Trabectedin

Trabectedin (also known as ecteinascidin 743 or ET-743, trade name Yondelis) is an antitumor chemotherapy drug sold by Pharma Mar S.A. and Johnson and Johnson under the brand name Yondelis. It is approved for use in Europe, Russia, and South Korea for the treatment of advanced soft-tissue sarcoma. It is also undergoing clinical trials for the treatment of breast, prostate, and paediatric sarcomas. The European Commission and the U.S. Food and Drug Administration (FDA) have granted orphan drug status to trabectedin for soft-tissue sarcomas and ovarian cancer. Trabectedin (also known as ecteinascidin 743 or ET-743, trade name Yondelis) is an antitumor chemotherapy drug sold by Pharma Mar S.A. and Johnson and Johnson under the brand name Yondelis. It is approved for use in Europe, Russia, and South Korea for the treatment of advanced soft-tissue sarcoma. It is also undergoing clinical trials for the treatment of breast, prostate, and paediatric sarcomas. The European Commission and the U.S. Food and Drug Administration (FDA) have granted orphan drug status to trabectedin for soft-tissue sarcomas and ovarian cancer. During the 1950s and 1960s, the National Cancer Institute carried out a wide-ranging program of screening plant and marine organism material. As part of that program, extract from the sea squirt Ecteinascidia turbinata was found to have anticancer activity in 1969.Separation and characterization of the active molecules had to wait many years for the development of sufficiently sensitive techniques, and the structure of one of them, Ecteinascidin 743, was determined by KL Rinehart at the University of Illinois in 1984. Rinehart had collected his sea squirts by scuba diving in the reefs of the West Indies. Recently, the biosynthetic pathway responsible for producing the drug has been determined to come from Candidatus Endoecteinascidia frumentensis, a microbial symbiont of the tunicate.The Spanish company PharmaMar licensed the compound from the University of Illinois before 1994 and attempted to farm the sea squirt with limited success. Yields from the sea squirt are extremely low - 1 tonne of animals is needed to isolate 1 gram of trabectedin - and about 5 grams were believed to be needed for a clinical trial so Rinehart asked the Harvard chemist E. J. Corey to search for a synthetic method of preparation. His group developed such a method and published it in 1996. This was later followed by a simpler and more tractable method which was patented by Harvard and subsequently licensed to PharmaMar. The current supply is based on a semisynthetic process developed by PharmaMar starting from safracin B, an antibiotic obtained by fermentation of the bacterium Pseudomonas fluorescens. PharmaMar have entered into an agreement with Johnson & Johnson to market the compound outside Europe. Trabectedin was first trialed in humans in 1996. In 2007, the EMEA gave authorization for the marketing of trabectedin, under the trade name Yondelis, for the treatment of patients with advanced soft-tissue sarcoma, after failure of anthracyclines and ifosfamide, or who are unsuited to receive these agents. The agency's evaluating committee, the CHMP, observed that trabectedin had not been evaluated in an adequately designed and analyzed randomized trial against current best care, and that the clinical efficacy data were mainly based on patients with liposarcoma and leiomyosarcoma. However, the pivotal study did show a significant difference between two different trabectedin treatment regimens, and due to the rarity of the disease, the CHMP considered that marketing authorization could be granted under exceptional circumstances. As part of the approval PharmaMar agreed to conduct a further trial to identify whether any specific chromosomal translocations could be used to predict responsiveness to trabectedin. Trabectedin is also approved in South Korea and Russia. In 2015 (after phase III study comparing with dacarbazine,) the US FDA approved trabectedin (Yondelis) for the treatment of liposarcoma and leiomyosarcoma that is either unresectable or has metastasized. Patients must have received prior chemotherapy with an anthracycline. In 2008, the submission was announced of a registration dossier to the European Medicines Agency and the FDA for Yondelis when administered in combination with pegylated liposomal doxorubicin (Doxil, Caelyx) for the treatment of women with relapsed ovarian cancer. In 2011, Johnson & Johnson voluntarily withdrew the submission in the United States following a request by the FDA for an additional phase III study to be done in support of the submission. Trabectedin is also in phase II trials for prostate, breast, and paediatric cancers. Trabectedin is composed of three tetrahydroisoquinoline moieties, eight rings including one 10-membered heterocyclic ring containing a cysteine residue, and seven chiral centers.