Navtemadlin (KRT-232): A Comprehensive Monograph on a Novel MDM2 Inhibitor for Oncologic Indications

1.0 Executive Summary

Navtemadlin is an investigational, orally bioavailable, small-molecule therapeutic representing a significant advancement in the targeted inhibition of the murine double minute 2 (MDM2) protein. Developed initially by Amgen as AMG-232 and now advanced by Kartos Therapeutics as KRT-232, Navtemadlin is engineered to be a potent and highly selective antagonist of the MDM2-p53 protein-protein interaction. Its mechanism of action is centered on the restoration of the tumor suppressor function of the p53 protein, a critical regulator of cellular homeostasis often referred to as the "guardian of the genome." In malignancies characterized by wild-type TP53 status but dysregulated by MDM2 overexpression, Navtemadlin competitively binds to MDM2, liberating p53 from negative regulation. This leads to p53 stabilization, accumulation, and subsequent transcriptional activation of target genes that orchestrate cell cycle arrest, senescence, and apoptosis in malignant cells.[1]

The clinical development of Navtemadlin has been most pronounced in myelofibrosis (MF), a severe hematologic malignancy with limited treatment options, particularly for patients who are relapsed or refractory (R/R) to Janus kinase (JAK) inhibitors. The landmark Phase III BOREAS trial (NCT03662126) demonstrated that Navtemadlin monotherapy achieved statistically significant and clinically meaningful improvements in key disease endpoints compared to the best available therapy (BAT). Specifically, Navtemadlin nearly tripled the rate of spleen volume reduction (SVR) of at least 35% and doubled the rate of total symptom score (TSS) improvement of at least 50% at 24 weeks.[4]