EO-4426 Program: Drug Class: “Dual” DNA Pol α & RNR Inhibitor
Edison Oncology is planning clinical trials of EO-4426 in solid tumors and hematologic malignancies in 1H 2026.
A First-in-Class Orally Bioavailable, Brain Penetrant - Dual Inhibitor of DNA Polymerase Alpha
(Pol α ) and Ribonucleotide Reductase (RNR) for the Treatment of Cancer
EO-4426 (tezacitabine) is an orally bioavailable, brain penetrating, small molecule anticancer drug that targets both DNA polymerase alpha (Pol α) and ribonucleotide reductase (RNR), two essential and complementary enzymes involved in DNA replication and repair. This dual-targeting mechanism represents a novel therapeutic strategy to exploit the vulnerabilities of cancer cells, particularly their dependence on rapid and efficient DNA replication.
Mechanism of Action
- Pol α Inhibition: Pol α is a critical component of the primase complex and is responsible for initiating DNA synthesis during replication. Inhibition of Pol α disrupts replication initiation, halting the progression of DNA replication forks.
- RNR Inhibition: RNR is essential for the de novo synthesis of deoxyribonucleotide triphosphates (dNTPs), the building blocks of DNA. Inhibiting RNR depletes intracellular dNTP pools, further impairing DNA synthesis and repair.
The simultaneous inhibition of Pol α and RNR induces severe replication stress, leading to replication fork collapse, DNA damage accumulation, and ultimately, cancer cell death.
Scientific and Clinical Rationale
- Unmet Need and Novelty: While several RNR inhibitors (e.g., hydroxyurea, gemcitabine, clofarabine) are FDA-approved for cancer treatment, there are currently no approved or clinical-stage oral and brain penetrant therapies specifically targeting DNA polymerase alpha.
- Targeting a Central Node in Replication: Pol α plays a foundational role in initiating DNA replication, making it a compelling target in rapidly dividing cancer cells. Compared to other polymerases like Pol θ, which is more involved in DNA repair and synthetic lethality approaches, Pol α offers broader and potentially more impactful therapeutic reach.
- CNS Penetration: EO-4426 crosses the blood brain barrier and has demonstrated anticancer activity in preclinical brain tumor models providing an opportunity for the treatment of brain metastases and primary brain tumors
- Broad Antitumor Potential: EO-4426 has demonstrated clinical activity across a wide range of tumor types, including lung, breast, colon, prostate, brain tumors, and leukemia, suggesting its utility across diverse cancer indications.
- Gemcitabine Resistance: EO-4426 dual mechanism of action supports the potential for activity gemcitabine-resistant cancers where Cytidine Deaminase (CDA) overexpression is a mechanism of resistance. CDA Biomarker Testing can be used to identify gemcitabine resistant patients, a major clinical challenge especially in the treatment of Pancreatic, NSCLC, Breast, and Bladder cancer.
Clinical Development History
EO-4426 has been studied in over 400 patients across multiple Phase 1 and Phase 2 clinical trials, both as a single agent and in combination with chemotherapeutics such as 5-FU and cisplatin. It has been evaluated in both intravenous and oral formulations.
- Safety Profile: In four Phase 1 studies, intravenous EO-4426 was well tolerated. The doselimiting toxicity was neutropenia, which was transient and reversible.
- Efficacy Signals: Clinical activity was observed in multiple cancer types, supporting its continued development and potential for broad applicability.
Pre-clinical activity
EO-4426 demonstrated promising activity against several cancers including brain tumors in preclinical models
Preclinical Tumor Models | Outcome |
|---|---|
D45 Brain Tumor | Median Survival:
EO4426: 46.5d
control: 20d |
SK-N-C brain tumor | 90d Survival: EO4426: 90% carmustine: 26% untreated: 23% |
MDA-MB-231 breast cancer | 90-100% cure (CR) |
L1210 leukemia | 80% cure (CR) |
Lewis lung carcinoma | 80% cure (CR) |
Future Clinical Development
EO-4426 is especially well-suited for treating cancers that exhibit CDA overexpression and have recurred following treatment with RNR inhibitors such as gemcitabine or hydroxyurea.
Given its unique mechanism and favorable clinical profile, EO-4426 represents a promising first-inclass oral therapeutic candidate capable of addressing high unmet needs in oncology.
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