Researchers in CSIR Biosciences have successfully developed an economically-competitive route for the preparation of an intermediate in the production of AZT and stavudine. This has the potential to stimulate the local production of active pharmaceutical ingredients (APIs), which is presently not undertaken in South Africa. This would enable especially African governments to supply more people with these life-saving drugs.
Antiretroviral production could become cheaper with new technology developed by Dr Moira Bode and her research team
The project, initiated in October 2004, was established to examine mechanisms of reducing the cost of manufacturing generic antiretrovirals, first through CSIR funding and later in the project, through Lifelab.
The project focused on reducing the cost of preparing nucleoside reverse transcriptase inhibitors (NRTIs) by using a biocatalytic step for preparation of one of the important intermediates in the preparation of drugs such as stavudine and AZT. To date, the approved therapies for HIV/Aids treatment include NRTIs and non-NRTIs, both acting against the viral enzyme reverse transcriptase; protease inhibitors, acting against the viral enzyme protease and entry inhibitors that hinder either entry or fusion of the virus to the mammalian cellular target. The first inhibitor of the viral enzyme integrase was approved by the Food and Drug Administration agency (FDA) in mid-October 2007.
According to the project leader, Dr Moira Bode, technology has been developed for the production of 5-methyluridine and thymidine. "5-Methyluridine itself can be an intermediate in the production of stavudine, but thymidine, which we prepare from 5-methyluridine, is the most valuable intermediate in the production of antiretrovirals such as stavudine and AZT. Some work was also done on producing AZT and stavudine but the final process package developed for Arvir was for a process to provide thymidine via 5-methyluridine," says Bode.
"In South Africa, with the number of people requiring ARV drugs estimated at approaching 1 million (where the CD4 count of the individual is less than 200), the local manufacturing of these drugs is an imperative."
The work conducted at CSIR Biosciences included total development of the biocatalysis reaction to produce 5-methyluridine as well as the chemistry to convert 5-methyluridine to thymidine. This involved, among other things, initial screening work to identify useful enzymes, the fermentations to produce enzymes and the process development for scale-up of the biocatalytic reaction, as well as the chemistry. The entire process was scaled at the CSIR to produce thymidine at kilogram scale.
Along the way the team experienced challenges in achieving optimal yields. "Initially, low yields were obtained in the biocatalysis reaction for enzyme production, as well as in the chemistry. Much development work was undertaken to turn this into a viable process. The belief the team members had in the process and its potential was largely responsible for their determination to make it work. Hard work allowed this to happen in the end," says Bode.
According to Dr David Walwyn, CEO of Arvir, the technology is owned by Arvir Technologies (Pty) Ltd, which is exploring various options for its commercialisation including the granting of licences to existing ARV API producers and the establishment of a new ARV API facility in South Africa. The latter will make AZT and other ARV products. "Due to the high risk nature of such a facility, negotiations are presently underway with government on how to support Arvir's projects and specifically how to ensure that the South African ARV treatment programme has access to a well-secured supply of high quality ARVs," says Walwyn.
A Patent Cooperation Treaty application will be filed. "Publications on certain aspects of the work will be possible. Two researchers are using this work to write up PhD theses," says Bode.
Enquiries: CSIR Communication