Sanofi-aventis affirms its commitment to Access to Medicines in the "Southern countries", with a policy of tiered drug prices geared to populations incomes

Contact : Dr. Robert SEBBAG +33 (0)1 53 77 47 80 +33 (0)6 08 17 21 83 EMBARGO UNTIL APRIL 15, 2005 – 1:00 p.m. (CET) In his address to the closing plenary session of BioVision – the World Life Sciences Forum - Jean-François Dehecq, Chairman and CEO of sanofi-aventis, set out the guiding principles of his Group's strategy in its Policy of Access to Medicines in the "Southern Countries". At a time when 80% of the world's population has little or no access to the most basic medicines, particularly in the Southern countries in which there are no public healthcare systems, the sanofi-aventis Group has pledged concrete action to make access to healthcare a key element of its strategy. In order to meet this major public health challenge, sanofi-aventis is committed to making products available to populations of the Southern countries at tiered prices, geared to the incomes of the populations concerned. "With innovative, profit-generating products and large-scale industrial facilities, the Group can play its part in this public health initiative by providing concrete responses for the Southern countries," stated Jean-François Dehecq. The Group has identified 6 therapeutic areas for which concrete solutions can be envisioned: five curative therapeutic fields – malaria, leishmaniasis, sleeping sickness, tuberculosis and epilepsy – as well as the preventive field of vaccines. In conjunction with UNICEF, GAVI (Global Alliance for Vaccine and Immunization) and the Vaccine Fund, Sanofi Pasteur, the vaccines business of the sanofi-aventis Group, practices a tiered pricing policy on a large number of vaccines: oral polio vaccine, measles, Diphtheria-Tetanus-Polio, antimeningococcal vaccine, Measles-Mumps-Rubella, yellow fever and Diphtheria-Tetanus-Polio - Haemophilus influenzae B. "These initiatives are part of a pro-active strategy rooted in the long heritage that makes up the sanofi-aventis Group today: Sanofi-Synthélabo, Rhône-Poulenc, Roussel, Mérieux, Lepetit, Pasteur, Hoechst…," added Mr. Dehecq. "Most of all, however, this is our duty as the world's third largest pharmaceutical group, founded on strong innovation, determination to maintain competitive industrial facilities and continued support for mature products” he concluded. Malaria A specific program known as Impact Malaria has been rolled out, focusing on four key areas: �� Research & Development of new families of compounds �� Setting up new therapeutic strategies based on existing products �� Making suitable products available at tiered pricing �� Setting up training, education and communication programs about the disease. R&D In the Group's Research division, in partnership with universities and the Inserm units in Lille, Montpellier and Toulouse, three new projects are currently under evaluation. New therapeutic strategies WHO recommends use of an artemisinin derivative in combination with a standard antimalarial drug to treat malaria attacks. The Group chose a co-formulation of artemisinin+amodiaquine known as Arsucam® which is now licensed in over 15 African countries. Although presented in co-blister format, this product meets clinicians' requirements with formats suitable for adults, children and infants. In order to improve use of the treatment and patient compliance, however, the sanofi-aventis Group recently signed an agreement with DNDi (Drugs for Neglected Disease initiative) to codevelop a fixed-dose combination of the two active ingredients in a single tablet, thereby reducing the treatment from eight tablets per day to just three tablets per day for three days. Making suitable products available at tiered prices All these medicines are or will be available at a "no profit no loss" price to the public sector, international organizations fighting malaria, non-governmental and religious organizations. Africa also has a private market operating through retail drugstores which have always stocked both standard-priced products and products at "no profit no loss" prices, as part of the accesscard to antimalarials (CAP) program. By bringing down pharmacists' and wholesalers' margins, the price of antimalarial drugs can be reduced by over 70%. Families with limited resources are issued with cards by pharmacists entitling them to buy these products at the lowest prices. The program is currently in operation in Cameroon, Gabon and Madagascar and is set to be extended to Sub-Saharan Africa. Information, education and communication programs Antimalarial drugs are only a part of the fight against the disease. Education and general information about the disease, how it is transmitted and how to fight the proliferation of vectors also represent the added value that the Group can provide "at the end of the line", to patients. Leishmaniasis This transmissible parasitic disease, carried by a small fly named the phlebotomine sandfly, exists in three forms: cutaneous leishmaniasis, mainly present in the Middle East and Mediterranean basin, mucocutaneous leishmaniasis, present throughout Latin America, and visceral leishmaniasis, or Kala Azar, present in the Indian subcontinent, Brazil, Ethiopia, Eritrea and Sudan. There is no prophylactic treatment available. Sanofi-aventis produces two curative treatments: Pentamidine® (pentamidine mesylate) and Glucantime® (meglumine antimoniate). Sanofi-aventis produces 5 million ampoules of Glucantime® a year. The Group is pursuing a volume-oriented policy and centralizing its production in order to substantially reduce the cost of the drug to certain countries so that a greater number of sufferers can be treated. Sleeping sickness In 2001, the Group signed a five-year $25 million partnership agreement with WHO. There are three planks to the program: �� Supply of drugs: the three active drugs currently available to fight the disease are produced by the Group: - Pentamidine® (pentamidine mesylate) - Arsobal® (melarsoprol) - Eflornithine® (difluoromethylornithine) �� Disease monitoring and control: screening must be systematic and is carried out by mobile teams touring the populations. Over $1.5 million is devoted to this plank of the program every year, with: - An increase in the numbers of mobile teams visiting villages in remote areas where the disease is endemic. - Mapping of the areas with a high concentration of cases and monitoring of the geographical spread of the disease. - Regional and cross-border cooperation between various national programs: 19 countries have already benefited from these actions. �� Research and Development: - there is a clear need for new medicines, and above all for treatments that are more easily administered. These R&D efforts are being carried out in conjunction with the Special Program for Research & Training in Tropical Diseases (TDR) and WHO. Sanofi-aventis is the only industrial partner engaged in the fight against this disease. Tuberculosis Sanofi-aventis is a key supplier of Rifampicin (one of the basic treatments for tuberculosis). The Group is committed to making Rifampicin affordable on retail markets in the Southern countries by restructuring and streamlining its industrial policy. More specifically in South Africa, sanofi-aventis markets a combination of four anti-tuberculosis drugs in a single tablet, Rifafour (rifampicin + isoniazid + ethambutol + pyrimethamine). The combination makes for better patient compliance with treatment. After approval by WHO, this product could be distributed in other countries. As with malaria, education and awareness concerning the disease play a crucial role. In South Africa, sanofi-aventis has joined forces with the Nelson Mandela Foundation and local health authorities in launching a program to train DOTS (Directly Observed Treatment Short-course) supporters – reflecting the fact that one of the keys to successfully fighting this disease is ensuring full compliance with the course of treatment (which lasts six months on average). The partnership initiated in South Africa will enable nine training centers to be built (one per province), of which four are already operational. By completion, the program will have produced 100,000 trained DOTS supporters, enough to monitor 1 million patients. This program, for which the Group provided $15 million in funding, will be completed in 2008 and its ambition is to serve as a model for other countries where the disease is endemic. Epilepsy There is little awareness of this disease in Southern countries, although it poses a major public health problem. In many countries, the physical symptoms associated with the disease mean that the sufferer is seen as bewitched or possessed by spirits, as a result of which they are marginalized or even excluded from their communities. Before epileptics can be treated, health workers have to be made aware of the existence of the disease and how it can be managed. Only then can effective treatment be instituted. Sanofi-aventis has launched a training program in Mali in collaboration with the NGO Santé Sud. Once the training is complete, valproic acid will be made available to health workers at a "no profit no loss" price. This is a pilot program that will subsequently be extended to other Southern countries. Vaccines Sanofi-aventis, through Sanofi Pasteur, is the leading producer of vaccines worldwide. Vaccination made it possible to eradicate smallpox, a scourge that has taken a heavy toll in human life. Poliomyelitis should be the second disease to be eradicated in the near future. Sanofi Pasteur is the leading producer worldwide of oral poliomyelitis vaccine, and is participating in this effort by donating 120 million doses to the eradication program (WHOUnicef-Rotary). A monovalent oral vaccine against type 1 polio - Monovalent Oral Polio Vaccine 1 or mOPV 1 – recently received approval in France. Once the vaccine is licensed by Egypt's National Organization for Drug Control and Research, a mass immunization campaign will be launched in Egypt, where only the type 1 virus remains in circulation. Since poliovirus types 2 and 3 have already been eliminated in Egypt, WHO is hoping to put an end to the transmission of polio by the end of this year. A vaccine for dengue is currently being developed, with the aim of eradicating this disease endemic to Asia, Latin America, the Caribbean and Polynesia. In 2006, an antimeningococcal vaccine active against the W-135 strain (present in sub-Saharan Africa and the Arabian Peninsula) will be made available to the health authorities at a price of less than $1 per shot. About sanofi-aventis Sanofi-aventis is the world’s 3rd largest pharmaceutical company, ranking number 1 in Europe. Backed by a world-class R&D organization, sanofi-aventis is developing leading positions in seven major therapeutic areas: cardiovascular disease, thrombosis, oncology, metabolic diesases, central nervous system, internal medicine, vaccines. Sanofi-aventis is listed in Paris (EURONEXT : SAN) and in New York (NYSE : SNY). Sanofi Pasteur, the vaccines business of the sanofi-aventis Group, sold 950 million doses of vaccine in 2004, making it possible to protect more than 500 million people across the globe, which is about 1.4 million per day. The company offers the broadest range of vaccines, providing protection against 20 bacterial and viral diseases. Forward Looking Statements This press release contains forward-looking statements as defined in the Private Securities Litigation Reform Act of 1995. Forward-looking statements are statements that are not historical facts. These statements include financial projections and estimates and their underlying assumptions, statements regarding plans, objectives and expectations with respect to future operations, products and services, and statements regarding future performance. Forwardlooking statements are generally identified by the words “expect,” “anticipates,” “believes,” “intends,” “estimates,” “plans” and similar expressions. Although sanofi-aventis’ management believes that the expectations reflected in such forward-looking statements are reasonable, investors are cautioned that forward-looking information and statements are subject to various risks and uncertainties, many of which are difficult to predict and generally beyond the control of sanofi-aventis, that could cause actual results and developments to differ materially from those expressed in, or implied or projected by, the forward-looking information and statements. These risks and uncertainties include those discussed or identified in the public filings with the SEC and the AMF made by sanofi-aventis, including those listed under “Risk Factors” and “Cautionary Statement Regarding Forward-Looking Statements” in sanofi-aventis’ annual report on Form 20-F for the year ended December 31, 2004. Other than as required by applicable law, sanofi-aventis does not undertake any obligation to update or revise any forward-looking information or statements. INFORMATION ON DISEASES I. Malaria By far the leading endemic tropical disease and still growing relentlessly, malaria currently affects over 90 countries, mostly in tropical and sub-tropical regions. Malaria is a disease caused by the plasmodium parasite, the most feared form of which is Plasmodium falciparum, responsible for the most severe forms of the disease which may rapidly prove fatal. Epidemiology 40% of the world's population lives in malaria-endemic regions, in the "mosquito belt". Over 2 billion people are thus exposed to the risk on a daily basis. In 2002, over 500 million malaria attacks were caused by the deadly Plasmodium falciparum1, including over 360 million cases in Africa. The direct mortality rate of the disease is less than 1% but this represents an annual toll of 1.5 to 2.7 million deaths, 90% of them concentrated in sub-Saharan Africa.2 Children aged between 6 months and 5 years (too young to have acquired immunity) and pregnant women (whose acquired immunity is weakened during pregnancy) pay the highest price. In France, the Centre National de Référence pour les Maladies d'Importation reports a growing number of cases - over 5,800 – including hundreds involving serious forms of the disease carrying a 10% mortality rate. Infant mortality Malaria-related mortality rates are higher than for mortality arising directly from the severe forms of the disease (the only mortality rate measured by WHO). Malaria-induced anemia and malnutrition, diarrhea and associated respiratory diseases are responsible for double the level of infant mortality attributable solely to the severe form of the disease, accounting for a further 2.5 million deaths. 3 In Africa, almost 80% of children suffering from a severe form of malaria die without ever visiting a healthcare structure, most of them never having received any form of antimalarial treatment. Of those children who are admitted to hospital, 10% to 20% still die and almost half of those deaths occur within 12 hours of admission, suggesting that effective treatment comes too late after the appearance of the first symptoms. Treatments available - To manage simple and/or uncomplicated attacks of malaria: While chloroquine was the ideal treatment for over 50 years, the emergence of chloroquineresistant parasites is now contributing to the explosive spread of malaria. As with other infectious diseases (tuberculosis, for example) or cancers, the use of combinations of drugs with different spectra of action is widely recommended. No sooner were the artemisinin derivatives added to the armamentarium than their potency and lack of side effects made them the product of 1 The Global distribution of clinical episodes of Plasmodium falciparum malaria: R.W. Snow et al: NATURE, Vol 434, 10 March 2005-04-12 2 WHO figures 1997, cited by J-M Saissy in Paludisme grave, 2001, ed. Arnette 3 Malaria and mortality: some epidemiological considerations. Ann Trop Med Parsitol 1997, 91:811-25, cited by J-M Saissy in Paludisme grave, 2001, ed. Arnette choice for combination with a conventional antimalarial drug. One such artemisinin-based combination therapy (ACT) is artesunate+amodiaquine (Arsucam®), currently presented in a coblister, which meets the recommendations made by WHO and malaria specialists around the world. News of the move to create a single-tablet fixed-dose combination, in close collaboration with DNDi, was hailed by the international press last week. - To manage simple malaria attacks and prevent them from developing into cerebral malaria: quinine remains the treatment of choice for severe forms of malaria and/or those requiring injectable treatment not contra-indicated on grounds of age, disease or pregnancy and breastfeeding. To allow treatment to be commenced as swiftly as possible before transfer to an appropriate health center, a new intrarectal form of administration has been developed, using a cannula syringe specifically graduated according to body weight in kilos and age group. II. Leishmaniasis This is another parasitic disease caused by flagellate protozoa of the Leishmania genus, transmitted by the bite of the female phlebotomine sandfly. Little is known of the biology of this insect since the adults are tiny in size and the larvae have so far proved impossible to detect. The phlebotomine sandfly is active at twilight and nocturnally, and its bite is painful. The disease may take three forms: • cutaneous leishmaniasis: mainly present in the Middle East and Mediterranean basin, • mucocutaneous leishmaniasis: present throughout Latin America • visceral leishmaniasis, or Kala Azar: present in the Indian subcontinent, Brazil, Ethiopia, Eritrea and Sudan. This is the most severe form, fatal if left untreated. Epidemiology Worldwide, 350 million people are exposed to the risk of this disease in 88 countries. WHO estimates that there are 1 to 2 million new cases per year and a total of 12 million people suffering from the disease, all forms combined. The infectivity coefficient for leishmaniasis is 8, compared to 100 for malaria. Between 1998 and 2003, the number of cases of leishmaniasis doubled in Brazil and increased five-fold in Kabul in Afghanistan. Treatments available There is no prophylactic treatment available. Sanofi-aventis produces two curative treatments: Pentamidine® (pentamidine mesylate) and Glucantime® (meglumine antimoniate). III. Sleeping sickness or human African trypanosomiasis This parasitic disease is caused by 2 sub-species of the genus Trypanosoma, transmitted by the bite of the bloodfeeding tsetse fly, Glossina. Epidemiology The disease is rife in Africa in endo-epidemic mode in foci that are variously distributed according to the sub-species concerned. An estimated 55 to 60 million individuals are exposed to this endemic disease and some 400,000 cases occur every year, but the exact prevalence of sleeping sickness is unknown due to the major difficulty of gaining access to sufferers, particularly in recent years. It is estimated that only 10% of all sufferers are identified. There is also an animal reservoir, particularly associated with one sub-species, which further complicates attempts at eradication. Brief physiopathology Once inoculated, the trypanosomes multiply in the blood and lymph. The disease evolves in two stages, first developing in the blood and lymph and later, at the advanced or neurological stage, attacking the central nervous system. - Early stage: parasite lysis causes disseminated inflammatory lesions with vascularities and suppression of cellular immunity. - Advanced or neurological stage: the parasite crosses the blood-brain barrier, causing meningitis and auto-immune demyelinating leucoencephalitis that lead to major sensory disorders, mental disorders and the characteristic disturbance of the sleep cycle which gives the disease its name. The sleep disorders gradually worsen until the sufferer sinks into a permanent stupor. The disease advances systematically in a matter of years towards extreme weakness and death, often precipitated by intercurrent infections associated with immunosuppression. The progress of the disease may be even more rapid with certain specific sub-species, often even before onset of the sleepy stage. Treatments available As from 15 July 2001, all patients receive free treatment for a five-year period: all the drugs involved have been made available to WHO. The three active drugs are all produced by the Group: - Pentamidine® (pentamidine mesylate) - Arsobal® (melarsoprol) - Eflornithine® (difluoro methyl ornithine) Results 80% to 90% of patients treated recover. 50% of associated fatalities, however, are drug-related (arsenical encephalopathy). The development of DFMO has brought new hope for sufferers. Sleeping sickness, it is important to remember, had been practically eradicated in Africa in the 1960s. Since then, however, conflicts across the continent and, above all, mass displacements of population have allowed the disease to return in force, aided and abetted by the lack of screening. IV. Tuberculosis4 Tuberculosis is now the leading cause of infectious mortality due to a single bacillus. Epidemiology In the space of 10 years, tuberculosis has caused 30 million deaths. Over the same period, prevalence of the disease has risen by 30% to a current level of around 10 million cases of active tuberculosis annually. A third of the world's population is infected. 98% of those infected live in developing countries. This massive increase is linked to a conjunction of three factors: - the HIV/AIDS epidemic - population growth - emergence of drug-resistant strains. Physiopathology The causes of human tuberculosis are Mycobacterium tuberculosis complex bacteria: Mycobacterium tuberculosis, M. bovis and M. africanum. Human tuberculosis is almost invariably caused by Mycobacterium tuberculosis, also known as Koch's bacillus (KB). Transmission in humans is by means of airborne droplets carrying respiratory secretions. The majority of those infected with primary tuberculosis infection following inhalation of the bacilli will recover spontaneously. However, the infection may lie dormant for years following apparent recovery from the primary infection. Active tuberculosis, generally the pulmonary form, results from a reactivation of the bacilli, which may occur at any moment. Lowered immunity favors reactivation: ageing, stress, malnutrition but most of all immunosuppression (corticoid treatments, chemotherapy and HIV infection). Dissemination via the lymphatic or blood system causes miliary or galloping tuberculosis and extrapulmonary localizations, which occur in 25% of cases overall and in around 70% of cases when HIV infection is also present. If left untreated, pulmonary tuberculosis is fatal in 50% of cases. Half of all untreated survivors (25%) recover spontaneously and the remainder continue to be chronic carriers and help to spread the disease. With appropriate and closely monitored treatment (e.g. DOTS), tuberculosis could be successfully treated in almost all cases. Multidrug-resistant tuberculosis (MDR-TB) causes up to 80% mortality in those who are immunocompromised. Treatment Treatment always consists of a combination of several antituberculosis drugs in order to avoid selection of resistant mutant strains but also to act against extra-cellular and intra-cellular bacilli. The first-line anti-tuberculosis drugs are: - isoniazid (INH) - rifampicin - pyrazinamide - ethambutol 4 Malintrop Afrique. Manuel des maladies infectieuses pour l'Afrique. E. Pichard, 2002, ed. John Libbey Second-line anti-tuberculosis treatments are very expensive and are kept in reserve for use in referral centers in the treatment of resistant forms of tuberculosis. WHO's Stop TB department recommends the DOTS (Directly Observed Treatment Shortcourse) strategy for tuberculosis control. There are several variants of this treatment observation program, but the aim is always the same: to ensure proper patient compliance with treatment and completion of the short course of treatment, and to avoid failure, drop-out and abandonment of treatment in order to prevent the emergence of drug resistance and the spread of drug-resistant bacilli. V. Epilepsy5 Of the 50 million epilepsy sufferers worldwide, 10 million live in Africa: 8 million of them receive inadequate treatment or no treatment at all. Epidemiology Identification of the annual number of new cases per 100,000 population (incidence) of epilepsy varies considerably from one African country to another (from 64 to 156). The incidence is, however, much higher than in the developed countries (40 to 70 per 100,000). The prevalence of the disease also varies widely, with extremes ranging from 2.2/1,000 in South Africa to an average of around 11/1,000 for Africa as a whole. In all the developing countries, most new cases of epilepsy are the outcome of a number of factors. In chronological order, these include for newborns: poor perinatal management, sequelae of perinatal disease, inadequately monitored labor, hypoxemia and hypoglycemia. In children (the population most at risk), the symptoms are febrile convulsions most commonly caused by malaria, respiratory diseases, upper respiratory tract infections and measles. Up to 20% of children who survive cerebral malaria suffer neurological sequelae. The severity of these cases of epilepsy is aggravated by malnutrition, inadequate levels of care, poor economic conditions and most of all by cultural conditions. Many of the clinical manifestations of epilepsy (convulsive movements, loss of consciousness, excessive salivation, etc.) are very often interpreted as signs that the victim is under an enchantment or as the spirits of the elders manifesting their displeasure. This interpretation generally leads to a consultation not with a physician but with a witchdoctor or other traditional healer. In cases of cerebral malaria, such attitudes lead inevitably either to the death of the child or, should the child survive without treatment but suffer sequelae or febrile convulsions, to the child or whole family being marginalized or even excluded from the community. Clinical manifestations in adults produce the same effects. Apart from the neurological manifestations of parasitic diseases (onchocercoses and neurocysticercoses), the most common origins of epilepsy are associated with the effects of viral encephalitis and in particular with HIV/AIDS. 5 Epilepsy in the African Region, WHO 2004 Senior Vice President, Corporate Communications: Nicole Cranois - Vice President, Media Relations: Jean-Marc Podvin Tel.:+33 1.53.77.42.23 - Fax: +33 1.53.77.42.65 - 174, avenue de FRANCE - 75013 Paris - France - www.sanofi-aventis.com