Zelenirstat Nmt Inhibitor in Patients with Relapsed/Refractory B-Cell Lymphoma and Acute Myelogenous Leukemia: Mechanistic Insights and Clinical Outcomes
Authors: Sangha Randeep , Kuruvilla John , Sehn Laurie H. , Weickert Michael , Beauchamp Erwan , Gamma Jay M. , Pemmaraju Naveen , Borthakur Gautam , Berthiaume Luc G. , Mackey John R. 
Published: December 2024

Background
Myristoylation, the N-terminal modification of proteins with the fatty acid myristate, regulates numerous membrane-bound signal transduction pathways driving cancer cell biology, including B cell receptor and Bruton tyrosine kinase signaling in lymphoma, and FLT3, c-Kit and Jak/Stat signaling in AML. This modification is catalyzed by two N-myristoyltransferases (NMT), NMT1 and NMT2. Aberrant NMT expression has been identified in cancer cells and inhibition of myristoylation represents a novel anticancer treatment strategy. Zelenirstat (PCLX-001) is an oral, highly bioavailable, small molecule NMT inhibitor with strong affinity for both NMT1 and NMT2. In vitro, hematologic cancer cell lines were exquisitely sensitive to zelenirstat, and even more so to the combination of zelenirstat with the Bcl2 inhibitor Venetoclax. Zelenirstat regressed subcutaneous tumors in xenograft models derived from lymphoma and acute myeloid leukemia (AML) cell lines, as well as in refractory DLBCL patient (pt) derived xenograft models. We recently completed a first in human phase I dose escalation study in patients with refractory solid tumors and relapsed/refractory (R/R) B cell lymphomas (https://doi.org/10.1007/s10637-024-01448-w). The success of this phase I study has triggered additional mechanistic studies of zelenirstat, as well as a phase IIA study of zelenirstat in R/R B cell lymphoma, and a Phase I dose escalation study of zelenirstat in R/R acute myelogenous leukemia.
Methods
AML cell lines treated with zelenirstat were analyzed for metabolic impacts using western blot, luciferase, in-gel activity, and Seahorse assays. In the phase IIA study of zelenirstat in R/R B-cell lymphoma, patients are receiving zelenirstat with daily oral administration at the recommended phase II dose of 210 mg daily until progression. Response assessments occur every second 28-day cycle. We also will soon be opening the study “A Phase 1 Study of Oral PCLX-001 in (R/R) Acute Myeloid Leukemia (AML)” at the MD Anderson Cancer Center. In this study, previously treated AML patients are receiving daily oral zelenirstat with careful attention to pharmacokinetics, as zelenirstat metabolism, in which CYPD 3A4 dominates, is expected to be modulated by concurrent azole antifungals commonly used in this setting. The primary objectives are to determine the safety and tolerability of zelenirstat in patients with R/R AML, and to determine the minimum safe and biologically effective dose. Secondary endpoints are the estimates of ORR, CR, CRp, Cri, Crh, and PR, and duration of response, time to progression, and overall survival.
Results
In AML cell lines, in addition to promoting the loss of various Src family kinases involved in growth signaling, treatment drove loss of NDUFAF4, AMPKß, and complex I involved in energy metabolism. Zelenirstat impaired oxidative metabolism, glycolysis, and reduced cellular ATP. In the phase IIA lymphoma study, two patients with DLBCL have been dosed, one who experienced PD, and one patient with three prior lines of therapy who achieved PR and PET metabolic response and continues study medication after eleven 28-day cycles of continuous therapy. No dose limiting toxicities have occurred. In the Phase I study of zelenirstat in R/R AML, first patient on study is expected in 2024. Updated clinical results will be presented.
Conclusions
In pre-clinical studies, zelenirstat treatment significantly reduces key myristoylated metabolic proteins and regulators, leading to metabolic suppression and cell death. Zelenirstat is safe and well tolerated at the 210 mg OD dose in patients with R/R DLBCL, and objective responses of significant duration have been observed in heavily pre-treated patients. The absence of severe toxicities to date, the attainment of plasma concentrations highly active in preclinical models, and pre-clinical and clinical evidence of anticancer activity support the ongoing development of zelenirstat as an oral, daily therapy for patients with R/R B-cell lymphoma and R/R AML.