RX-3117 is a next generation orally bioavailable nucleoside analog that is activated (phosphorylated) by the enzyme Uridine Cytidine Kinase (UCK) and inhibits both DNA and RNA synthesis which induces apoptotic cell death of tumor cells. UCK is overexpressed in multiple human tumors, but has a very limited presence in normal tissues. This unique specificity for cancer cells may lead to an improved efficacy and safety profile in cancer patients. This profile differs from existing nucleoside compounds (such as gemcitabine) which are activated by the enzyme DCK which is highly expressed in both cancer cell and in normal healthy tissue leading to significant toxicities at therapeutic doses. RX-3117 also mediates the downregulation of DNA methyltransferase 1 (DNMT1), which is an enzyme responsible for the methylation of cytosine residues on newly synthesized DNA and is also a key target for anti-cancer therapies. RX-3117 has broad spectrum anti-tumor activity against 80 different human cancer cell lines (including Non-Small Cell Lung Cancer (NSCLC), breast, ovarian, pancreas, colon, renal, brain, bladder, cervical) and efficacy in 12 different mouse xenograft models (including colorectal, non-small cell lung, pancreatic and renal cell carcinoma) superior to that of gemcitabine.

RX-3117 has shown robust and compelling anti-tumor effects across a broad variety of tumor types in animal models (Colon, Non-Small Cell Lung, Small Cell Lung, Pancreatic, Renal, Ovarian and Cervical). In addition RX-3117 has been shown to be fully efficacious in human cancer cells from patients that are resistant to gemcitabine. Gemcitabine resistance, which occurs in approximately 25% of patients receiving gemcitabine, represents a major unmet medical need.

In August 2012, Rexahn reported the completion of an exploratory Phase I clinical trial of RX-3117 in cancer patients conducted in Europe. The trial investigated the oral bioavailability, safety and tolerability of RX-3117 in nine cancer patients with solid tumors. Groups of three patients received single doses of RX-3117 and were assessed for safety, tolerability and plasma exposure. In this study, oral administration of RX-3117 demonstrated an oral bioavailability of up to 56% and a plasma half-life (T1/2) of 14 – 21 hours. In addition, RX-3117 was safe and well tolerated in all subjects throughout the dose range tested with no post-dose adverse events, laboratory abnormalities or ECG changes noted through 7 days post-treatment.

In January, 2014, Rexahn initiated a multi-center dose-escalation Phase Ib trial which will evaluate the safety, tolerability, dose-limiting toxicities and maximal tolerated dose (MTD) of RX-3117 in patients with solid tumors. Secondary endpoints will include characterizing the pharmacokinetic profile of RX-3117 and evaluating the preliminary anti-tumor effects of RX-3117.

The trial is expected to enroll up to 30 patients from multiple sites in the United States. Patients will receive RX-3117 orally 3 times a week for 3 weeks followed by 1 week off, and will have the ability to continue on the drug for up to 8 cycles of treatment. The decision to enroll the next group of patients and escalate the dose will be made after 1 cycle of treatment, based on safety and tolerability. Patients will be assessed for tumor progression by CT or MRI prior to the start of therapy and after every 2 cycles of therapy.

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