OXI-4503 (Combretastatin A1 Diphosphate): A Dual-Mechanism Vascular Disrupting Agent

I. Introduction

OXI-4503, also known as combretastatin A1 diphosphate (CA1P), is an investigational small molecule therapeutic agent derived from combretastatin A1, a natural product isolated from the South African bush willow tree, Combretum caffrum.[1] It is formulated as a solid diphosphate prodrug.[3] OXI-4503 has been primarily investigated for the treatment of various cancers and tumors, including solid tumors and hematologic malignancies such as acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS).[5] The compound is characterized by a unique dual mechanism of action, functioning both as a potent vascular disrupting agent (VDA) that targets established tumor blood vessels and, following metabolic activation within the tumor microenvironment, as a direct cytotoxic agent against tumor cells.[1]

II. Chemical and Physical Properties

• Drug Name: OXI-4503 [User Query]
• Synonyms: Combretastatin A1 diphosphate (CA1P), Combretastatin A-1 phosphate, Combretastatin A-1 bis(phosphate) [2]
• Drug Type: Small Molecule [User Query]
• CAS Number: 288847-35-8 [4]
• DrugBank ID: DB05143 [5]
• Physical State: Solid [User Query]
• Chemical Formula (Parent): C18​H22​O12​P2​ [5]
• Molecular Weight (Parent): 492.3076 g/mol [5]
• Nature: OXI-4503 is a diphosphate prodrug of combretastatin A1 (CA1, OXi4500).[1] It requires in vivo dephosphorylation to release the active CA1 metabolite.[2] Salt forms such as dipotassium (DBSALT001872) and tetrasodium (3D67LX3H83) salts exist.[3]

III. Mechanism of Action

OXI-4503 exhibits a distinctive dual mechanism, combining vascular disruption with direct tumor cell cytotoxicity, setting it apart from many other vascular targeted therapies.[1]

Vascular Disrupting Agent (VDA) Activity

As a VDA, OXI-4503 primarily targets the established vasculature within tumors, exploiting differences between tumor blood vessels and those in normal tissues.[1] Following dephosphorylation to its active metabolite, combretastatin A1 (CA1), the drug binds with high affinity to the colchicine-binding site on the β-subunit of tubulin.[1] This interaction inhibits microtubule assembly and promotes rapid microtubule depolymerization within endothelial cells.[1] The disruption of the endothelial cytoskeleton leads to profound changes in cell shape, mitotic arrest, and ultimately apoptosis of the endothelial cells lining the tumor blood vessels.[2] This process causes a rapid shutdown of tumor blood flow, leading to extensive tumor cell death and necrosis due to the withdrawal of oxygen and nutrients.[1] Preclinical studies demonstrated that OXI-4503 is a highly potent VDA, inducing tumor vascular shutdown at significantly lower doses than the related compound combretastatin A-4 phosphate (CA4P), with an ED$_{50}$ of 3 mg/kg compared to 43 mg/kg for CA4P in one model.[10] In the context of AML, OXI-4503 disrupts bone marrow endothelial cells (BMECs), which are known to provide a protective niche for leukemia cells.[6] This disruption alters endothelial cell shape and downregulates intercellular adhesion molecules, potentially releasing quiescent leukemia cells and making them more susceptible to chemotherapy.[6]

Direct Cytotoxicity via Orthoquinone Metabolite

In addition to its VDA effects, OXI-4503 possesses direct cytotoxic activity against tumor cells.[1] Preclinical data indicate that the active metabolite, combretastatin A1, is further metabolized by oxidative enzymes, such as tyrosinase and peroxidases.[3] These enzymes are often found at elevated levels within solid tumors and tumor infiltrates.[3] This metabolic process generates a reactive orthoquinone chemical species.[1] This orthoquinone metabolite is believed to exert direct cytotoxic effects.[1] Potential mechanisms for this cytotoxicity include the binding of the quinone to thiol-specific antioxidant proteins and DNA within tumor cells, as well as the enhancement of oxidative stress through increased production of superoxide and hydrogen peroxide.[1] This direct cytotoxic component complements the VDA activity.

Significance of the Dual Mechanism

The combination of potent vascular disruption and direct cytotoxicity offers a potential therapeutic advantage. Standard VDAs often induce necrosis primarily in the tumor core, leaving a peripheral rim of viable, potentially resistant tumor cells that can lead to regrowth.[8] The orthoquinone metabolite generated from OXI-4503 provides a secondary mechanism that could potentially target these surviving peripheral tumor cells, as well as directly impacting cancer cells independently of vascular shutdown.[1] This dual action was particularly relevant to its investigation in AML, where OXI-4503 could target both the protective bone marrow vasculature (via VDA activity) and the leukemia cells themselves (via direct cytotoxicity and disruption of BMEC support).[6]

IV. Preclinical Studies

Extensive preclinical investigations have evaluated the activity of OXI-4503 both as a single agent and in combination regimens.

Monotherapy Activity

Preclinical studies consistently demonstrated that OXI-4503 possesses significant single-agent antitumor activity across a range of xenograft tumor models.[10] Administration of OXI-4503 led to a rapid and dose-dependent shutdown of tumor blood flow, resulting in extensive tumor cell necrosis.[10] Notably, unlike some other VDAs which primarily cause central tumor necrosis, OXI-4503 showed effects on peripheral tumor regions as well, although central regions were still more affected.[10] This potent vascular disruption translated into significant effects on tumor growth, with complete tumor growth repression observed at doses above 12.5 mg/kg and tumor regression, including complete responses in some animals, at doses above 25 mg/kg in certain models.[10] Vascular disrupting activity was observed at concentrations tenfold below the direct cytotoxic threshold, highlighting its potent effect on tumor vasculature.[1]

Combination Therapy

Preclinical data indicated that OXI-4503 exhibits synergistic or additive antitumor effects when combined with various standard cancer treatments [User Query]. This includes conventional chemotherapy agents, molecularly targeted therapies (such as tumor angiogenesis inhibitors), and radiation therapy [User Query]. The combination of VDAs like OXI-4503 with anti-angiogenic agents (AAs) has a strong rationale: VDAs target the established, often poorly formed vessels in the tumor core, while AAs inhibit the formation of new vessels, potentially targeting the peripheral tumor regions spared by VDAs.[8] Combining these approaches aims to achieve a more comprehensive attack on the tumor vasculature.[8]

Activity in Acute Myeloid Leukemia (AML) Models

A significant focus of preclinical work involved AML models, driven by OXI-4503's dual mechanism. Studies demonstrated single-agent activity in murine xenograft models of both extramedullary leukemia (chloroma) and systemic AML.[6] OXI-4503 was shown to disrupt the supportive function of bone marrow endothelial cells (BMECs) for AML clones.[6] BMECs are known to protect AML cells from chemotherapy.[9] By disrupting this protective microenvironment, OXI-4503 could sensitize AML cells to conventional agents like cytarabine (ARA-C).[6] Indeed, the combination of OXI-4503 and cytarabine proved significantly more effective than either agent alone in human AML xenograft models.[6] This strong preclinical evidence, targeting both the leukemia cells directly (cytotoxicity) and their protective niche (VDA effect on BMECs), provided a compelling rationale for investigating OXI-4503 in combination with cytarabine for patients with relapsed or refractory (R/R) AML.[6]

V. Clinical Development

OXI-4503 has been evaluated in several Phase 1 and Phase 1b clinical trials, primarily in advanced solid tumors and AML/MDS.

Phase 1 in Advanced Solid Tumors (NCT00977210)

This first-in-human study evaluated escalating doses of OXI-4503 administered intravenously over 10 minutes on days 1, 8, and 15 of a 28-day cycle in 43 patients with advanced solid tumors.[1] Doses ranged from 0.06 mg/m$^2$ to 15.4 mg/m$^2$.[1] The study established a maximum tolerated dose (MTD) of 8.5 mg/m$^2$, although dose escalation up to 14 mg/m$^2$ was possible after excluding hypertensive patients, with observed toxicity (temporary reversible cerebrovascular events) at the highest doses.[1] Common drug-related adverse events included transient hypertension, tumor pain, anemia, lymphopenia, nausea, vomiting, and fatigue.[1] Dose-limiting toxicities (DLTs) included atrial fibrillation, increased troponin, blurred vision, diplopia, and tumor lysis syndrome.[1] Pharmacokinetic analysis showed dose-dependent linear increases in peak plasma concentrations (Cmax​) and area under the curve (AUC).[1] Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) confirmed dose-dependent antivascular effects, with significant reductions in tumor perfusion observed in the majority of patients treated at doses of 11 mg/m$^2$ or higher.[1] A partial response (PR) was observed in one heavily pretreated patient with ovarian cancer treated at 14 mg/m$^2$.[1] Based on the observed tumor response and maximal perfusion reductions, the recommended Phase 2 dose (RP2D) was suggested to be in the range of 11 to 14 mg/m$^2$.[1] This trial provided initial confirmation of OXI-4503's VDA activity and manageable safety profile in humans.

Phase 1 in Relapsed/Refractory AML and MDS (NCT01085656)

This Phase 1 trial evaluated single-agent OXI-4503 in patients with R/R AML and MDS.[6] A total of 18 patients were treated.[6] The study demonstrated a manageable safety profile for single-agent OXI-4503 in this patient population.[6] However, this trial was ultimately terminated.[7]

Phase 1b Combination Therapy in R/R AML and MDS (NCT02576301)

Building on the preclinical rationale and single-agent safety data, this multicenter Phase 1b study evaluated OXI-4503 in combination with the standard AML chemotherapy agent cytarabine (ARA-C), termed the OXA regimen.[6] The study enrolled 29 patients (27 R/R AML, 2 R/R MDS) across four centers between December 2015 and January 2019.[6] Patients were heavily pretreated, with most having failed two or more prior lines of therapy.[6] The study successfully defined the MTD of OXI-4503 as 9.76 mg/m$^2$ when administered in combination with ARA-C at 1 g/m$^2$.[6] The safety profile of the combination was considered manageable. Drug-related serious adverse events (SAEs) occurred in 4 patients (14%) and included febrile neutropenia (n=2), pneumonia/acute respiratory failure (n=1), and hypotension (n=1).[6]

In 26 evaluable AML patients, the OXA regimen demonstrated encouraging signs of clinical activity. The overall response rate (ORR) was 19%, comprising 2 complete remissions (CR), 2 complete remissions with incomplete hematologic recovery (CRi), and 1 partial response (PR).[6] Notably, the median overall survival (OS) for the 4 patients achieving CR/CRi was 528 days (95% CI: 434–NA), significantly longer than the median OS of 113 days (95% CI: 77–172) for the 22 non-responding patients (p=0.0006).[6] These results provided clinical validation for the combination approach, suggesting that OXI-4503 could overcome resistance mechanisms in R/R AML, potentially by disrupting the protective BMEC niche and exerting direct cytotoxicity, thereby enhancing the efficacy of cytarabine in this challenging patient population.[6] The status of this trial (NCT02576301) has been reported as "Unknown" in recent database entries, indicating uncertainty about its continuation or completion beyond the reported Phase 1b results.[12]

Other Trials

A Phase 1b/2 study (NCT00960557) evaluating OXI-4503 monotherapy in patients with primary or secondary hepatic tumors was completed.[14]

VI. Regulatory Status

OXI-4503 received specific regulatory designations aimed at facilitating its development for acute myeloid leukemia.

• FDA Orphan Drug Designation (ODD): On November 21, 2012, the U.S. Food and Drug Administration granted Orphan Drug Designation to OXI-4503 (combretastatin A-1 phosphate) for the treatment of acute myelogenous leukemia (AML) (Designation #382412).[5] This designation is granted to drugs intended for rare diseases or conditions (affecting fewer than 200,000 people in the U.S.) and provides incentives such as potential market exclusivity upon approval, tax credits for clinical testing, and development grants.[5]
• EMA Orphan Designation: On December 14, 2015, the European Commission granted orphan designation (EU/3/15/1587) to combretastatin A1 diphosphate for the treatment of AML in the European Union, sponsored by Diamond BioPharm Limited (UK).[5] The designation was based on the seriousness of AML, its prevalence below the orphan threshold (<5 in 10,000 people in the EU), and the potential for significant benefit over existing therapies, particularly for patients with relapsed disease.[16]
• FDA Fast Track Designation: OXI-4503 also received Fast Track designation from the FDA for the treatment of AML.[11] This designation is intended to facilitate the development and expedite the review process for drugs that treat serious conditions and fill an unmet medical need.[11]

The successful attainment of these regulatory designations underscores the recognition of the high unmet medical need in R/R AML and the potential of OXI-4503 to address it. These designations were particularly significant following the strategic decision by the developer, Mateon Therapeutics, to prioritize the AML program after encountering setbacks with a related compound (CA4P) in a non-orphan indication (ovarian cancer).[17] The incentives and expedited pathways associated with ODD and Fast Track likely reinforced the focus on the AML development path for OXI-4503.

VII. Development Status and Corporate History

The development of OXI-4503 has been associated with several corporate entities and strategic shifts over time. Initial development appears linked to Oxigene, with Mateon Therapeutics subsequently driving the key clinical trials.[5]

In September 2017, Mateon Therapeutics announced a significant corporate restructuring following the failure of its Phase 2/3 FOCUS study evaluating CA4P (a related combretastatin VDA) in platinum-resistant ovarian cancer.[17] Due to a lack of efficacy signal for CA4P, Mateon terminated that study and its further development.[17] Concurrently, the company announced a strategic pivot to prioritize the development of OXI-4503 specifically for AML, citing the promising clinical outcomes observed in early cohorts of the Phase 1b OXA trial (NCT02576301) and the significant unmet need in R/R AML.[11] This restructuring involved substantial reductions in personnel and operating expenses.[17]

Around 2020, Mateon Therapeutics underwent a reverse merger with Oncotelic, Inc., resulting in Oncotelic becoming a wholly owned subsidiary of Mateon.[18] The merged entity, referred to as Mateon/Oncotelic, aimed to leverage expertise in oncology drug development, focusing on immuno-oncology, first-in-class RNA therapeutics (like OT-101), and small molecule drugs, including OXI-4503.[18]

As of the latest available information from the provided sources, Oncotelic Therapeutics lists OXI-4503 in its pipeline as being in Phase 1b development for R/R AML.[9] However, the pivotal Phase 1b combination trial (NCT02576301), which generated the encouraging response data cited during the 2017 restructuring, is currently marked with an "Unknown" status in clinical trial registries, with an original estimated study completion date in 2020.[12] This discrepancy raises questions about the active development status of OXI-4503. The corporate turbulence, including the significant restructuring at Mateon in 2017 due to the CA4P failure and the subsequent merger with Oncotelic which broadened the company's therapeutic focus, may have impacted the resources and momentum behind the OXI-4503 program, potentially contributing to the apparent stall in clinical progression despite the positive Phase 1b signals reported up to 2019.[6]

VIII. Conclusion

OXI-4503 (combretastatin A1 diphosphate) is an investigational anticancer agent possessing a unique dual mechanism of action, functioning as both a potent vascular disrupting agent (VDA) through tubulin binding in endothelial cells and as a direct cytotoxic agent via a reactive orthoquinone metabolite formed preferentially in the tumor microenvironment.[1] Preclinical studies demonstrated significant single-agent antitumor activity and synergistic effects in combination with chemotherapy, targeted agents, and radiation.[10] A strong preclinical rationale supported its use in AML, based on its ability to disrupt the protective bone marrow endothelial cell niche and exert direct cytotoxicity against leukemia cells, thereby sensitizing them to standard chemotherapy like cytarabine.[6]

Clinical development included a completed Phase 1 study in solid tumors that established safety, pharmacokinetics, and a recommended dose range, while also providing DCE-MRI evidence of vascular disruption.[1] A subsequent Phase 1b study combining OXI-4503 with cytarabine (OXA regimen) in heavily pretreated R/R AML patients established an MTD for the combination and showed encouraging clinical activity, including complete remissions and a significant survival benefit for responders, validating the preclinical combination strategy.[6] The development program for AML was supported by Orphan Drug designations from both the FDA and EMA, as well as FDA Fast Track designation.[5]

Despite this demonstrated potential, particularly in the challenging setting of R/R AML, the development trajectory of OXI-4503 appears uncertain. Following a strategic prioritization in 2017 by Mateon Therapeutics after setbacks with another compound, and a subsequent merger forming Oncotelic Therapeutics around 2020, the key Phase 1b AML trial (NCT02576301) now carries an "Unknown" status in clinical trial registries.[12] While still listed in the Oncotelic pipeline [9], the lack of recent updates on active clinical progression suggests development may have stalled or been deprioritized, potentially influenced by corporate restructuring and shifting priorities. Further information is required to ascertain the current definitive development status of OXI-4503.

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