PD-0325901 (MEK 1/2 Inhibitor)
PD-0325901 is an investigational oral, small molecule, selective inhibitor of MEK1 and MEK2, which are proteins that play key roles in the MAPK signaling pathway. The MAPK pathway is critical for cell survival and proliferation, and inappropriate activation of this pathway, as is the case when certain mutations occur in the NF1 gene, has been shown to help enable tumor growth. PD-0325901 has demonstrated an ability to block the activity of the MAPK pathway, which may help arrest uncontrolled cellular growth.
Results of a Phase 2 investigator-sponsored study in NF1-associated PN demonstrated tumor shrinkage in 42 percent of adolescents and adults (n=19). In this study, PD-0325901 given at 2mg/m2 on a 3-week on, 1-week off schedule was well-tolerated, with the most common dose-limiting toxicity being acneiform rash in 3/19 patients (16%). Five patients required a dose reduction, but no patients discontinued therapy due to adverse events. There were no grade 4 or higher toxicities and historical ocular and cardiovascular adverse events seen with the compound and class were not seen at this dose and schedule.
The U.S. Food and Drug Administration (FDA) has granted Orphan Drug designation for PD-0325901 for the treatment of NF1. SpringWorks is preparing to initiate a Phase 2b clinical trial evaluating PD-0325901 as a monotherapy for the treatment of patients with neurofibromatosis type 1 (NF1)-associated plexiform neurofibromas (PN), a rare and devastating condition for which there are currently no approved therapies.
How it is Designed to Work
MEK1 and MEK2 occupy pivotal positions in the MAPK pathway (RAS-RAF-MEK-ERK), a critical signaling network regulating cell growth and survival. The NF1 gene encodes a protein called neurofibromin, which acts as a negative repressor of RAS activation. NF1 mutations can result in the loss of neurofibromin activity, which leads to MAPK pathway overactivation, uncontrolled cellular growth, and tumor formation.
- Weiss, B., et al. NFM-06. NF106: Phase 2 Trial of the MEK Inhibitor PD-0325901 in Adolescents and Adults with NF1-related Plexiform Neurofibromas: An NF Clinical Trials Consortium Study. Neuro Oncol. 2018 June 22; 20(2):143-143. doi: 10.1093/neuonc/noy059.514.
- Jousma, E., et al. Preclinical assessments of the MEK inhibitor PD‐0325901 in a mouse model of neurofibromatosis type 1. Pediatr Blood Cancer. 2015 Oct;62(10):1709-16. doi: 10.1002/pbc.25546. Epub 2015 Apr 22.
- Walter, J., et al. MEK inhibition exhibits efficacy in human and mouse neurofibromatosis tumors. J Clin Invest. 2013;123(1):340-347. doi: 10.1172/JCI60578.
MEK Inhibitor Combinations in Cancer
MEK inhibitors represent a promising backbone for targeted combination therapies in cancer, given the critical role that the MAPK pathway plays in the growth and proliferation of a large number of tumor types (including lung cancer, pancreatic cancer, colorectal cancer, and others). A Phase 1b clinical trial, being conducted under a global clinical collaboration agreement between SpringWorks Therapeutics and BeiGene, is enrolling patients to evaluate PD-0325901 in combination with lifirafenib, a RAF dimer inhibitor, in patients with a range of solid tumor types that harbor mutations in MAPK pathway genes (such as RAS and RAF).
SpringWorks is also actively pursuing additional collaborations and partnerships to evaluate PD-0325901 in combination with other rational anti-cancer agents across a range of tumor types.