zelenirstat (PCLX-001) / Pacylex Pharmaceuticals - LARVOL DELTA

Oral n-myristoyltransferase inhibitor zelenirstat for adults with Relapsed/Refractory Acute Myeloid Leukemia (AML): A phase 1 trial in progress (ASH 2025) - P1 | "This TiP abstract summarizes the rationale and design of the first study of Zelenirstat in R/R AML. The trial will inform the safety profile, biologically effective dosing, and early signals of activity of NMT inhibition in AML and lay the groundwork for future combination strategies with venetoclax and other synergistic drugs."

Clinical • P1 data • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Solid Tumor • LYN

Zelenirstat Nmt Inhibitor in Patients with Relapsed/Refractory B-Cell Lymphoma and Acute Myelogenous Leukemia: Mechanistic Insights and Clinical Outcomes (ASH 2024) - "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 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."

Clinical • Clinical data • IO biomarker • Acute Myelogenous Leukemia • B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor • BTK • FLT3 • KIT

A First-in-Human, Open-Label, Phase I Dose Escalation Trial of Daily Oral Nmt Inhibitor Zelenirstat in Patients with Relapsed/Refractory B-Cell Lymphomas and Advanced Solid Tumors (ASH 2023) - "Additional pts, including a phase IIA study in pts with R/R B-cell NHL, are accruing at this dose for further safety and activity exploration. The absence of severe toxicities, attainment of plasma concentrations highly active in preclinical models, and early evidence of antitumor activity support the ongoing development of zelenirstat for pts with R/R B-cell lymphomas and advanced solid tumors."

Clinical • First-in-human • Metastases • P1 data • Alopecia • B Cell Lymphoma • Bladder Cancer • Colorectal Cancer • Diffuse Large B Cell Lymphoma • Febrile Neutropenia • Gastrointestinal Cancer • Gastrointestinal Disorder • Genito-urinary Cancer • Hematological Malignancies • Immunology • Lung Cancer • Lymphoma • Malignant Pleural Mesothelioma • Melanoma • Mesothelioma • Mucositis • Neutropenia • Non Small Cell Lung Cancer • Non-Hodgkin’s Lymphoma • Ovarian Cancer • Pancreatic Cancer • Pleural Mesothelioma • Sarcoma • Solid Tumor • Stomatitis • Thrombocytopenia • MUC16

Elucidating the role of N-myristoylation in the excessive membrane localization of PD-L1 in hypoxic cancers and developing a novel NMT1 inhibitor for combination with immune checkpoint blockade therapy. (PubMed, J Exp Clin Cancer Res) - "These findings provide robust theoretical support for the translational application of combining NMT1 inhibitors and ICB therapy in cancers under hypoxic conditions. This study introduces a combined cancer therapy strategy named "spatial blockade plus signaling inhibition of PD-L1."."

Checkpoint inhibition • IO biomarker • Journal • Retrospective data • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • HIF1A • PD-L1

N-myristoylation inhibitor zelenirstat reduces mitochondrial complex I activity, OXPHOS, glycolysis, and cancer stem cell growth in triple-negative breast cancer (TNBC) cells (AACR 2025) - "Both zelenirstat and NDUFAF4 KO individually reduced mammosphere formation and produced dose-dependant additive effects on CSC growth when combined.Overall, our results indicate that N-myristoylation is required for optimal energy production, cancer cell respiration, and CSC growth. In addition to inhibiting cell growth signaling, our data indicate that zelenirstat reduces OXPHOS and glycolysis, which may reduce CSC survival and prevent metastasis."

Cancer stem • Breast Cancer • Hematological Malignancies • Oncology • Solid Tumor • Triple Negative Breast Cancer

Study of PCLX-001 in R/R Advanced Solid Malignancies and B-cell Lymphoma (clinicaltrials.gov) - P1 | N=29 | Completed | Sponsor: Pacylex Pharmaceuticals | Recruiting ➔ Completed | N=60 ➔ 29

Enrollment change • Trial completion • B Cell Lymphoma • B Cell Non-Hodgkin Lymphoma • Hematological Malignancies • Lung Cancer • Lymphoma • Non Small Cell Lung Cancer • Non-Hodgkin’s Lymphoma • Oncology • Small Cell Lung Cancer • Solid Tumor • CD20

Pacylex Pharmaceuticals Announces the first Acute Myeloid Leukemia (AML) patient dosed with zelenirstat in a new Phase 1/2 clinical trial (Pacylex Press Release) - "Today, Pacylex announced the launch of a new clinical trial of oral zelenirstat in refractory/relapsed Acute Myeloid Leukemia (AML) patients and the dosing of the first patient."

Trial status • Acute Myelogenous Leukemia

Study of Oral PCLX-001 in R/R Acute Myeloid Leukemia (clinicaltrials.gov) - P1 | N=35 | Recruiting | Sponsor: Pacylex Pharmaceuticals | Not yet recruiting ➔ Recruiting

Enrollment open • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

HIV-1 N-myristoylation-dependent hijacking of late endosomes/lysosomes to drive Gag assembly in macrophages. (PubMed, J Cell Sci) - "Additionally, myristoylation inhibition by PCLX-001 decreased Gag presence on endosomes and inhibited VCCs formation, in both cell-line- and primary macrophages. In conclusion, we presented evidence supporting the idea that HIV-1 manipulates the LEL trajectory to guide Gag to VCCs in an N-myristoylation-dependent manner."

Journal • Human Immunodeficiency Virus • Infectious Disease

Pacylex Pharmaceuticals' CEO Presents Zelenirstat for Cancers at the BIO Investors Forum (Pacylex Press Release) - "Today, Pacylex announced that CEO, Michael Weickert will present progress in clinical development of oral zelenirstat, the first in class NMTi for heme cancers, and initial analysis of zelenirstat and other NMTis as ADC payloads, at the BIO Investor Forum, October 15-16, 2024, at the Fairmont Hotel, in San Francisco, CA, United States....Five attributes make zelenirstat an attractive payload candidate: 1) clinical validation of safety, 2) clinical validation of anti-cancer activity, 3) multiple mechanisms of anti-cancer activity that disrupt novel cancer signaling and survival pathways as well as metabolism, 4) activity in models of drug-resistant cancer, 5) limited acquired resistance despite long-term drug exposure. Pacylex has exclusive license to 503 NMTis, 27 of which have single-digit nM IC50s against human NMT1."

Clinical • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor

Pacylex Pharmaceuticals' Publishes a New Myristoylation Inhibitor Mechanism of Anti-Cancer Activity in Molecular Cancer Therapeutics (Pacylex Press Release, Mol Cancer Ther) - "Today, Pacylex announced the publication of a new study in Molecular Cancer Therapeutics...describing how NMT inhibition by zelenirstat affects Acute Myeloid Leukemia (AML) cells, with a particular focus on describing the mechanism of action in the leukemia stem cell population....Zelenirstat treatment results in the loss of the myristoylated mitochondrial complex I assembly factor NDUFAF4, complex I assembly and activity, oxidative phosphorylation, and respiration in AML cells. The study also demonstrated that the 54 gene myristoylation inhibition sensitivity signature, MISS-54, was highest in AML patients with the shortest life expectancy, suggesting that zelenirstat could address a large unmet medical need in the AML patient population."

Preclinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

Pacylex Pharmaceuticals' Publishes a New Myristoylation Inhibitor Mechanism of Anti-Cancer Activity in Molecular Cancer Therapeutics (Pacylex Press Release, Mol Cancer Ther) - "Today, Pacylex announced the publication of a new study in Molecular Cancer Therapeutics...describing how NMT inhibition by zelenirstat affects Acute Myeloid Leukemia (AML) cells, with a particular focus on describing the mechanism of action in the leukemia stem cell population....Zelenirstat treatment results in the loss of the myristoylated mitochondrial complex I assembly factor NDUFAF4, complex I assembly and activity, oxidative phosphorylation, and respiration in AML cells. The study also demonstrated that the 54 gene myristoylation inhibition sensitivity signature, MISS-54, was highest in AML patients with the shortest life expectancy, suggesting that zelenirstat could address a large unmet medical need in the AML patient population."

Preclinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

Zelenirstat Inhibits N-Myristoyltransferases to Disrupt Src Family Kinase Signalling and Oxidative Phosphorylation Killing Acute Myeloid Leukemia Cells. (PubMed, Mol Cancer Ther) - "Zelenirstat also impairs mitochondrial complex I and oxidative phosphorylation, which are critical for LSC survival. These findings suggest that targeting N-myristoylation with zelenirstat represents a novel therapeutic approach for AML, with promise in patients with currently poor outcomes."

Journal • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology

Study of Oral PCLX-001 in R/R Acute Myeloid Leukemia (clinicaltrials.gov) - P1 | N=35 | Not yet recruiting | Sponsor: Pacylex Pharmaceuticals

New P1 trial • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

Final results of a first-in-human phase I dose escalation trial of daily oral zelenirstat, a n-myristoyltransferase inhibitor, in patients with advanced solid tumors and relapsed/refractory B-cell lymphomas. (ASCO 2024) - P1 | "Zelenirstat is well-tolerated, reaches plasma concentrations highly active in preclinical models, and shows preliminary signs of encouraging anticancer activity. NMT inhibition represents a new target for ongoing research efforts and further clinical development of zelenirstat is warranted."

Clinical • Metastases • P1 data • Diffuse Large B Cell Lymphoma • Fatigue • Gastrointestinal Disorder • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor

A first-in-human phase I trial of daily oral zelenirstat, a N-myristoyltransferase inhibitor, in patients with advanced solid tumors and relapsed/refractory B-cell lymphomas. (PubMed, Invest New Drugs) - "Zelenirstat is well-tolerated, achieves plasma exposures expected for efficacy, and shows early signs of anticancer activity. Further clinical development of zelenirstat is warranted."

Journal • Metastases • P1 data • Appendix Cancer • Colon Cancer • Colorectal Cancer • Fatigue • Gastrointestinal Cancer • Gastrointestinal Disorder • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor

Pacylex Pharmaceuticals Reports Zelenirstat Phase 1 safety and efficacy data at ASCO 2024 (Pacylex Press Release) - P1 | N=60 | NCT04836195 | Sponsor: Pacylex Pharmaceuticals | "Today Pacylex announced that complete Phase 1 clinical study results for zelenirstat, a proprietary, potent, NMTi, will be presented at the American Society of Clinical Oncology (ASCO)...The Phase 1 dose escalation safety and tolerability study was conducted in 29 patients with refractory/relapsed (r/r) lymphoma and refractory solid tumors who averaged 4 lines of prior therapy. Zelenirstat, administered as a once daily oral medication, was well-tolerated in Phase 1 patients up to the recommended Phase 2 dose (RP2D) with no dose limiting toxicities observed in 6 dose levels....The 7 patients receiving the recommended Phase 2 dose had significantly better progression free and overall survival than the 17 treated at lower doses; 57% had stable disease or better for six months or longer, despite having 5 different types of cancer."

P1 data • Hematological Malignancies • Lymphoma • Oncology • Solid Tumor

Multiomics analysis identifies oxidative phosphorylation as a cancer vulnerability arising from myristoylation inhibition. (PubMed, J Transl Med) - "Targeting of both, oxidative phosphorylation and cell signaling partly explains the lethal effects of zelenirstat in select cancer types. While the prognostic value of the sensitivity score MISS-54 remains to be validated in patients, our findings continue to warrant the clinical development of zelenirstat as cancer treatment."

Journal • Colon Cancer • Colorectal Cancer • Gastrointestinal Cancer • Hematological Disorders • Hematological Malignancies • Lymphoma • Oncology • Ovarian Cancer • Solid Tumor

Pacylex Pharmaceuticals Announces First Patient Dosed in a Phase 2a Study of zelenirstat in Patients with Refractory Metastatic Colorectal Cancer (Pacylex Press Release) - "Pacylex is excited to announces that the first patient has been dosed in our Phase 2a expansion study in patients with refractory metastatic colorectal cancer....The Company has an ongoing Phase 2a study of patients with B-cell non-Hodgkin lymphoma. This colorectal cancer Phase 2a expansion study will enroll up to 20 subjects to assess the preliminary clinical activity and confirm the safety of zelenirstat in refractory colorectal cancer."

Trial status • Colorectal Cancer • Gastrointestinal Cancer • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor

N-myristoylation inhibitor zelenirstat: New mechanistic insights and efficacy signals from a first in human phase I study (AACR 2024) - "Zelenirstat has a unique dual impact on growth signaling and OXPHOS. Having previously demonstrated pre-clinical efficacy in hematologic cancers in vitro and in vivo, we now demonstrate the therapeutic potential of zelenirstat in patients with refractory advanced solid malignancies, warranting further clinical evaluation in these indications."

Clinical • P1 data • Colon Cancer • Colorectal Cancer • Gastrointestinal Cancer • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Ovarian Cancer • Pancreatic Cancer • Solid Tumor • ABL1 • CEACAM5

Pacylex Pharmaceuticals Reports Zelenirstat Disrupts Oxidative Phosphorylation in Cancer Cells at AACR 2024 (Pacylex Press Release) - P1 | N=60 | NCT04836195 | Sponsor: Pacylex Pharmaceuticals | "Today Pacylex announced that new data demonstrating that zelenirstat, a proprietary, potent, NMTi, reduces Complex I formation and oxidative phosphorylation in the mitochondria of cancer cells, will be presented at the American Association for Cancer Research (AACR)...This new insight may help account for the effect zelenirstat had on refractory/ relapsed (r/r) cancers in a recent Phase 1 study whose results are also presented...A poster will be presented describing the Company’s Phase 1 study safety results and efficacy signals, as well as evidence for profound disruption of Complex I formation in mitochondria of cancer cell with concomitant loss of oxidative phosphorylation....'The evidence that zelenirstat disrupts energy production in the mitochondria of cancer cells has profound implications for cancer treatment since mitochondrial oxidative phosphorylation is required for metastasis...'"

P1 data • Hematological Malignancies • Oncology • Solid Tumor

Phase I Trial of PCLX-001 in R/R Advanced Solid Malignancies and B-cell Lymphoma (clinicaltrials.gov) - P1 | N=60 | Recruiting | Sponsor: Pacylex Pharmaceuticals | Trial primary completion date: Feb 2024 ➔ Oct 2024

Metastases • Trial primary completion date • Hematological Malignancies • Lung Cancer • Lymphoma • Non Small Cell Lung Cancer • Non-Hodgkin’s Lymphoma • Oncology • Small Cell Lung Cancer • Solid Tumor • CD20

A first-in-human, open-label, phase I trial of daily oral zelenirstat, an NMT inhibitor, in patients with relapsed/refractory advanced cancer including gastrointestinal cancers. (ASCO-GI 2024) - P1 | "Zelenirstat was well-tolerated on a continuous daily oral schedule at doses as high as 210 mg/d, establishing the MTD to be 210 mg. The absence of severe toxicities, attainment of plasma concentrations highly active in preclinical models, and early evidence of clinical benefit in patients with refractory colon cancer warrant further trials. Updated data will be presented."

Clinical • Metastases • P1 data • Colon Cancer • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • HCK

Pacylex Pharmaceuticals Reports Phase 1 Safety and Efficacy Results for Zelenirstat in Colorectal and other Cancers (Pacylex Press Release) - P1 | N=60 | NCT04836195 | Sponsor: Pacylex Pharmaceuticals | "Today we are excited to announce that the results of its Phase 1 dose escalation safety and tolerability study for zelenirstat...in refractory/ relapsed colorectal and other cancers, will be presented January 20, 2024, at the upcoming ASCO Gastrointestinal Cancers Symposium....A recommended Phase 2 dose (RP2D) for expansion studies was established. Zelenirstat prolonged progression free and overall survival in Phase 1 solid tumor patients receiving the RP2D. Prolonged Stable Disease was observed in patients with colorectal (320 + days on treatment and continuing with non-RECIST criteria reductions of approximately 50% in CEA (carcinoembryonic antigen) and tumor volumes) and appendiceal (160+ days on treatment and continuing with stable disease) cancer treated with the RP2D. The Company has initiated dosing in a Phase 2a expansion study of patients with B-cell non-Hodgkin lymphoma."

P1 data • Trial status • Colorectal Cancer • Gastrointestinal Cancer • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor

Phase I Trial of PCLX-001 in B-cell Non-Hodgkin Lymphoma and Advanced Solid Malignancies (clinicaltrials.gov) - P1 | N=60 | Recruiting | Sponsor: Pacylex Pharmaceuticals | Trial completion date: Jul 2024 ➔ Oct 2024 | Trial primary completion date: Jun 2023 ➔ Feb 2024

Metastases • Trial completion date • Trial primary completion date • Hematological Malignancies • Lung Cancer • Lymphoma • Non Small Cell Lung Cancer • Non-Hodgkin’s Lymphoma • Oncology • Small Cell Lung Cancer • Solid Tumor • CD20