Canadian firm Bioxel has manufactured the first industrial-scale current good manufacturing practice (cGMP) batch of its key intermediate for docetaxel, the active pharmaceutical ingredient (API) of Sanofi-Aventis's blockbuster chemotherapy drug Taxotere, whose first patents will expire at the end of 2007.
By completing this milestone, Bioxel is on track to supplying drug firms with docetaxel when it comes off patent, making Taxotere, which generated worldwide sales of $2.2bn (€1.7bn) in 2005, vulnerable to generic competition.
Since docetaxel can only be manufactured through a semi-synthetic route, it represents a challenge for generic drugmakers because the route of synthesis and the corresponding intermediates are well protected by the originator.
Therefore, a thorough due diligence on freedom to operate coupled with sustainability of API supply are key criteria for selecting a docetaxel API supply partner.
Docetaxel is a taxane, a class of cyclic diterpenoids produced by the plants of the genus Taxus (yews).
Taxane-based drugs accounted for worldwide sales of approximately $5bn in 2005, driven by a demand for the treatment of cancer and other diseases, including psoriasis, rheumatoid arthritis, Alzheimer's disease and cardiovascular disease.
Historically, semi-synthesis of docetaxel has started with an intermediate taxane, 10-deacytylbaccatin III (10-DAB), isolated from the European yew Taxus baccata, however Bioxel has developed a cyclic side chain addition process using chiral auxiliaries coupled to a unique baccatin, 9-dydro-13-acetylbaccatin III (9-DHB), found in high levels in the Canada yew Taxus canadensis.
"This achievement is significant for Bioxel as it clearly demonstrates our ability to manufacture semi-synthetic taxanes using a high-efficiency patent protected route that will allow us to meet the demands of leading pharmaceutical companies," said Bioxel CEO Pascal Delmas.
"Bioxel will be sampling its clients with docetaxel API during the fourth quarter of 2006 and we plan to complete the validation of our manufacturing process in 2007."
Advantages of Bioxel's synthetic process are that the side chain materials are readily synthesised from low cost ingredients, the side chain addition is high yielding and chiral purity is preserved through the process.
The first part of the synthesis involves transformation of 9-DHB into proprietary intermediates that are protected at the 7, 9 and 13-positions on the baccatin ring.
The next step involves the addition of the side chain corresponding to docetaxel with a unique chiral auxiliary that directs the side chain addition in the proper sterochemical configuration.
After addition, the auxiliary is cleaved, the hydroxyl groups are de-protected and the API is purified.
Because cytotoxicity occurs only in the final steps, high levels of containment are not required until the end of the process where the volumes are relatively low.
Bioxel already manufactures and sells natural cGMP paclitaxel, another taxane, to specialty pharmaceutical companies and generic formulation manufacturers.