CB-5339 / Cleave Therap, CASI - LARVOL DELTA

Synthetic lethal targeting of PSMC2-dependent p97-adapted proteasome complexes that confer chemoresistance in multiple myeloma (ASH 2025) - "While proteasome inhibitors (PIs), e.g.,bortezomib (Btz), have transformed MM care, many patients do not respond to therapy, and drugresistance inevitably emerges through molecular mechanisms that remain incompletely characterized.Here, we hypothesized that the expression of proteasome genes in patient tumor cells could informresponses to Btz and identify novel, actionable therapeutic targets to improve patient outcome.Methods. The phase III APEX trial randomized MM patients that had consented to genomic analyses oftumor samples obtained prior to treatment to receive either Btz or high-dose dexamethasone (Dex)...Using this pipeline,we discovered that PSMC2 overexpressing cells were highly sensitive to CB-5339; an p97/VCP inhibitorwell-tolerated in vivo. Taken together, we establish a data-driven platform to leverage cancer genomicsusing precision oncology to identify and exploit proteasomal adaptations that confer chemoresistance."

Synthetic lethality • Hematological Malignancies • Multiple Myeloma • Targeted Protein Degradation • PSMC2

Single-Cell Genomics and Proteomics Reveals Venetoclax-Resistant Monocytic Differentiation of TP53 LOH Clones in TP53 Mutant AML (ASH 2023) - " Patients 1 and 3 received treatment with CD47AB (Magrolimab), 5'-Azacitidine (Aza), and Venetoclax (Ven); Patient 2 received IMGN632 (CD123-targeting ADC), Aza and Ven. Patient 4 received p97 Inhibitor CB-5339; Patient 5 received CD47 inhibitor (ALX148), Aza, Ven... This study establishes a genotype-phenotype connection through single-cell proteogenomic profiling of TP53-mutated AML, describing the clonal evolution and immunophenotypic dynamics during treatment while proposing a potential mechanism of resistance."

IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • BCL2L1 • CD123 • CD14 • CD33 • CD34 • CD36 • CD68 • CD8 • EIF4EBP1 • ETV6 • IDH1 • IL3RA • ITGAM • KIT • SCARB1 • TP53

PSMC2 Overexpression Promotes Synthetic Lethality Sensitizing Multiple Myeloma Cells to p97 Inhibition (ASH 2024) - "Gene expression profiles from bone marrow CD138+ cells of MM patients enrolled on the phase III APEX trial revealed that PSMC2 overexpression correlated with reduced response to bortezomib therapy as well as inferior progression-free and OS (Median OS for PSMC2 high vs. PSMC2 low 300 days vs. 625 days n=380, Kaplan-Meier (KM) curves significant by log-rank test with p=7x10-6) Similarly, results from the MMRF CoMMpass study demonstrated that PSMC2 overexpression correlated with reduced OS (Median OS for PSMC2 high v low 1300 days vs. not reached, n=221 Kaplan-Meier (KM) curves significant by log-rank test with p=0.014)...To target this interaction therapeutically, we cotreated PI-exposed MM patient cells with Btz and the ATP-competitive p97 inhibitor CB-5339 (CB), revealing synergistic effects (Btz LD50 2.5 nM vs. 7.5 nM, 2 nM vs 8 nM, 2 vs. 8 nM for patient samples treated with the first two patients treated with 0 or 100 nM CB and the third patient treated with 0 and 50..."

Synthetic lethality • Hematological Malignancies • Multiple Myeloma • Oncology • Targeted Protein Degradation • CDC37 • ERN1 • HSP90AA1 • HSPA5 • PSMC2 • SDC1

Harnessing p97/VCP: A Transformative AAA+ ATPase Target for Next-Generation Cancer Therapeutics. (PubMed, Cancers (Basel)) - "This review explores p97's molecular structure, diverse cellular roles, and clinical potential with a particular focus on CB-5083 and CB-5339, the only p97 inhibitors to date that have advanced into clinical trials. We discuss their mechanisms of action, clinical trial outcomes, and the transformative potential of rational combination strategies to maximize their therapeutic potential. By integrating foundational biological insights with translational perspectives, we highlight p97 as a precision target for cancer treatment."

Journal • Review • Oncology • Targeted Protein Degradation

CRISPR screens identify the ATPase VCP as a druggable therapeutic vulnerability in cholangiocarcinoma. (PubMed, Proc Natl Acad Sci U S A) - "To address this, we combined CB-5339 with senolytic agents (ABT-263 and conatumumab), which selectively eliminate senescent CCA cells, resulting in enhanced tumor suppression both in vitro and in vivo. Clinical analysis showed that VCP overexpression in CCA patients correlates with poor prognosis. Our study unveils a "one-two punch" strategy, targeting VCP-mediated senescence followed by senolytic clearance, offering a promising therapeutic approach for CCA."

Journal • Biliary Cancer • Cholangiocarcinoma • Oncology • Solid Tumor

Dual Targeting using SAHA and Diethyldithiocarbamate (DDC)-Metal Complexes Augments Sodium Iodide Symporter Function in Thyroid and Breast Cancer (ATA 2025) - "SAHA (vorinostat) was used as a candidate HDACi. Results Clinically trialled VCP inhibitors CB-5083 and CB-5339 markedly induced 125I uptake in multiple thyroid and breast cancer cells, as well as in human primary thyrocytes (up to 4.0-fold; P<0.001)...Biodistribution studies revealed no differences in 99mTc uptake in other major tissues, or any change in body weight. Conclusion Our study identifies a new combinatorial strategy to stimulate NIS activity in vivo, with potential clinical application for improving radionuclide-based therapies and imaging across multiple cancer settings."

Breast Cancer • Oncology • Solid Tumor • Thyroid Gland Carcinoma

PSMC2 Genomic Gain Promotes P97-Proteasome Complexation and Unveils Synthetic Lethal Vulnerability in Chemoresistant Multiple Myeloma (SOHO 2025) - "Moreover, CB-5339 is an orally available, well-tolerated agent that synergizes with bortezomib to overcome chemoresistance. We have established a data-driven platform that leverages tumor genomics with synthetic lethality to exploit proteasomal adaptations that confer chemoresistance in cancer patients."

Synthetic lethality • Hematological Malignancies • Multiple Myeloma • Oncology • Solid Tumor • PSMC2 • SDC1 • VCP

CASI Pharmaceuticals Enters Into Definitive Agreement for the Divestiture of Assets in China (ACCESSWIRE) - "CASI Pharmaceuticals...announced that it has entered into a definitive Equity and Assets Transfer Agreement...with Kaixin Pharmaceuticals Inc...and CEO of the Company and two direct wholly-owned subsidiaries of the Company in China...pursuant to which the Company shall sell and transfer, and Kaixin Pharmaceuticals shall purchase and acquire, 100% equity interests in both Target Companies...and all licensing rights, distribution rights, supply arrangements and related rights related to BI-1206 (in China), CID-103 (in Asia excluding Japan) and Thiotepa (in China excluding Hong Kong, Macau and Taiwan)...for an aggregate purchase price of $20.0 million, which shall include assumption of up to $20.0 million of indebtedness of the Company....After the closing of the Transaction, the Company expects to retain the rights related to CID-103 (in Japan and non-Asian regions), EVOMELA, FOLOTYN, CNCT19 and CB-5339, and remain firmly committed to progressing CID-103 at an accelerated pace."

Commercial • Hematological Malignancies • Immunology • Solid Tumor

Epigenetic approaches to deliver a targeted radiotherapy for triple negative breast cancer (AACR 2025) - "Remarkably, in MDA-MB-231 cells, Cu(DDC)2 combined with the VCP inhibitor CB5339, significantly increased NIS expression and radioiodide uptake leading to a prominent decrease in cell proliferation and survival. These studies, along with ongoing drug strategies in TNBC xenograft and PDX tumors, combine to support the concept that SLC5A5/NIS expression can be restored and offer the possibility of promoting radioiodide as a novel BrCa radiotherapy."

Breast Cancer • Endocrine Cancer • Oncology • Solid Tumor • Thyroid Gland Carcinoma • Triple Negative Breast Cancer • PRAME • RARA • TNFA

Epigenetic approaches to deliver a targeted radiotherapy for triple negative breast cancer (SABCS 2023) - "Remarkably, in MDA MB 231 cells, Cu(DDC)2 combined with the VCP inhibitor CB5339, resulted in a significant additive increase in RAI uptake and a prominent decrease in cell proliferation and survival. These studies combined with future murine and PDX testing of CRISPR-edited tumors and drug exposures will develop a comprehensive analyses of the mechanisms that control SLC5A5 expression across breast cancer cell types, how this can be most effectively targeted to restore NIS expression, and exploited to promote RAI as a novel targeted BRCA radiotherapy."

Breast Cancer • HER2 Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • BRCA • HER-2 • PRAME • RARA

Study of CB-5339 in Acute Myeloid Leukemia or Myelodysplastic Syndrome (clinicaltrials.gov) - P1 | N=55 | Completed | Sponsor: Cleave Therapeutics, Inc. | Recruiting ➔ Completed

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

CASI Pharmaceuticals Acquires Global Intellectual Property Rights to Cleave Therapeutics' VCP/P97 Inhibitor CB-5339 (PRNewswire) - P1 | N=60 | NCT04402541 | Sponsor: Cleave Therapeutics, Inc. | "CASI Pharmaceuticals, Inc...announced the execution of the Assignment Agreement (the 'Agreement') with Cleave Therapeutics, Inc. ('Cleave'), pursuant to which CASI obtained all rights and global intellectual property rights related to CB-5339, a novel VCP/p97 inhibitor, as well as all remaining CB-5339 drug substance and drug product. Additionally, CASI will assume responsibility of the United States ('US') CB-5339 Investigational New Drug ('IND') application....In a Phase 1 clinical trial in patients with acute myeloid leukemia and myelodysplastic syndrome, the drug was well tolerated in 55 patients and demonstrated signs of clinical activity. Two patients remain on CB-5339 under compassionate use protocols at two leading US cancer centers."

Licensing / partnership • P1 data • Acute Myelogenous Leukemia • Hematological Malignancies • Indolent Lymphoma • Leukemia • Lymphoma • Multiple Myeloma • Myelodysplastic Syndrome • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor

Inhibitors of the ATPase p97/VCP: From basic research to clinical applications. (PubMed, Cell Chem Biol) - "In this review, we focus on the development of various p97 inhibitors, including the ATPase inhibitors CB-5083 and CB-5339, which reached clinical trials by demonstrating effective anti-tumor activity across various tumor models, providing an effective alternative to targeting protein degradation for cancer therapy. Here, we provide an overview of how different p97 inhibitors have evolved over time both as basic research tools and effective UPS-targeting cancer therapies in the clinic."

Journal • Review • CNS Disorders • Oncology • Targeted Protein Degradation

CASI PHARMACEUTICALS AND CLEAVE THERAPEUTICS ANNOUNCE CLINICAL TRIAL APPLICATION APPROVAL FOR CB-5339 IN PATIENTS WITH MULTIPLE MYELOMA IN CHINA (PRNewswire) - "CASI Pharmaceuticals, Inc...announces that the China National Medical Products Administration (NMPA) has approved the Company's Clinical Trial Application (CTA) for CB-5339, a first-in-class VCP/p97 inhibitor from Cleave Therapeutics. CASI is planning a Phase 1 development program in China of CB-5339 as a single agent to evaluate the PK/safety profile, select the Recommended Phase 2 Dose, and assess early signs of clinical efficacy. The Phase 1 development program is expected to start in 2023."

New P1 trial • Hematological Malignancies • Multiple Myeloma • Oncology

Efficacy of Vcp/p97 Inhibitor, CB-5339, Alone and in Combinations Against High-Risk AML, Including Those with Genetic Lesion in TP53 (ASH 2022) - "Valosin-containing protein (VCP)/p97 or p97 is an AAA+ type ATPase involved in quality control of cellular proteins in normal and transformed cells, especially under cellular stress. Finally, in a tail-vein infused, luciferase transduced, aggressive xenograft model of MOLM13 cells, after AML engraftment, co-treatment for 3 weeks with CB-5339 (50 mg/kg/day, PO) and either venetoclax (30 mg/kg/day, PO) or OTX015 (30 mg/kg/day, PO), as compared to treatment with vehicle or each drug alone, significantly reduced the AML burden and improved median and overall survival of the NSG mice, without inducing significant toxicity. Taken together, these findings highlight that CB-5339 induces lethal ER stress in AML cells regardless of the TP53 status, and underscore the promise of CB-5339 treatment alone and in rational combinations in exerting efficacy against AML, including those with high-risk genetic alterations in TP53 or chromosome 3q26 lesions and EVI1 overexpression."

Clinical • Acute Myelogenous Leukemia • CNS Disorders • Oncology • Psychiatry • Targeted Protein Degradation • ATF3 • ATF4 • BBC3 • CD86 • CXCR4 • FBXO32 • FLT3 • FOXA1 • HSPA5 • IL7R • ITGAM • MDM2 • MDM4 • MECOM • TLR4 • TP53

CASI PHARMACEUTICALS ANNOUNCES THIRD QUARTER 2022 FINANCIAL RESULTS (PRNewswire) - "'Through our partner Juventas, the CNCT-19 New Drug Application (NDA) submission to the National Medical Products Administration (NMPA) is on track, and we are in preparation for the anticipated CNCT-19 launch in China....We expect CB-5339 to receive Clinical Trial Application approval from the NMPA in early 2023; Meanwhile, our CID-103's Phase I study continues'."

New trial • Non-US regulatory • Trial status • Hematological Malignancies • Multiple Myeloma • Oncology

Study of CB-5339 in Acute Myeloid Leukemia or Myelodysplastic Syndrome (clinicaltrials.gov) - P1 | N=60 | Recruiting | Sponsor: Cleave Therapeutics, Inc. | Trial completion date: Jul 2022 ➔ Jul 2023 | Trial primary completion date: Apr 2022 ➔ Jul 2023

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

Comparative oncology assessment of a novel inhibitor of valosin-containing protein in tumor-bearing dogs. (PubMed, Mol Cancer Ther) - "An efficacy signal was detected in 33% (2/6) dogs with multiple myeloma, consistent with a mechanism of action relating to induction of proteotoxic stress in a tumor type with abundant protein production. Clinical trials of CB-5339 in humans with acute myelogenous leukemia and multiple myeloma are ongoing."

Journal • Acute Myelogenous Leukemia • Gastrointestinal Disorder • Hematological Malignancies • Leukemia • Lymphoma • Multiple Myeloma • Oncology • Solid Tumor

NMS-873 Leads to Dysfunctional Glycometabolism in A p97-Independent Manner in HCT116 Colon Cancer Cells. (PubMed, Pharmaceutics) - "Adenosine triphosphate (ATP)-competitive p97 inhibitor CB-5339, the successor of CB-5083, is being evaluated in Phase 1 clinical trials for anti-cancer therapy. We then used proteome integral solubility alteration with a temperature-based method (PISA T) to identify NDUFAF5 as one of the potential targets of NMS-873 in the mitochondrial complex I. We also demonstrated that glycolysis inhibitor 2-DG enhanced the anti-proliferative effect of NMS-873. The polypharmacology of NMS-873 can be advantageous for anti-cancer therapy for colon cancer."

Journal • Colon Cancer • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor

CASI PHARMACEUTICALS ANNOUNCES PRELIMINARY FOURTH QUARTER AND FULL-YEAR 2021 REVENUES AND PROVIDES BUSINESS UPDATES (PRNewswire) - '"In 2021, our commercial franchise has thoroughly prepared for the anticipated China NDA filing of CD19 CAR-T program, which we currently expect to be in late 2022 or early 2023'...'During 2022, we anticipate the start of the BI-1206 phase I trial in China; CB-5339 is expected to receive CTA approval from NMPA during 2022'..."

New trial • Non-US regulatory • Hematological Malignancies • Oncology

[VIRTUAL] Trials in Progress: A Phase I Study to Evaluate the Safety and Pharmacokinetic Profiles of CB-5339 in Participants with Relapsed/Refractory Acute Myeloid Leukemia or Relapsed/Refractory Intermediate or High-Risk Myelodysplastic Syndrome (ASH 2020) - P1 | "In addition, evidence of synergy was exhibited with standard of care AML therapy, a combination of an anthracycline and cytarabine. Up to 60 participants (20 in dose escalation and 40 in dose expansion) will be enrolled at approximately 10 sites in the U.S and Australia. Recruitment is ongoing and this trial is registered with clinicaltrials.gov: NCT04402541."

Clinical • P1 data • PK/PD data • Acute Myelogenous Leukemia • Acute Promyelocytic Leukemia • Graft versus Host Disease • Hematological Malignancies • Immunology • Infectious Disease • Leukemia • Myelodysplastic Syndrome • Oncology • Pneumonia • Respiratory Diseases • Transplantation • MLL

Testing the Safety of CB-5339 in Patients With Cancer (clinicaltrials.gov) - P1; N=0; Withdrawn; Sponsor: National Cancer Institute (NCI); Terminated ➔ Withdrawn

Clinical • Trial withdrawal • Hematological Malignancies • Indolent Lymphoma • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor

Testing the Safety of CB-5339 in Patients With Cancer (clinicaltrials.gov) - P1; N=1; Terminated; Sponsor: National Cancer Institute (NCI); N=40 ➔ 1; Trial completion date: Mar 2023 ➔ Jul 2021; Active, not recruiting ➔ Terminated; Trial primary completion date: Mar 2023 ➔ Jul 2021; Other - Clinical development of the agent has been discontinued

Clinical • Enrollment change • Trial completion date • Trial primary completion date • Trial termination • Hematological Malignancies • Indolent Lymphoma • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor

Testing the Safety of CB-5339 in Patients With Cancer (clinicaltrials.gov) - P1; N=40; Active, not recruiting; Sponsor: National Cancer Institute (NCI); Recruiting ➔ Active, not recruiting

Clinical • Enrollment closed • Hematological Malignancies • Indolent Lymphoma • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor

Targeting acute myeloid leukemia dependency on VCP-mediated DNA repair through a selective second-generation small-molecule inhibitor. (PubMed, Sci Transl Med) - "We further demonstrated that combining DNA-damaging agents, such as anthracyclines, with CB-5339 treatment synergizes to impair leukemic growth in an MLL-AF9-driven AML murine model. These studies support the clinical testing of CB-5339 as a single agent or in combination with standard-of-care DNA-damaging chemotherapy for the treatment of AML."

Journal • Acute Myelogenous Leukemia • Ataxia • Hematological Malignancies • Immunology • Leukemia • Movement Disorders • Oncology • Primary Immunodeficiency