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

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

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

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

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

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 | Not yet recruiting | Sponsor: EMD Serono

First-in-human • Monotherapy • New P1/2 trial • 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

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 (DKK 2026) - "We comparatively treated p53 wildtype / abemaciclib-sensitive and -resistant MCF-7, as well as p53-mutated T-47D estrogen receptor-positive breast cancer cells in-vitro with the mdm2 inhibitor AMG-232 and an mdm2 PROTAC degrader. The study provides the basis to evaluate the therapeutic applicability of anti-mdm2 PROTAC degraders in an appropriate preclinical in-vivo setting, for example in humanized tumor mice. Disclosure Statement: The authors declare no conflict of interest. / The authors declare the following (Wenn Ihr"

IO biomarker • P53mut • P53WT • Preclinical • Breast Cancer • Estrogen Receptor Positive Breast Cancer • Eye Cancer • Hormone Receptor Breast Cancer • Retinal Disorders • Retinoblastoma • Solid Tumor • Targeted Protein Degradation • CD276 • E2F1 • ER • PD-L1 • PD-L2 • TP53

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 | Recruiting | Sponsor: Telios Pharma, Inc. | Active, not recruiting ➔ Recruiting | Trial completion date: Sep 2021 ➔ Feb 2024 | Trial primary completion date: Sep 2021 ➔ Feb 2024

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=18 | Active, not recruiting | Sponsor: EMD Serono Research & Development Institute, Inc. | Trial completion date: Jun 2020 ➔ Sep 2021 | Trial primary completion date: May 2019 ➔ Sep 2021

First-in-human • Monotherapy • Trial completion date • 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=60 | Recruiting | Sponsor: EMD Serono Research & Development Institute, Inc. | N=20 ➔ 60

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

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=80 | Active, not recruiting | Sponsor: Telios Pharma, Inc. | Recruiting ➔ Active, not recruiting | N=58 ➔ 80

Enrollment change • Enrollment closed • 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=20 | Recruiting | Sponsor: EMD Serono Research & Development Institute, Inc. | N=60 ➔ 20 | Trial primary completion date: Jun 2019 ➔ Oct 2019

Enrollment change • First-in-human • Monotherapy • 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=130 | Active, not recruiting | Sponsor: Telios Pharma, Inc. | Recruiting ➔ Active, not recruiting

Enrollment closed • 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=80 | Active, not recruiting | Sponsor: Telios Pharma, Inc. | Trial completion date: Feb 2024 ➔ Dec 2024

First-in-human • Monotherapy • Trial 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=20 | Active, not recruiting | Sponsor: EMD Serono Research & Development Institute, Inc. | Recruiting ➔ Active, not recruiting | N=60 ➔ 20 | Trial primary completion date: Oct 2019 ➔ Nov 2018 | Trial completion date: Dec 2019 ➔ Oct 2019

Enrollment change • Enrollment closed • First-in-human • Monotherapy • Trial completion date • 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=18 | Active, not recruiting | Sponsor: EMD Serono Research & Development Institute, Inc. | Trial primary completion date: Aug 2018 ➔ May 2018

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

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

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

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

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