Thymitaq (Zarix).

Abstract

Zarix is developing Thymitaq (nolatrexed dihydrochloride) for the potential treatment of cancer. It is conducting a phase III trial in the US, Canada, South Africa and certain European countries [382746], [397955], [4061471, after review and comment by the FDA. One clinical trial may be sufficient for registration [405928]. In April 2000, Thymitaq was designated a Fast Track product for the treatment of unresectable hepatocellular carcinouna (HCC) by the FDA [364887], based on the survival analysis (intent-to-treat) of the Agouron phase II data and medical necessity [405928]. The company was expected to file an NDA in 2002 [367559]. However, as of April 2001, the company was expecting to file an NDA in the third quarter of 2003 [405928]. In January 1999, Zarix licensed worldwide rights to Thymitaq from Agouron [311213]. Agouron discontinued development of Thymitaq, based on an interim analysis of phase II/III trials which showed that although the compound was effective as a single agent in head and neck and liver tumors, it was not sufficiently better than existing therapeutics to justify further development [211844], [270994]. However, in its efforts to complete the monitoring of these studies, Zarix discovered that a great majority of patients obtained stabilization of disease with Thymitaq treatment [405928]. Zarix will focus development efforts on the treatment of HCC. Zarix is developing Thymitaq in an iv formulation for the treatment of HCC and, in May 2000, planned to initiate phase III trials in the fourth quarter of 2000 [364887]. Patient enrollment in a pivotal, phase III trial in patients with unresectable HCC comparing Thymitaq to doxorubicin was initiated in September 2000. Unresectable HCC is the first indication being pursued for FDA approval and the trial design was deemed acceptable in August 2000. The study is a multicenter, multinational trial that will utilize approximately 50 sites. It is anticipated that patient accrual will be completed within 24 months [378514], 1382746], [384018]. The company plans to file for regulatory approval of the product in North America, Europe and Japan, and will pursue development of the drug in a variety of oncology indications [311213]. The multicenter study is to be conducted as a global program with sites in the US, Canada, Europe and South Africa. In January 2001, the Canadian Therapeutic Products Directorate indicated that the design of the phase IX trial was acceptable. Zarix expected patient enrollment in Canadian clinical sites to begin in Spring 2001 [397955], [405928]. By April 2001, patient enrollment was underway in the US, Italy, Canada, Romania, South Africa and the UK. At this time, Zarix also expected to initiate trials in the Czech Republic and Germany in the near future and Poland in the summer of 2001 [406147]. By May 1997, three clinical trials had been conducted in a total of 149 patients with HCC [405928]. In two US phase II trials, patients with unresectable HCC treated with Thymitaq had a median survival (intent-to-treat) of over 23 weeks with published survivals (intent-to-treat) of less than 15 weeks. Thymitaq has no end-organ toxicity. Side effects are typical of other antimetabolites but are of shorter duration [364887], [405928].