Rubitecan: 9-NC, 9-Nitro-20(S)-camptothecin, 9-nitro-camptothecin, 9-nitrocamptothecin, RFS 2000, RFS2000

Rubitecan [Orathecin, 9-nitrocamptothecin, 9NC, RFS 2000] is a topoisomerase I inhibitor extracted from the bark and leaves of the Camptotheca acuminata tree, which is native to China. Rubitecan is an oral compound being developed for the treatment of pancreatic cancer and other solid tumours by SuperGen. One of the major benefits of rubitecan is that it can be administered in an outpatient setting, so patients can be treated in their homes. Rubitecan was isolated by the Stehlin Foundation in the US. SuperGen is currently awaiting regulatory approval in the US and the EU for rubitecan in the treatment of pancreatic cancer. At the BIO-2004 conference, SuperGen announced it is seeking a partner for rubitecan for territories outside the US. SuperGen acquired exclusive worldwide rights to rubitecan from the Stehlin Foundation in 1997 except in Mexico, Canada, Spain, Japan, the UK, France, Italy and Germany. SuperGen has also received approval from the US FDA to use its own manufactured rubitecan in clinical trials. SuperGen and the Stehlin Foundation have an 8-year research agreement that secures global rights to other camptothecins and additional anticancer compounds for the former. In December 1999, SuperGen and Abbott signed a worldwide sales and marketing agreement for rubitecan. Under the terms of the agreement, Abbott had exclusive distribution and promotion rights for rubitecan outside the US, and co-promotion rights with SuperGen within the US. In return, Abbott made an initial equity investment in SuperGen. SuperGen and Abbott Laboratories ended their collaboration agreement in February 2002 by mutual consent with SuperGen stating that the dissolution of the agreement was based on commercial motivation rather than anything to do with rubitecan's safety or efficacy. Abbott no longer has rights or obligations to purchase shares of SuperGen stock or an option to purchase up to 49% of the company. For its part, SuperGen will no longer receive milestone payments worth up to $US57 million. SuperGen has formed a clinical and business alliance with US Oncology (created by the merger between American Oncology Resources and Physician Reliance Network in the US), and will collaborate on clinical trials of rubitecan. SuperGen believes that this relationship will increase the patient population available for trials and enable it to market the drug directly to Oncologists. SuperGen and Capital Research and Management Company have completed a $US16.6 million private placement transaction that will enable future funding for the rubitecan programme as well as other oncology programmes. In July 2004, SuperGen's European subsidiary, EuroGen Pharmaceuticals, submitted a Marketing Authorisation Application for rubitecan in the treatment of pancreatic cancer. The application will be reviewed under the EMEA Centralised Procedure. In June 2003, the EMEA granted SuperGen orphan drug status for rubitecan for the treatment of pancreatic cancer. The US FDA has also granted orphan drug status for rubitecan in the treatment of pancreatic cancer and fast-track status for rubitecan for the treatment of locally advanced or metastatic pancreatic cancer that is resistant or refractory to chemotherapy. SuperGen has conducted three phase III pivotal trials in patients with pancreatic cancer. A phase III randomised trial in chemotherapy-naive patients was conducted at 132 centres throughout the US. The trial enrolled approximately 994 patients who were randomised to receive rubitecan or gemcitabine. Enrollment was completed in October 2001. Another phase III trial has compared rubitecan with the most appropriate chemotherapy in chemotherapy-resistant patients. Enrollment of over 400 patients at 200 medical centres across the US was completed in June 2001. Results from the trial were presented at the 39th Annual Meeting of the American Society of Clinical Oncology (ASCO-2003) [Chicago, US; 31 May - 3 June 2003], after they had been compiled, analysed and submitted to the FDA. The results of the study showed that rubitecan could not help all chemotherapy-resistant patients, but could increase survival in those that do respond. The other phase III pivotal trial was conducted in patients with pancreatic cancer who had failed treatment with gemcitabine. This trial completed enrollment in October 2001, and had enrolled approximately 448 patients. SuperGen is conducting phase II trials of rubitecan in patients with solid tumours in the UK, Italy, France, Germany, the Netherlands and Denmark. Each trial will enroll 100-150 patients with various tumour types, including colorectal, lung, breast, gastric, prostate, cervical and head and neck cancers. Phase I/II trials are underway to investigate rubitecan as a radiosensitiser in patients with lung cancer, and phase II trials in patients with breast cancer are also being conducted. A phase II study in ovarian cancer patients is also being conducted. Results from an ongoing phase II study in cancer patients have shown that rubitecan was effective against chordomas, a rare type of bone cancer. Phase II studies are also underway in haematological malignancies including myelodysplastic syndrome (preleukaemia) and chronic myelomonocytic leukaemia. In February 2000, SuperGen announced that its IND submission for rubitecan had been approved by the Therapeutics Products Programme of Canada. The company stated that it intended to begin clinical trials in Canada in the near future. In February 2004, SuperGen announced an offering of shares of its common stock to finance the commercialisation of rubitecan capsules. In July 2003, SuperGen was granted a US patent covering combination therapies with chemotherapeutic anthracycline agents and structural modifications that may one day lead to next-generation rubitecan compounds. In December 2002, SuperGen was granted US patent No. 6,482,830, covering its polymorphic formulations of rubitecan. The patent also covers a class of polymorphs that are similar to the one at the centre of rubitecan. In addition, SuperGen was also issued US patent No. 6,485,514 in December 2002, covering the local delivery of rubitecan via stents and/or catheters to sites of proliferating cells. Stent- or catheter-delivered rubitecan may be beneficial in certain types of cardiac procedures, such as ablation or angioplasty, as well as for direct injection into a certain number of solid tumours. SuperGen is also developing an inhaled, liposomal formulation of rubitecan. It acquired the worldwide rights to this formulation from the Clayton Foundation in December 1999. Inhaled rubitecan is in clinical trials in the US for the treatment of lung cancer and pulmonary metastatic cancer.