Endostatin (EntreMed).
EntreMed has licensed the worldwide rights to the angiogenesis inhibitor Endostatin, a 20 kDa C-terminal fragment of collagen XVIII, from the Children's Hospital of Boston, a teaching affiliate of Harvard Medical School. It is being developed as a potential cancer treatment and may also be useful in certain types of blindness and arthritis [227427]. EntreMed filed an IND for Endostatin in June 1999 [334125] and as of September 1999, phase I trials were underway [341462]. As of April 2000, the company had initiated plans for testing low doses of Endostatin in cancer patients using continuous infusion and sc administration in a further phase I study to be conducted in Europe [361594]. A phase I trial of Endostatin which will evaluate the safety and efficacy of Endostatin at a range of doses in no more than 100 cancer patients has been initiated. The trial will take place at the University of Texas MD Anderson Medical Center and the University of Wisconsin Cancer Center in Madison. The National Cancer Center will be sponsoring the trial, which is expected to be completed in late 2000. As of March 2000, there had been no serious adverse events attributable to Endostatin administration. The first report from this trial is expected in autumn 2000 [341462], [366312]. The mechanism of action for Endostatin remains unclear, although reports from the 91st AACR Meeting in April 2000 showed that recombinant human endostatin bound to a number of tropomyosin cDNAs in a library screen [362039]. In preclinical studies, repeated administration of Endostatin consistently shrank primary tumors and did not produce any drug resistance. In mice, a variety of tumors which had progressed to 1 to 2% of total body weight, regressed to microscopic, dormant lesions following Endostatin treatment [231418], [231470], [270673]. Types of cancers which respond to Endostatin include lung, skin, vascular and fibrosarcomas. Toxicology studies in cynomolgus monkeys showed that bolus injections of human endostatin at doses up to 300 mg/kg produced no toxic effects [317916]. Research presented at the 91st Annual Meeting of the AACR (San Francisco, April 2000), demonstrated that peritumoral administration of Endostatin, at concentrations 2000-fold less than that required to inhibit tumor progression in previously published reports using systemic dosing, significantly deters the development of a variety of tumors in mice [361584]. Other research presented at the meeting demonstrated a role for tropomysin as a molecular target for Endostatin [361680]. In August 1997, EntreMed and the NCI signed letters of intent to commence research collaborations for developing anti-angiogenic therapies, including Endostatin, in preclinical and clinical studies [258354], while in August 1998, EntreMed entered into an agreement with Covance Biotechnology Services for the production of Endostatin [304919]. In August 1999, Entremed and Cell Genesys entered a collaboration to combine Entremed's Endostatin genes with Cell Genesys's gene delivery system as a possible treatment for cancer [336909]. In December 1999, EntreMed signed an agreement with Chiron for the production of bulk Endostatin for phase II clinical trials [350397]. In April 1999, analysts at First Security Van Kasper predicted a US launch for Endostatin in 2004, with first-year revenues of US 320 million dollars, including 70 million dollars in royalties to EntreMed. European launch was predicted for 2005, with total revenues from Europe and the US for that year of US 760 milion dollars (160 million dollars royalties to EntreMed), rising to 1600 million dollars (335 million dollars royalties to EntreMed) in 2007 [370813].
Grosios
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University of Leeds, Molecular Medicine Unit, Clinical Sciences Building, Level 6, St James's University Hospital, Leeds, LS9 7TF, UK. medkg@stjames.leeds.ac.uk