RX-3117

RX-3117 – A Novel Next Generation Nucleoside Compound

RX-3117 is a novel, investigational, oral small molecule nucleoside compound being developed for the treatment of pancreatic cancer, bladder cancer, and other malignancies. Once intracellularly activated (phosphorylated) by the enzyme Uridine Cytidine Kinase, or ‘UCK2’, it is incorporated into the DNA and RNA of cells and inhibits both DNA and RNA synthesis, which induces apoptotic cell death of tumor cells. 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.

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.

An initial Phase 1 clinical trial in cancer patients conducted demonstrated the oral bioavailability of RX-3117 which appeared to be safe and well tolerated in all subjects throughout the dose range tested.

Final results from a Phase 1b clinical trial of RX-3117 presented at the American Society of Clinical Oncology Annual Meeting in June 2016 showed evidence of single agent activity. Patients in the study had generally received four or more cancer therapies prior to enrollment. In this study, 12 patients experienced stable disease persisting for up to 276 days and three patients showed evidence of tumor burden reduction. A maximum tolerated dose of 700 mg was identified in the study.  At the doses tested to date, RX-3117 appeared to be safe and well tolerated with a predictable pharmacokinetic profile following oral administration. RX-3117 is currently in development for the treatment of metastatic pancreatic cancer and advanced bladder cancer.

Pancreatic Cancer

Rexahn completed a two-stage Phase 2a clinical trial of RX-3117 in patients with relapsed or refractory pancreatic cancer. Preliminary data were presented at the European Society of Medical Oncology (ESMO) Congress in October 2016 and the final data were presented at the American Society of Clinical Oncology Gastrointestinal Cancers (ASCO GI) 2018 Annual Meeting. The Phase 2a clinical trial was a multicenter, open-label single-agent study of RX-3117 conducted at 8 clinical centers in the United States.  Patients in the trial received a 700 mg daily oral dose of RX-3117, five times weekly for three weeks in a 28-day cycle for up to eight treatment cycles, or until their disease progressed. A total of 46 patients with metastatic pancreatic cancer were enrolled into the study.  Seventy eight percent of the patients had received two or more prior cytotoxic therapies and 93% of the patients had progressed after receiving gemcitabine therapy.

Forty-three patients were included in the final efficacy analysis.  Of these, 31% of patients had an increase in progression free survival for two months or more and five patients, or 12%, had disease stabilization for greater than four months.  One patient who had three prior treatments for metastatic pancreatic cancer (including gemcitabine) had a partial response (≥ 30% reduction in total tumor volume

A Phase 2a clinical proof-of-concept study of RX-3117 in combination with Abraxane (nab-paclitaxel) in first line metastatic pancreatic patients is ongoing. The study is an open-label evaluation of the safety and efficacy of RX-3117 in combination with Abraxane in patients who have had no prior chemotherapies. The study is a two-stage study.  The first stage is designed to determine the optimum dose of RX-3117 and Abraxane to be evaluated in the second stage. Up to 50 patients will be enrolled into the second stage of the study and the primary endpoint is progression free survival.

Advanced Bladder Cancer

In 2016, Rexahn initiated a two-stage Phase 2a clinical trial in advanced and metastatic bladder cancer. The clinical trial is a multicenter, open-label single-agent study of RX-3117 being conducted at 5 clinical centers in the United States. RX-3117 is being administered orally five times weekly on a three weeks on, one week off dosing schedule.  The study is following a two-stage design.  In the initial stage, 10 patients with advanced and metastatic bladder cancer were enrolled.  Since there was an increase in progression free survival of greater than 4 months in 20% of the patients or a reduction in tumor size, an additional cohort of patients were enrolled. At the 2017 European Society for Medical Oncology (ESMO) congress Rexahn presented the initial data from this trial. Four of ten patients treated with RX-3117 exhibited progression free survival of greater than 5 months and one of these patients is continuing in the study with stable disease at 259 days.  Two patients had reductions of 19% and 15% in tumor size. As a result, the study began enrolling an additional 10 patients in this second stage. There were no dose-limiting toxicities identified in the study.  Updated interim data were presented at the American Society of Clinical Oncology Genitourinary Cancers (ASCO GU).

A total of 27 patients with advanced bladder cancer were enrolled into the study. Patients in the study had actively progressing bladder cancer with distant metastases to multiple sites including the liver, lung, lymph nodes and pelvis.  Eighty-seven percent of the patients had received two or more prior therapies including gemcitabine (85% of patients) and immunotherapy (67% of patients). Twenty-one patients were included in the updated efficacy analysis.  Of these, 33% experienced progression free survival for two months or more and four patients, or 19%, had disease stabilization for greater than four months with one of these patients having stable disease for 301 days.  Four patients had a reduction in tumor size ≥ 15%. RX-3117 was safe and well tolerated. Enrollment in this trial is ongoing.

RX-3117 has received Orphan Drug designation for the treatment of pancreatic cancer. RX-3117 has also received a positive opinion from European Medicines Agency for 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

Mi Young Yang et. al. A Novel Cytidine Analog, RX-3117, Shows Potent Efficacy in Xenograft Models, even in Tumors that are Resistant to Gemcitabine. Anticancer Research 34: 6951-6960 (2014)