pexmetinib (ARRY-614)

P1/2, N=70, Active, not recruiting, Jason J. Luke, MD | N=144 --> 70 | Trial completion date: Jun 2027 --> Nov 2027 | Trial primary completion date: Mar 2026 --> Nov 2027 | Recruiting --> Active, not recruiting

We found four compounds:1D6-Foretinib GSK1363089; 15F6-Poziotinib (HM781-36B); 15F9-Dasatinib monohydrate; 15A10-Pexmetinib (ARRY-614); acts as potent inhibitors of necroptosis (Necroptosis Blocking Compounds, NBCs) by blocking the RIPK3 kinase activity. In our study, we explored the role of NBCs in neuroprotection after traumatic brain injury. It's effectiveness in traumatic brain injury animal models and favorable safety profiles make it a potential candidate for the advances of new therapies for necroptosis-associated neuroinflammatory disorders.

P1/2, N=144, Recruiting, Jason J. Luke, MD | Trial completion date: Jun 2024 --> Jun 2027 | Trial primary completion date: Mar 2023 --> Mar 2026

PKT mice were treated daily with pexmetinib, gemcitabine and paclitaxel chemotherapy, or combination therapy for downstream analysis and survival studies. Both pharmacologic and genetic inhibition of p38α significantly reduced IL1A transcription and protein levels in human and murine PDAC tumor cell lines. These findings provide a new therapeutic opportunity to target the p38α MAPK pathway for suppression of IL1α-mediated stromal activation and combination with chemotherapy to overcome therapeutic resistance by modulating the stromal and immune microenvironment in PDAC.

Ptf1acre/+;LSL-KrasG12D/+; Tgfbr2flox/flox (PKT) mice were treated with vehicle control, the p38 inhibitor, pexmetinib (30mg/kg, daily PO), gemcitabine (30mg/kg IP) and paclitaxel (10mg/kg, IP), or combined chemotherapy and pexmetinib, for 2.5 weeks prior to sacrifice. These findings elucidate a novel mechanism of IL-1/p38 pathway inhibition in reprogramming the inflammatory stroma and overcomes the immunosuppressive TME of PDAC resulting in overcoming therapeutic resistance and improving survival in a genetic mouse model of PDAC. These data provides preclinical evidence to pursue targeted p38 MAPK inhibition to improve outcomes in PDAC.

Furthermore, Pexmetinib suppressed breast cancer-associated osteolysis in vivo. These results suggest that Pexmetinib may be a promising drug for the treatment of breast cancer-induced osteolysis.

P1/2, N=144, Recruiting, Jason J. Luke, MD | Trial completion date: Nov 2021 --> Jun 2024 | Trial primary completion date: Nov 2021 --> Mar 2023