tapotoclax (AMG 176) / Amgen, BeOne Medicines - LARVOL DELTA

CSF1R-CSF1 axis blockade with axatilimab effectively targets leukemia stem cells and monocytes in AML resistant to BH3 mimetics (ASH 2025) - "Background : The BCL2 inhibitor venetoclax (VEN), in combination with hypomethylating agents, ishighly effective in inducing remissions in AML...The effects on cytokine production, AML blasts, stem cells, andmonocytes were evaluated. MV4-11 cells with acquired resistance to BH3 mimetics targeting BCL2 or MCL1,peculiarly to VEN and VEN plus MCL-1 inhibitor AMG176, exhibited elevated levels of cytokinesincluding CSF1, TGF-1ß, IL-4, and IL-10 compared to parental cells... CSF1, TGF-1ß, IL-4, IL-10, and numerous other cytokines are increased in BH3mimetic resistant AML cell lines and patient samples. Inhibition of CSF1R targets ERK and AKTsignaling and significantly enhances the cytotoxic effects of BH3 mimetics against AML cells,stem/progenitor cells, and monocytes resistant to VEN. Furthermore, blockage of CSF1R-CSF1axis suppresses multiple cytokines in vitro and in vivo, and markedly improves the therapeuticefficacy of BH3 mimetics in a VEN/AZD5991/Decitabine..."

IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Multiple Myeloma • ANXA5 • CSF1R • IL10 • IL4 • TP53

Advances in the Management of Relapsed/Refractory CLL and Richter Transformation (ICML 2025) - P=N/A, P2, P3 | "BRUIN CLL-321 is a phase 3, registrational study that evaluated pirtobrutinib compared to the investigator's choice of idelalisib plus rituximab (IdelaR) or bendamustine plus rituximab (BR) [23]...Nemtabrutinib is now being evaluated in the registrational, phase 3 BELLWAVE-010 trial (NCT05947851) for patients with R/R CLL, comparing nemtabrutinib plus venetoclax to venetoclax plus rituximab...An ongoing, open-label, first-in-human phase 1/2 study is evaluating the BTK degrader BGB-16673 as monotherapy in patients with R/R CLL [27, 28]...NX-2127 is an investigational, first-in-class BTK degrader currently being evaluated in a phase 1 trial for patients with relapsed or refractory B-cell malignancies, CLL [29, 30]...NX-5948 is another investigational and more selective BTK degrader in an ongoing Phase 1a/1b clinical trial...This trial aims to establish lisaftoclax plus acalabrutinib as a potential alternative to venetoclax-based BTKi combination..."

IO biomarker • Acute Myelogenous Leukemia • B Cell Lymphoma • Chronic Lymphocytic Leukemia • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Leukemia • Non-Hodgkin’s Lymphoma • Oncology • Richter's Syndrome • Small Lymphocytic Lymphoma • BCL2L1 • TP53

Depletion of the Mitochondrial E3 Ligase MARCH5 Induces Synthetic Lethality to BCL2 Inhibitor (Venetoclax) Therapy in Cell Lines Representative of Diverse Blood Cancers (ASH 2023) - "We devised a novel augmentation on the conventional CRISPR/Cas9 KO/DO screen utilizing two MCL cell lines (Jeko1, Z138) which were both resistant to apoptosis induced by VEN +/- ibrutinib (IBR)(Fig 1)...The screen method was repeated in Jeko1 cells using the MCL1 inhibitor AMG176 and BCL-XL inhibitor A1331853, and again yielded BCL2 as well as novel hits, including MARCH5 KO as a sensitizing hit to BCL-XL inhibition...Degron dTAG-mediated depletion of MARCH5 demonstrated synergy with venetoclax in MOLM13 (AML) and Z138 (MCL) cell lines, and enhanced in vitro killing of MOLM13 by VEN + azacytidine, and killing of Jeko1 and Z138 by VEN + IBR...MARCH5 depletion also sensitizes blood cancer cell lines to BCL-XL inhibition. Addition of MARCH5 depletion to VEN-combination treatment improved MCL and AML killing in vitro, and this target should be prioritized for accelerated drug development."

Preclinical • Synthetic lethality • Acute Myelogenous Leukemia • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Mantle Cell Lymphoma • Multiple Myeloma • Oncology • Targeted Protein Degradation • ANXA5 • BCL2L1 • TP53

The Hyperbolic NAMPT Inhibitor RPT1G Synergizes with BCL-2 Family Inhibitors and Helps Overcome Venetoclax Resistance in Acute Myeloid Leukemia Cells (ASH 2024) - "While RPT1G exhibits mostly additive or modestly synergistic effects with AML standard-of-care agents, cytarabine and azacitidine, the synergy between RPT1G and venetoclax was maintained in MV4; 11 cells in the presence of either agent. Moreover, RPT1G strongly synergizes with olaparib, a poly(ADP-ribose) polymerase inhibitor, and olaparib further enhanced the synergy between RPT1G and venetoclax...Of note, navitoclax or AMG-176 further enhanced the synergy between RPT1G and venetoclax in MV4; 11-VR cells...In summary, the first-in-class hyperbolic NAMPT inhibitor RPT1G exhibited strong synergy with agents targeting anti-apoptotic BCL-2 family proteins in AML cells, both alone and in the presence of other standard-of-care agents. Given the crucial roles of NAMPT and BCL-2 family proteins in the survival and treatment-resistance of LSCs, RPT1G is emerging as an ideal candidate to be included in novel combinatorial therapies to enhance treatment efficacy of BCL-2 family..."

Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • B Cell Lymphoma • Leukemia • Lymphoma • Oncology • BCL2L1 • GLI2 • NAMPT

Saga of MCL1 inhibitors in multiple myeloma. (PubMed, Biochem Pharmacol) - P1 | "In 2016, the first MCL1 SMI, AMG 176, advanced to a phase 1 clinical trial for relapsed/refractory (R/R) MM patients and was sponsored by Amgen (NCT02675452)...Adverse side effects and particularly cardiotoxicity present a significant barrier to the widespread clinical use of MCL1 inhibitors. This review explores the history and progress of MCL1 inhibition in MM through highlighting molecular methods of inhibition, early and current preclinical small molecule inhibitors, and past and present MCL1 inhibitor clinical trials for R/R MM."

Journal • Review • B Cell Lymphoma • Cardiovascular • Hematological Malignancies • Leukemia • Lymphoma • Multiple Myeloma • Oncology • BCL2 • BCL2L1

Targeting MCL-1 to Overcome Therapeutic Resistance and Improve Cancer Mortality. (PubMed, Health Sci Rep) - "The structural foundations for the design of MCL-1 inhibitors are revisited, the pharmacological profiles of the leading drugs (S63845, AZD5991, AMG 176) in advanced clinical development are summarized, and emerging strategies, such as combination therapies with inhibitors of anti-apoptotic proteins such as BCL-2, PROTAC strategies designed to degrade MCL-1, and reversible-binding chemotypes to maximize MCL-1 inhibition and minimize toxicity, are reviewed. The key to clinical success will be to carefully develop more intensive dosing regimens, rationally combine agents, and develop trial designs that prioritize the evaluation of new agents that maximize antitumor activity without the risk of off-target toxicities. Continued translational research and adaptive clinical trials are critical to fully realize the therapeutic potential of MCL-1 inhibition across various cancer contexts."

IO biomarker • Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Immune Modulation • Immunology • Leukemia • Lung Cancer • Multiple Myeloma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • BCL2

AMG 176 First in Human Trial in Participants With Relapsed or Refractory Multiple Myeloma and Participants With Relapsed or Refractory Acute Myeloid Leukemia (clinicaltrials.gov) - P1 | N=141 | Terminated | Sponsor: Amgen | Completed ➔ Terminated; sponsor decision, unrelated to safety

Trial termination • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Multiple Myeloma • Oncology

A selective BRM (SMARCA2) inhibitor for the treatment of BRG1 (SMARCA4) mutant cancers (AACR 2025) - "ZN-7035 monotherapy demonstrated anti-tumor activity and synergistic tumor growth inhibition in combination with AMG176, a MCL1 inhibitor, in an NCI-H838 xenograft model carrying BRG1 loss-of-function mutation. ZN-7035 is a highly potent, selective, orally available, small-molecule, enzymatic inhibitor of BRM. Preclinical findings highlight that ZN-7035-based combination therapies have the potential to be effective and safe treatments for patients with tumors harboring BRG1 mutations."

Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRT80 • SMARCA2 • SMARCA4

AMG 176 With Azacitidine in Subjects With Myelodysplastic Syndrome /Chronic Myelomonocytic Leukemia (clinicaltrials.gov) - P1 | N=7 | Terminated | Sponsor: Amgen | Completed ➔ Terminated; Sponsor decision, unrelated to safety.

Monotherapy • Trial termination • Chronic Myelomonocytic Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology

A phase I study of the myeloid cell leukemia 1 (MCL1) inhibitor tapotoclax (AMG 176) in patients with myelodysplastic syndromes after hypomethylating agent failure. (PubMed, Leuk Res) - No abstract available

Journal • P1 data • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology

Tapotoclax Demonstrates Safety, Yields Anti-Leukemic Effects but No Responses in MDS Following HMAs (OncLive) - "Treatment with tapotoclax (AMG 176) was tolerable and led to reductions in bone marrow blasts and transfusion dependence in patients with high-risk myelodysplastic syndromes (MDS) after hypomethylating agents (HMAs), according to data from a phase 1 study (NCT05209152)....All patients were transfusion dependent at baseline, and 71% of patients experienced a reduction of at least 2 packed red blood cell units between cycles 1 and 2. Additionally, 1 patient (14%) achieved transfusion independence for approximately 7 weeks....During the study, patients received a median of 3 cycles of tapotoclax (range, 2-4). One patient developed arrhythmias with premature atrial and ventricular contractions that were possibly related to tapotoclax; however, these resolved without dose interruptions or reductions."

P1 data • Hematological Malignancies • Myelodysplastic Syndrome • Oncology

A Phase I Study of the Myeloid (SOHO 2024) - P1 | "This phase 1 study demonstrated that tapotoclax was safe and tolerated in a high-risk cohort of patients with HMA failure MDS. No DLTs were observed, and cardiac AEs self-resolved without dose reductions. Given its manageable toxicity profile and transient antileukemic and transfusion-independent effect, the use of tapotoclax in combination with HMA or other therapies may warrant further consideration."

P1 data • Hematological Malignancies • Myelodysplastic Syndrome • Oncology • Peritoneal Cancer

AMG 176 First in Human Trial in Participants With Relapsed or Refractory Multiple Myeloma and Participants With Relapsed or Refractory Acute Myeloid Leukemia (clinicaltrials.gov) - P1 | N=142 | Completed | Sponsor: Amgen | Active, not recruiting ➔ Completed

Trial completion • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Multiple Myeloma • Oncology

Prognostic signature based on S100 calcium-binding protein family members for lung adenocarcinoma and its clinical significance. (PubMed, Comput Methods Biomech Biomed Engin) - "Finally, small molecular compounds targeting prognostic genes were screened using CellMiner database, and molecular docking confirmed the binding of AMG-176, Estramustine, and TAK-632 with prognostic genes. In conclusion, we generated a prognostic signature with robust and reliable predictive ability, which may provide guidance for prognosis and treatment of LUAD."

IO biomarker • Journal • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

TARGETING MCL1-DRIVEN ANTI-APOPTOTIC PATHWAYS OVERCOMES BLAST PROGRESSION AFTER HYPOMETHYLATING AGENT RESISTANCE IN CHRONIC MYELOMONOCYTIC LEUKEMIA (EHA 2024) - "NF-kB–mediated anti-apoptotic responses induce oncogenic dependencies in RASmCMML that can be therapeutically targeted."

IO biomarker • Chronic Myelomonocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • CD34 • CD8 • PRF1 • PTPRC

A PHASE I STUDY OF THE MYELOID CELL LEUKEMIA 1 (MCL1) INHIBITOR TAPOTOCLAX (AMG 176) IN PATIENTS WITH MYELODYSPLASTIC SYNDROMES AFTER HYPOMETHYLATING AGENT FAILURE (EHA 2024) - P1 | "This phase 1 study demonstrated that tapotoclax was safe and tolerated in a high-risk cohort of patients withMDS after HMA failure. No DLTs were observed, and cardiac AEs self-resolved without dose reductions. Thoughno patients responded, some patients experienced transient blast reduction and decreased RBC transfusionburden."

Clinical • P1 data • Atrial Fibrillation • Bone Marrow Transplantation • Cardiovascular • Fatigue • Hematological Malignancies • Infectious Disease • Leukemia • Myelodysplastic Syndrome • Oncology • Peritoneal Cancer • Transplantation

A phase I study of the myeloid cell leukemia 1 (MCL1) inhibitor tapotoclax (AMG 176) in patients with myelodysplastic syndromes after hypomethylating agent failure. (ASCO 2024) - P1 | "This phase 1 study demonstrated that tapotoclax was safe and tolerated in a high-risk cohort of pts with MDS after HMA failure. No DLTs were observed, and cardiac AEs self-resolved without dose reductions. Though no pts responded, some pts experienced transient blast reduction and decreased RBC transfusion burden."

Clinical • P1 data • Acute Myelogenous Leukemia • Atrial Fibrillation • Bone Marrow Transplantation • Cardiovascular • Fatigue • Hematological Malignancies • Infectious Disease • Leukemia • Myelodysplastic Syndrome • Oncology • Peritoneal Cancer • Transplantation

Combinations of Cdc-like kinase (CLK) inhibitors with targeted oncology agents or standard chemotherapy in patient-derived multi-cell type tumor spheroids (AACR 2024) - "Among the standard chemotherapeutic drugs, doxorubicin and SN-38 demonstrated additive and greater-than-additive cytotoxicity in various spheroid types when combined with either CLK inhibitor...These agents included the XPO1 inhibitor, eltanexor, the MCL-1 inhibitor, tapotoclax, the α-isoform-specific PI3K inhibitor, inavolisib, and the pan-PI3K inhibitor, copanlisib. Notably, combinations of the CLK inhibitors with the KRAS G12D variant-specific inhibitor, MRTX-1133, showed selective activity against all tumor cell lines harboring this genetic variant. Interestingly, a strong antagonistic interaction between paclitaxel and CC-671 was observed in all thirty spheroid types, while no such interaction was observed with cirtuvivint. This project was funded in part with federal funds from the NCI, NIH, under contract no. HHSN261201500003I."

Clinical • Melanoma • Oncology • Solid Tumor • KRAS

AMPK inhibition sensitizes acute leukemia cells to BH3 mimetic-induced cell death. (PubMed, Cell Death Differ) - "BH3 mimetics, including the BCL2/BCLXL/BCLw inhibitor navitoclax and MCL1 inhibitors S64315 and tapotoclax, have undergone clinical testing for a variety of neoplasms...Building on the observation that BH3 mimetic monotherapy induces AMP kinase (AMPK) activation in multiple acute leukemia cell lines, we report that the AMPK inhibitors (AMPKis) dorsomorphin and BAY-3827 sensitize these cells to navitoclax or MCL1 inhibitors...Conversely, dorsomorphin synergizes with navitoclax or the MCL1 inhibitor S63845 to induce cell death in primary acute leukemia samples ex vivo and increases the antitumor effects of navitoclax or S63845 in several xenograft models in vivo with little or no increase in toxicity in normal tissues. These results suggest that AMPK inhibition can sensitize acute leukemia to multiple BH3 mimetics, potentially allowing administration of lower doses while inducing similar antineoplastic effects."

IO biomarker • Journal • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • Thrombocytopenia • AMPK • BCL2 • BCL2L1 • BCL2L2

Uncovering metabolic and apoptotic vulnerabilities in multiple myeloma (EACR-AACR 2024) - "Apoptotic vulnerabilities were determined by sensitivity to BH3 mimetics (BCL2 inhibitor: venetoclax; MCL1: AMG176 and BCLXL: A1331852) by annexin v/propidium iodide staining...JJN3 and KMS27 showed a reliance on OXPHOS metabolism, while KMS12BM were the least dependent on OXPHOS. Next, the sensitivity of MM cells to a complex I inhibitor (IACS010759) was investigated...Conclusion Next, we aim to uncover the mechanism of the increased reliance on BCLXL. Through these innovative assays, we hope to uncover the metabolic and apoptotic vulnerabilities in MM patient samples, to potentially identify personalised therapies for enhanced survival."

Hematological Disorders • Hematological Malignancies • Multiple Myeloma • Oncology • ANXA5 • BCL2L1

AMG 176 First in Human Trial in Participants With Relapsed or Refractory Multiple Myeloma and Participants With Relapsed or Refractory Acute Myeloid Leukemia (clinicaltrials.gov) - P1 | N=142 | Active, not recruiting | Sponsor: Amgen | Trial primary completion date: Jan 2024 ➔ Sep 2024

Trial primary completion date • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Multiple Myeloma • Oncology

AMG 176 With Azacitidine in Subjects With Myelodysplastic Syndrome /Chronic Myelomonocytic Leukemia (clinicaltrials.gov) - P1 | N=9 | Completed | Sponsor: Amgen | Recruiting ➔ Completed | N=120 ➔ 9 | Trial completion date: Dec 2026 ➔ Dec 2023 | Trial primary completion date: Dec 2025 ➔ Dec 2023

Combination therapy • Enrollment change • Monotherapy • Trial completion • Trial completion date • Trial primary completion date • Chronic Myelomonocytic Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology

AMG 176 First in Human Trial in Participants With Relapsed or Refractory Multiple Myeloma and Participants With Relapsed or Refractory Acute Myeloid Leukemia (clinicaltrials.gov) - P1 | N=142 | Active, not recruiting | Sponsor: Amgen | Recruiting ➔ Active, not recruiting

Enrollment closed • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Multiple Myeloma • Oncology

AMG 176 First in Human Trial in Participants With Relapsed or Refractory Multiple Myeloma and Participants With Relapsed or Refractory Acute Myeloid Leukemia (clinicaltrials.gov) - P1 | N=175 | Recruiting | Sponsor: Amgen | Trial completion date: Mar 2025 ➔ Aug 2024

Trial completion date • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Multiple Myeloma • Oncology • BAX • CASP3 • MCL1

AMG 176 With Azacitidine in Subjects With Myelodysplastic Syndrome /Chronic Myelomonocytic Leukemia (clinicaltrials.gov) - P1 | N=120 | Recruiting | Sponsor: Amgen | Trial completion date: Mar 2026 ➔ Dec 2026 | Trial primary completion date: Mar 2025 ➔ Dec 2025

Combination therapy • Monotherapy • Trial completion date • Trial primary completion date • Chronic Myelomonocytic Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology