bocodepsin (OKI-179) / OnKure - LARVOL DELTA

Outcomes with targeted therapy for NRAS-mutated melanoma: A systematic review and meta-analysis. (ASCO 2025) - "The targeted therapies investigated included Binimetinib (n = 299; 56.7%), Naporafenib plus Rineterkib (n = 29; 5%), Naporafenib plus Trametinib (n = 24; 4.5%), Trametinib (n = 17; 3.2%), Naporafenib plus Ribociclib (n = 15; 2.8%), and Binimetinib plus Bocodepsin (n = 9; 1.7%). Targeted therapies in NRAS-mutated melanoma show modest efficacy with frequent adverse effects. Innovative approaches, including novel therapeutic agents with different mechanisms of action, are urgently needed to improve clinical outcomes and address this unmet medical need."

IO biomarker • Retrospective data • Review • Dermatitis • Dermatology • Immunology • Melanoma • Oncology • Solid Tumor

Nautilus, a phase 1b/2 trial of combining oral HDAC inhibitor (HDACi) with MEK inhibitor (MEKi) in patients with NRAS-mutated metastatic melanoma (MM). (ASCO 2025) - P1/2 | "The combination of bocodepsin and binimetinib in patients with NRAS-mutant melanoma is tolerable with manageable AEs and no high grade rash. Initial response data in patients with NRAS-mutant melanoma are supportive of potential combinatorial activity of a MEK inhibitor and HDACi bocodepsin. Further investigation is crucial as MM patients with disease progression after immunotherapy remain in need of rational therapeutic options."

Clinical • IO biomarker • Metastases • P1/2 data • Melanoma • Oncology • Solid Tumor • NRAS

NAUTILUS: OKI-179 Plus Binimetinib in Patients with Advanced Solid Tumors in the RAS Pathway (Phase 1b) and NRAS-mutated Melanoma (Phase 2) (clinicaltrials.gov) - P1/2 | N=36 | Completed | Sponsor: OnKure, Inc. | Active, not recruiting ➔ Completed | Trial completion date: Apr 2026 ➔ Jan 2025 | Trial primary completion date: Mar 2026 ➔ Jan 2025

Trial completion • Trial completion date • Trial primary completion date • Melanoma • Oncology • Solid Tumor • BRAF • GNAQ • KIT • NF1 • NRAS

Combined Inhibition of Histone Deacetylases and Bromodomain Proteins Normalizes Gene Expression and Reverses Sugen/Hypoxia-induced Pulmonary Hypertension (ATS 2024) - "Cells were treated with HDACi (OKI-5) or BRDi (JQ1) or the combination of both. Combination of HDACi and BRDi in low doses is effective in normalizing the persistent activation of PH-Fibs and improving hemodynamics and pulmonary vascular remodeling in Sugen/hypoxia PH rats, offering promise for epigenetic-targeted combination therapies in PAH."

Epigenetic controller • IO biomarker • Cardiovascular • Hypertension • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases • BCL2 • BRD4 • CDKN1A • CXCL12

NAUTILUS: OKI-179 Plus Binimetinib in Patients With Advanced Solid Tumors in the RAS Pathway (Phase 1b) and NRAS-mutated Melanoma (Phase 2) (clinicaltrials.gov) - P1/2 | N=36 | Active, not recruiting | Sponsor: OnKure, Inc. | Recruiting ➔ Active, not recruiting | Phase classification: P1b ➔ P1/2 | N=73 ➔ 36

Enrollment change • Enrollment closed • Metastases • Phase classification • Melanoma • Oncology • Solid Tumor • BRAF • GNAQ • KIT • NF1 • NRAS

Overcoming doxorubicin resistance in triple-negative breast cancer using the class I-targeting HDAC inhibitor bocodepsin/OKI-179 to promote apoptosis. (PubMed, Breast Cancer Res) - "The addition of bocodepsin to doxorubicin resulted in synergistic antiproliferative activity in vitro, improved tumor growth inhibition in vivo, and promotion of apoptosis which makes this a promising combination to overcome doxorubicin resistance in TNBC. Bocodepsin is currently in clinical development and has a favorable toxicity profile compared to other HDAC inhibitors supporting the feasibility of evaluating this combination in patients with TNBC."

Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • ANXA5

First-in-Human Dose-Escalation Study of the Novel Oral Depsipeptide Class I-Targeting HDAC Inhibitor Bocodepsin (OKI-179) in Patients with Advanced Solid Tumors. (PubMed, Cancers (Basel)) - "(4) OKI-179 has a manageable safety profile at the recommended phase 2 dose (RP2D) of 300 mg daily on a 4:3 schedule with prophylactic oral antiemetics. OKI-179 is currently being investigated with the MEK inhibitor binimetinib in patients with NRAS-mutated melanoma in the phase 2 Nautilus trial."

Journal • Metastases • P1 data • Fatigue • Hematological Disorders • Melanoma • Oncology • Ovarian Cancer • Solid Tumor • Thrombocytopenia • NRAS

First-in-Human Dose-Escalation Study of the Novel Oral Depsipeptide Class I-Targeting HDAC Inhibitor Bocodepsin (OKI-179) in Patients with Advanced Solid Tumors (Multidisciplinary Digital Publishing Institute) - P1 | N=34 | NCT03931681 | Sponsor: OnKure, Inc. | "Patients (n = 34) with advanced solid tumors were treated with OKI-179 orally once daily in three schedules....The mean duration of treatment was 81.2 (range 11–447) days. The most frequent adverse events in all patients were nausea (70.6%), fatigue (47.1%), and thrombocytopenia (41.2%). The maximum tolerated dose (MTD) of OKI-179 was 450 mg with 4:3 and 200 mg with continuous dosing. Dose-limiting toxicities included decreased platelet count and nausea. Prolonged disease control was observed, including two patients with platinum-resistant ovarian cancer. Systemic exposure to the active metabolite exceeded the preclinical efficacy threshold at doses lower than the MTD and was temporally associated with increased histone acetylation in circulating T cells."

P1 data • Ovarian Cancer

Elucidating the direct effects of the novel HDAC inhibitor bocodepsin (OKI-179) on T cells to rationally design regimens for combining with immunotherapy. (PubMed, Front Immunol) - "In vivo comparisons demonstrated that stopping OKI-179 treatment during PD-1 blockade was superior to continuous treatment. These findings provide novel insight into the direct effects of HDAC inhibitors on T cells and that treatment schedules that take into account acute T cell effects should be considered when combined with immunotherapies in order to fully harness the tumor-specific T cell responses in patients."

IO biomarker • Journal • Colorectal Cancer • Gastrointestinal Cancer • Hematological Disorders • Hematological Malignancies • Oncology • Solid Tumor • CD4 • CD8

Utilizing a novel HDAC inhibitor bocodepsin (OKI-179) to overcome doxorubicin resistance in triple-negative breast cancer (AACR-NCI-EORTC 2023) - No abstract available

Late-breaking abstract • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer

Novel strategy for RAS-pathway targeting: Initial results from a phase 1b/2 clinical trial of the oral HDAC inhibitor bocodepsin (OKI-179) combined with binimetinib in patients with RAS-pathway mutated solid tumors and NRAS-mutated melanoma (AACR-NCI-EORTC 2023) - No abstract available

Clinical • Late-breaking abstract • P1/2 data • Melanoma • Oncology • Solid Tumor

Novel strategy for RAS-pathway targeting: Initial results from a phase 1b/2 clinical trial of the oral HDAC inhibitor bocodepsin (OKI-179) combined with binimetinib in patients with RAS-pathway mutated solid tumors and NRAS-mutated melanoma* (AACR-NCI-EORTC 2023) - No abstract available

Clinical • P1/2 data • Melanoma • Oncology • Solid Tumor

The class I selective, oral HDAC inhibitor bocodepsin enhances the response to MAPK pathway inhibitors in multiple tumor types with mutations in MAPK pathway signaling proteins. (AACR-NCI-EORTC 2023) - No abstract available

Oncology

Rationale and design of a phase 1b/2 trial of OKI-179, an oral class 1-selective depsipeptide HDAC inhibitor, in combination with tamoxifen in patients with previously treated metastatic ER+ HER2- breast cancer (SABCS 2021) - No abstract available

Clinical • Combination therapy • P1/2 data • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Oncology • Solid Tumor • ER • HER-2

OKI-179 Plus Binimetinib in Patients With Advanced Solid Tumors in the RAS Pathway (Phase 1b) and NRAS-mutated Melanoma (Phase 2) (clinicaltrials.gov) - P1b | N=73 | Recruiting | Sponsor: OnKure, Inc.

New P1 trial • Melanoma • Oncology • Solid Tumor • BRAF • GNAQ • KIT • NF1 • NRAS

OnKure Therapeutics Announces First Patient Dosed in the Phase 1b/2 Nautilus Trial of OKI-179 in Combination with Binimetinib in Patients with Advanced NRAS-Mutated Melanoma (GlobeNewswire) - "OnKure, Inc...announced that the first patient has been dosed in the Phase 1b/2 Nautilus trial of OKI-179, the Company’s oral Class I histone deacetylase (HDAC) inhibitor, in combination with binimetinib (MEKTOVI®), Pfizer’s MEK inhibitor, in patients with advanced NRAS-mutated melanoma."

Trial status • Melanoma • Oncology

Theclass Iselective, oral HDAC inhibitor OKI-179 increases tumor regressions when combined with the MEK inhibitor binimetinib inmodels of NRAS melanoma (AACR 2022) - "Here we show synergistic activity of combining OKI-179 with the MEK inhibitor binimetinib (bini) or bini + RAF-inhibitor encorafenib (enco/bini) in both CDX and PDX models of NRAS-mutated melanoma and BRAF-mutated colorectal cancer (CRC). These data show the potential for OKI-179 to synergize with RAS-pathway inhibitors across multiple indications. To investigate, a Phase1b/2 trial of OKI-179 with binimetinib in NRAS melanoma will initiate in early 2022."

Late-breaking abstract • Colorectal Cancer • Gastrointestinal Cancer • Melanoma • Oncology • Solid Tumor • BRAF • NRAS

OnKure Therapeutics Announces Promising Preclinical Data on OKI-179 in RAS-Mutated Tumor Models Presented in a Late-Breaking Session at AACR (GlobeNewswire) - "The Company plans to initiate the OKI-179-230 Phase 1b/2 trial of OKI-179 in combination with Pfizer’s MEK inhibitor, binimetinib, in advanced NRAS-mutated melanoma (the Nautilus trial) in the coming weeks...'The preclinical data highlighting our HDAC inhibitor’s synergy with RAS pathway agents are extremely promising, and based on the anti-tumor activity seen, strongly support the clinical development of this combination across multiple indications, including in cancer types less sensitive to RAS pathway inhibition alone'...In cell-line derived xenograft models, OKI-179, binimetinib as a single agent, and binimetinib + encorafenib combination demonstrated tumor growth delay, but few regressions. OKI-179 combined with binimetinib in NRAS-mutated melanoma or combined with binimetinib + encorafenib in BRAF-mutated colorectal xenografts showed significantly increased regressions compared to either single agent following two weeks of dosing."

New P1/2 trial • Preclinical • Colorectal Cancer • Gastrointestinal Cancer • Melanoma • Oncology • Skin Cancer • Solid Tumor

Preclinical development of the class I selective histone deacetylase inhibitor OKI-179 for the treatment of solid tumors. (PubMed, Mol Cancer Ther) - "OKI-179 demonstrated anti-tumor activity in preclinical cancer models with a favorable pharmacokinetic profile and on-target pharmacodynamic effects. Based on its potency, desirable class I HDAC inhibition profile, oral bioavailability, and efficacy against a broad range of solid tumors, OKI-179 is currently being evaluated in a first-in-human phase I clinical trial with plans for continued clinical development in solid tumor and hematologic malignancies."

Epigenetic controller • Journal • Preclinical • Hematological Disorders • Hematological Malignancies • Lymphoma • Oncology • Solid Tumor • T Cell Non-Hodgkin Lymphoma

OnKure Therapeutics Announces Positive Topline First-in-Human Phase 1 Results for OKI-179 (Businesswire) - P1, N=34; NCT03931681; Sponsor: OnKure, Inc; "OnKure, Inc...announced positive topline results from the first-in-human Phase 1 trial of OKI-179, the Company’s oral Class 1 histone deacetylase (HDAC) inhibitor....OKI-179 was shown to be safe and generally well-tolerated as a single agent using intermittent dosing schedules of either 4 days on/3 days off or 5 days on/2 days off for 21 days. The most common adverse events were nausea, fatigue and anemia. Nausea was manageable with antiemetics...Based on these favorable results, the Company expects to initiate a Phase 1b/2 trial of OKI-179 in combination with binimetinib in patients with NRAS mutant melanoma where checkpoint inhibitor therapy has failed in the first half of 2022."

New P1/2 trial • P1 data • Melanoma • Oncology

A Study of OKI-179 in Patients With Solid Tumors (clinicaltrials.gov) - P1; N=34; Completed; Sponsor: OnKure, Inc.; Active, not recruiting ➔ Completed; Trial completion date: Jun 2023 ➔ Nov 2021; Trial primary completion date: Apr 2023 ➔ Nov 2021

Clinical • Trial completion • Trial completion date • Trial primary completion date • Oncology • Solid Tumor • MRI

A Study of OKI-179 in Patients With Solid Tumors (clinicaltrials.gov) - P1; N=40; Active, not recruiting; Sponsor: OnKure, Inc.; Recruiting ➔ Active, not recruiting

Clinical • Enrollment closed • Oncology • Solid Tumor • MRI

Marine Power on Cancer: Drugs, Lead Compounds, and Mechanisms. (PubMed, Mar Drugs) - "This review provides a summary of the anticancer effects and mechanisms of action of selected marine compounds, including cytarabine, eribulin, marizomib, plitidepsin, trabectedin, zalypsis, adcetris, and OKI-179. The future development of anticancer marine drugs requires innovative biochemical biology approaches and introduction of novel therapeutic targets, as well as efficient isolation and synthesis of marine-derived natural compounds and derivatives."

Journal • Review • Breast Cancer • Hematological Malignancies • Hodgkin Lymphoma • Lymphoma • Oncology • Solid Tumor

[VIRTUAL] Initial results from a Phase 1 Trial of OKI-179, an oral Class 1-selective Depsipeptide HDAC inhibitor, in patients with advanced solid tumors (AACR-NCI-EORTC 2020) - P1 | "OKI-179 is a novel, oral pro-drug analog of largazole, a compound in the romidepsin-depsipeptide class of natural products. OKI-179 is well-tolerated and has a favorable PK profile with expected target modulation. Promising stabilization of disease was observed, and dose escalation continues to identify the MTD. An update on clinical and translational data will be presented."

Clinical • P1 data • Hematological Malignancies • Nasopharyngeal Carcinoma • Oncology • Ovarian Cancer • Solid Tumor

[VIRTUAL] Phase 1 study of OKI-179, an oral class 1-selective depsipeptide HDAC inhibitor, in patients with advanced solid tumors: Final results. (ASCO 2021) - P1 | "OKI-179 has a manageable safety profile, with thrombocytopenia being the on-target DLT . It has a favorable PK profile and demonstrated on-target PD effects at tolerable doses . The MTD and RP2D for OKI-179 was 450 mg daily for intermittent dosing and 200 mg daily for continuous dosing ."

Clinical • P1 data • Anemia • Anorexia • Breast Cancer • Fatigue • Hematological Disorders • Hormone Receptor Breast Cancer • Melanoma • Nasopharyngeal Carcinoma • Oncology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Pancreatic Cancer • Solid Tumor • Thrombocytopenia