navtemadlin (KRT-232)

Study objectives are to isolate the contribution of add-on navtemadlin by assessing SVR and TSS 24-weeks after randomization from the pre-randomization baseline and to demonstrate that this contribution is clinically meaningful using established SVR and TSS endpoints from the pre-ruxolitinib treatment baseline. Secondary endpoints include progression-free survival, leukemia-free survival, and OS.Clinical Trial Registration: NCT06479135 (ClinicalTrials.gov); EUCT 2023-504724-25-00 (EUClinicalTrials.EU).

P1, N=39, Completed, National Cancer Institute (NCI) | Active, not recruiting --> Completed | Trial completion date: Feb 2026 --> Sep 2025

P1, N=32, Terminated, National Cancer Institute (NCI) | N=86 --> 32 | Trial completion date: Dec 2025 --> Aug 2025 | Active, not recruiting --> Terminated | Trial primary completion date: Dec 2025 --> Aug 2025; Drug supply issues

We identified two clinical CB1 antagonists, MePPEP and otenabant, and the statin drug atorvastatin as promising repurposing candidates based on their high predicted potency and binding affinity toward MDM2. Quantum mechanical (ONIOM) optimizations and molecular dynamics simulations confirmed the stability and favorable interaction profiles of the selected protein-ligand complexes, resembling that of navtemadlin, a known MDM2 inhibitor. This multiscale, accuracy-boosted workflow introduces a novel data-curation strategy that substantially enhances AI model performance and enables efficient drug repurposing against challenging cancer targets.

We also identified two drugs, AMG232 and Nutlin-3, that exhibited treatment effects similar to P. chinensis in A549 cells. Western blot analysis confirmed the alteration of the relevant proteins, aligning with our computational predictions. Furthermore, 23-hydroxybetulinic acid, a key active compound of P. chinensis, demonstrated the ability to inhibit the p53-MDM2 interaction by binding to the same pocket on the MDM2 protein.

P1, N=86, Active, not recruiting, National Cancer Institute (NCI) | N=32 --> 86 | Trial primary completion date: Mar 2019 --> Dec 2025

Navtemadlin efficacy was highly dependent on adequate brain penetration. Our translational PK/efficacy model suggests that the minimum effective tumor exposures were achieved only in a minority of GBM patients.

Our research revealed that AMG232 effectively inhibited angiogenesis and exhibited cytotoxic effects on MM cells by downregulating key angiogenic factors and impairing endothelial cell functions. These results suggest that AMG232 has significant potential as a therapeutic agent for targeting angiogenesis in MM treatment.

P1, N=39, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Feb 2025 --> Feb 2026

We also observed up-regulation of oligodendrocyte differentiation genes with navtemadlin treatment and enrichment of oligodendrocyte transcription factor 2 (OLIG2)-positive cells at relapse, suggesting an unexplored mechanism of navtemadlin tolerance in GBM. Overall, these results indicated that clinically achievable doses of navtemadlin exert pharmacodynamic effects on GBM and suggest that combined treatment with temozolomide may be a route to more durable survival benefits.

P1, N=32, Active, not recruiting, National Cancer Institute (NCI) | Suspended --> Active, not recruiting | N=86 --> 32 | Trial completion date: Dec 2024 --> Feb 2026

These preclinical in vivo data provide a rationale for further clinical development of this combinatorial targeted therapy approach.