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spastic paraparesis through chronic cyanide poisoning, in times of drought or social upheaval, caused by improper processing of cassava. However, the crop is rarely used in the developed world, and thus has been something of an orphan crop in terms of genetic research. This situation could soon change as a result of the discovery made by Hughes and her colleagues. Colleagues in Spain, led by Marta Izquierdo at the University of Madrid (Madrid, Spain), thought that by transposing the genes for linamarase into a disarmed retrovirus (Moloney murine monkey leukaemia virus pBabepuro) they would have a vector that could be used to target cancer cells with a deadly payload. If the cancer cells were pretreated with linamarin, using a syringe needle, then the virus unleashed to infect them would produce enough linamarase to trigger cyanogenesis, resulitng in lethal amounts of hydrogen cyanide being released within the target cells.

Hughes is currently collaborating with her Spanish colleagues in the transfer of the cassava gene, cloned in Newcastle, to be used to modify the retrovirus. The Madrid team has now tested the potentially cyanogenic virus on a rat intracerebral glioblastoma tumour model, and after only one week of treatment with the constant local release of small amounts of cyanide through linamarin breakdown they found that they could eradicate the tumours. Approximately three weeks after the start of the treatment, magnetic resonance imaging revealed a total absence of tumoural mass and, in its place, a residual hypointense (dark) patch on the image at the site of injection. The team believes that this is fibrous scar tissue or the remains of haematoma. In addition to the direct effect within targeted cells, the team noted that the treatment was made more effective by what they describe as the bystander effect. The release of cyanide in one cell also tends to kill neighbouring cells.

The researchers point out that the mode of action is rather different from the more common killing of nearby unmodified cells through connection expression and cell communication through gap junctions. Instead, the freely diffusing cyanide ion and hydrogen cyanide gas can readily pass between cells. Brain tumour treatment The team is now looking at how the process might work in human brain tumour tissue samples, such as glioblastoma, glioma and neuroblastoma, and are hoping to improve the efficacy of the treatment by genetically modifying the cassava gene. My next step will be to modify the genetic material with a view to making the treatment more effective when applied to mammalian cells. I believe it will be possible to obtain higher yields of active linamarase, for example, explains Hughes, by site-directed mutagenesis to change to the pH optimum, for example.

The futures bright; but for whom?

Debbie Tranter, Pharmaceutical Science & Technology Today, tel: 44 1223 315961, fax: 44 1223 464430, e-mail: pstt@current-trends.com

The early years of the 21st century may well see US-based pharmaceutical and biotech companies grazing on very green pastures indeed. This is the prediction heralded in a recent report by Jonathon de Pass at Evaluate Plc (London, UK), a corporate research company covering the biopharmaceutical industry. The recently published report, The Worlds 50 Best Selling Drugs A Review 19882002, is based on analysts consensus sales forecasts and offers some intriguing facts and figures, blasts from the past and future forecasts that combine to provide captivating and thought-provoking information. Future forecasts Money-spinning drugs The report predicts that by 2002, the lions share of the worlds 25 most commercially successful

drugs will be marketed by US companies, almost forcing their once dominant European adversaries completely out of the picture. During the last decade, US companies have considerably strengthened their grip on the 50 top-selling drugs; their share has increased from just 19 drugs in 1988 to a staggering 32 in 1998. In addition, they now market 80% of the worlds top 10 best selling drugs. European firms however, are seemingly floundering, and, according to the consensus analysts, it is anticipated that they will market only three out of the worlds top 25 drugs by 2002. At present, it seems that the US is winning the battle of the marketing strategies by identifying the drugs that have a powerful appeal to informed US consumers. Those drugs that deal with disorders that are largely age-related, such

as arthritis, high cholesterol levels and impotence, have found a niche with the potential for immense revenue levels. Such timing is unfortunate for the Europeans as the industry is now embracing novel technologies that are furnishing a plethora of quality research leads. US firms have the industrys most lucrative products and will therefore be able to outstrip their European peers in terms of research expenditure. UK-based companies, such as Glaxo Wellcome and SmithKline Beecham, are losing their previously major share of the worlds best selling drugs, and this is mainly down to US patent expiration and depleting stocks of blockbuster drugs. In an attempt to weather the storm, secure larger pools of funds for product development and reclaim some territory lost to the US, further

1461-5347/99/$ see front matter 1999 Elsevier Science. All rights reserved. PII: S1461-5347(99)00183-2

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mergers of European-based firms may well take place. However, this will not necessarily facilitate the selection of the best selling development candidates of the future. In addition, it is expected that such mergers will have little effect on the rankings of the top selling products. Merged companies may soar up industry league tables as a result of their enormity, but they are not seen to have any greater share of the most commercially successful drugs. Discovery and development of lifestyle drugs The drive by pharmaceutical companies to discover and develop lifestyle drugs will continue into the foreseeable future. These drugs, used for treating non-acute conditions of early ageing, are expected to become the mainstay of the most commercially successful product list. For example, the anti-impotence drug, Viagra, with sales approaching US$4 billion per annum, is expected to be the worlds 6th best selling drug, and cholesterol-reducing drugs are seen to assume the highest positions. By 2002, it is anticipated that five of the top 10 best selling drugs will be used to treat such disorders that were seldom given any consideration two decades ago. In 1988, only two lifestyle drugs were marketed, whereas this figure had risen to 10 in 1998 and it seems that this trend is set to continue. Anticipated aspects of the 50 most successful selling drugs in 2002 Revenues and patent expirations It is anticipated that the development of blockbuster drugs will continue to generate significant levels of revenue; it is forecasted that cumulative sales of blockbuster drugs will increase by 10% per annum, whereas the two most commercially successful drugs in 2002 are ex-

pected to furnish a joint revenue in excess of $10 billion. It appears that the well-established business model of the long-lived drug that produces large amounts of revenue will remain applicable. Patent expirations may provide worrying prospects that can be applied to both US and European-based companies; the total sales value of the top 50 products facing patent expirations over the next three years is approximately US$9 billion. UK companies have been severely affected by such expirations, their share of the top 50 having fallen from 14 in 1993 to just seven in 1998. Current status It is has been reported that almost 50% of the best selling drugs are for the treatment of agerelated conditions such as cardiovascular disorders, malignancies, ulcers and arthritis; this figure has remained consistent over the last decade. Best selling drugs are most likely to be used for the treatment of cardiovascular disease, followed by infectious disease and CNS disorders such as schizophrenia and depression. However, drugs used for treating CNS disorders are now being used more often than anti-infectives, for which utilization levels are in decline. Japanese companies are proving to be competitive in certain niche areas and have originated several of the top 50 drugs on the market; such drugs are, however, marketed through US or European companies. In addition, and in contrast to their previous research activities, Japanese firms are now exploring several therapeutic areas as well as the anti-infective field. Finally, it is interesting to note that biotechnology companies have now provided five of the worlds 50 top branded products, having provided none in 1988.

2002 and beyond Several factors mean that analysts are struggling to predict the future shape of their industries and winning-oriented tactics beyond 2002. The inevitable upsurge in patent expirations will significantly alter the status of the best selling drugs and, as such, will act as a catalyst for further company mergers. It is possible that a plethora of novel drugs will result from the revolutionary technological advances that are currently sweeping through the pharmaceutical industry; this will expedite the pace of medical advances and will lead to more intense competition and a curbing of product lifecycles. Another factor to consider is the knowledge and expectations of patients. The consumer is now better-educated on health issues and is demanding branded products. Indeed, it is expected that the growth in the market for lifestyle drugs will be more rapid than in those drugs developed for the treatment of serious illnesses. A result of these significant shifts is that R&D costs will rocket in order to provide support for the abundance of newly generated leads. It is anticipated that blockbuster drugs will be superseded as the pace of R&D and medical progress accelerates, and that genomics will permit the targeting of drugs to specific groups of patients and will contract the market for each drug. It is thought that much of these changes will probably come to pass. However, the practicalities of such issues may fail to provide a clear road for these to take place. For example, an abundance of developmental drugs could pose problems with regard to patient recruitment for clinical trials, and the R&D bottlenecks may simply shift to a different stage in the development process.

Contributions to Pharmaceutical Science & Technology Today We welcome suggestions for short reports, opinion articles and full reviews for publication in Pharmaceutical Science & Technology Today. Potential authors should contact the Editorial Office in the first instance with a brief outline of the scope of the proposed contribution. Article proposals should be directed to: The Editor, Pharmaceutical Science & Technology Today, Elsevier Trends Division, 68 Hills Road, Cambridge, UK CB2 1LA (tel: 44 1223 315961, fax: 44 1223 464430, e-mail: pstt@elsevier.co.uk).

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