S65487 / HitGen, Novartis, Servier - LARVOL DELTA

PK and PK/PD Modeling of Bcl2 Inhibitor S65487 in Patients With AML and Investigation of Nonlinearity With Microdosing. (PubMed, CPT Pharmacometrics Syst Pharmacol) - "This optimized model demonstrated significant improvement, reducing the difference in the description of exposure for the microdose study from 5- to 1-fold, without compromising the description at therapeutic doses. This modified model has a wider range of applicability across doses and could support the extrapolation of microdose study results to therapeutic doses in future research."

Journal • PK/PD data • Acute Myelogenous Leukemia • B Cell Lymphoma • Lymphoma • Oncology • BCL2 • BCL2L11

CL1-65487-003: Phase I/II Trial of S65487 Plus Azacitidine in Acute Myeloid Leukemia (clinicaltrials.gov) - P1/2 | N=57 | Active, not recruiting | Sponsor: Institut de Recherches Internationales Servier | Completed ➔ Active, not recruiting

Enrollment closed • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology

CL1-65487-003: Phase I/II Trial of S65487 Plus Azacitidine in Acute Myeloid Leukemia (clinicaltrials.gov) - P1/2 | N=57 | Completed | Sponsor: Institut de Recherches Internationales Servier | Active, not recruiting ➔ Completed

Trial completion • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology

Evaluating Protein Interaction Potential of BCL2 Protein for the Direct Assessment of Inhibitor-Target Engagement in Hematological Cancer (ASH 2024) - "The protein interactions of BCL2 were modulated by treating the cell line with BCL2-specific compounds—venetoclax, sonrotoclax, and S65487—during cell culture for 4 hours. Our analysis can be expanded to other anti-apoptotic proteins easily. Our approach can provide kinetic characteristics of BH3 mimetics as well as pharmacodynamic information valuable for clinical trial optimization."

IO biomarker • Hematological Malignancies • Oncology • BCL2

Trial in Progress: An Open Label Phase I/II, Multicenter Study Evaluating Safety, Pharmacokinetics and Efficacy of S65487, a BCL-2 Inhibitor Combined with Azacitidine in Adults with Previously Untreated Acute Myeloid Leukemia Ineligible for Intensive Treatment (ASH 2023) - P1/2 | "Pharmacodynamic analyses are conducted as exploratory objectives in both parts of the study. In particular, the disruption of the BCL2/BIM complex is followed in peripheral-blood mononuclear cells to guide the estimation of the RP2D."

Clinical • P1/2 data • PK/PD data • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Myeloproliferative Neoplasm • Oncology

A First in Human Study of VOB560 in Combination with MIK665 in Patients with Relapsed/Refractory Non-Hodgkin Lymphoma, Acute Myeloid Leukemia, or Multiple Myeloma (ASH 2024) - P1 | "Patients who developed troponin increase underwent cardiac MRI, which showed no observable functional or structural changes to the heart.Conclusions : Early clinical data of VOB560 in combination with MIK665 reported an acceptable safety profile in patients with hematological malignancies. The observed activity in the AML patients supports the notion that targeting MCL1 and BCL2 is a promising approach in hematological malignancies."

Clinical • Combination therapy • First-in-human • P1 data • Acute Myelogenous Leukemia • Anemia • B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Follicular Lymphoma • Hematological Disorders • Leukemia • Lymphoma • Metabolic Disorders • Multiple Myeloma • Nephrology • Neutropenia • Oncology • Renal Disease • Thrombocytopenia • BCL2

CL1-65487-003: Phase I/II Trial of S65487 Plus Azacitidine in Acute Myeloid Leukemia (clinicaltrials.gov) - P1/2 | N=57 | Active, not recruiting | Sponsor: Institut de Recherches Internationales Servier | Trial completion date: Apr 2025 ➔ Dec 2025 | Trial primary completion date: Sep 2024 ➔ Dec 2025

Trial completion date • Trial primary completion date • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology

Study of a New Intravenous Drug, Called S65487, in Patients With Acute Myeloid Leukemia, Non Hodgkin Lymphoma, Multiple Myeloma or Chronic Lymphocytic Leukemia (clinicaltrials.gov) - P1 | N=60 | Terminated | Sponsor: Institut de Recherches Internationales Servier | Completed ➔ Terminated; The study was prematurely terminated on 14th March 2023 for strategic considerations due to the limited efficacy seen with this treatment in monotherapy. This decision was not based on any safety concerns.

Trial termination • Acute Myelogenous Leukemia • Chronic Lymphocytic Leukemia • Follicular Lymphoma • Hematological Malignancies • Leukemia • Lymphoma • Multiple Myeloma • Non-Hodgkin’s Lymphoma • Oncology

VOB560-MIK665 Combination First in Human Trial in Patients With Hematological Malignancies (Relapsed/Refractory Non-Hodgkin Lymphoma, Relapsed/Refractory Acute Myeloid Leukemia, or Relapsed/Refractory Multiple Myeloma) (clinicaltrials.gov) - P1 | N=37 | Terminated | Sponsor: Novartis Pharmaceuticals | Active, not recruiting ➔ Terminated; Business reasons

Combination therapy • Trial termination • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Lymphoma • Multiple Myeloma • Non-Hodgkin’s Lymphoma • Oncology

PHASE I STUDY OF S65487, A BCL2 INHIBITOR COMBINED WITH AZACITIDINE IN ADULTS WITH PREVIOUSLY UNTREATED ACUTE MYELOID LEUKEMIA INELIGIBLE FOR INTENSIVE CHEMOTHERAPY (EHA 2024) - P1/2 | "This combination was well tolerated. S65 at a dose of 300 mg (Sch3) combined with AZA wasestablished as the RP2D based on safety, promising preliminary activity, and robust PD analyses. A Phase IIstudy is underway testing outcomes with this combination at its RP2D."

Clinical • IO biomarker • P1 data • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • FLT3 • IDH1 • IDH2 • NRAS • TP53

CL1-65487-003: Phase I/II Trial of S65487 Plus Azacitidine in Acute Myeloid Leukemia (clinicaltrials.gov) - P1/2 | N=57 | Active, not recruiting | Sponsor: Institut de Recherches Internationales Servier | Recruiting ➔ Active, not recruiting | N=109 ➔ 57

Enrollment change • Enrollment closed • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology

CL1-65487-003: Phase I/II Trial of S65487 Plus Azacitidine in Acute Myeloid Leukemia (clinicaltrials.gov) - P1/2 | N=109 | Recruiting | Sponsor: Institut de Recherches Internationales Servier | Trial completion date: Jan 2026 ➔ Mar 2025 | Trial primary completion date: Jun 2024 ➔ Sep 2024

Trial completion date • Trial primary completion date • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology

Study of a New Intravenous Drug, Called S65487, in Patients With Acute Myeloid Leukemia, Non Hodgkin Lymphoma, Multiple Myeloma or Chronic Lymphocytic Leukemia (clinicaltrials.gov) - P1 | N=60 | Completed | Sponsor: Institut de Recherches Internationales Servier | Active, not recruiting ➔ Completed | Trial completion date: Jul 2023 ➔ Nov 2023 | Trial primary completion date: Jul 2023 ➔ Nov 2023

Trial completion • Trial completion date • Trial primary completion date • Acute Myelogenous Leukemia • Chronic Lymphocytic Leukemia • Follicular Lymphoma • Hematological Malignancies • Leukemia • Lymphoma • Multiple Myeloma • Non-Hodgkin’s Lymphoma • Oncology

VOB560-MIK665 Combination First in Human Trial in Patients With Hematological Malignancies (Relapsed/Refractory Non-Hodgkin Lymphoma, Relapsed/Refractory Acute Myeloid Leukemia, or Relapsed/Refractory Multiple Myeloma) (clinicaltrials.gov) - P1 | N=37 | Active, not recruiting | Sponsor: Novartis Pharmaceuticals | Trial primary completion date: Dec 2023 ➔ Jun 2024

Combination therapy • Trial primary completion date • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Lymphoma • Multiple Myeloma • Non-Hodgkin’s Lymphoma • Oncology

VOB560-MIK665 Combination First in Human Trial in Patients With Hematological Malignancies (Relapsed/Refractory Non-Hodgkin Lymphoma, Relapsed/Refractory Acute Myeloid Leukemia, or Relapsed/Refractory Multiple Myeloma) (clinicaltrials.gov) - P1 | N=37 | Active, not recruiting | Sponsor: Novartis Pharmaceuticals | Trial completion date: Dec 2023 ➔ Apr 2024

Combination therapy • Trial completion date • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Lymphoma • Multiple Myeloma • Non-Hodgkin’s Lymphoma • Oncology

Phase I/II Trial of S65487 Plus Azacitidine in Acute Myeloid Leukemia (clinicaltrials.gov) - P1/2 | N=89 | Recruiting | Sponsor: Institut de Recherches Internationales Servier | Trial completion date: Jan 2025 ➔ Jan 2026 | Trial primary completion date: Feb 2024 ➔ Jun 2024

Trial completion date • Trial primary completion date • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology

VOB560-MIK665 Combination First in Human Trial in Patients With Hematological Malignancies (Relapsed/Refractory Non-Hodgkin Lymphoma, Relapsed/Refractory Acute Myeloid Leukemia, or Relapsed/Refractory Multiple Myeloma) (clinicaltrials.gov) - P1 | N=37 | Active, not recruiting | Sponsor: Novartis Pharmaceuticals | Trial completion date: Sep 2024 ➔ Dec 2023 | Trial primary completion date: Sep 2024 ➔ Dec 2023

Combination therapy • Trial completion date • Trial primary completion date • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Lymphoma • Multiple Myeloma • Non-Hodgkin’s Lymphoma • Oncology

Phase I/II Trial of S65487 Plus Azacitidine in Acute Myeloid Leukemia (clinicaltrials.gov) - P1/2 | N=83 | Recruiting | Sponsor: Institut de Recherches Internationales Servier | N=62 ➔ 83 | Trial completion date: Jun 2025 ➔ Jan 2025 | Trial primary completion date: Jun 2025 ➔ Feb 2024

Enrollment change • Trial completion date • Trial primary completion date • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology

VOB560-MIK665 Combination First in Human Trial in Patients With Hematological Malignancies (Relapsed/Refractory Non-Hodgkin Lymphoma, Relapsed/Refractory Acute Myeloid Leukemia, or Relapsed/Refractory Multiple Myeloma) (clinicaltrials.gov) - P1 | N=37 | Active, not recruiting | Sponsor: Novartis Pharmaceuticals | Trial completion date: Mar 2025 ➔ Sep 2024

Trial completion date • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Lymphoma • Multiple Myeloma • Non-Hodgkin’s Lymphoma • Oncology

VOB560-MIK665 Combination First in Human Trial in Patients With Hematological Malignancies (Relapsed/Refractory Non-Hodgkin Lymphoma, Relapsed/Refractory Acute Myeloid Leukemia, or Relapsed/Refractory Multiple Myeloma) (clinicaltrials.gov) - P1 | N=37 | Active, not recruiting | Sponsor: Novartis Pharmaceuticals | Recruiting ➔ Active, not recruiting | N=170 ➔ 37

Combination therapy • Enrollment change • Enrollment closed • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Lymphoma • Multiple Myeloma • Non-Hodgkin’s Lymphoma • Oncology

[VIRTUAL] Identification of S65487/VOB560 as a potent and selective intravenous 2nd-generation BCL-2 inhibitor active in wild-type and clinical mutants resistant to Venetoclax (AACR 2021) - P1 | "Strong and persistent tumor regression in xenograft models of lymphoid malignancies in mouse and rat were observed at well tolerated doses following weekly IV administration of S65487 in combination with the MCL-1-specific inhibitor, S64315/MIK665. Altogether, these data demonstrate that S65487/VOB560 has significant therapeutic potential against human lymphoid and myeloid malignancies as well as in patients with Venetoclax resistant leukemias. Clinical studies are currently ongoing with S65487/VOB560 (NCT03755154)."

Clinical • IO biomarker • Acute Myelogenous Leukemia • Chronic Lymphocytic Leukemia • Leukemia • Lymphoma • Oncology • BCL2L1

VOB560-MIK665 Combination First in Human Trial in Patients With Hematological Malignancies (Relapsed/Refractory Non-Hodgkin Lymphoma, Relapsed/Refractory Acute Myeloid Leukemia, or Relapsed/Refractory Multiple Myeloma) (clinicaltrials.gov) - P1 | N=170 | Recruiting | Sponsor: Novartis Pharmaceuticals | Trial completion date: Oct 2025 ➔ Mar 2025 | Trial primary completion date: Oct 2025 ➔ Mar 2025

Combination therapy • Trial completion date • Trial primary completion date • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Lymphoma • Multiple Myeloma • Non-Hodgkin’s Lymphoma • Oncology

Phase I/II Trial of S65487 Plus Azacitidine in Acute Myeloid Leukemia (clinicaltrials.gov) - P1/2 | N=81 | Recruiting | Sponsor: Institut de Recherches Internationales Servier | Trial completion date: Mar 2024 ➔ Jun 2025 | Trial primary completion date: Mar 2024 ➔ Jun 2025

Trial completion date • Trial primary completion date • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology

Study of a New Intravenous Drug, Called S65487, in Patients With Acute Myeloid Leukemia, Non Hodgkin Lymphoma, Multiple Myeloma or Chronic Lymphocytic Leukemia (clinicaltrials.gov) - P1 | N=60 | Active, not recruiting | Sponsor: Institut de Recherches Internationales Servier | Recruiting ➔ Active, not recruiting | Trial completion date: Mar 2024 ➔ Jul 2023 | Trial primary completion date: Mar 2024 ➔ Jul 2023

Enrollment closed • Trial completion date • Trial primary completion date • Acute Myelogenous Leukemia • Chronic Lymphocytic Leukemia • Follicular Lymphoma • Hematological Malignancies • Leukemia • Lymphoma • Mantle Cell Lymphoma • Multiple Myeloma • Non-Hodgkin’s Lymphoma • Oncology

VOB560-MIK665 Combination First in Human Trial in Patients With Hematological Malignancies (Relapsed/Refractory Non-Hodgkin Lymphoma, Relapsed/Refractory Acute Myeloid Leukemia, or Relapsed/Refractory Multiple Myeloma) (clinicaltrials.gov) - P1 | N=170 | Recruiting | Sponsor: Novartis Pharmaceuticals | Trial completion date: Jan 2025 ➔ Oct 2025 | Trial primary completion date: Jan 2025 ➔ Oct 2025

Combination therapy • Trial completion date • Trial primary completion date • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Lymphoma • Multiple Myeloma • Non-Hodgkin’s Lymphoma • Oncology