citarinostat (ACY-241) / BMS - LARVOL DELTA

Immune profiling of smoldering multiple myeloma patients treated in a phase lb study of PVX-410 vaccine targeting XBP1/CD138/CS1 antigens, and citarinostat, a histone deacetylase inhibitor (HDACi) with and without lenalidomide. (PubMed, Blood Cancer J) - No abstract available

Journal • Hematological Malignancies • Multiple Myeloma • Oncology • Smoldering Multiple Myeloma • SDC1 • XBP1

Study of ACY-241 Alone and in Combination With Pomalidomide and Dexamethasone in Multiple Myeloma (clinicaltrials.gov) - P1 | N=85 | Terminated | Sponsor: Celgene | Phase classification: P1a/1b ➔ P1 | Trial completion date: Jan 2024 ➔ Jun 2024 | Active, not recruiting ➔ Terminated | Trial primary completion date: Jan 2024 ➔ Jun 2024; Lack of efficacy

Combination therapy • Phase classification • Trial completion date • Trial primary completion date • Trial termination • Hematological Malignancies • Multiple Myeloma • Oncology

Selective HDAC6 Inhibitor ACY 241 in Combination With Nivolumab in Patients With Unresectable Non Small Cell Lung Cancer (clinicaltrials.gov) - P1 | N=17 | Terminated | Sponsor: Celgene | Active, not recruiting ➔ Terminated; Lack of efficacy

Combination therapy • Trial termination • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

A Study of PVX-410, a Cancer Vaccine, and Citarinostat +/- Lenalidomide for Smoldering MM (clinicaltrials.gov) - P1 | N=19 | Active, not recruiting | Sponsor: Massachusetts General Hospital | Phase classification: P1b ➔ P1 | Trial completion date: Jun 2023 ➔ Sep 2024 | Trial primary completion date: Jun 2023 ➔ Sep 2024

Epigenetic controller • Phase classification • Trial completion date • Trial primary completion date • Hematological Malignancies • Multiple Myeloma • Oncology

Selective HDAC6 Inhibitor ACY 241 in Combination With Nivolumab in Patients With Unresectable Non Small Cell Lung Cancer (clinicaltrials.gov) - P1 | N=16 | Active, not recruiting | Sponsor: Celgene | Phase classification: P1b ➔ P1 | Trial completion date: Jun 2023 ➔ Jan 2024 | Trial primary completion date: Jun 2023 ➔ Jan 2024

Combination therapy • Phase classification • Trial completion date • Trial primary completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

ACY-241, a histone deacetylase 6 inhibitor, suppresses the epithelial-mesenchymal transition in lung cancer cells by downregulating hypoxia-inducible factor-1 alpha. (PubMed, Korean J Physiol Pharmacol) - "This study confirms that HDAC6 knockdown and ACY-241 treatment effectively decrease HIF-1α expression under normoxia, thereby suppressing the epithelial-mesenchymal transition. These findings highlight the potential of selective HDAC6 inhibition as an innovative therapeutic strategy for lung cancer."

Epigenetic controller • Journal • Lung Cancer • Oncology • Solid Tumor • CDH1 • HDAC6 • HIF1A • ZEB1

Immune Profiling and Responses of Smoldering Multiple Myeloma Patients Treated in a Phase Ib Study of Pvx-410 Vaccine Targeting XBP1/CD138/CS1 Antigens, and Citarinostat, a Histone Deacetylase Inhibitor (HDACi) with and without Lenalidomide (ASH 2023) - "There was one grade 3 trAE: specifically, a thromboembolic event in one patient who was receiving lenalidomide and despite aspirin prophylaxis, but who fully recovered. PB and marrow transcriptome profiling along with the immunogenicity studies are in progress and will be presented. We will evaluate whether PB mononuclear cells have the potential to replace BM as a surrogate for genetic and immunological surveillance in SMM, as we anticipate that further understanding of the immune alterations among patients with SMM and the response to immunomodulatory therapy may provide insight on early intervention and prevention of progression to symptomatic disease."

Clinical • Epigenetic controller • P1 data • Anemia • Cardiovascular • Fatigue • Hematological Disorders • Hematological Malignancies • Multiple Myeloma • Neutropenia • Oncology • CD8 • IFNG • IL2 • SDC1 • TNFA • XBP1

Study of ACY-241 Alone and in Combination With Pomalidomide and Dexamethasone in Multiple Myeloma (clinicaltrials.gov) - P1a/1b | N=85 | Active, not recruiting | Sponsor: Celgene | Trial completion date: Jul 2023 ➔ Jan 2024 | Trial primary completion date: Jun 2023 ➔ Jan 2024

Combination therapy • Trial completion date • Trial primary completion date • Hematological Malignancies • Multiple Myeloma • Oncology

Structure and Function of Kdac1, a Class II Deacetylase from the Multidrug-Resistant Pathogen Acinetobacter baumannii. (PubMed, Biochemistry) - "We show that Kdac1 catalyzes the deacetylation of free acetyllysine and acetyllysine tetrapeptide assay substrates, and we also report the X-ray crystal structures of unliganded Kdac1 as well as its complex with the hydroxamate inhibitor Citarinostat...Structural comparisons with two other prokaryotic lysine deacetylases reveal conserved residues in the L1 and L12 loops that similarly support tetramer assembly. These studies provide a structural foundation for understanding enzymes that regulate protein function in bacteria through reversible lysine acetylation, serving as a first step in the exploration of these enzymes as possible targets for the development of new antibiotics."

Journal • HDAC1

Discovery of the First Irreversible HDAC6 Isoform Selective Inhibitor with Potent Anti-Multiple Myeloma Activity. (PubMed, J Med Chem) - "To the best of our knowledge, this is the first research reporting the irreversible inhibition of HDAC6. It was also demonstrated that compared with ACY-241 (a reversible HDAC6 inhibitor in clinical trials), the irreversible HDAC6 selective inhibitor 4 exhibited not only superior anti-multiple myeloma activity but also improved therapeutic index."

Journal • Hematological Malignancies • Multiple Myeloma • Oncology

Selective Histone Deacetylase Inhibitor ACY-241 Plus Nivolumab for Refractory Advanced NSCLC: Results From a Phase 1b Study (WCLC 2017) - P1b; "No DLTs have been observed with ACY-241 at 180 or 360 mg. Preliminary antitumor activity has been observed with the combination treatment. Updated pharmacokinetic data will be presented at the meeting."

Checkpoint inhibition • P1 data • Non Small Cell Lung Cancer

A Study of PVX-410, a Cancer Vaccine, and Citarinostat +/- Lenalidomide for Smoldering MM (clinicaltrials.gov) - P1b | N=19 | Active, not recruiting | Sponsor: Massachusetts General Hospital | Recruiting ➔ Active, not recruiting | Trial completion date: May 2022 ➔ Jun 2023 | Trial primary completion date: May 2022 ➔ Jun 2023

Enrollment closed • Epigenetic controller • Trial completion date • Trial primary completion date • Hematological Malignancies • Multiple Myeloma • Oncology

Selective HDAC6 Inhibitor ACY 241 in Combination With Nivolumab in Patients With Unresectable Non Small Cell Lung Cancer (clinicaltrials.gov) - P1b | N=16 | Active, not recruiting | Sponsor: Celgene | Trial completion date: Jun 2022 ➔ Jun 2023 | Trial primary completion date: Jun 2022 ➔ Jun 2023

Combination therapy • Trial completion date • Trial primary completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Study of ACY-241 Alone and in Combination With Pomalidomide and Dexamethasone in Multiple Myeloma (clinicaltrials.gov) - P1a/1b | N=85 | Active, not recruiting | Sponsor: Celgene | Trial completion date: Jun 2022 ➔ Jul 2023 | Trial primary completion date: Jun 2022 ➔ Jul 2023

Combination therapy • Trial completion date • Trial primary completion date • Hematological Malignancies • Multiple Myeloma • Oncology

HDAC8-Selective Inhibition by PCI-34051 Enhances the Anticancer Effects of ACY-241 in Ovarian Cancer Cells. (PubMed, Int J Mol Sci) - "Overall, co-inhibition of HDAC6 and HDAC8 through selective inhibitors synergistically suppresses cancer cell proliferation and metastasis in p53 wild-type ovarian cancer cells. These results suggest a novel approach to treating ovarian cancer patients and the therapeutic potential in developing HDAC6/8 dual inhibitors."

Journal • Oncology • Ovarian Cancer • Solid Tumor • HDAC6 • TP53

Coupling the immunomodulatory properties of the HDAC6 inhibitor ACY241 with Oxaliplatin promotes robust anti-tumor response in Non-small cell lung cancer (IMMUNOLOGY 2022) - "Finally, ACY241 treatment led to significantly enhanced tumor-associated T cell effector functionality in lung cancer-bearing mice and in patient-derived tumors when combined with the chemotherapy drug Oxaliplatin. Collectively, our studies support ACY241 as a promising HDAC6 inhibitor which coupled with Oxaliplatin promotes robust therapeutic outcomes in a pre-clinical model of NSCLC."

IO biomarker • Immune Modulation • Inflammation • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Coupling the immunomodulatory properties of the HDAC6 inhibitor ACY241 with Oxaliplatin promotes robust anti-tumor response in non-small cell lung cancer. (PubMed, Oncoimmunology) - "Finally, coupling these ACY241-mediated effects with the chemotherapy drug Oxaliplatin led to significantly enhanced tumor-associated T cell effector functionality in lung cancer-bearing mice and in patient-derived tumors. Collectively, our studies highlight the molecular underpinnings of the expansive immunomodulatory activity of ACY241 and supports its suitability as a partner agent in combination with rationally selected chemotherapy agents for therapeutic intervention in NSCLC."

Journal • Hematological Disorders • Hematological Malignancies • Immune Modulation • Inflammation • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CCL4

Phase Ib Study of the Histone Deacetylase 6 Inhibitor Citarinostat in Combination With Paclitaxel in Patients With Advanced Solid Tumors. (PubMed, Front Oncol) - P1b | "Citarinostat 360 mg once daily is considered the recommended phase II dose for use in combination with paclitaxel 80 mg/m every 3 of 4 weeks. This trial is registered on ClinicalTrials.gov (NCT02551185)."

Combination therapy • Epigenetic controller • Journal • P1 data • Gene Therapies • Hematological Disorders • Neutropenia • Oncology • Solid Tumor • STAT3

Discovery of HDAC6-Selective Inhibitor NN-390 with in Vitro Efficacy in Group 3 Medulloblastoma. (PubMed, J Med Chem) - "NN-390 demonstrated a 45-fold increased potency over HDAC6-selective clinical candidate citarinostat. In summary, HDAC6-selective molecules demonstrated in vitro therapeutic potential against Group 3 MB."

Journal • Preclinical • Brain Cancer • Medulloblastoma • Oncology • Pediatrics • Solid Tumor

Upregulation of CD38 expression on multiple myeloma cells by novel HDAC6 inhibitors is a class effect and augments the efficacy of daratumumab. (PubMed, Leukemia) - "We therefore investigated the potential of the histone deacetylase (HDAC) inhibitor ricolinostat to up-regulate CD38 on MM cells, thereby enhancing the performance of CD38-specific therapies. We also evaluated next-generation HDAC6 inhibitors (ACY-241, WT-161) and observed similar increase of CD38 levels suggesting that the upregulation of CD38 expression on MM cells by HDAC6 inhibitors is a class effect. This proof-of-concept illustrates the potential benefit of combining HDAC6 inhibitors and CD38-directed immunotherapy for MM treatment."

Clinical • IO biomarker • Journal • Hematological Disorders • Hematological Malignancies • Multiple Myeloma • Oncology • CD38 • PCR

Study of ACY-241 Alone and in Combination With Pomalidomide and Dexamethasone in Multiple Myeloma (clinicaltrials.gov) - P1a/1b; N=85; Active, not recruiting; Sponsor: Celgene; Trial completion date: Jun 2021 ➔ Jun 2022; Trial primary completion date: May 2021 ➔ May 2022

Clinical • Combination therapy • Trial completion date • Trial primary completion date • Hematological Malignancies • Multiple Myeloma • Oncology

Prolactin drives a dynamic STAT5A/HDAC6/HMGN2 cis -regulatory landscape exploitable in ER+ breast cancer (SABCS 2021) - "Gene set enrichment analysis identifies significant overlap of ERα regulated genes with genes regulated by prolactin, particularly prolactin regulated genes with promoters or enhancers co-occupied by both STAT5A and HDAC6. Lastly, the therapeutic efficacy of ACY-241 is demonstrated in in vitro and in vivo breast cancer models, where we identify synergistic ACY-241 drug combinations and observe differential sensitivity of ER + models relative to ER - models."

Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • ER • STAT5 • STAT5AWqe

Preclinical evaluation of novel HDAC6 selective inhibitors N008 with potent in vitro and in vivo profiles in non-solid tumor and solid tumors (SABCS 2021) - "The compounds exhibited a priority selectivity than clinical candidates ACY-1215 and ACY-241.Lead compounds inhibited non-solid tumor such as MM.1S, REC-1, and SK-MEL-5 with the IC50 up to 1 micromole, which were equal or better compared with positive control ACY-241 (2-5 micromole). Compounds of series N008 exhibited a priority potency than the clinical candidate ACY-241 on HDAC6 inhibition and selectivity with promising drug-like profiles. In CDX models, lead compounds possessed better in vivo efficacy than ACY-241 in both monotherapy and combination therapy with bortezomib, as well as very promising safety profiles. These data reveal optimistic expectation for the clinical development of novel HDAC6 selective inhibitors on anti-cancer indications, especially on both non-solid and solid tumors such as multiple myeloma and breast cancer."

Preclinical • Breast Cancer • Hematological Malignancies • Lymphoma • Multiple Myeloma • Oncology • Peripheral T-cell Lymphoma • Solid Tumor • T Cell Non-Hodgkin Lymphoma • HDAC1

ACY-241, an HDAC6 inhibitor, overcomes erlotinib resistance in human pancreatic cancer cells by inducing autophagy. (PubMed, Arch Pharm Res) - "Therefore, HDAC6 may be involved in the suppression of autophagy and acquisition of resistance to erlotinib in ER pancreatic cancer cells. ACY-241 to overcome erlotinib resistance could be an effective therapeutic strategy against pancreatic cancer."

Journal • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Solid Tumor • HDAC6

Selective Histone Deacetylase Inhibitor ACY-241 (Citarinostat) Plus Nivolumab in Advanced Non-Small Cell Lung Cancer: Results From a Phase Ib Study. (PubMed, Front Oncol) - P1b | "Responses were observed in patients with advanced NSCLC. https://clinicaltrials.gov/ct2/show/NCT02635061 (identifier, NCT02635061)."

Epigenetic controller • IO biomarker • Journal • P1 data • Immune Modulation • Infectious Disease • Inflammation • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pneumonia • Pulmonary Disease • Respiratory Diseases • Solid Tumor