RX-3117

RX-3117 – A Novel Next Generation Nucleoside Compound

RX-3117 is an oral prodrug activated by the enzyme Uridine Cytidine Kinase, or ‘UCK2’, which is only present in cancer cells. Once activated by UCK2, RX-3117 inhibits DNA and RNA synthesis leading to cancer cell death. Because UCK2 is overexpressed in multiple human tumors – but has a very limited presence in normal tissues, RX-3117 offers the potential for a targeted anti-cancer therapy with an improved efficacy and safety profile.

Preclinical studies of RX-3117 in patient-derived, cancer cell xenograft models have demonstrated broad anti-tumor activity and – most importantly, an ability to treat cancer cells that have become resistant to gemcitabine, a widely-used chemotherapy. Unfortunately, resistance to gemcitabine occurs in up to approximately 25% to 40% of cancer patients over time, reducing overall treatment efficacy and further limiting options for patients.

RX-3117 has shown broad spectrum anti-tumor activity against over 100 different human cancer cell lines and efficacy in 17 different mouse xenograft models. In preclinical mouse xenograft studies, RX-3117 demonstrated superior efficacy to gemcitabine. In addition, RX-3117 retained its full anti-tumor activity in human cancer cell lines made resistant to the anti-tumor effects of gemcitabine, supporting a unique, highly-targeted mechanism of action.

RX-3117 is currently being evaluated in a Phase Ib/IIa multi-center, open-label clinical study in patients with relapsed or refractory pancreatic cancer and advanced bladder cancer. The study has a two-stage design. In the initial stage, 10 patients with relapsed or refractory pancreatic cancer and 10 patients with advanced bladder cancer will be enrolled. If responses are observed within the first 10 response-evaluable subjects, 40 additional subjects could be enrolled.

In the Phase Ib/IIa study, RX-3117 is being administered orally five times weekly on a three weeks on, one week off dosing schedule. The primary endpoint of the Phase Ib/IIa trial is an assessment of the progression free survival rate or an objective clinical response rate and reduction in tumor size. Secondary endpoints include time to disease progression, overall response rate and duration of response, as well as pharmacokinetic assessments and safety parameters.

RX-3117 has received Orphan Drug designation for the treatment of pancreatic cancer.

Publications
Zhao LX et. al. Design, synthesis, and anticancer activity of fluorocyclopentenyl-pyrimidines. Nucleic Acid Symposium Series. Oxford University Press; 2005 (49): 107-108.

Jeong LS et. al. Synthesis and antitumor activity of fluorocyclopentenyl-pyrimidines. Nucleosides, Nucleotides, and Nucleic Acids, 2007 (26): 713-716.

Won Jun Choi et. al. Fluorocyclopentenyl-cytosine with Broad Spectrum and Potent Antitumor Activity. Journal of Medicinal Chemistry. 2012 (55): 4521-4525

Peter GJ et. al. Metabolism, mechanism of action and sensitivity profile of fluorocyclopentenylcytosine (RX-3117; TV-1360). Invest New Drugs (2013) 31:1444–1457