This Phase 1a, single center, open-label, repeat dose study will evaluate the safety, efficacy, and Pharmacokinetics of ascending doses of OBP-801 in patients with advanced solid tumors.

Start Date01 Mar 2015

Sponsor / Collaborator

Oncolys BioPharma, Inc.

100 Clinical Results associated with Spiruchostatin A

100 Translational Medicine associated with Spiruchostatin A

100 Patents (Medical) associated with Spiruchostatin A

Literatures (Medical) associated with Spiruchostatin A

01 Aug 2022·Pharmacology & Therapeutics

“RB-reactivator screening” as a novel cell-based assay for discoveries of molecular targeting agents including the first-in-class MEK inhibitor trametinib (trade name: Mekinist)

Review

Author: Sakai, Toshiyuki

The retinoblastoma gene (RB) was discovered as the first tumor-suppressor gene. It was subsequently shown to be inactivated in most malignant tumors, particularly at the protein level. Therefore, many activated oncogenes as well as inactivated tumor-suppressor genes inactivate the function of the RB protein. I hypothesized that most of the molecular-targeting agents against activated oncogenes may reactivate the function of RB, and proposed screening systems for agents up-regulating the expression of cyclin-dependent kinase inhibitors, such as p15, p27, and p21, which convert the phosphorylated inactive form of the RB protein to the unphosphorylated active form. I termed this screening as "RB-reactivator screening". Using the screening systems for agents that up-regulate the expression of p15, p27, and p21, we discovered the novel MEK inhibitor trametinib, the novel RAF/MEK inhibitor CH5126766/RO5126766/VS-6766, and the histone deacetylase inhibitor YM753/OBP-801, respectively. Trametinib exerted remarkable effects in patients with advanced BRAF mutant melanoma, and was approved in the USA as the first-in-class MEK inhibitor (trade name: Mekinist) in 2013. The British Pharmacological Society selected trametinib as the Drug Discovery of the Year in 2013. The combination of trametinib and the BRAF inhibitor dabrafenib was approved for advanced BRAF mutant melanoma in the USA, EU, Japan, and many other countries. Additionally, the US Food and Drug Administration (FDA) granted Breakthrough Therapy Designation for the combination of trametinib and dabrafenib in the treatment of patients with advanced BRAF mutant non-small cell lung cancer in 2015, and this combination was subsequently approved in the EU, USA, and Japan. In 2018, this combination was also approved for locally advanced or metastatic BRAF V600-mutant anaplastic thyroid cancer in the USA after it had been granted Breakthrough Therapy Designation by the FDA. I describe here the characterization of our original screening system, RB-reactivator screening, by which these three molecular-targeting agents that advanced into clinical trials were identified.

01 Apr 2022·Investigational New DrugsQ3 · MEDICINE

Phase Ia dose escalation study of OBP-801, a cyclic depsipeptide class I histone deacetylase inhibitor, in patients with advanced solid tumors

Q3 · MEDICINE

Article

Author: Danforth, Dailan ; Urata, Yasuo ; Ungerleider, Richard S ; Weise, Amy ; Vaishampayan, Ulka ; Heath, Elisabeth I

Background Dysregulation of histone deacetylases (HDACs) is common in cancer and is critical to the development and progression of the majority of tumors. This first-in-human Phase Ia study assessed the safety, efficacy, and pharmacokinetics (PK) of OBP-801, a cyclic depsipeptide class I HDAC inhibitor. Methods Adult patients with advanced solid tumors were treated in 3 dose cohorts (1.0 mg/m², 2.0 mg/m² or 2.8 mg/m²) of OBP-801 that was administered via intravenous infusion weekly. Initially, an accelerated titration design was used that was followed by a 3 + 3 dose escalation strategy. Primary objective was assessment of safety. Secondary objectives included determination of PK and objective response rate. Results Seventeen patients were enrolled, of which 8 patients were evaluable for efficacy. Drug-related ≥ Grade 3 treatment-emergent adverse events included abdominal pain, anemia, fatigue, gamma glutamyl-transferase increase, hypertriglyceridemia and vomiting. No dose-limiting toxicity was observed in the 1.0 mg/m² cohort. The PK data showed that OBP-801 and its active metabolite OBP-801-SH exposure increased proportionally and more than proportionally, respectively. No accumulation of either agent was noticed after repeat administration. Best response was stable disease (37.5%), with one patient each in the three cohorts. Conclusion Further investigations of the OBP-801 1.0 mg/m² dose will be needed to better understand the efficacy of the agent, either alone or in combination. Trial registration: NCT02414516 (ClinicalTrials.gov) registered on April 10, 2015.

01 Jan 2022·Pediatrics International

The histone deacetylase inhibitor OBP‐801 has in vitro/in vivo anti‐neuroblastoma activity

Article

Author: Nakagawa, Norio ; Yagyu, Shigeki ; Kaneda, Daisuke ; Hosoi, Hajime ; Miyachi, Mitsuru ; Konishi, Eiichi ; Iehara, Tomoko ; Sugimoto, Yohei ; Kikuchi, Ken ; Sakai, Toshiyuki

AbstractBackgroundPatients with high‐risk neuroblastoma have a poor prognosis; new therapeutic agents are therefore required. We investigated the antitumor effects of OBP‐801, a novel histone deacetylase inhibitor, its underlying mechanism, and its potential as a therapeutic agent for patients with neuroblastoma.MethodsThe study included five human neuroblastoma cell lines: IMR32, GOTO, KP‐N‐RTBM, SK‐N‐AS, and SH‐SY5Y. We investigated cell proliferation, cell cycle status, protein expression patterns, and apoptosis in neuroblastoma cells after OBP‐801 treatment in vitro. Cell survival rate and cell cycle were analyzed using the WST‐8 assay and flow cytometry, respectively. Apoptosis was detected using annexin V staining, and the expression of apoptosis‐related proteins was investigated by western blotting. The antitumor activity of OBP‐801 was examined in an in vivo xenograft mouse model.ResultsDose–effect curve analysis showed that the mean half‐maximal inhibitory concentration value was 5.5 ± 5.9 nM for the MYCN‐amplified cell lines (IMR32, GOTO, and KP‐N‐RTBM) and 3.1 ± 0.7 nM for the MYCN‐nonamplified cell lines (SK‐N‐AS and SH‐SY5Y). OBP‐801 inhibited cell proliferation and growth in all the cell lines. It induced G2/M phase arrest through the p21 (CDKN1A) pathway, increasing histone H3 levels and, subsequently, apoptosis in human neuroblastoma cells. OBP‐801 suppressed the growth of neuroblastoma cells in the mouse xenograft model.ConclusionsOverall, OBP‐801 induces M‐phase arrest and apoptosis in neuroblastoma cells via mitotic catastrophe. Our results indicate that OBP‐801 is a promising therapeutic agent with fewer adverse effects for patients with neuroblastoma.

100 Deals associated with Spiruchostatin A

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R&D Status

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Indication	Highest Phase	Country/Location	Organization	Date
Glaucoma	Phase 1	JP	Oncolys BioPharma, Inc.	05 Jul 2019
Glaucoma	Phase 1	JP	Kyoto Prefectural University of Medicine	05 Jul 2019
Lung Cancer	Phase 1	JP	Oncolys BioPharma, Inc.	05 Jul 2019
Eye Diseases	Phase 1	JP	Oncolys BioPharma, Inc.	31 Jul 2018
Eye Diseases	Phase 1	JP	Kyoto Prefectural University of Medicine	31 Jul 2018
Advanced Malignant Solid Neoplasm	Phase 1	US	Oncolys BioPharma, Inc.	01 Mar 2015
Neoplasms	Phase 1	JP	Oncolys BioPharma, Inc.	13 Oct 2009

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT02414516 (Pubmed \| Invest New Drugs) Manual	Phase 1	HR-positive/HER2-low Solid Tumors	17	Spiruchostatin A	(dnhkagiqeb) = none in the 1.0 mg/m² cohort cfweqvxusb (kxrxqypfrt ) View more	Positive	06 Oct 2021

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