On June 22, 2016 Karyopharm Therapeutics Inc. (Nasdaq:KPTI), a clinical-stage pharmaceutical company reported dosing of the first patient in a Phase 1 clinical trial evaluating KPT-9274, an oral, first-in-class, dual-acting p21-activated kinase 4 (PAK4) and nicotinamide phosphoribosyltransferase (NAMPT) inhibitor, in patients with advanced solid malignancies (including sarcoma, colon and lung cancer) or non-Hodgkin’s lymphoma (NHL) whose disease has relapsed after standard therapy(s) (NCT02702492) (Press release, Karyopharm, JUN 22, 2016, View Source [SID1234517065]).

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This first-in-human, multi-center, open-label, dose-escalation trial is expected to enroll up to 175 patients. The primary endpoints of this study are to determine the recommended Phase 2 dose (RP2D) and the maximum tolerated dose (MTD) of KPT-9274 administered alone and with extended release niacin, and to evaluate safety and tolerability. The key secondary endpoint is to assess anti-tumor activity in patients predicted to be more sensitive to PAK4/NAMPT inhibition, including those with NAPRT-deficient tumors and tumors harboring IDH1 mutations.

"Our first-in-class, oral, small molecule PAK4 and NAMPT modulator, KPT-9274, has synergistic anti-tumor effects through several mechanisms including immune cell activation by inhibiting ß-catenin, reduction of NAD levels which tumor cells use as a key energy source, blockade of DNA damage repair mechanisms, and induction of tumor cell apoptosis," said Sharon Shacham, PhD, MBA, President and Chief Scientific Officer of Karyopharm. "We are encouraged by the preclinical profile of KPT-9274, highlighted at the 2015 American Society of Hematology (ASH) (Free ASH Whitepaper) and 2016 American Association of Cancer Research annual meetings, which support the novel mechanism and demonstrated encouraging preclinical anti-tumor activity. To our knowledge, we are the only company with a compound in clinical development that directly targets both PAK4 and NAMPT. This important Phase 1 study will continue to build upon the body of scientific evidence supporting KPT-9274’s safety and efficacy, and we look forward to reporting top-line data next year."

This Phase 1 clinical study is supported by extensive preclinical data demonstrating KPT-9274’s anti-cancer activity against hematological and solid tumors while showing minimal toxicity to normal cells in vitro. Preclinical studies demonstrate that by blocking PAK4, KPT-9274 potently inhibits ß-catenin as well as certain Ras oncogene-dependent pathways. ß-catenin is believed to be a key mediator of immune suppression, including resistance to immune-activating therapies. In addition, both ß-catenin and Ras are key growth signaling pathways for many common tumors such as colon and lung cancers. NAMPT, which can be found in a complex with PAK4 within the cell, is a pleiotropic protein with intra- and extra-cellular functions as an enzyme, cytokine, growth factor and hormone, and is thought to play a role in cellular energy metabolism. Hematologic and solid tumor cells become dependent on both PAK4 and NAMPT pathways and are therefore susceptible to single-agent cytotoxicity by KPT-9274. In mouse and rat xenograft studies, orally administered KPT-9274 showed robust anti-cancer activity with favorable tolerability. Based on in vitro and in vivo activity, Karyopharm believes KPT-9274 holds significant potential for the treatment of a wide variety of both solid and hematological cancers.

About KPT-9274

KPT-9274 is a first-in-class, orally bioavailable, small molecule immunometabolic modulator that works through non-competitive dual inhibition of p21-activated kinase 4 (PAK4) and nicotinamide phosphoribosyltransferase (NAMPT). Co-inhibition of these targets is believed to lead to synergistic anti-tumor effects through suppression of ß-catenin by blocking PAK4, leading to both immune cell activation and inhibition of tumor growth, energy depletion through NAMPT inhibition, blockade of DNA repair, cell cycle arrest and ultimately apoptosis. KPT-9274 may therefore have both immune-activating and direct antitumor effects. In contrast, normal cells are less sensitive to inhibition by KPT-9274 due in part to their relative genomic stability and lower metabolic demands.