RX-3117 – A Novel Next Generation Nucleoside Compound

RX-3117 is an orally bioavailable, small molecule, investigational anti-cancer therapy that targets a unique biological pathway implicated in the development and metastasis of numerous cancers.

A novel, cancer-cell specific nucleoside analogue, RX-3117, is a 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.

An exploratory Phase I clinical trial of RX-3117 showed that oral administration of a 50 mg dose of RX-3117 achieved oral bioavailability of 56% and a plasma half-life (T1/2) of 14 hours. In addition, RX-3117 appeared to be safe and well tolerated in all subjects throughout the dose range tested.

Interim results from a separate Phase Ib clinical trial of RX-3117 in patients with advanced and metastatic solid tumors were presented in September 2015 at the European Cancer Congress. The results showed that, at the dose levels tested to date, RX-3117 appeared to show evidence of tumor reduction (9%), which was observed in one patient, and stable disease, which was observed in five patients persisting from between 112 and 276 days before disease progression occurred. In addition, RX-3117 appeared to be safe and well tolerated with a predictable pharmacokinetic profile. The most frequently reported treatment emergent adverse events in the Phase Ib trial were mild to moderate fatigue, gastrointestinal disturbances, anemia, pyrexia, decreased appetite and dehydration.

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.

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