Rexahnís RX-5902 shows its mettle
ROCKVILLE, Md.—Rexahn Pharmaceuticals Inc. recently announced that preclinical data for its cancer therapeutic Supinoxin (RX-5902) appeared in the Journal of Cellular Biochemistry. The article, titled “A Novel Anti-Cancer Agent, 1-(3,5- Dimethoxyphenyl)-4-[(6-fluoro-2-methoxyquinoxalin-3-yl)aminocarbonyl] piperazine (RX-5902), Interferes with β-Catenin Function through Y593 phospho-p68 RNA Helicase,” was coauthored by Rexahn scientists and Dr. Zhi-Ren Liu, a professor in the department of biology at Georgia State University.
Supinoxin is an oral, small-molecule inhibitor of Phosphorylated-p68 (P- p68), an RNA helicase. Rexahn notes on its website that “P-p68, which is selectively expressed in cancer cells and is absent in normal tissue, increases the activity of multiple cancer-related genes, including cyclin-D1, c-Jun and c-Myc, and plays a role in tumor progression and metastasis. Overexpression of P-p68 has been observed in solid tumors, such as melanoma, colon, ovarian and lung.”
“We further demonstrated RX-5902 inhibited the β-catenin dependent ATPase activity of p68 RNA helicase in an in-vitro system,” the paper’s abstract states. “Furthermore, we showed that treatment of cancer cells with RX-5902 resulted in the downregulation of the expression of certain genes which are known to be regulated by the β-catenin pathway, such as c-Myc, cyclin-D1 and p-cJun. Therefore, our study indicates that the inhibition of Y593 phospho-p68 helicase- β-catenin interaction by direct binding of RX-5902 to Y593phospho-p68RNA helicase may contribute to the anticancer activity of this compound.”
“The ability of Supinoxin to directly bind to P-p68 and abolish the effects of P-p68 in upregulation of these oncogenes is very exciting,” Liu noted in a press release. “This novel pathway holds great promise for treatment of cancer patients.”
“The specificity of this mechanism of action for cancer cells and the efficacy seen in multiple preclinical models utilizing human cancer cells continues to generate significant interest in Supinoxin. Once the current Phase 1 clinical trial is complete, we will provide an update on the safety, tolerability, dose-limiting toxicities, maximal tolerated dose (MTD), pharmacokinetics and preliminary antitumor effects seen with Supinoxin,” commented Dr. Peter D. Suzdak, CEO of Rexahn.
Rexahn’s Phase 1 trial is a dose-escalation study evaluating Supinoxin’s safety, tolerability, dose-limiting toxicities and MTD in patients with solid cancer tumors who have previously failed treatment with approved therapies. Secondary endpoints for the study include pharmacokinetic analysis and the drug’s preliminary antitumor effects. It is expected that the study will conclude in the first half of this year. In July 2014, the company announced that it had completed enrollment into four dose groups—25, 50, 100 and 150 mg—with no drug-related adverse events reported. Enrollment for the fifth dose group, 225 mg, was ongoing, and the MTD had not yet been achieved.
So far, Supinoxin has proven capable of inhibiting cancer cell proliferation in 18 human cancer cell lines—including breast, ovarian, colon, pancreas and stomach cancers—and has demonstrated potent activity in drug-resistant cancer cells. In xenograft models of melanoma, renal, pancreatic and ovarian cancers, Supinoxin demonstrated “excellent antitumor activity and survival benefits,” Rexahn adds. According to preliminary pharmacokinetic data, Supinoxin has roughly 51 percent oral bioavailability. In preclinical animal models grafted with human cancer cells from melanoma, pancreatic, renal or ovarian tumors, Supinoxin treatment led to a significant reduction in tumor growth.
Rexahn is currently developing two other drug candidates with unique mechanisms of action. Archexin is an antisense drug candidate that targets the cancer cell signaling protein Akt-1, and is the only specific Akt-1 inhibitor in clinical development. Akt-1’s activated form plays a role in cancer cell growth, survival, angiogenesis and drug resistance, and is present or elevated in more than 12 human cancer cell lines. Rexahn has completed a Phase 1 clinical trial of Archexin in patients with solid tumors, and the compound was found to be safe and well tolerated. Rexahn has also conducted a small Phase 2a trial in patients with advanced pancreatic cancer, in which Archexin in combination with gemcitabine was found to be safe and well tolerated.
Rexahn is also advancing RX-3117, a next-generation orally bioavailable nucleoside analog that is activated by the uridine cytidine kinase and inhibits DNA and RNA synthesis, inducing apoptosis in tumors cells. This compound has demonstrated robust antitumor effects in animal models of several tumor types, including colon, non-small cell lung, small cell lung, pancreatic, renal, ovarian and cervical cancers. Additionally, RX-3117 was fully efficacious in human cancer cells taken from patients who are gemcitabine-resistant.