OBP-801

Summary

OBP-801 (also known as YM753 or Spiruchostatin B analogue) is an investigational cyclic depsipeptide that functions as a class I histone deacetylase (HDAC) inhibitor. It is being explored for cancer therapy, particularly in solid tumours such as myxofibrosarcoma and neuroblastoma, and for ophthalmic applications to reduce fibrosis after glaucoma filtration surgery. The compound is administered intravenously in clinical studies, while pre‑clinical ocular work used subconjunctival injection or eye‑drop formulations.

Mechanism of Action

OBP-801 binds to the catalytic pocket of class I HDAC enzymes, blocking removal of acetyl groups from histones and non‑histone proteins. This increases acetylation of histone H3, leading to transcriptional activation of cyclin‑dependent kinase inhibitors such as p21 (CDKN1A), p27 and p15. The up‑regulated CDK inhibitors cause G2/M cell‑cycle arrest and trigger apoptotic pathways, including mitotic catastrophe. In fibroblastic cells, HDAC inhibition down‑regulates profibrotic genes (e.g., TGF‑β3, MMP‑2, COL1A) thereby limiting extracellular‑matrix deposition.

What the Research Shows

Pre‑clinical work shows OBP-801 suppresses proliferation of myxofibrosarcoma cell lines, induces G2 arrest and apoptosis, and enhances the activity of pazopanib and Akt‑mTOR inhibitors. In neuroblastoma, nanomolar IC50 values were reported across MYCN‑amplified and non‑amplified lines; the agent caused G2/M arrest via p21, increased histone H3 acetylation, and reduced tumour growth in mouse xenografts. A Phase Ia dose‑escalation trial in patients with advanced solid tumours (1.0‑2.8 mg/m2 IV weekly) demonstrated dose‑proportional pharmacokinetics, stable disease in 37.5% of evaluable patients, and grade ≥ 3 adverse events such as abdominal pain, anemia and hypertriglyceridaemia. In a rabbit model of glaucoma filtration surgery, subconjunctival or topical OBP‑801 lowered expression of fibrotic markers, preserved bleb morphology and reduced intra‑ocular pressure without observable toxicity.

Reported Benefits

Evidence from cell‑based and animal studies indicates that OBP-801 can halt tumour cell growth, promote apoptosis, and potentiate other anticancer agents, suggesting a role in hard‑to‑treat sarcomas and neuroblastoma. Early‑phase clinical data show disease stabilisation in a subset of patients with advanced solid tumours. In ocular surgery models, the compound reduces scar formation and maintains filtration blebs, potentially improving outcomes after glaucoma procedures.

Limitations of the Evidence

All anti‑cancer efficacy data are limited to in‑vitro cell lines, mouse xenografts, and a small Phase Ia trial with modest response (stable disease only). No regulatory approval exists, and optimal dosing, long‑term efficacy and survival benefit remain undefined. The ocular findings are confined to rabbit experiments; human safety and efficacy for eye use have not been demonstrated. Reported adverse events in the human trial highlight a need for careful safety monitoring.

Safety Considerations

In the Phase Ia study, treatment‑related grade ≥ 3 adverse events included abdominal pain, anemia, fatigue, elevated gamma‑glutamyl‑transferase, hypertriglyceridaemia and vomiting; no dose‑limiting toxicity was observed at the lowest dose (1 mg/m2). Pharmacokinetic data showed no drug accumulation with weekly dosing. In the rabbit glaucoma model, subconjunctival injection or eye‑drop administration produced no observable ocular toxicity. Overall, safety signals are limited to systemic chemotherapy‑type toxicities at higher doses, and ocular use appears well tolerated in animals.

How It Is Administered

Clinical investigations have used OBP-801 as an intravenous infusion given once weekly, with dose cohorts ranging from 1.0 to 2.8 mg/m2. Pre‑clinical ophthalmic studies employed either subconjunctival injection or topical eye‑drop formulations in rabbits. Formulation details beyond route of administration are not described in the available abstracts.

Routes of Administration

Goals & Uses

• Combination anticancer therapyOncologyLow
• Antitumor activity in solid tumorsOncologyModerate
• Epigenetic reprogramming of cancer cellsOncology/EpigeneticsModerate
• Hematologic malignancy treatmentOncologyLow

Contraindications

• Severe hepatic impairmentOrganModerateLiver function concerns
• Known hypersensitivity to cyclic depsipeptide HDAC inhibitorsAllergyHigh
• Severe cardiac arrhythmia or QTc prolongationCardiovascularHigh

Adverse Effects

• ThrombocytopeniaHematologicCommonLow platelet count
• QTc prolongationCardiacUncommon
• Nausea/vomitingGastrointestinalCommon
• NeutropeniaHematologicUncommonLow neutrophil count
• FatigueGeneralCommonLow energy or tiredness
• Elevated liver enzymesHepaticUncommonIncrease in AST/ALT or other hepatic markers

Drug Interactions

• Anticoagulants (e.g., warfarin)Moderate
• QTc-prolonging agents (e.g., antiarrhythmics, certain antipsychotics)High
• Strong CYP3A4 inhibitorsModerate

Population Constraints

• PregnancyReproductive SafetyAbsolute
• Severe renal impairmentOrgan ImpairmentRelative
• Pediatric patientsAgeRelative
• BreastfeedingReproductiveAbsolute

Regulatory Status

• European UnionUnknownNo EMA approval; clinical activity primarily in Japan.
• United StatesInvestigationalNo FDA approval; IND status not publicly confirmed; investigational use only.
• United KingdomUnknownNo MHRA approval on record.

OBP-801 has been evaluated in Phase I clinical trials primarily in Japan. It does not hold approved status in any major jurisdiction as of the available data. It is a research/investigational compound.

Evidence & Sources

• The HDAC inhibitor OBP-801 suppresses the growth of myxofibrosarcoma cells
  Journal ArticleLowKawarazaki A, et al.2020-01-01T00:00:00.000000Z
• "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)
  Journal ArticleModerateSakai T2022-01-01T00:00:00.000000Z
• The histone deacetylase inhibitor OBP-801 has in vitro/in vivo anti-neuroblastoma activity
  Journal ArticleLowKaneda D, et al.2022-01-01T00:00:00.000000Z
• Phase Ia dose escalation study of OBP-801, a cyclic depsipeptide class I histone deacetylase inhibitor, in patients with advanced solid tumors
  Journal ArticleModerateHeath EI, et al.2022-01-01T00:00:00.000000Z
• Pluripotent epigenetic regulator OBP-801 maintains filtering blebs in glaucoma filtration surgery model
  Journal ArticleLowYamamoto Y, et al.2020-01-01T00:00:00.000000Z

Frequently Asked Questions