A Phase 1 Study of AMG 176 as Monotherapy and in Combination With Azacitidine in Higher-Risk Myelodysplastic Syndrome and Chronic Myelomonocytic Leukemia

The main objective is to assess the safety, tolerability, and efficacy of AMG 176 as monotherapy and in combination with the 7-day regimen of azacitidine for the treatment of Higher-Risk Myelodysplastic Syndrome and Chronic Myelomonocytic Leukemia (HR-MDS/CMML).

Start Date14 Nov 2022

Sponsor / Collaborator

Amgen, Inc.

NCT03797261

/ TerminatedPhase 1

Phase 1b Study of Venetoclax and AMG 176 in Patients With Relapsed/Refractory Hematologic Malignancies

This dose-escalation study evaluating the safety, pharmacokinetics and preliminary efficacy of venetoclax in combination with AMG 176 in participants with relapsed or refractory acute myeloid leukemia (AML) and participants with Non-Hodgkin's lymphoma (NHL)/diffuse large B-cell lymphoma (DLBCL).
This study will include a dose escalation phase to identify the maximum tolerated dose/recommended phase 2 dose (MTD/RPTD) of venetoclax plus AMG 176 as well as a dose expansion phase to confirm safety, explore efficacy, and confirm the suitability of the preliminary RPTD.

Start Date18 Mar 2019

Sponsor / Collaborator

AbbVie, Inc.

[+2]

NCT02675452

/ CompletedPhase 1

A Phase 1 First in Human Study Evaluating the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of AMG 176 in Subjects With Relapsed or Refractory Multiple Myeloma and Subjects With Relapsed or Refractory Acute Myeloid Leukemia

At least one dose level of AMG 176 will achieve acceptable safety and tolerability in participants with relapsed or refractory multiple myeloma and participants with relapsed or refractory acute myeloid leukemia

Start Date13 Jun 2016

Sponsor / Collaborator

Amgen, Inc.

100 Clinical Results associated with AMG-176

100 Translational Medicine associated with AMG-176

100 Patents (Medical) associated with AMG-176

Literatures (Medical) associated with AMG-176

02 Jul 2024·Journal of Biomolecular Structure and Dynamics

A multitier virtual screening study of phytoconstituents as Myeloid Cell Leukemias 1 inhibitors

Article

Author: Liu, Wenjun ; Sadiq, Mohd ; Khatoon, Zeenat ; Hasan Khan, Shaheer ; Khalid, Mohammad ; Faizan Siddiqui, Mohd ; Wahab, Shadma

Myeloid Cell Leukemia 1 (MCL1) is an anti-apoptotic protein that plays a critical role in regulating cell survival, particularly in cancer cells. It is a member of the BCL-2 family of proteins, which control the intrinsic pathway of apoptosis. MCL1 has emerged as a promising target for cancer therapy because it is overexpressed in a wide range of cancers, including breast, lung, prostate, and hematologic malignancies. Due to its remarkable role in cancer progression, it has been reflected as a promising drug target for cancer therapy. A few MCL1 inhibitors have been identified previously, but further research is needed to develop novel, effective and safe MCL1 inhibitors that can overcome resistance mechanisms and minimize toxicity in normal cells. In this study, we aim to search for compounds that target the critical binding site of MCL1 from phytoconstituent library from the IMPPAT database. To accomplish this, a multitier virtual screening approach involving molecular docking and molecular dynamics simulations (MDS) were used to evaluate their suitability for the receptor. Notably, certain screened phytoconstituents have appreciable docking scores and stable interactions toward the binding pocket of MCL1. The screened compounds underwent ADMET and bioactivity analysis to establish their anticancer properties. One phytoconstituent, Isopongaflavone, was identified that exhibiting higher docking and drug-likeness than the already reported MCL1 inhibitor, Tapotoclax. Isopongaflavone and and Tapotoclax, along with MCL1, were subjected to 100 nanoseconds (ns) MDS study to verify their stability inside the binding site of MCL1. The MDS findings demonstrated a strong binding affinity between Isopongaflavone and the MCL1 binding pocket, resulting in reduced conformational fluctuations. 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.

01 Apr 2024·Cell Death & Differentiation

AMPK inhibition sensitizes acute leukemia cells to BH3 mimetic-induced cell death

Article

Author: Patnaik, Mrinal M ; Hu, Lei ; Ye, Kaiqin ; Venkatachalam, Annapoorna ; Smith, B Douglas ; Jia, Jia ; Wang, Hongzhi ; Deng, Qingmei ; Kaufmann, Scott H ; Wu, Xinyan ; Flatten, Karen S ; Meng, X Wei ; Ghiaur, Gabriel ; Zhong, Jun ; Dai, Haiming ; Ji, Wenbo ; Pandey, Akhilesh ; Saliba, Antoine N ; Peterson, Kevin L ; Webster, Jonathan A ; Schneider, Paula A ; Csizmar, Clifford M

BH3 mimetics, including the BCL2/BCLX_L/BCLw inhibitor navitoclax and MCL1 inhibitors S64315 and tapotoclax, have undergone clinical testing for a variety of neoplasms. Because of toxicities, including thrombocytopenia after BCLX_L inhibition as well as hematopoietic, hepatic and possible cardiac toxicities after MCL1 inhibition, there is substantial interest in finding agents that can safely sensitize neoplastic cells to these BH3 mimetics. 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. Cell fractionation and phosphoproteomic analyses suggest that sensitization by dorsomorphin involves dephosphorylation of the proapoptotic BCL2 family member BAD at Ser75 and Ser99, leading BAD to translocate to mitochondria and inhibit BCLX_L. Consistent with these results, BAD knockout or mutation to BAD S75E/S99E abolishes the sensitizing effects of dorsomorphin. 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.

23 May 2023·Proceedings of the National Academy of Sciences of the United States of AmericaQ1 · CROSS-FIELD

Design of rigid protein-protein interaction inhibitors enables targeting of undruggable Mcl-1.

Q1 · CROSS-FIELD

Article

Author: Schade, Markus ; Carbajo, Rodrigo J ; Packer, Martin ; Johannes, Jeffrey W ; Chiarparin, Elisabetta ; Embrey, Kevin ; Bodnarchuk, Michael S ; Degorce, Sébastien L ; Rawlins, Philip B ; Hird, Alexander W ; Hargreaves, David

The structure-based design of small-molecule inhibitors targeting protein-protein interactions (PPIs) remains a huge challenge as the drug must bind typically wide and shallow protein sites. A PPI target of high interest for hematological cancer therapy is myeloid cell leukemia 1 (Mcl-1), a prosurvival guardian protein from the Bcl-2 family. 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. Our X-ray data reveal high plasticity of Mcl-1 and a remarkable ligand-induced pocket deepening. 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.

News (Medical) associated with AMG-176

12 Dec 2023

·synapse.patsnap.com

Understanding Mcl-1 Inhibitors and Methods to Keep Abreast of Their Recent Developments

Mcl-1, also known as myeloid cell leukemia-1, is a protein that plays a crucial role in regulating cell survival and apoptosis (programmed cell death) in the human body. It belongs to the Bcl-2 family of proteins, which are involved in maintaining the balance between cell survival and death. Mcl-1 is primarily found in various tissues, including the immune system, and is particularly important for the survival of immune cells. Dysregulation of Mcl-1 expression or function has been implicated in various diseases, including cancer, where it can promote tumor cell survival and resistance to chemotherapy. Therefore, targeting Mcl-1 has emerged as a potential therapeutic strategy in the pharmaceutical industry for the treatment of cancer and other diseases. Overexpression of MCL-1 is common in many types of tumors and is closely related to tumorigenesis, poor prognosis, and drug resistance. MCL-1 is located in mitochondria, and its core role in regulating the mitochondrial apoptosis pathway makes it an attractive target for cancer treatment. Therefore, Mcl-1 inhibitors are considered an attractive method for treating recurrent or refractory malignant tumors. Although the development of MCL-1 inhibitors has made significant progress, there are still some problems in the development process: firstly, most reported Mcl-1 inhibitors have poor antitumor activity due to poor physicochemical properties of the drug, low membrane permeability, and high serum protein binding rate; secondly, some Mcl-1 inhibitors that have entered the clinical trial stage (AZD5991, AMG-176, etc.) have caused the clinical trial to be terminated due to side effects (NCT03218683, NCT03797261). The analysis of the target Mcl-1 reveals a competitive landscape with multiple companies actively developing drugs in different stages. Novartis AG, Les Laboratoires Servier SAS, Servier Group, Ligand Pharmaceuticals, Inc., Amgen, Inc., AbbVie, Inc., and BeiGene Ltd. are among the companies growing fastest under this target. The approved indications for drugs targeting Mcl-1 cover a wide range of hematologic and solid tumors, indicating the potential of Mcl-1 as a therapeutic target for various cancers. Small molecule drugs are progressing most rapidly, with the presence of biosimilars indicating intense competition. The United States, European Union, and China are the countries/locations developing fastest under the target Mcl-1, with notable progress in other countries as well. Overall, the target Mcl-1 presents a promising opportunity for the development of innovative drugs in the pharmaceutical industry. How do they work?Mcl-1 inhibitors are a type of drugs that specifically target and inhibit the activity of the protein called Mcl-1. Mcl-1 is a member of the Bcl-2 family of proteins, which play a crucial role in regulating programmed cell death, also known as apoptosis. From a biomedical perspective, Mcl-1 inhibitors are of great interest in cancer research and therapy. Mcl-1 is often overexpressed in various types of cancer cells, leading to increased cell survival and resistance to chemotherapy or other treatments. By inhibiting Mcl-1, these inhibitors can promote cancer cell death and enhance the effectiveness of anticancer therapies. Mcl-1 inhibitors can be designed as small molecules or as biologics such as antibodies. They work by binding to Mcl-1 and preventing its interaction with other proteins involved in cell survival pathways. This disruption of Mcl-1 function triggers apoptosis in cancer cells, ultimately leading to their destruction. The development of Mcl-1 inhibitors holds promise for the treatment of cancers where Mcl-1 plays a significant role in promoting tumor cell survival. Clinical trials are underway to evaluate the safety and efficacy of Mcl-1 inhibitors as potential cancer therapeutics. List of Mcl-1 InhibitorsThe currently marketed Mcl-1 inhibitors include: S-64315ABBV-467AMG-176AMG-397AZD-5991GS-9716PRT-1419483-LMANJ-810APG-3526For more information, please click on the image below. What are Mcl-1 inhibitors used for?Mcl-1 inhibitors have shown promise in various cancer types, including hematological malignancies such as leukemia and lymphoma, as well as solid tumors like lung, breast, and colorectal cancers. For more information, please click on the image below to log in and search. How to obtain the latest development progress of Mcl-1 inhibitors?In the Synapse database, you can keep abreast of the latest research and development advances of Mcl-1 inhibitors anywhere and anytime, daily or weekly, through the "Set Alert" function. Click on the image below to embark on a brand new journey of drug discovery!

21 Oct 2021

·www.biospace.com

AstraZeneca Cancer Trial Hit with Clinical Hold Following Cardiac Issues

Nathan Stirk/Getty Images A trial assessing an experimental AstraZeneca cancer drug has been placed on clinical hold due to safety concerns. The trial pause comes two years after Amgen was also forced to pause a study of a drug within the same class. AstraZeneca quietly announced the study on clinicaltrials.gov, but did not issue any formal statement regarding the pause. The company said the trial, which assesses AZD5991 in subjects with relapsed or refractory hematologic malignancies, was paused to allow “further evaluation of safety related information.” The pause was put into place on Oct. 19, according to the site. AZD5991 is a direct inhibitor of Mcl-1, a difficult target for oncology drugs and a well-known drug-resistance driver. AstraZeneca’s experimental drug is designed to target apoptosis, which is the process of programmed cell death in hematological cancer. AstraZeneca was assessing AZD5991 in combination with Roche’s venetoclax in patients with relapsed or refractory acute myeloid leukemia (AML), as well as a monotherapy treatment. Venetoclax, co-developed by Roche and AbbVie, is a small molecule inhibitor of the BCL-2 protein. According to multiple outlets, the trial was placed on clinical hold following signs of heart issues in one patient who received the combination treatment. In a statement sent to Fierce Biotech, the first outlet to report on the hold, the company noted “asymptomatic elevation in cardiovascular laboratory parameters.” According to the report, this occurred in an AML patient who had additional comorbidities. AstraZeneca noted there were no safety signs in individuals who received AZD5991 as a monotherapy. “It is important to note that the asymptomatic elevation has since resolved. We are now in the process of conducting a full analysis of the study data and working closely with the FDA for the benefit of the patients,” an AstraZeneca spokesperson said according to the report. The study was designed to be a three-part, open-label, non-randomized trial designed to test the safety, tolerability, pharmacokinetics, and preliminary anti-tumor activity of ascending doses of AZD5991 alone or in combination with venetoclax in patients with relapsed or refractory hematologic malignancies. The safety concern noted in the AstraZeneca study is similar to what Amgen faced two years ago when its study was placed on clinical hold. Earlier this year, California-based Amgen opted to scrap its study of AMG 397, an oral MCL-1 inhibitor. As BioSpace previously reported, the Amgen study was terminated to shift focus to studies of AMG 176, an intravenously dosed inhibitor of MCL-1. That asset is currently being assessed in a Phase I study for hematological malignancies.

Small molecular drug

07 Feb 2021

·www.biospace.com

Amgen Q4 Report: Five Halted or Killed Cancer Programs, Revenue Up 7%

Amgen Chief Executive Officer Bob Bradway. (Polk/Getty Images for International Medical Corps) Amgen released its fourth-quarter and full-year 2020 results today, and although there was good news financially, there was also news of five cancer programs that have either been halted or abandoned. One of the programs was the company’s BCMA BiTE (bispecific T cell engager) program for pavurutamab (AMG 701), which Amgen was developing to replace AMG 420. The company stated, “Enrollment in the Phase I study has been paused while we discuss protocol modifications to optimize safety monitoring and mitigation with the FDA. Currently enrolled patients who are demonstrating benefit may continue to receive investigational product and the Company expects to resume patient enrollment in H1 2021.” BiTE is a class of artificial bispecific monoclonal antibodies. They direct the body’s immune system, specifically the cytotoxic activity of T cells, against cancer cells. They are fusion proteins made up of two single-chain variable fragments of different antibodies. Also paused was AMG 673, a CD33-targeting BiTE for acute myelogenous leukemia (AML). They are delaying that program while they determine if AMG 330 would be a better choice. Three other programs were halted altogether. One is AMG 596, abandoned because of reprioritization of their R&D programs. The Phase I trial of AMG 397, an oral MCL-1 inhibitor, was halted to shift to intravenous MCL-1 inhibitor AMG 176, which is being evaluated in a Phase I study for hematologic malignancies. And then Imlygic (talimogene laherparepvec)’s Phase III in combination with Merck’s checkpoint inhibitor Keytruda (pembrolizumab) for melanoma—it was halted over futility. In the Q4 conference call, Chief Executive Officer Bob Bradway and R&D Chief David Reese focused on the progress of the company’s BiTE platform, despite the apparent slashing of several of its programs. “Rather than calling it targeted protein degradation, we’re describing it as our induced proximity platform,” Bradway said. “The intention there as I said, it’s just to be clear that we think the technology that we’re building can be used not just to degrade proteins, but other molecules as well. So we’re excited about it. This is as I said again in my remarks, this is a long-term research strategy and Dave and his team and I spent a lot of time with each other, trying to think about how to position for the long-term.” He then seems to hint there may be some M&A activity in their future in this area, saying, “it will be both internal and external and remind you that we acquired New Evolution now years ago for the purpose of helping to build out the set of capabilities and I would imagine, we’ll continue to look as I said, both internally and externally.” Otherwise, for the fourth quarter, Amgen reported total revenues increased 7% to $6.6 billion compared to the fourth quarter of 2019. Product sales grew 8% globally, driven by 13% volume growth across the portfolio, including Otezla (apremilast), MVASI (bevacizumab-awwb), Canjinti (trastuzumab-anns), and Repatha (evolcumab). Amgen acquired Otezla for $13.4 billion from Celgene, after Celgene was acquired by Bristol Myers Squibb and they were forced to divest the drug by the U.S. Securities and Exchange Commission (SEC). For the full year, total revenues grew 9% to $25.4 billion. GAAP earnings per share (EPS) dropped 3% to $2.76 for the fourth quarter and 4% to $12.31 for the full year, driven mostly by the Otezla acquisition, and partially offset by increased revenues. GAAP operating income for the fourth quarter decreased 2% to $2 billion and GAAP operating margin decreased 3.1% to 31.7%, also driven by amortization of intangible assets from the Otezla buy. For the full year, GAAP operating income decreased 6% to $9.1 billion. The company generated $9.9 billion of free cash flow for the full year compared to $8.5 billion in 2019. Total revenue guidance for 2021 is $25.8 billion to $26.6 billion, with EPS guidance of $12.12 to $13.17 on a GAAP basis. “In a year marked by the disruption of COVID-19, we served patients around the world without interruption, advanced our pipeline and delivered strong financial performance, all while keeping our employees safe,” Bradway said. “As we move into 2021, we look forward to commercializing our pipeline successes.” Featured Jobs on BioSpace

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100 Deals associated with AMG-176

R&D Status

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Indication	Highest Phase	Country/Location	Organization	Date
Relapse multiple myeloma	Phase 1	Australia	Amgen, Inc.	13 Jun 2016
Relapse multiple myeloma	Phase 1	Japan	Amgen, Inc.	13 Jun 2016
Relapse multiple myeloma	Phase 1	Germany	Amgen, Inc.	13 Jun 2016
Relapse multiple myeloma	Phase 1	Canada	Amgen, Inc.	13 Jun 2016
Relapse multiple myeloma	Phase 1	United States	Amgen, Inc.	13 Jun 2016
Relapsing acute myeloid leukemia	Phase 1	Germany	Amgen, Inc.	13 Jun 2016
Relapsing acute myeloid leukemia	Phase 1	Japan	Amgen, Inc.	13 Jun 2016
Relapsing acute myeloid leukemia	Phase 1	Australia	Amgen, Inc.	13 Jun 2016
Relapsing acute myeloid leukemia	Phase 1	Canada	Amgen, Inc.	13 Jun 2016
Relapsing acute myeloid leukemia	Phase 1	United States	Amgen, Inc.	13 Jun 2016

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT05209152 (MDS-537, SOHO2024)	Phase 1	Myelodysplastic Syndromes	7	Tapotoclax 120 mg/m2	fpeevlahnh(bzkwlpshby) = unsustained blast reduction after cycle 3 washhcscry (cbbqnjgnvz ) View more	Positive	04 Sep 2024
NCT05209152 (MDS-537, SOHO2024)	Phase 1	Myelodysplastic Syndromes	7	Tapotoclax 240 mg/m2		Positive	04 Sep 2024
NCT05209152 (EHA 12024 \| EHA 22024) Manual	Phase 1	Myelodysplastic Syndromes	7	TAPOTOCLAX	(xyfjdvvlba) = none btvhfizgyn (jwkgsqbnae ) View more	Positive	14 May 2024

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