murizatoclax (AMG 397) / Amgen - LARVOL DELTA

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

NA1-115-7, from Zygogynum pancheri, is a new selective MCL-1 inhibitor inducing the apoptosis of hematological cancer cells but non-toxic to normal blood cells or cardiomyocytes. (PubMed, Biomed Pharmacother) - "Synthetic inhibitors targeting these proteins have been developed, and some hematological malignancies are now widely treated with a BCL-2 inhibitor (venetoclax)...Six MCL-1 inhibitors (S64315, AZD-5991, AMG-176, AMG-397, ABBV-467 and PRT1419) have been evaluated in clinical trials since 2016, but some were affected by safety issues and none are currently used clinically...Importantly, a similar treatment with NA1-115-7 was not toxic to erythrocytes, peripheral blood mononuclear cells, platelets, or cardiomyocytes. These results highlight the potential of natural products for use as specific BH3 mimetics non-toxic to normal cells, and they suggest that NA1-115-7 may be a promising tool for use in cancer treatment."

IO biomarker • Journal • Hematological Disorders • Hematological Malignancies • Lymphoma • Oncology • BCL2L1

Optimization and scale-up of a diastereoselective epoxide formation/nucleophilic ring-opening sequence to access a late stage intermediate of AMG 397 (ACS-Fall 2022) - "Additionally, a unique multi-phasic crystallization was developed, which facilitated the filtration/isolation processes by producing material with superior particle properties. These improved process conditions were successfully demonstrated on manufacturing scale."

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

Molecular Complexity as a Driver for Innovation in Pharmaceutical Process Development (ACS-Sp 2022) - "The Mcl1 inhibitor AMG 397, is a recent example of this trend of increasing complexity for clinical candidates. The continued advance of novel synthetic methods and subsequent translation to efficient and scalable processes has enabled process chemists to overcome the challenges associated with this increasing complexity, and to deliver processes that meet the criteria for sustainability and green chemistry. The presentation will highlight case studies from the Amgen Process Chemistry laboratories."

[VIRTUAL] Beyond BCL-2 Inhibition in Acute Myeloid Leukemia: Other Approaches to Leverage the Apoptotic Pathway (SOHO 2021) - "However, 10–50% of newly diagnosed patients with AML may not respond to venetoclax and HMA or LDAC, and 3–15% patients may not respond to venetoclax with intensive or non-intensive chemotherapy.1–6 In addition, up to 40% of responding patients may relapse with low rates of response of 20% to salvage therapy and poor overall survival of 2 months after relapse.7 Clinical and biological factors associated with primary and acquired resistance to venetoclax include secondary AML, monocytic differentiation, complex cytogenetics, mutations in TP53, BAX, dependence on other anti- apoptotic proteins, altered metabolism of nicotinamide, fatty acids, and oxidative phosphortylation.3,8–14 Several novel inhibitors of BCL-2 are currently being tested in clinic, including BGB 11417, APG-2575, LP-108 and others...There is strong pre-clinical rationale for targeting MCL-1 alone as well as in conjunction with BCL-2 inhibition in AML.15 Recently several selective and highly potent MCL-1..."

IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • Solid Tumor • BCL2L1 • BIRC5 • CFLAR • MDM2 • TNFRSF10A • TNFRSF10B • XIAP

Safety, Tolerability, Pharmacokinetics and Efficacy of AMG 397 in Subjects With Selected Relapsed or Refractory Hematological Malignancies (clinicaltrials.gov) - P1; N=24; Terminated; Sponsor: Amgen; Active, not recruiting ➔ Terminated; Strategic decision given our current development of AMG 176 (a similar MCL-1 inhibitor) that is in clinic, and not because of safety concerns

Clinical • Trial termination • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Lymphoma • Multiple Myeloma • Myelodysplastic Syndrome • Non-Hodgkin’s Lymphoma • Oncology

Amgen Reports Fourth Quarter And Full Year 2020 Financial Results (Amgen Press Release) - "...the Company expects to enter AMG 757 into expansion cohorts over the next several months...Clinical development of AMG 673, a half-life extended BiTE molecule targeting CD33, is paused while we gather further information on the CD33 program through progression of AMG 330. Clinical development of AMG 596, a BiTE molecule targeting EGFR variant III for glioblastoma, has been stopped as we prioritize our portfolio. Phase 1 development of the oral MCL-1 inhibitor AMG 397 was paused with focus shifting to the intravenous MCL-1 inhibitor AMG 176, currently in Phase 1 for the treatment of hematologic malignancies."

Pipeline update • Trial status • Glioblastoma • Hematological Malignancies • Lung Cancer • Oncology • Small Cell Lung Cancer

Safety, Tolerability, Pharmacokinetics and Efficacy of AMG 397 in Subjects With Selected Relapsed or Refractory Hematological Malignancies (clinicaltrials.gov) - P1; N=24; Active, not recruiting; Sponsor: Amgen; Recruiting ➔ Active, not recruiting; N=160 ➔ 24

Clinical • Enrollment change • Enrollment closed • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Lymphoma • Multiple Myeloma • Myelodysplastic Syndrome • Non-Hodgkin’s Lymphoma • Oncology

Targeting MCL-1 in hematologic malignancies: Rationale and progress. (PubMed, Blood Rev) - "Several MCL-1 inhibitors have entered clinical trials, including AZD5991, S64315, AMG 176, and AMG 397. A key area of investigation is whether MCL-1 inhibitors will complement the activity of BCL-2 inhibitors, such as venetoclax, and synergistically enhance anti-tumor efficacy when given in combination with other anti-cancer drugs. Another important question is whether a safe therapeutic window can be found for this new class of inhibitors. In summary, inhibition of MCL-1 shows potential as a treatment for hematologic malignancies and clinical evaluation of MCL-1 inhibitors is currently underway."

IO Biomarker • Journal • Review • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Lymphoma • Multiple Myeloma • Non-Hodgkin’s Lymphoma • Oncology

Safety, Tolerability, Pharmacokinetics and Efficacy of AMG 397 in Subjects With Selected Relapsed or Refractory Hematological Malignancies (clinicaltrials.gov) - P1; N=160; Recruiting; Sponsor: Amgen; Active, not recruiting ➔ Recruiting; N=24 ➔ 160; Trial completion date: Oct 2022 ➔ Feb 2024

Clinical • Enrollment change • Enrollment open • Trial completion date • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Lymphoma • Multiple Myeloma • Myelodysplastic Syndrome • Non-Hodgkin’s Lymphoma • Oncology

[VIRTUAL] Interdiction at a protein-protein interface: Discovery of AMG 397, a potent, selective and orally efficacious MCL-1 inhibitor (ACS-Fall 2020) - "Several development candidates, all administered intravenously, have entered clinical trials including AMG 176, which is currently in Phase I clinical development for hematologic malignancies. AMG 397 is also selective against other pro-survival BCL-2 family proteins and competitive for binding to MCL-1 with pro-apoptotic BCL-2 family members. This presentation will describe the discovery highlights and preclinical evaluation of AMG 397."

Leukemia • Non-Hodgkin’s Lymphoma • Oncology • BCL2

"Amgen presents the preclinical profile of AMG-397, the 1st orally administered MCL-1 inhibitor in clinical development for hematologic malignancies. #ACSFall2020" (@Cortellis)

Hematological Disorders • Hematological Malignancies • Oncology

[VIRTUAL] Discovery and preclinical evaluation of AMG 397, a potent, selective and orally bioavailable MCL1 inhibitor (AACR-II 2020) - "Several MCL1 inhibitors have entered clinical trials including AMG 176, currently in Phase I clinical development for hematologic malignancies. AMG 397 was also tested in the MOLM-13 orthotopic model of AML where twice weekly administration at 10, 30 and 60 mg/kg achieved 47% tumor growth inhibition (TGI), 99% TGI and 75% regression respectively. Combination of AMG 397 at 10 mg/kg twice weekly and 50 mg/kg of venetoclax daily achieved 45% regression in the same model."

Preclinical • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Multiple Myeloma • Oncology • BCL2 • CASP3

Safety, Tolerability, Pharmacokinetics and Efficacy of AMG 397 in Subjects With Multiple Myeloma, NHL, and AML (clinicaltrials.gov) - P1; N=24; Active, not recruiting; Sponsor: Amgen; Trial completion date: Apr 2023 ➔ Oct 2022; Trial primary completion date: Mar 2023 ➔ Oct 2022

Clinical • Trial completion date • Trial primary completion date

Safety, Tolerability, Pharmacokinetics and Efficacy of AMG 397 in Subjects With Multiple Myeloma, NHL, and AML (clinicaltrials.gov) - P1; N=24; Active, not recruiting; Sponsor: Amgen; Trial completion date: Sep 2022 ➔ Apr 2023; Trial primary completion date: Aug 2022 ➔ Mar 2023

Clinical • Trial completion date • Trial primary completion date

Amgen highlights new data from Kyprolis (carfilzomib) and oncology pipeline at IMW 2019 (PRNewswire) - "Data featured from Amgen's hematology franchise will include oral presentations from Phase 1 studies of AMG 420, the anti-B-cell maturation antigen (BCMA) bispecific T cell engager (BiTE®) and AMG 176...A Phase 1 dose escalation study of AMG 701...is underway with data expected for presentation in 2020...The Phase 1 dose escalation clinical trial for AMG 397 (NCT03465540) is on a clinical hold to evaluate a safety signal for cardiac toxicity...the AMG 176 Phase 1 trial (NCT02675452) has been placed on a voluntary hold for new enrollment....Completion of the Phase 3 CANDOR study evaluating KYPROLIS in combination with dexamethasone and DARZALEX® (daratumumab) (KdD) compared to KYPROLIS and dexamethasone alone in patients with relapsed or refractory multiple myeloma is expected in the second half of 2019."

P1 data • P3 data • Trial status

Safety, Tolerability, Pharmacokinetics and Efficacy of AMG 397 in Subjects With Multiple Myeloma, NHL, and AML (clinicaltrials.gov) - P1; N=24; Active, not recruiting; Sponsor: Amgen; Trial completion date: Aug 2023 ➔ Sep 2022

Clinical • Trial completion date

Safety, Tolerability, Pharmacokinetics and Efficacy of AMG 397 in Subjects With Multiple Myeloma, NHL, and AML (clinicaltrials.gov) - P1; N=24; Active, not recruiting; Sponsor: Amgen; Recruiting ➔ Active, not recruiting; N=90 ➔ 24; Trial completion date: Sep 2022 ➔ Aug 2023; Trial primary completion date: Feb 2021 ➔ Aug 2022

Clinical • Enrollment change • Enrollment closed • Trial completion date • Trial primary completion date

Safety, Tolerability, Pharmacokinetics and Efficacy of AMG 397 in Subjects With Multiple Myeloma, NHL, and AML (clinicaltrials.gov) - P1; N=90; Recruiting; Sponsor: Amgen; Trial completion date: Feb 2022 ➔ Sep 2022; Trial primary completion date: Aug 2020 ➔ Feb 2021

Clinical • Trial completion date • Trial primary completion date

Safety, Tolerability, Pharmacokinetics and Efficacy of AMG 397 in Subjects With Multiple Myeloma, NHL, and AML (clinicaltrials.gov) - P1; N=90; Recruiting; Sponsor: Amgen; Trial completion date: Oct 2021 ➔ Feb 2022; Trial primary completion date: May 2020 ➔ Aug 2020

Clinical • Trial completion date • Trial primary completion date