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

Comparative Efficacy of Drug Therapies on Spleen Size and Symptom Reduction in Myelofibrosis: A Frequentist Network Meta-Analysis (SOHO 2026) - "Single-agent JAKis demonstrated variable efficacy similar to or worse than that of ruxolitinib, with an OR of 0.88 (95%CI:0.58–1.34) for momelotinib, 0.52 (95% CI, 0.05–6.05) for fedratinib, 0.35 (95% CI, 0.04–3.20) for bezacitinib, 0.17 (95% CI, 0.02–1.41) for jaktinib, and 0.16 (95% CI, 0.02–1.52) for pacritinib...Compared with BAT, pacritinib showed an OR of 3.43 (95% CI, 0.39–29.76), navtemadlin 3.26 (95% CI, 0.92–11.53), and momelotinib 3.10 (95% CI, 1.13–8.53)... In JAKi-naïve myelofibrosis, combination strategies with navitoclax or pelabresib added to ruxolitinib demonstrated the greatest spleen responses. Ruxolitinib remains similar or superior to single-agent JAKis in spleen or symptom response. In ruxolitinib-exposed patients with myelofibrosis, fedratinib, momelotinib, and pacritinib showed clinically meaningful activity compared with BAT, and fedratinib was numerically better than others."

Retrospective data • Myelofibrosis • Oncology

A PHASE 1B STUDY OF NAVTEMADLIN IN COMBINATION WITH DECITABINE AND VENETOCLAX IN ACUTE MYELOID LEUKEMIA (EHA 2025) - P1 | "NAV in combination with DAC and DAC/VEN is well tolerated and associated with promising responses in R/R AML. MCL-1/BIM heterodimer expression may help predict patients who are most likely to respond."

Combination therapy • IO biomarker • P1 data • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Neutropenia • Oncology • BCL2 • BCL2L1 • GDF15 • MCL1

BRAINTOX: uremic toxins in chemotherapy response in the brain (EANO 2026) - "Then, U87MG cells were co-treated with p-cresyl sulfate or indoxyl sulfate and ten selected drugs in a drug screening platform (drugs: Temozolamide, Dacomitinib, Selinexor, Panobinostat, Ixazomib, AMG232, Bortezomib, Lazertinib, Temsirolimus, Carmilzomib). The uremic toxins p-cresyl sulfate and indoxyl sulfate were enriched in brain tumor tissue samples of IDH wt patients compared to IDH mut patients, validating the findings of the discovery cohort. IDH wt patients have higher levels of uremic toxins in the circulation compared to patients with IDH mutant adult-type diffuse gliomas and the toxins reach the tumor site. Further experiments shall elucidate the mechanism by which uremic toxins reach the tumor cells and whether they modulate drug responsiveness."

Brain Cancer • Diffuse Glioma • Glioblastoma • Glioma • Oncology • Solid Tumor

Closing the disease modification gap: Emerging therapies in myelofibrosis beyond JAK inhibition. (PubMed, Semin Hematol) - "We discuss BET inhibitors (pelabresib), PIM kinase inhibitors (TP-3654), telomerase inhibition (imetelstat), nuclear export inhibition (selinexor), LSD1 inhibition (bomedemstat), MDM2 antagonism (navtemadlin), mutant CALR-directed immunotherapies, and activin receptor ligand traps (elritercept). Strategies such as high-molecular-risk mutation profiling and variant allele frequency monitoring to assess disease progression and clonal burden will also be discussed. As the focus of MPN management shifts towards curative nontransplant options, a combination of improved access to clinical trials and accounting for patient-reported outcomes will be vital if we are to realize the promise of these next-generation therapies."

IO biomarker • Journal • Fibrosis • Hematological Disorders • Immunology • Myelofibrosis • Myeloproliferative Neoplasm • Oncology • Transplantation • CALR

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

AN OPEN-LABEL, GLOBAL, PHASE (PH) 1B/2 STUDY ADDING NAVTEMADLIN (NVTM) TO RUXOLITINIB (RUX) IN PATIENTS (PTS) WITH PRIMARY OR SECONDARY MYELOFIBROSIS (MF) WHO HAVE A SUBOPTIMAL RESPONSE TO RUX (EHA 2023) - P1b/2 | "Nvtm added to rux in MF pts with suboptimal response to rux provides clinically meaningful improvement in SVR and TSS at any stable rux dose with an acceptable safety profile. This data supports further investigation in a recently commenced Ph 3 study (BOREAS-2). Myelofibrosis, Ruxolitinib, TP53, Apoptosis"

Clinical • P1/2 data • Gastrointestinal Disorder • Myelofibrosis • Oncology • BCL2 • BCL2L1 • CD34 • MCL1

NRG-DT001 phase Ib trial of neoadjuvant navtemadlin (previously AMG232 and KRT232) concurrent with preoperative radiotherapy in wild-type p53 soft tissue sarcoma of the extremity and body wall. (ASCO 2022) - P1 | "Neoadjuvant navtemadlin concurrent with standard dose preoperative RT is well tolerated in patients with WT p53 STS at extremity or body wall, and the 120 mg PO daily of navtemadlin, 5 days per week dose should be used to design future trials of RT with extremity STS. Incorporating NGS sequencing results as an integral biomarker in a clinical trial of neoadjuvant radiotherapy and a radiosensitizer is feasible."

Clinical • P1 data • Oncology • Sarcoma • Soft Tissue Sarcoma • Solid Tumor • MDM2 • TP53

DISEASE-MODIFYING ACTIVITY OF NAVTEMADLIN (NVTM) CORRELATED WITH SURVIVAL OUTCOMES IN JANUS KINASE INHIBITOR (JAKI) RELAPSED OR REFRACTORY (R/R) MYELOFIBROSIS (MF) PATIENTS (PTS) (EHA 2023) - P2/3 | "In JAKi R/R MF pts treated with nvtm, improved OS and PFS were associated with reductions in driver gene VAF and circulating CD34 + cell counts, highlighting the disease modifying effects of this therapy. BOREAS, a global Phase 3 study investigating single agent nvtm in TP53 WT JAKi R/R MF pts, is enrolling (NCT03662126). relapsed/refractory, Myelofibrosis, Janus Kinase inhibitor, TP53"

Clinical • Tumor mutational burden • Anemia • Hematological Disorders • Myelofibrosis • Pain • Thrombocytopenia • CD34 • MDM2 • TMB

TP53 reactivation as a target for precision medicine in diffuse midline glioma (EANO 2026) - "A phase I clinical trial of the MDM2 inhibitor navtemadlin in adults with high-grade glioma revealed that this compound is blood-brain-barrier penetrant and exerts a pharmacodynamic effect... By leveraging functional genomics, single-cell sequencing, cellular barcoding, and epigenetic methods, we ultimately aim to elucidate how modulation of these three classes of targets enhances the effects of TP53 reactivation, advancing drug combinations for the treatment of DMG."

Brain Cancer • Diffuse Midline Glioma • Glioma • High Grade Glioma • Oncology • Solid Tumor • TP53

Targeting MDM2 stabilization to enhance TP53 reactivation in Diffuse Midline Glioma (EANO 2026) - "In this context, a window of opportunity trial in adult glioma patients showed that MDM2 inhibitor navtemadlin penetrates the blood-brain barrier but achieves limited responses as a single-agent treatment... Altogether, we explore combined inhibition of MDM2 and USP7 as a therapeutic approach to reactivate p53 in TP53 wild-type DMGs. By bridging single-cell sequencing technologies and functional characterization, our efforts will dissect the effects of this combination treatment to advance targeted therapies in this subset of fatal pediatric brain tumors."

Brain Cancer • Diffuse Midline Glioma • Glioma • Oncology • Solid Tumor • TP53 • USP7

Navtemadlin (KRT-232) activity after failure of anti-PD-1/L1 therapy in patients (pts) with TP53WT Merkel cell carcinoma (MCC). (ASCO 2022) - P1b/2 | "Navtemadlin is the first targeted agent to show promising single-agent activity in heavily pretreated MCC pts who failed anti-PD-1/L1 therapy. This study demonstrates that upregulation of the p53 pathway is a viable therapeutic strategy in MCC."

Clinical • IO biomarker • Anemia • Genetic Disorders • Hematological Disorders • Merkel Cell Carcinoma • Neuroendocrine Tumor • Non-melanoma Skin Cancer • Oncology • Solid Tumor • Thrombocytopenia • MDM2 • TMB

Targeting OPC transcriptional states enhances the effect of p53 reactivation in diffuse midline glioma (EANO 2026) - "Targeting the OPC-like program with the OLIG2-inhibitor CT-179 and navtemadlin enhanced apoptosis in DMG models, induced selective tumor cell death at nanomolar concentrations in organoid assembloids, and was validated in vivo in PDX models. Lineage-specific transcriptional states critically influence response to p53 reactivation in HGG. Adaptive accumulation of an OPC-like state drives resistance to MDM2 inhibition by modulating p53 signaling and blocking apoptosis. Targeting OLIG2-driven OPC programs enhances therapeutic benefits of p53 reactivation and provides rationale for combination strategies in HGG."

Brain Cancer • Diffuse Midline Glioma • Glioma • High Grade Glioma • Oncology • Solid Tumor • OLIG2

Ipsen…announced today it has completed the acquisition of Kartos Therapeutics, a clinical-stage biopharmaceutical company adding late-stage MDM2 inhibitor navtemadlin in Phase III clinical development in myelofibrosis (GlobeNewswire) - "Navtemadlin is an investigational oral MDM2 inhibitor being developed as an add-on therapy to ruxolitinib for patients with myelofibrosis who have a suboptimal response to ruxolitinib."

M&A • Myelofibrosis

Ipsen to acquire Kartos Therapeutics, expanding hemato-oncology late-stage pipeline (Ipsen Press Release) - "Top-line data from the ongoing Phase III registrational trial POIESIS is expected in 2027...The acquisition adds navtemadlin, an investigational MDM2 inhibitor designed to restore the natural tumor-suppressing function of p53, a critical tumor-suppressor in myelofibrosis...Under the terms of the agreement and plan of merger, Ipsen through a fully-owned subsidiary, will pay $450 million upfront at closing. Kartos Therapeutics shareholders are also eligible to receive additional milestone payments of up to $1.3 billion including a significant regulatory approval milestone and sales-based milestones....This late-stage transaction is expected to be accretive to Ipsen’s core operating income from 2029, with limited dilution to 2026 full-year guidance."

M&A • P3 data: top line • Myelofibrosis

Testing the Addition of an Anti-cancer Drug, Navtemadlin, to the Usual Treatments (Cytarabine and Idarubicin) in Patients With Acute Myeloid Leukemia (clinicaltrials.gov) - P1 | N=24 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Jun 2026 ➔ Jun 2027 | Trial primary completion date: Jun 2026 ➔ Jun 2027

Trial completion date • Trial primary completion date • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology

Testing a New Chemotherapy Drug, KRT-232 (AMG-232) in Combination With Decitabine and Venetoclax in Patients With Acute Myeloid Leukemia (clinicaltrials.gov) - P1 | N=58 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Jun 2026 ➔ Jun 2027 | Trial primary completion date: Jun 2026 ➔ Jun 2027

Trial completion date • Trial primary completion date • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • CD4 • TP53

The Path Forward in MF: Small Molecules in the Limelight. (PubMed, Cancers (Basel)) - "However, a substantial percentage of patients fail to achieve sustained benefit, are intolerant, or become refractory; real-world and clinical trial data indicate that approximately half of treated patients discontinue ruxolitinib treatment within 3 years and up to approximately 75% within 5 years, with poor outcomes after discontinuation (median survival in several series is approximately 12-14 months)...These include agents targeting telomerase (imetelstat), epigenetic regulation via BET inhibition (pelabresib/CPI-0610), the MDM2-p53 axis (navtemadlin/KRT-232), erythroid maturation and the bone marrow microenvironment (luspatercept), PI3K signaling (parsaclisib), and PIM inhibitors (nuvisertib). Early clinical data show promising results for symptom and splenic control in specific settings and, importantly, suggest potential disease-modifying activity (improvements in marrow fibrosis and molecular responses) for some compounds. This review summarizes the biological..."

Journal • Review • Chronic Eosinophilic Leukemia • Fibrosis • Hematological Disorders • Immunology • Myelofibrosis • Myeloproliferative Neoplasm • Oncology

A real time imaging based functional precision medicine (FPM) assay for glioblastoma (AACR 2026) - "Ex vivo growth response was evaluated for the DNA damaging agent, Temozolomide (TMZ) – currently used as the standard of care for GBM patients, and KRT-232 – an MDM2 inhibitor currently in clinical trials. These results show feasibility and value of incorporating real-time functional growth monitoring to improve quality-control in functional precision medicine patient diagnostics. With further validation, this assay could become a valuable therapy guidance tool for clinicians."

Brain Cancer • Glioblastoma • Oncology • Solid Tumor • TP53

Preclinical evaluation of a novel orally bioavailable MDM2 PROTAC, NW-8-461, in acute leukemia and myelofibrosis (AACR 2026) - "NW-8-461 exhibits markedly enhanced antiproliferative activity, demonstrating approximately 10-fold and 100-fold greater potency in cell viability assays compared with RG7388 and AMG232, respectively. In an orthotopic RS4; 11-Luc leukemia model, treatment with NW-8-461 at 25 mg/kg for 16 days resulted in complete eradication of leukemia cells in 7/7 mice and significantly superior efficacy compared with the MDM2 inhibitor RG7388. These results establish NW-8-461 as a differentiated and highly selective MDM2 degrader with strong therapeutic potential for p53-wild-type malignancies."

Late-breaking abstract • Preclinical • Hematological Malignancies • Leukemia • Myelofibrosis • Oncology • GSPT1 • IKZF1 • IKZF3 • MDM2 • SALL4

In vivo synergy is observed with AMG-232 and radiotherapy in endometrial cancer (AACR 2025) - "Overall, these findings further support the use of MDM2 inhibitors to improve radiotherapy response in EC. The improved tumor response that we observed at clinically relevant doses further highlights the potential of these agents to either enhance responses to current therapeutic strategies, or to lower the radiotherapy dose necessary for complete response."

Preclinical • Endometrial Cancer • Oncology • Solid Tumor

POIESIS: a phase III study of add-on navtemadlin in JAK inhibitor-naïve myelofibrosis patients with a suboptimal response to ruxolitinib. (PubMed, Future Oncol) - P3 | "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)."

Clinical • Journal • P3 data • Hematological Malignancies • Leukemia • Myelofibrosis • Oncology • CD34

MS200662_0001: Phase I/II, FIH, Dose Escalation Trial of TL-895 and Expansion of TL-895 Monotherapy and Combination Therapy With Navtemadlin in Tx-Naïve and R/R CLL/SLL Subjects (clinicaltrials.gov) - P1/2 | N=130 | Recruiting | Sponsor: Telios Pharma, Inc. | Active, not recruiting ➔ Recruiting | N=80 ➔ 130 | Trial completion date: Dec 2024 ➔ Dec 2025 | Trial primary completion date: Dec 2023 ➔ Dec 2024

Enrollment change • Enrollment open • First-in-human • Monotherapy • Trial completion date • Trial primary completion date • B Cell Lymphoma • Chronic Lymphocytic Leukemia • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Leukemia • Lymphoma • Mantle Cell Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Small Lymphocytic Lymphoma

MS200662_0001: Phase I/II, FIH, Dose Escalation Trial of TL-895 and Expansion of TL-895 Monotherapy and Combination Therapy With Navtemadlin in Tx-Naïve and R/R CLL/SLL Subjects (clinicaltrials.gov) - P1/2 | N=60 | Recruiting | Sponsor: EMD Serono | Not yet recruiting ➔ Recruiting

Enrollment open • First-in-human • Monotherapy • B Cell Lymphoma • Chronic Lymphocytic Leukemia • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Leukemia • Lymphoma • Mantle Cell Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Small Lymphocytic Lymphoma

MS200662_0001: Phase I/II, FIH, Dose Escalation Trial of TL-895 and Expansion of TL-895 Monotherapy and Combination Therapy With Navtemadlin in Tx-Naïve and R/R CLL/SLL Subjects (clinicaltrials.gov) - P1/2 | N=18 | Active, not recruiting | Sponsor: EMD Serono Research & Development Institute, Inc. | Trial primary completion date: May 2018 ➔ May 2019

First-in-human • Monotherapy • Trial primary completion date • B Cell Lymphoma • Chronic Lymphocytic Leukemia • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Mantle Cell Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Small Lymphocytic Lymphoma

MS200662_0001: Phase I/II, FIH, Dose Escalation Trial of TL-895 and Expansion of TL-895 Monotherapy and Combination Therapy With Navtemadlin in Tx-Naïve and R/R CLL/SLL Subjects (clinicaltrials.gov) - P1/2 | N=58 | Active, not recruiting | Sponsor: Telios Pharma, Inc. | N=18 ➔ 58

Enrollment change • First-in-human • Monotherapy • B Cell Lymphoma • Chronic Lymphocytic Leukemia • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Leukemia • Lymphoma • Mantle Cell Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Small Lymphocytic Lymphoma