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“Big pharma” is forever being lambasted for the seemingly extraordinarily high cost of medications. The casual observer might feel that there is a large discrepancy between the price charged for the drug compared with the cost of its manufacture. However, this calculation ignores the tremendous cost involved in the process by which a new molecule becomes a registered medicine. As mentioned in my last blog, the process starts in the laboratory with promising data leading to testing in human subjects. Only about one compound in 1,000 will actually make it to human testing. The average cost of running a US-based clinical trial per patient is $5,404 for phase I, $6,538 for phase II and $7,635 for phase III. It has been estimated that it may cost as much as $800m to put a new drug on the market. Preceding this long and expensive path of approval by the medicines agencies is the complicated procedure of producing a pharmaceutically acceptable formulation.
The effort that was required to produce a dosage form of paclitaxel (the active ingredient in the anticancer drug taxol) that could be used safely in humans, and the development of its “green” synthesis, is a case in point.
Paclitaxel was first discovered in the bark of the western yew, Taxus brevifolia, a small tree that grows primarily in the old-growth forests of the Pacific North-West of the USA. Its toxic properties have been known for more than 2,000 years. Paclitaxel was isolated as a result of a systematic search for naturally occurring anticancer agents initiated by the US National Cancer Institute.
Collection of bark and material from other parts of this tree was first undertaken in 1962, with the bark in particular showing excellent cytotoxic activity. A large re-collection was then made for fractionation, in 1965.
Isolation of paclitaxel proved to be a challenging task, because it was present only in very small amounts in the bark. It was not until 1969 that adequate amounts could be prepared for structure elucidation. The biological activity of paclitaxel was not particularly impressive in comparison with that of other anticancer agents. Additionally, it was a costly compound to develop as a drug, both because of its lack of aqueous solubility and the difficulty of performing isolation.
Fortunately for cancer patients, the decision was made to continue testing paclitaxel against various tumours during the early 1970s. It showed excellent activity against the B16 melanoma, P1534 leukaemia and the MX-1 mammary xenograft, and based on this encouraging activity the NCI decided in 1977 to proceed with full-scale preclinical development and clinical trials.
In 1979 it was discovered that paclitaxel promoted the assembly of tubulin into stable microtubules, explaining its antimitotic properties. The period 1978-82 saw the completion of preclinical studies. The solubility problem was solved by the development of an emulsion formulation in polyoxyethylated castor oil. Phase I clinical trials were initiated in 1983, accompanied by some severe and even fatal allergic responses. The allergic reactions were minimised by adopting a pre-medication protocol of steroids and antihistamines. Phase II clinical trials began in 1985, with spectacular results.
The continuity of supply was not guaranteed, however, because the yew bark of a single tree contains only about 0.0004% paclitaxel and stripping the bark from the trees kills them. Yews take 200 years to mature and form part of a sensitive ecosystem. The complexity of the paclitaxel molecule made commercial production by chemical synthesis from simple compounds impractical. Synthesis involves about 40 steps, with an overall yield of approximately 2%.
In 1991, a semisynthetic route to paclitaxel synthesis was achieved using the naturally occurring 10-deacetylbaccatin III (10-DAB), present in the leaves and twigs of the European yew. This can be isolated without harm to the trees. The semi-synthetic process is complex, requiring 11 chemical transformations and seven isolations. It presents environmental concerns, requiring 13 solvents along with 13 organic reagents and other materials. The company developed a more sustainable process via plant cell fermentation (PCF) technology, using a feedstock of renewable nutrients: sugars, amino acids, vitamins and trace elements. Paclitaxel is extracted directly from plant cell cultures, and then purified by chromatography and finally isolated by crystallisation. By replacing leaves and twigs with plant cell cultures, BMS improved the sustainability of the paclitaxel supply, allowing year-round harvest, and eliminated solid biomass waste. Compared to the semisynthesis from 10-DAB, the PCF process has no chemical transformations, thereby eliminating six intermediates. During its first five years, the PCF process eliminated an estimated 32 metric tons of hazardous chemicals and other materials, eliminating 10 solvents and six drying steps and saving a considerable amount of energy. With all this it took only 10 years or so before BMS’s patent rights expired, leaving the field open for generic equivalents to flood the market. It hardly seems fair.
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“Tears fill my eyes with pity. Absolutely acknowledging some recent advances in therapy and development costs while using just one of a few examples does not take away my scepticism about pricing of new drugs. Why not spend some blog time on price-setting for Imigran and Zofran? And recently Alimta came to market – a chemically simple molecule, yet sold at an enormous price.” – Rob Moss, hospital pharmacist, Netherlands