navtemadlin (KRT-232) / Amgen, Kartos Therap - LARVOL DELTA

Discovery of drug combinations with momelotinib to improve myelofibrosis outcomes (ASH 2025) - "The VAF screen identified numerous inhibitors of signaling pathways operating parallel to the JAK-STAT signaling pathway including SHP2 (migoprotafib), PI3K (copanlisib), MEK (cobimetinib), agents targeting BET (BMS-986158), and STAT transcriptional targets, including BCLxL (navitoclax). The hepcidin screen identified inhibitors that combined to further suppress expression of the HiBiT transgene including CDK4 (atirmociclib) and MDM2 (navtemadlin). Notably, selinexor, an XPO1 inhibitor, combined positively with momelotinib to both kill malignant cells and suppress hepcidin expression. These results highlight several promising drug combinations that could enhance outcomes for MF patients by effectively controlling anemia and halting disease progression. These discoveries provide the scientific justification to identify optimal combination regimens aimed at addressing the multifaceted challenges of myelofibrosis."

IO biomarker • Myelofibrosis • ACVR1 • BCL2L1 • BMP6 • CDK4 • JAK1

MODULE 4: Future Directions in the Management of MF (ASH 2024) - "This program is supported by educational grants from CTI BioPharma, a Sobi Company, Geron Corporation, GSK, Incyte Corporation and Karyopharm Therapeutics.Mechanism of antitumor activity of navitoclax and biological rationale for its evaluation for MF Available efficacy and safety findings from the Phase III TRANSFORM-1 study of navitoclax in combination with ruxolitinib versus ruxolitinib alone for patients with previously untreated MF Potential role of navitoclax in the up-front setting and ongoing evaluation for relapsed/refractory (R/R) disease in the Phase III TRANSFORM-2 study Rationale for the evaluation of BET inhibitors for MF; updated findings from the Phase III MANIFEST-2 study combining pelabresib to ruxolitinib for JAK inhibitor-naïve disease Scientific justification for the evaluation of selinexor for MF; early efficacy and safety findings with selinexor as monotherapy and in combination with ruxolitinib Ongoing evaluation of the combination of..."

Myelofibrosis • Oncology

KT-253, a Highly Potent and Selective MDM2 Protein Degrader, Eliminates Malignant Myelofibrosis Stem/Progenitor Cells (ASH 2024) - P1 | "Using UKE-1 cells, a p53 WT JAK2V617F+ cell line, KT-253 treatment was shown to lead to >10-fold increase in the degree of cell growth inhibition and apoptosis as compared to the MDM2 SMI AMG-232 (100nM vs 1000nM). In conclusion, KT-253 is a highly potent and effective MDM2 degrader which upregulates p53 activity in MF CD34+ cells and can selectively reduce the numbers of JAK2V617F+ colonies formed while sparing the reservoir of colonies with WT JAK2. These data provide a compelling rationale for evaluating the therapeutic potential KT 253 in MF patients."

Chronic Eosinophilic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Myelofibrosis • Myeloproliferative Neoplasm • Oncology • Solid Tumor • Targeted Protein Degradation • CD34 • CDKN1A • MDM2

NRG-DT001 PHASE IB TRIAL OF NEOADJUVANT NAVTEMADLIN AND RADIOTHERAPY IN TP53 WILD-TYPE SOFT TISSUE SARCOMA: PRELIMINARY EFFICACY ANALYSIS (CTOS 2025) - No abstract available

Clinical • P1 data • Oncology • Sarcoma • Soft Tissue Sarcoma • Solid Tumor • TP53

POIESIS: A Randomized, Double-Blind, Placebo-Controlled, Multicenter, Global Phase 3 Study of Navtemadlin as Add-on to Ruxolitinib in JAK Inhibitor-Naïve Patients With Myelofibrosis Who Have a Suboptimal Response to Ruxolitinib (MPN 2025) - No abstract available

Clinical • P3 data • Myelofibrosis

Ferroptosis-related genes MDM2 and CDKN1A as potential biomarkers for COPD. (PubMed, J Inflamm (Lond)) - "MDM2 and CDKN1A could be potential targets for COPD by regulating neutrophil-involving inflammation. One drug with potential clinical application value was identified."

Biomarker • Journal • Chronic Obstructive Pulmonary Disease • Immunology • Inflammation • Pulmonary Disease • Respiratory Diseases • CDKN1A • MDM2

ASTX295 a Novel Potent MDM2 Antagonist Induces More Than One Mechanism of Programmed Cell Death (PCD) in Lymphoid Malignancies (ASH 2024) - P1 | "Previous studies have shown in vitro activity in acute myeloid leukemia both alone and in combination with decitabine...Activity of ASTX295 was compared with AMG232 and Idasanutlin...ASTX295 in combination with the specific BCL2 inhibitor Venetoclax in the GRANTA519 cell line (CI value 0.2) and KARPAS384 (CI value 0.4) demonstrated strong synergy, despite as monotherapy resulting in <50% fall in viability...ASTX295 like other MDM2i showed synergy with BCL2i in DLBCL and MCL models. ASTX295 induced multiple forms of PCD; the precise form of non-caspase dependent PCD remains under investigation."

IO biomarker • Acute Myelogenous Leukemia • Diffuse Large B Cell Lymphoma • Hematological Disorders • Hematological Malignancies • Leukemia • Lymphoma • Oncology • T Cell Non-Hodgkin Lymphoma • Thrombocytopenia • ANXA5 • CDKN1A

TL-895, a Highly Selective, Covalent Inhibitor of Bruton's Tyrosine Kinase (BTK), Sensitizes Myeloproliferative Neoplasm (MPN)-Blast Phase Stem Cells to Navtemadlin By Targeting Intrinsic Dysregulated MDM2/p53 and NF-Κb Pathways and Disrupting the Protective Tumor Microenvironment (TME) (ASH 2023) - P1/2, P2 | "Our results indicate that BTKi therapy might increase susceptibility of MPN-BP SC to MDM2i therapy, by upregulating p53 activity and dampening NF-κB signaling, and also by disrupting protective TME interactions that sustain MPN-BP SC. This novel combination merits further clinical investigation in advanced phase MPN."

Biomarker • IO biomarker • Tumor microenvironment • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Myelofibrosis • Myeloproliferative Neoplasm • Oncology • ATF3 • BCL2L1 • BTG2 • CD34 • CDK1 • CDKN1A • DDB2 • EIF4EBP1 • ETV6 • KRAS • MDM2 • PTPRC • S100A10 • WT1

Population Pharmacokinetic and Pharmacodynamic Analysis of Navtemadlin in Patients with Relapsed and Refractory (R/R) Myelofibrosis (MF) and Other Myeloid or Solid Tumor Malignancies (ASH 2023) - P1b/2, P2/3 | "Other tested covariates, including body weight, creatinine clearance, aspartate transaminase, alanine transaminase, bilirubin, albumin, alpha 1-acid glycoprotein, race, UGT1A1 genotype, recent ruxolitinib treatment in MF, and CYP3A4 inducer/inhibitor concomitant medications, were not significant. Tumor type influenced navtemadlin exposure with simulated exposure in R/R MF patients at the selected Phase 3 dose of 240 mg comparable to exposures in MCC patients at 180 mg, the selected Phase 2 dose for that indication. Cancer-associated inflammation and/or treatment history, as well as age and female sex, may increase navtemadlin exposure. The PD marker MIC-1 responds to navtemadlin in a concentration-dependent fashion."

Clinical • PK/PD data • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Merkel Cell Carcinoma • Multiple Myeloma • Myelofibrosis • Non-melanoma Skin Cancer • Oncology • Skin Cancer • Solid Tumor • CRP • CYP3A4 • GDF15 • UGT1A1

POIESIS: A Randomized, Double-Blind, Placebo-Controlled, Multicenter, Global Phase 3 Study of Navtemadlin As Add-on to Ruxolitinib in JAK Inhibitor-Naïve Patients with Myelofibrosis Who Have a Suboptimal Response to Ruxolitinib (ASH 2024) - P3 | "Spleen imaging (MRI/CT) will be assessed by blinded central review and TSS will be assessed by MFSAF v4.0. This study is currently enrolling."

Clinical • IO biomarker • P3 data • B Cell Lymphoma • Fibrosis • Hematological Malignancies • Immunology • Leukemia • Lymphoma • Myelofibrosis • Non-Hodgkin’s Lymphoma • Oncology • BCL2 • CD34

TET2 and TP53 Mutations Cooperate in Leukemia Development and Modulate the Response to Inflammation (ASH 2024) - "Methods We genetically combined deletion mutation alleles of Tet2 and Tp53 in a mouse model with Mx1-Cre and Scl-CreERT2 to allow for somatic excision of Tet2 with administration of PIPC or Tamoxifen...By qPCR induction of NLRP11 was similar to MDM2 when cells were treated with the p53 activator AMG232 (MDM2 inhibitor)...It is also a sensor of ribotoxic stress, i.e. ribosome stalling due to cellular stress and chemotherapy such as daunorubicin...Mutations provide growth advantage to stem cells at steady state and also with inflammatory stress, including IFNγ induced senescence. TP53 regulates NLRP1, a component of this inflammatory stress response, contributing to greater HSPC tolerance of this stress pathway and thus contributes to the cooperativity with pro-inflammatory TET2-mutations."

Acute Myelogenous Leukemia • Bone Marrow Transplantation • Hematological Malignancies • Leukemia • Myeloproliferative Neoplasm • Oncology • Solid Tumor • IFNG • JAK1 • MDM2 • NLRP1 • PPM1D • TET2 • TNFA • TP53

Disease-Modifying Activity of Navtemadlin Correlates with Clinical Responses in a Randomized, Multicenter, Global Phase 3 Study (BOREAS) in JAK-Inhibitor Relapsed/Refractory Myelofibrosis (ASH 2024) - P2/3, P3 | "Aim : To assess changes in biomarkers of disease burden and correlations with SVR in the global, randomized phase 3 BOREAS study (NCT03662126), navtemadlin monotherapy vs best available therapy (BAT : hydroxyurea, chemotherapy, IMiDs, and supportive care) for pts with TP53WT MF who were R/R to JAKi. Changes in CD34+ counts, driver mutation burden, and serum inflammatory cytokine levels with navtemadlin treatment were significantly correlated with magnitude of SVR; demonstrating an effect between navtemadlin-induced disease modification and SVR, a key clinical outcome predictive of QoL and overall survival. Biomarkers of disease modification and associated clinical correlations will be further explored with navtemadlin as add-on therapy to ruxolitinib treatment in JAKi-naïve MF pts who have a suboptimal response to ruxolitinib in the global phase 3 POIESIS study (NCT06479135)."

Clinical • IO biomarker • P3 data • Tumor mutational burden • B Cell Lymphoma • Fibrosis • Hematological Malignancies • Immunology • Lymphoma • Myelofibrosis • Non-Hodgkin’s Lymphoma • Oncology • BCL2 • CALR • CD34 • IL6 • TMB • TNFA

Results from the Randomized, Multicenter, Global Phase 3 BOREAS Study: Navtemadlin Versus Best Available Therapy in JAK Inhibitor Relapsed/Refractory Myelofibrosis (ASH 2024) - P2/3, P3 | "Pts were randomized 2 : 1 to receive navtemadlin monotherapy 240 mg once-daily (Day 1-7/28-day cycle) or BAT (monotherapy or combinations : hydroxyurea, chemotherapy, IMiDs, and supportive care; JAKi were excluded)...Baseline characteristics were well balanced between the arms and included : int-1/int-2/high-risk MF per DIPSS (34%/50%/15%), median spleen volume of 2310 cm3, median TSS of 20.8, prior therapy range of 1-6 (99% had ruxolitinib [rux]), median time from initial MF diagnosis was 47.6 months, 34% of pts had platelets <100x109/L, 48% had a bone marrow fibrosis of grade 3, 70% had the JAK2V617F driver mutation, and 77% had ≥1 high molecular risk mutation (≥2 in 23%)...The rate of SVR35 and TSS50 at Week 24 was three-fold and two-fold higher with navtemadlin vs BAT, validating the novel approach of MDM2 inhibition in pts with MF. Further studies of navtemadlin in MF are warranted, including as add-on therapy to rux treatment in JAKi-naive pts who..."

Clinical • IO biomarker • P3 data • Anemia • B Cell Lymphoma • Fibrosis • Hematological Disorders • Hematological Malignancies • Immunology • Lymphoma • Myelofibrosis • Neutropenia • Non-Hodgkin’s Lymphoma • Oncology • Thrombocytopenia • BCL2 • CD34

Navtemadlin, a Novel MDM2 Inhibitor, Potentiated Venetoclax-Induced Antitumor Efficacy in TP53 Wild-Type Acute Myeloid Leukemia (AML) (ASH 2023) - "A proof-of-concept study with idasanutlin (idasa), a first-generation MDM2 inhibitor and ven demonstrated manageable safety and encouraging efficacy in relapsed/refractory AML patients (Daver et al. Nvtm, a potent second-generation MDM2 inhibitor, rapidly restored p53 function, induced apoptosis in p53WT AML MOLM-13 by impeding cell cycle, viability, clonogenicity potential, and reducing both glycolysis and oxidative phosphorylation. Nvtm combined with ven significantly enhanced these effects. Importantly, this combination blocked stromal cell-mediated (contact and soluble factors) cytoprotection."

Clinical • IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • FLT3 • IL6 • TP53

MODULE 4: Novel Agents Under Investigation for MF (ASH 2025) - "This program is supported by educational grants from Blueprint Medicines, Bristol Myers Squibb, GSK, and Incyte Corporation. Rationale for the inhibition of BET proteins in MF; mechanism of action of pelabresib Key efficacy and safety findings from the Phase III MANIFEST-2 study combining pelabresib with ruxolitinib for patients with JAK inhibitor-naïve disease; potential role of BET inhibition as monotherapy and/or in combination with JAK inhibition Similarities and differences between pelabresib and investigational BET inhibitors (INCB57643); available data and ongoing evaluation of these agents Mechanism of antitumor activity of navtemadlin and biological rationale for its evaluation for patients with MF Design, eligibility criteria and key efficacy and safety endpoints of the Phase III BOREAS trial evaluating navtemadlin monotherapy for patients with MF whose disease was resistant or refractory to JAK inhibitors Ongoing Phase III POIESIS study of adding..."

Anemia • Hematological Disorders

NRG-DT001: Navtemadlin and Radiation Therapy in Treating Patients With Soft Tissue Sarcoma (clinicaltrials.gov) - P1 | N=39 | Completed | Sponsor: National Cancer Institute (NCI) | Active, not recruiting ➔ Completed | Trial completion date: Feb 2026 ➔ Sep 2025

P53WT • Trial completion • Trial completion date • Oncology • Sarcoma • Soft Tissue Sarcoma • Solid Tumor • CD4 • TP53

Individualizing Treatment Selection in MF (SOHO 2025) - P3 | "These include the activin receptor ligand trap luspatercept, the telomerase inhibitor imetelstat, the selective inhibitor of nuclear export selinexor, the human double minute 2 inhibitor navtemadlin, and the bromodomain and extra-terminal protein inhibitor pelabresib...Elritercept — another activin receptor ligand trap — and the anti-hemojuvelin antibody DISC-0974 are being developed for anemia of MF...Currently, these patients are observed or managed for thrombotic risk similarly to those with essential thrombocythemia (ET) — receiving hydroxyurea for control of cytoses, ruxolitinib for symptoms, or interferon for long-term disease modification. Encouraging data on ruxolitinib in patients with intermediate-1-risk MF, along with analyses from the COMFORT trials demonstrating the benefits of early initiation of ruxolitinib in patients with intermediate-2/high-risk MF and intriguing evidence of event-free survival (EFS) improvement with both ruxolitinib and..."

Clinical • Essential Thrombocythemia • Hematological Malignancies • Myelodysplastic Syndrome • Myelofibrosis • Myeloproliferative Neoplasm • Non-melanoma Skin Cancer • Oncology • Polycythemia Vera • Skin Cancer • Solid Tumor • ACVR1 • IRAK1

Is Combination Therapy Here for MPN? (SOHO 2025) - "2 Outside of the potential benefit of type 2 (AJ1-11095) and JAK2 V617F-selective (INCB160058) inhibitors under phase 1 evaluation, the research community has focused efforts on developing rational JAK inhibitor-based combination therapy regimens...3 Data from prospective and retrospective studies suggest a correlation between spleen reduction and OS with ruxolitinib and pacritinib...Nevertheless, the combination of pelabresib and ruxolitinib was well tolerated, and biomarkers of disease modification — including reduction in bone marrow fibrosis, driver mutation allele frequency, and inflammatory cytokine expression levels — all favored the combination, supporting the proposed mechanism of action and published preclinical synergy...11 The phase 3 trial will aim to confirm this activity in patients who have received at least 18 weeks of ruxolitinib therapy and meet rigorously defined criteria for suboptimal response, after which these patients will be randomized to..."

Combination therapy • IO biomarker • Myelofibrosis • Myeloproliferative Neoplasm • Oncology • CD34 • XPO1

ALLIANCE-ABTC-1604: Testing the Ability of AMG 232 (KRT 232) to Get Into the Tumor in Patients With Brain Cancer (clinicaltrials.gov) - P1 | N=32 | Terminated | Sponsor: 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

Enrollment change • Trial completion date • Trial primary completion date • Trial termination • Brain Cancer • Glioblastoma • Gliosarcoma • Oncology • Sarcoma • Solid Tumor • MGMT • TP53

Selective Cleaning Enhances Machine Learning Accuracy for Drug Repurposing: Multiscale Discovery of MDM2 Inhibitors. (PubMed, Molecules) - "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."

Journal • Oncology • BCL2 • MDM4

Anticancer effects and mechanisms of Pulsatilla chinensis, Bupleurum chinense and Polyporus umbellatus on human lung carcinoma and hepatoma cells. (PubMed, Comput Struct Biotechnol J) - "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."

Journal • Hepatocellular Cancer • Liver Cancer • Lung Cancer • Oncology • Solid Tumor • E2F1 • TNFA

ALLIANCE-ABTC-1604: Testing the Ability of AMG 232 (KRT 232) to Get Into the Tumor in Patients With Brain Cancer (clinicaltrials.gov) - P1 | N=86 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | N=32 ➔ 86 | Trial primary completion date: Mar 2019 ➔ Dec 2025

Enrollment change • Trial primary completion date • Brain Cancer • Glioblastoma • Gliosarcoma • Oncology • Sarcoma • Solid Tumor • MGMT • TP53

Pre-clinical Modeling of Navtemadlin Pharmacokinetics, Pharmacodynamics, and Efficacy in IDH-wildtype Glioblastoma. (PubMed, Clin Cancer Res) - "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."

Journal • PK/PD data • Preclinical • Brain Cancer • Glioblastoma • Oncology • Solid Tumor • ABCG2 • MDM2 • TP53

TP53-MUTATED AML: A MULTI-OMICS APPROACH TO UNDERSTAND HETEROGENEITY AND THERAPEUTIC VULNERABILITIES (EHA 2025) - "Standard therapies, including intensive chemotherapy, allogeneic hematopoietic stem cell transplantation, and venetoclax-based regimens, offer minimal survival benefit...A single TP53-mut sample was mature, harbouring the mutation with 37% VAF, alongside a KMT2A rearrangement and GATA2 and NRAS mutations—features associated with mature AMLs.The in vitro drug sensitivity analysis identified four MDM2 inhibitors—Idasanutlin, AMG-232, NVP-CGM097, and SAR40583—as the compounds to which TP53-mut cases were most resistant among the 527 tested (11/12 TP53-mut cases exhibiting resistance (p=0.0042)... Identifying actionable vulnerabilities in poor-risk AML remains challenging. Our findings highlight TP53-mut AML's distinct biology, including its enrichment in the Primitive subtype, resistance to MDM2 inhibitors, and differential ADC target expression. While validation in larger cohorts is needed, these insights could guide tailored therapeutic strategies for this..."

Heterogeneity • IO biomarker • Acute Myelogenous Leukemia • Bone Marrow Transplantation • Hematological Malignancies • Leukemia • Oncology • CD123 • CD33 • CD34 • CLEC12A • CXCR4 • GATA2 • HAVCR2 • IL3RA • KIT • KMT2A • NRAS • TP53

MDM2 Targeting via Proteolysis Targeting Chimeras (Protac) is efficient in P53 Wildtype, P53-Mutated, and Abemaciclib resistant Estrogen Receptor-positive Cell Lines and Superior to MDM2 inhibition (DGS 2025) - "Moreover, there is profound evidence that MDM2-Specific Protac Degraders are efficient even in tumor cells harboring p53 loss-of-fun-function mutations. We Comparated P53 Wildtype / Abemaciclib-sensitive and-resistant P53-Mutated T-47d Estrogen Receptor-positive Breast Cells With the MDM2 inhibitor AMG-232 and MDM2 Protac Degrader. Protac Treatment CONSIDERABLY ATTENUBLY ATTENUBLY ATTENUTE CELL PROLIFERATIONS AND WAS SUPERIOR TO MDM2 Inhibition in P53 Wildtype and even in P53-Mutaed Cells. Proliferation-Associated Pathways Were Significantly But Differential Affected, Including P73, Retinoblastoma, and the Transcription Factor E2F. MCH-I AND CD276 Were Significantly Down Regulated.summary: The Data Provide Deeper Insight Into Protac-Induced Molecular Mechanisms in Luminal Breast Cells With and Without P53 Mutations."

IO biomarker • P53mut • P53WT • Preclinical • Breast Cancer • Eye Cancer • Hormone Receptor Breast Cancer • Oncology • Retinoblastoma • Solid Tumor • CD276 • ER • PD-L1 • PD-L2 • TP53