Dr Max Summerhayes (principal oncology pharmacist, Guy's and St Thomas's hospitals NHS trust) reports on a recent visit to the French pharmaceutical company Pierre Fabre, a company best known in Britain for its vinca alkaloid vinorelbine
As Samuel Jackson's character in "Pulp Fiction" observed, the French do things differently. Fortunately for Western civilisation, the differences extend beyond reinventing the "Big Mac" as the "Royale" and I was fascinated, during a recent visit to Pierre Fabre facilities in south-west France, to observe that even the French pharmaceutical industry still retains some uniquely Gallic characteristics.
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Le Carla - Pierre Fabre's private hotel |
In 1965, a cosmetics division was added to the company and, in 1998, the company acquired Dolisos, the second-largest homoeopathic medicine company in France. Thus, at a time when many multinational pharmaceutical companies are divesting themselves of any activities not related to the discovery and marketing of prescription medicines, Pierre Fabre is actively building a broad-based company. It has four divisions devoted to prescription products, preventive health care and OTC medicines, homoeopathy and phytotherapy (trading under the Dolisos name) and dermatological and cosmetic products.
This last group is characterised by the rather up-market, clinical-looking products seen in most French pharmacies, suggesting an influence from Mr Fabre's days behind a shop counter.
The Pierre Fabre group had a combined turnover of 7.3 billion frs in 1999 - up from 4.5 billion frs in 1992 - with just over half accounted for by pharmaceuticals, 36 per cent by cosmetics and 10 per cent by homoeopathy and phytotherapy. Almost half of the company's sales, including about one-third of pharmaceutical sales, are outside France.
Although Pierre Fabre is a substantial company, it is still in the small-medium bracket for a pharmaceutical company with an international presence and has adopted a strategy of combining organic growth (fuelled by an investment in research which exceeds 20 per cent of sales, compared with 10-15 per cent for most research and development-based drug companies) with strategic alliances with other companies. Such arrangements serve to spread the financial risks involved in the clinical development of drugs discovered in Pierre Fabre's own laboratories, as well as enhancing the company's product portfolio by licensing in suitable products from outside.
Several Pierre Fabre staff expounded this strategy during my visit. It is a reiteration of the policy set out by the new company chairman, Jean-Luc Bellingard, during a recent interview published in Scrip1. He said that there were plenty of successful companies wanting to work with Pierre Fabre to help it exploit its rich research and development pipeline and that, as long as this remained the case, the company would continue to stand aside from the current spate of merger and acquisition activity.
This is an option open to Pierre Fabre, which is a private company with the overwhelming proportion of its shares still in the hands of its founder. However, a "public interest foundation" with a minority shareholding in the company was recently established. This manoeuvre was designed, in part, to prevent any future hostile bids for the company.
Like all ethical pharmaceutical companies, Pierre Fabre depends upon the productivity of its researchers and, while in Castres, I visited the company's research centre there, to hear and see more of the way the company organises its research programme. But first, I enjoyed an overnight stay at Le Carla, Pierre Fabre's private hotel on a hillside outside Castres. Le Carla is an institution that, surely, only a French company could have nurtured and another product of the company's property acquisitions over the years. It is housed in the former summer home of a wealthy wool merchant and has an excellent dining room supplied by the company's own vineyard and mineral water spring, the latter also used in the production of its Avene dermatological products.
The company's founder still works each day at an office in the grounds of Le Carla with windows overlooking a beautiful wooded valley.
By contrast, the Pierre Fabre research centre at Peraudel is a pleasant, if unremarkable, building first opened in 1968 and currently housing 220 staff doing chemical and pre-clinical pharmacological research. Jean Luius Vidaluc from the Peraudel Centre told us that their work is focused on finding new drugs for treating cancer and diseases of the central nervous and cardiovascular systems. The research is complemented by activities at the company's two other drug discovery sites: the Pierre Fabre immunology centre, near Geneva, which employs 120 staff primarily interested in oncology and chest medicine, and the Natural Substances Research Centre near Toulouse.
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Miguel Delgado: discussed development of new vinca alkaloid |
Professor Potier's team also discovered docetaxel (Taxotere; Aventis), another important treatment for breast and lung cancer, in which Pierre Fabre also has an interest. The company has recently signed a contract with Aventis to pack the product, for the American market at its FDA-approved finishing plant in Pau in the French Pyrenees. This is currently being expanded to increase its capacity to 7m injectable cytotoxic doses (as well as 50m non-cytotoxic ampoules and injection vials) per year. It already packs 11 injectable products of the company's own manufacture, plus another 18 on behalf of other major manufacturers.
Vinorelbine was first launched commercially in November, 1989, and is now licensed as a treatment for non-small cell lung cancer and/or breast cancer in more than 80 countries. Last year its sales totalled US$170m, representing over 100,000 treated patients.
As Jamal Gasmi (associate medical director, Pierre Fabre Oncology) explained, the vinorelbine story is not yet complete. The alkaloid has useful activity against other tumours too and a clinical trial programme is in place which, it is intended, will result in approval to promote the drug for a variety of other malignancies, including prostate cancer and multiple myeloma. There are also plans to make the product more user-friendly with the launch of an oral formulation sometime during the next 12-18 months.
Neither is vinorelbine the end of Pierre Fabre's interest in vinca alkaloids. Dr F. Miguel Delgado (medical director, Pierre Fabre Oncology) explained that initial attempts to improve on the activity of the natural compounds vincristine and vinblastine had involved chemical modification of the vindoline part of the molecule and had, largely, failed.
Professor Potier's team at the CNRS had concentrated on altering the catharanthine moiety, which is now known to be responsible for the effects of vinca alkaloids on tubulin depolymerisation. Vinorelbine was a product of this approach as is vinflunine, a vinca alkaloid with selective fluorination of one of the carbon atoms - C20 - in the catharanthine nucleus. C20 is known to be important for the cytotoxic action of vinca compounds, but is almost inaccessible to modification by conventional chemical means.
Pierre Fabre has circumvented this problem by the use of superacidic chemistry, which involves reacting vinca alkaloids with a mixture of a Lewis acid and hydrogen fluoride in a Teflon reaction vessel. Remarkably, although the reaction conditions are several orders of magnitude more acidic than sulphuric acid, the vinca skeleton is not denatured, but is selectively fluorinated in the desired position.
In animal studies, vinflunine exhibits a broad spectrum of antitumour activity and little propensity for causing neuropathy - the hallmark toxicity of other vinca compounds. This may be a result of its relatively low affinity for tubulin.
Vinflunine has also shown activity in phase I clinical trials and is about to be tested, in phase II studies, against renal cell carcinoma, melanoma and bladder cancer.
A little further behind vinflunine is another semi-synthetic product of the Pierre Fabre/CNRS collaboration - F12167, an etoposide derivative which inhibits the enzymes topoisomerase I and II. Both are important in facilitating the relaxation of coiled DNA during its replication and both are targets for existing anticancer drugs - the captothecins, which inhibit topoisomerase 1, and the epipodophylotoxins, which inhibit topoisomerase 2. However, no agent in routine use inhibits both topoisomerases and one with this capability is an exciting therapeutic prospect.
Both vinflunine and F12167 are some way behind in their development compared with two other Pierre Fabre oncology products, Cytefuran (an oral formulation of 5-fluorouracil in combination with the degradation inhibitor eniluracil) which is under investigation for breast and colorectal cancer, and Busulfex , an intravenous formulation of busulphan for use in patients receiving high-dose chemotherapy for haematological malignancies.
Both of these products are licensed from other companies - Pierre Fabre acquired the European distribution rights to Cytefuran from Glaxo Wellcome and those for Busulfex from Orphan Medical.
Appropriately, Busulfex will be one of the first formulations to be assessed under the new European orphan drug approval process.
Although my main purpose in visiting Pierre Fabre was to find out more about its oncology division, I also learnt that the company has an extensive portfolio of products under development in its other areas of interest. These include 5HT1 antagonists for migraine, anxiety and depression, a sodium channel blocker for the treatment of angina and F12511, a hypolipidaemic with the potential to become the company's first blockbuster product. Although only just starting clinical trials in hyperlipidaemia and atherosclerosis, F12511 appears to be potent, well tolerated and devoid of the interaction problems associated with the statins.
I was fascinated by my brief visit to Castres and Pau, and find it thought provoking to consider that the whole Pierre Fabre group would probably not exist in its present form if the pharmacist's training and professional experience were not so broad-based, covering both pure and applied sciences ranging from pharmacognosy to clinical pharmacology, underpinned by a strong entrepreneurial awareness that enables innovation to be harnessed in the interests of patients and commerce.
Declaration The author's visit to France was organised and paid for by Pierre Fabre UK. This is the sole extent of the relationship between the author and the company.