anti-MM activity.

In addition, KPT-8602 showed synergistic activity against MM when combined with bortezomib, carfilzomib, doxorubicin, melphalan, topotecan, or VP16 as shown in proliferation and/or apoptosis assays on parental or drug-resistant cell lines, or patient derived MM samples. KPT-8602 was shown to have anti-MM activity in human tumor xenograft models as a single agent or in combination with melphalan. Promising preclinical efficacy included apparent cures in difficult murine models of AML and CLL.

KPT-8602 represents a novel chemical series with pharmacological properties distinct from selinexor with more reversible binding to XPO1, similar potency in cell-based assays and substantially reduced brain penetration.