tapotoclax (AMG 176) / Amgen, BeiGene - LARVOL DELTA

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 • Hematological Disorders • Leukemia • Lymphoma • Oncology • BCL2L1 • GLI2 • NAMPT

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

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 Disorders • Hematological Malignancies • Leukemia • Lymphoma • Mantle Cell Lymphoma • Multiple Myeloma • Oncology • Targeted Protein Degradation • ANXA5 • BCL2L1 • TP53

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

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: Oct 2025 ➔ Mar 2025 | Trial primary completion date: Sep 2024 ➔ Dec 2023

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

A multitier virtual screening study of phytoconstituents as Myeloid Cell Leukemias 1 inhibitors. (PubMed, J Biomol Struct Dyn) - "One phytoconstituent, Isopongaflavone, was identified that exhibiting higher docking and drug-likeness than the already reported MCL1 inhibitor, Tapotoclax...This investigation proposes Isopongaflavone as a promising candidate for the development of innovative anticancer therapeutics, pending the necessary validation procedures. Also, the findings provide valuable information for designing MCL1 inhibitors based on the protein's structure.Communicated by Ramaswamy H. Sarma."

Journal • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • Solid Tumor • BCL2 • MCL1

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: Jan 2025 ➔ Oct 2025 | Trial primary completion date: Feb 2024 ➔ Sep 2024

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

Decoding the mechanism behind MCL-1 inhibitors: A pathway to understanding MCL-1 protein stability. (PubMed, Oncotarget) - No abstract available

Journal • Hematological Malignancies • Leukemia • Oncology

CLL Targets Beyond BTKi and Bcl2i (ICLLM 2023) - "1, 2 Treatment of CLL cells with entospletinib, but not other BCR-signaling inhibitors, led to a disruption of BAFF-BCR cross-talk and downmodulation of MCL1 mRNA and protein, thus implicating SYK in transduction of multiple pro-survival signals emanating from the tumor microenvironment.1 Entospletinib has shown promising clinical activity in CLL, alone or in combination with obinutuzumab, including in patients with high-risk disease such as TP53 aberrant.3, 4 The drug is very well tolerated, however its development in CLL has been halted. Meanwhile, we have shown that luxeptinib, a dual SYK/BTK kinase inhibitor, has activity in BTK inhibitor-resistant lymphoid models in vitro.5 Luxeptinib is now being investigated in lcinical trials in hematologic malignancies...The early results of MS-553, a selective PKC-β inhibitor, indicates that this agent is tolerable and effective both as single agent and in combination with venetoclax.8 Proteolysis-targeting chimeras (PROTACs)..."

IO biomarker • Acute Myelogenous Leukemia • Chronic Lymphocytic Leukemia • Diffuse Large B Cell Lymphoma • Hematological Disorders • Hematological Malignancies • Immune Modulation • Leukemia • Lymphoma • Mantle Cell Lymphoma • Metabolic Disorders • Multiple Myeloma • Neutropenia • Non-Hodgkin’s Lymphoma • Oncology • Richter's Syndrome • Small Lymphocytic Lymphoma • Targeted Protein Degradation • CD19 • CD4 • CD8 • IGH • IKZF1 • IKZF3 • NF-κβ • PRKCB • ROR1 • SYK • TP53

Design of rigid protein-protein interaction inhibitors enables targeting of undruggable Mcl-1. (PubMed, Proc Natl Acad Sci U S A) - "Despite being previously considered undruggable, seven small-molecule Mcl-1 inhibitors have recently entered clinical trials. Here, we report the crystal structure of the clinical-stage inhibitor AMG-176 bound to Mcl-1 and analyze its interaction along with clinical inhibitors AZD5991 and S64315...Nuclear Magnetic Resonance (NMR)-based free ligand conformer analysis demonstrates that such unprecedented induced fit is uniquely achieved by designing highly rigid inhibitors, preorganized in their bioactive conformation. By elucidating key chemistry design principles, this work provides a roadmap for targeting the largely untapped PPI class more successfully."

Journal • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • BCL2

AMG176, an MCL-1 inhibitor, is active in pre-clinical models of aggressive B-cell lymphomas. (PubMed, Leuk Lymphoma) - "AMG176 exhibited impressive synergy with venetoclax and chemotherapeutic agents, less so with proteasomal inhibitors, and antagonism with anti-CD20 monoclonal antibodies. The activity of AMG176 could not be confirmed in murine models of BCL. Combination therapy targeting MCL-1 and BCL-2 may provide an alternative therapeutic approach in BCL, however optimal patient selection will remain the key to obtaining high response rates and tolerability."

IO biomarker • Journal • Preclinical • Burkitt Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • BCL2