The Italian Pharmaceutical Industry

Via Placido Riccardi 19 20132 Milano Italy Tel. ++39-02-45409122 / 27203492 Fax ++39-02-27203492 barbanti@pharmaebiotech.
com
The Italian Pharmaceutical Industry Table of Contents

1. OVERVIEW
1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 1.9 Bulk Drugs and Pharmaceuticals Products Production Italian Imports Italian Exports Types of Packages Prevailing in Italy Pharmaceuticals in Liquid Form Pharmaceuticals in Solid Form Various Pharmaceutical Products Trends and Demographics
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3 3 3 5 5 6 6 7 7 1
Paolo Barbanti The Italian pharmaceutical industry: trends and business opportunities
1.10 Medicines in demand 1.11 Dealing with Demographics 1.12 Implications for Research 1.13 Distribution 1.14 Market Structure 1.15 New price-setting Models 1.16 Changes in Distribution Margins 1.17 The Introduction of Generics 1.18 Attempts to influence General Practitioner Prescribing
8 9 9 11 11 13 14 14 15
2. A SELECTED TARGET OF ITALIAN COMPANIES

2.1 Alfa Wassermann 2.2 Bouty 2.3 Chiesi Farmaceitci 2.4 Domp 2.5 Menarini 2.6 Recordati 2.7 Sigma Tau
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17 25 36 41 53 58 68
Overview
Bulk Drugs and Pharmaceutical Products Production
Italian pharmaceutical sector produces pharmaceutical products and medicine worth 17.6 billion Euros, and is an important segment in the Italian economy. In recent years, Italian pharmaceuticals industry has shown a positive trend in development. The average annual growth has been around 56%. Consumption: Italian consumption of pharmaceutical products is estimated to be about 6.5 billion Euros (2003). Most major international pharmaceutical companies have a hold in Italy. These include Roche, GSK, Pfizer, Novartis, Bayer, Sanofi-Aventis, Lilly etc. They also dominate the Italian pharmaceutical industry and control about 60 to 65% of the total pharmaceutical trade. While there are a large number of Italian companies in the pharmaceutical sector, they are relatively small compared to these multinationals. Italy does not have any homebred large multinational pharmaceutical company, which could be matched up to the multinationals of USA, Germany, Switzerland or UK.
Italian Imports
Italian imports include products such as: Acyclic alcohols, Cyclic alcohols, Ethers-peroxide, Ketone, Quinine, Carboxylic acids, Amino-alcohols, Carboxyamide, Nitrile, Heterocyclic compounds, Pro-vitamin, Vegetable alkaloids, Antibiotics, Glands, Antis era, Vaccines, Medicaments, Penicillin and Streptomycin etc. Details regarding the figures of the Italian import of the last three years are given below: YEAR 2002 2003 2004 Value in Euro (million) 10279.6 10768.8 11349.0 3
Analyzing the aforementioned figures, it is noticeable, that there has been an increasing trend in Italian import concerning the said period of time. While in the year of 2002, the Italian import was worth 10,279.6 million Euros, it increased to 1,349.0 million Euros in 2004. Italian import in 2003 exceeded the import of 2002 by 4.76%, and the import of 2004 exceeded that of 2003 by 5.39%. About 62% of the total products are imported into Italy are from Switzerland, Germany, U.K, France and Belgium Details regarding the import of pharmaceutical products coming from key countries are given below: Key Countries Exporting to Italy (2004) Country 2003 Value in Euro (million) 10768.8 1727 1278 1515 1220 1098 821 1036 690 247 188 116 134 38 135 16 18 2004 Value in Euro (million) 11349.0 2079 1383 1110 1302 1180 875 988 884 256 265 114 145 39 206 13 14
Total Imports Switzerland Germany United Kingdom France U.S.A. Belgium Ireland Netherlands Sweden Spain China Denmark Austria Israel Australia India
Market Share in Italian Imports: (Year 2004) Country Switzerland Germany United Kingdom France U.S.A. Belgium Ireland Market share in Italian Imports 18.3 12.9 9.7 11.4 10.4 7.7 8.7 4
Netherlands Sweden Spain China Denmark Austria Israel Australia India
7.7 2.2 2.3 1.0 1.2 0.3 1.8 0.1 0.1
Italian Export
Details of Italian Export of Drugs and Pharmaceuticals are given below: YEAR 2002 2003 2004 Value in Euro (million) 10139.6 9740.9 9525.3
During 2003, Italian export decreased by 3.9% comparing to that of 2002. In the year 2004, it was registered that a decrease of 2.2% in Italian export comparing to that of 2003, took place. Italian pharmaceutical products are mainly exported to Belgium, Germany, U.K. Switzerland and USA. They constitute about 60% of the total Italian export of these products.
Types of packages prevailing in Italy
For the pharmaceutical industry, the primary function of packaging remains mainly that of protecting the product and making it easy and functional to use. To give a clearer picture of the trends regarding the various types of packaging, some forms are provided below to give the general idea.
Pharmaceuticals in liquid form

The area of medicines in liquid form includes those taken orally, by injection, as well as ophthalmic and otological products. The packaging used, therefore, comprises vials and bottles of various sizes. Of oral liquid products, 30.7% are packed in small or large plastic bottles; 27.4% are packed in glass objects either glassware containers or glass tubes, and 41.9% are in glass bottles. Current trends are towards a growth in the use of plastics bottles for syrups, whereas when small glass bottles are concerned, more container glass is being used, to the detriment of glass tubes. Where injectable medicines are concerned, the packaging still consists of vials in glass tubes or small bottles in glass tubes or glass containers. There is a trend in the market towards the use of freeze-dried products with a consequent increase in the number of small bottles, which obviously creates a need for vials for sterile water. About 47% of the market is made up of packaging using vials only, while, approximately 53% of the packaging consists of both vials and small bottles. The vials are made of glass tube, while the small bottles are both packed in glass containers and glass tubes. Regarding liquid pharmaceuticals not taken orally (ophthalmic and ontological products, etc.) there is a marked trend towards using plastic bottles which account for 94.4% of the entire market, and small glass bottles account for 5.6% only.
Pharmaceuticals in Solid Form

Approximately 93% of the packaging for solid medicines to be taken orally (tablets, capsules and soluble powder) is in the form of blister packs. Other important types of packaging are: small bottles, plastic tubes and bags in bonded materials (paper-aluminum-PE), which have a 4% share of the entire market. The remaining 3% is made up of rigid aluminium tubes, small glass bottles and strips of bonded material (card-aluminium-PE). With regard to powder products for external use, 56.2% of the packaging used is rigid aluminium tubes, and the remaining 43.8% packages are available in rigid plastic tubes (this field is currently on the increase). Products for rectal or vaginal use, depending on their pharmaceutical specialty, are usually in cellpacks or push-through packs. Plastic materials and thin aluminium foil are also found in this type of packaging. Paolo Barbanti The Italian pharmaceutical industry: trends and business opportunities 6
Various Pharmaceutical Products

As for creams, gels, etc., about 92.5% of the products are packed in flexible tubes (specifically, 68.5% in aluminium and 24% in bonded material, namely, plastic-aluminium. There seems to be a slight trend towards the plastic-aluminium option. The remaining 7.5% of this type of pharmaceutical product is packed in sachets of bonded material (card-aluminium-PE). The packaging used for spray products is plastic bottles fitted with mechanical dispensers (21.7%) or the classic metal aerosol (78.3%). The trend towards aerosols, in aluminium or tinned strip, is on the increase.
Comments and Market Situation:
Italian pharmaceutical sector manufactures products that worth 17.6 billion Euros and the average annual growth rate is around 5-6%. Most major international pharmaceutical companies like Roche, GSK, Pfizer, Novartis, Bayer, Sanofi-Aventis, Lilly etc. have a hold in Italy and they control about 65% of the total pharmaceutical trade in Italy. Italy imports bulk drugs and pharmaceutical products that worth 10.2 billion Euros. Around 62% of the total import which enters Italy comes from Germany, Switzerland, France, U.K. and Belgium (2003). Italy exports bulk drugs and Pharmaceutical products the worth of which is 10.1 billion Euros. About 60% of the total Italian export is mainly sent to Belgium, Germany, U.K. Switzerland and USA (2003). The Italian market of pharmaceuticals is determined by products supplied by large Italian and foreign multinationals. The foreign multinationals have their own distribution networks with specialised sale outlets for marketing products at the level of pharmacies, hospitals, health insurance companies etc. The Italian pharmaceutical industries have similar distribution networks for the purpose of expanding their sales.
Trends and demographics

In terms of value, Italys pharmaceutical market is the fourth largest in Europe and represents around 13% of the regional total. The continuing demand for pharmaceuticals has put pressure on the governments overall funding of healthcare, which stands at around 9% of Gross Domestic Product (GDP). As has been observed in many other countries, the growth in pharmaceutical spending has begun to outstrip the growth in total healthcare spending.
Medicines in demand
As a percentage of the total healthcare spending, the current expenditure on pharmaceuticals in Italy stands at around 22%, which is higher than that of France and Germany and even the USA. However, such figures must be examined carefully because although new medicines contribute to healthcare spending increases in the short term, they can result in net healthcare savings on the long run because of reduced hospitalization rates, as well as reduced mortality and morbidity. Globally speaking, Italy is ranked sixth with respect to annual pharmaceutical spending per person in terms of purchasing power parity (PPP). Given below are the top six rankings: Country Pharma-products spending/Person (EURO per annum) 1302 568 456 409 365 304
1. USA 2. JAPAN 3. FRANCE 4. GERMANY 5. UK 6. ITALY Pharma-products spending / Person
Products that are in the cardiovascular, alimentary/metabolism, central nervous system, respiratory and anti-infective therapeutic classes, represent the majority of sales in the Italian pharmaceutical Paolo Barbanti The Italian pharmaceutical industry: trends and business opportunities 8
market. During 2005, these categories represented around 70% of the total pharmaceutical sales in Italy, which was interestingly paralleled to the distribution pattern in the USA, the leading global market. There is also a recent rise in sales of dermatology, analgesic, ophthalmology, as well as cough and anti-influenza products.
Dealing with Demographics
Demographic factors will have a major impact on the make-up of the Italian pharmaceutical market in the future. Although ageing of the population is affecting healthcare policy in most countries, it is particularly relevant to Italy since the country may have one of the oldest populations in the world by 2050. This is a result of the fact that the country might have the highest percentage in the world of population aged 65 and over (18.1%), and the lowest percentage of population aged 15 and below (14.1%).
This scenario presents the pharmaceutical industry with both opportunities and challenges. On one hand there will be increased demand for medicines aimed to tackle conditions that predominantly affect the elderly and this will benefit companies carrying out R&D in these fields. However, in view of several economic studies that have analyzed the effect of population ageing on healthcare spending, the government is likely to expand its cost containment approach to healthcare. It is the changing nature of the demand for healthcare that has prompted the Italian authorities to develop a more proactive approach to its policies. The recent Italian Sanitary Program (Piano Sanitario Nazionale) has placed a greater emphasis on preventative measures in healthcare. This involves preparing a plan for educating people in order to make them understand that changes in their lifestyle may help them avoid serious medical conditions in the future. However, the success of such initiatives depends on the governments ability to have a good communication with the public together with involving those who provide their healthcare.
Implications for Research
The leading pharmaceutical markets are also major fields for R&D, and Italy is no exception in this matter. The country is ranked fourth in the world in terms of life sciences R&D spending, and has a well-organized network of academic and private institutions which are engaged in research projects. As a result of Italys National Health Plan, which focuses on certain priority disease fields, over 250 research projects have been approved so far and these are valued at over 60 million Euros.
Selected Priority Research Areas
Cardiovascular diseases Oncology Infectious diseases Neurodegenerative conditions Immune system disorders Molecular medicine and genetic diseases
Italys emphasis on an industrial application of this medical research provides an incentive for the involvement of a large range of pharmaceutical and biotech companies. Italy is already an important location for clinical trials, with about 600 studies being carried out each year in a variety of therapeutic areas, and its popularity is likely to increase. In particular, as the target population for new medicines in future therapeutic areas will often be the elderly, clinical trials will need to reflect this important part of the population. At present, there are a number of reports that highlight how the elderly remain under-represented in clinical trials. Thus, the profile of Italys population makes the country an ideal location for clinical trials as for improving this situation. However, much will depend on the industrys abilities to communicate with the local medical community and patients to encourage their involvement in these types of clinical trials. Italy represents an attractive market for Paolo Barbanti The Italian pharmaceutical industry: trends and business opportunities 10
the pharmaceutical industry, because despite the governments efforts to slow healthcare spending by targeting pharmaceuticals, there will inevitably be an increase in the demand for new medicines. The pharmaceutical industrys challenge is how best to show that use of their products will help Italy meet its healthcare targets in the long term. The country also represents a vibrant environment for industry research but this will require companies to demonstrate to the medical community and patients that their projects have relevance to the healthcare needs of the population.
Distribution
Market Structure
Italys NHS allows both private and public pharmacies to coexist. Private pharmacies are owned by pharmacists who function as independent contractors under the NHS. Public ones, mainly municipal, are managed by pharmacists employed by the municipality in which the pharmacy is located. Despite this administrative division, both types of pharmacies are licensed to sell commercial products and, on behalf of the local health unit, pharmaceuticals. Commercial goods mainly include bandages, contraceptives, items for personal hygiene, baby products (such as diapers and infant formula) and cosmetics (some pharmacies also sell homeopathic products). Pharmaceuticals include drugs and dietary goods and can only be sold if a consumer has a prescription from a general practitioner. All the revenue goes directly to the owner of the pharmacy: to the pharmacist if the pharmacy is private, and to the municipality if the pharmacy is municipal, which then pays a salary to the pharmacist running the pharmacy. Pharmacies revenue is a percentage, set by law (usually the Finance Act) of the overall price before VAT: the most recent rate, set in 1996, is 26.7%. This rate does not take into account special
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discounts that pharmacies might be able to negotiate with manufacturers. Conversely, local health units are responsible for reimbursement.
Pharmacies cater to 86.4% of the total Italian demand; there are 16,642 pharmacies in Italy and 252 wholesalers. Hospitals cater to the balance 13.6 % of the total Italian demand.
The turning-point for Italys pharmaceutical sector was 1, January 1994, when Law 537/1993 came into force. The pressure to contain expenditure and an impressive series of scandals favoured the most radical change ever in Italys pharmaceutical policy. Since 1994, regulatory policies have:

redefined the positive list; implemented a nationwide drug expenditure budget; created new price-setting models; changed distribution margins; introduced generics; and attempted to influence the prescribing of general practitioners.
In 1994, the National Committee for Pharmaceuticals was established. The 1978 positive list was abolished, and drugs were reclassified into four groups:

group A: drugs for severe and chronic illness group B: drugs of therapeutic importance not included in group A group C: drugs not included in groups A and B group H: drugs provided only by hospitals.
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Cost-sharing rules were also modified in 1994: for pharmaceuticals in group A, patients pay 1.55 Euro if the prescription includes only one item or 3.10 Euros for more than one item; and for pharmaceuticals in group B, patients pay only 50% of the price. Consumers pay the whole cost for pharmaceuticals in group C, which are not covered by the NHS. The new list was established according to four criteria: 1) clinical efficacy, documented by evidence-based criteria; 2) risk-benefit balance of the therapy; 3) acceptability of the therapy to patients; and 4) cost of the therapy. The National Committee for Pharmaceuticals also introduced caveats for some drugs; these can be considered guidelines for the use of pharmaceuticals.
New price-setting Models
Pharmacists freely determine the prices of commercial goods; prices for each pharmaceutical product are fixed centrally through a negotiation process involving the National Committee for Pharmaceuticals and the representatives of the major pharmaceutical companies. In 1994, the pricesetting system for drugs was modified. The Committee on Pharmaceuticals (CIP Farmaci), the body charged with regulating drug prices, was abolished, and a year later the Interdepartmental Committee on Economic Planning (CIPE) announced a new method for determining drug prices based on cost estimates derived mainly from information from private companies that effectively replaced the previous one. According to the new system, prices can be freely set without exceeding the average European price. The average European price was based on the five most sold drugs, including generics. Only France, Germany, Spain and the United Kingdom were taken into consideration in deriving the average European price. Foreign prices were converted into Italian currency based on purchasing power parity (PPP), a price index used for international comparative studies. The principle of similarity was adopted to identify the European equivalents of Italian products: the same active ingredient, the same route of administration, the same or therapeutically comparable pharmaceutical form and a similar dosage.
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The pharmaceutical industry criticized the new model: in particular, restricting the comparison to only four countries, including generics in calculating the average European price and using PPP. As a result of the industrys dissatisfaction, the Interdepartmental Committee on Economic Planning (CIPE) introduced a sort of reference price in 1996, based on the principle of the same prices for the same drugs. The basic idea is that products in group A and group B that use the same active ingredient, have the same method of administration and have the same or a comparable pharmaceutical form should have the same prices per unit of compound. This pricing mechanism exists only for products in groups A and B, since the prices for group C pharmaceuticals are freely established by the private sector. Further, in 1997, the Interdepartmental Committee on Economic Planning defined a new price system for innovative drugs authorized by the European Agency for the Evaluation of Medicinal Products. Prices are set by negotiation between the National Committee for Pharmaceuticals and private companies, using the following criteria: a) costeffectiveness; b) foreign prices; c) internal market forecasts; and d) investment made by the company related to the introduction of a new drug. Since July 1998, the average European price method (used for non-innovative drugs) has been modified to include all European countries and current exchange rates.
Changes in Distribution Margins
Controlling public pharmaceutical expenditure also required focusing on pharmacies. Wholesale and pharmacy margins were traditionally set as a fixed markup on ex-factory prices and have not varied much during the last 15 years. From 1981 to 1997 the wholesale margin has changed from 8.0% to 6.65% and the pharmacy margin of drug prices excluding VAT from 25.0% to 26.7% In 1992, a fixed compulsory rebate on pharmacy margins was introduced for products covered by the NHS. The rebate was initially set as a fixed proportion of the price (2.5% of the price excluding VAT, and 3% since 1995). From 1997, pharmacists were forced to apply a discount to products covered by the NHS. Different discount rates apply to different price ranges to make the pharmacys margin regressive (decreasing with the price). The discount was 3.75% for prices less than 25.8 Euros; 6% for those between 25.8 Paolo Barbanti The Italian pharmaceutical industry: trends and business opportunities 14
Euro and 51.6 Euros; 9% for those between 51.6 Euros and 103.3 Euros; and 12.5% for prices equal to 103.3 Euros or bigger than that.
The Introduction of Generics
Despite all the interest in cost containment, Italys authorities have not given generic drugs much attention. As a consequence, their use is very limited. The 1995 Finance Act introduced the term generic into legislation. The law provides pricing incentives to promote generics, stating that, if the product is marketed at a price at least 20% lower than the equivalent speciality, it is automatically listed in the same co-payment group. Other incentives come from the financial accountability of regions over health care and the consequent process of management improvement and cost containment in the local health authorities of the NHS. Because wholesale and pharmacy margins were traditionally set as fixed mark-ups, this has made the distribution of expensive drugs more profitable. Since 1997, the pharmacy margin on NHScovered products, became inversely related to the products price. However, the regressive effect is still very slight and does not favour the use of generics. As a matter of fact, the generics market in Italy is still negligible. The latest data show that generics account for only 3% of all prescribed medicine units which are sold. However, recently as regional acts passed (Tuscany being one of the most active regions), the aim is now to promote the prescription of generics by distributing lists of generics among general practitioners and to encourage them to prescribe generics. These reforms are nevertheless still in their early stages, and nationwide implementation is far from being accomplished.
Attempts to influence General Practitioner Prescribing
The prescriptions of general practitioners have never been strictly controlled. Only after the series of scandals affecting the whole pharmaceutical system, the 1992 reform of the NHS created greater incentives and opportunities for making general practitioners accountable for their prescribing activities, such as an expenditure budget for each general practitioner and incentives for general practitioners to achieve this target. The specific impact of each new regulatory measure is difficult to assess, even though the reclassification of drugs by the National Committee for Pharmaceuticals substantially affected NHS drug expenditure. In particular, since 1993, the measures described Paolo Barbanti The Italian pharmaceutical industry: trends and business opportunities 15
above have had two main effects. Firstly, they dramatically reduced NHS pharmaceutical expenditure from 1993 to 1995. The introduction of guidelines from the National Committee for Pharmaceuticals and the introduction of a nationwide drug expenditure budget largely achieved this aim. Secondly, much of the reduction in NHS pharmaceutical expenditure resulted by shifting costs from the public sector to the patients. The demand for drugs is steep: despite an increase in the prices of drugs in group C, consumption has increased. Nevertheless, these cost-containment strategies were not long-run manoeuvres but just emergency measures to stop the never-ending increase of drug expenditure. This could explain why expenditure increased again rapidly from 1996 to 1999.
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A selected target of Italian Companies
ALFA WASSERMANN
A concrete and successful strategy based on commitment to research and development, production using the modern technologies and an industrial mentality oriented towards internationalization - all this has enabled Alfa Wassermann to occupy an important place in the international pharmaceutical business. This is the strategy at the heart of the company's continued development and the success of its products in various areas. In the prescription pharmaceuticals, Normix is without doubt the product which has given the greatest satisfaction. This antibiotic, indicated for the treatment of a wide range of gastroenteric disorders, is not just a market leader in Italy, but has also been recognised by the FDA and approved for sale in the USA under the brand name Xifaxan . For the non prescription specialities, Alfa Wassermann can boast Neoborocillina , a historic brand known to all Italian families. Alfa Wassermann, Inc. is the worldwide leader in the technology of ultra centrifugation. Its equipment is used by all the major vaccine manufacturers. Research has become a keystone in Alfa Wassermann's corporate strategy, responding to the constant demand for innovation. The result has been pharmaceutical products of great importance for the growth of the group. Particularly significant is the success of Sulodexide (Vessel), a heparinoid with an anti-thrombotic and profibrinolytic action, and Parnaparin (Fluxum), a low molecular weight heparin for prophylaxis and treatment of venous thromboembolism But the most prestigious result of Alfa Wassermann's research is Rifaximin (Normix), a topical intestinal antibiotic. Leader on the Italian market and registered in a number of countries throughout the world,
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Rifaximin has also been launched on the USA market after having obtained FDA approval, the maximum recognition for a drug developed through Italian research. Salix Pharmaceuticals Inc., the US company responsible for selling Rifaximin under the name Xifaxan, is quoted on the American Nasdaq. The Manufacturing Division of Alfa Wassermann is based in Alanno (Pescara). The modern production and packing plant is equipped with the most avant-garde technology to guarantee production processes at the highest possible levels covering the needs of the company and its licensees, the Alanno plant also has a long tradition of contract manufacturing for third parties. The Alanno factory is authorised for production by the Italian Ministry of Health and monitored by regular inspections certifying total compliance with cGMP standards. In the spirit of and in compliance with this certification, the Quality Control laboratories carry out regular validation of all the analytical methods used to analyse primary materials and intermediate and finished products. The Alfa Wassermann production unit at Alanno covers a surface area of 100,000 m with a covered area of 17,000 m divided into 11 departments in seven blocks of buildings. It produces 30 million items per year for Alfa Wassermann and other Italian and international pharmaceutical companies. Alfa Wassermann S.p.A. was founded in 1948 and is a consolidated presence on the Italian pharmaceuticals market, researching, producing and selling both prescription and self-medication specialities. The headquarters and research laboratories are located at the original premises in Bologna, while there is a modern production unit at Alanno (Pescara). The International and Diagnostic Divisions are based in Milan. Alfa Wassermann SpA promotes its products by means of a network of representatives who visit general practitioners, specialists and pharmacists as well as public and private laboratories. With a workforce of over 650 people, the company also acts as a holding company for the group. One of the strong points of Alfa Wassermann SpA is that more than 60% of turnover is generated by its own products, developed by in-house research. These include market leaders such as Normix, an innovative antibiotic with a topical intestinal activity, discovered and patented by Alfa Wassermann. Other important specialities are Alfaferone (Alfa natural interferon) and Fluxum Paolo Barbanti The Italian pharmaceutical industry: trends and business opportunities 18
(Parnaparin - patented low molecular weight heparin). Alfa Wassermann has also a Division marketing and selling non prescription specialities with an extensive network of direct promoters to pharmacies. The Division owns a wide range of products acknowledged as efficacious and is a market leader in the oral disinfectant segment with the widely known and appreciated Neoborocillina. Alfa Wassermann is also present in the human in vitro diagnostic sector. The Diagnostics Division sells a wide range of systems and reagents and also distributes the products of leading Japanese and American manufacturers in Italy. In 1989, Alfa Wassermann set its own International Division with two main aims - to increase exports of its speciality drugs by exploring new territories and to promote the international development of its original products with a network of strategic alliances. Today Alfa Wassermann operates with a portfolio of 11 products in more than 60 countries throughout the world and an efficient network of distributors, efficiently backed by an in-house organisation able to provide all the assistance required. Normix (Rifaximin) is one of the main products abroad and has significant growth prospects. The product internationalization plan is starting to give results. At present, Rifaximin is registered in 12 countries and in October 2004 the product, under the name Spiraxin, was introduced into the market in Spain by Bama-Geve S.L. and another Alfa Wassermann licensee company. But the most important goal was, without doubt, the launch of the drug on the USA market under the name Xifaxan. The results obtained by the International Division include the setting up of Euro Alliance, a cooperation agreement with other European pharmaceutical companies for research and development of new drugs. For more than thirty years, Alfa Wassermann, Inc. instruments and products have been used in analysis laboratories all over the world for a wide range of diagnostic applications. These instruments are designed and produced with the aid of the most advanced technology, guaranteeing the accuracy of the laboratories' analyses. Currently Alfa Wassermann, Inc. supplies hospital and private analysis laboratories and veterinary clinics with a line of clinical chemical analysers (ACE Alera) offering a high degree of automation and reliability. Paolo Barbanti The Italian pharmaceutical industry: trends and business opportunities 19
Alfa Wassermann, Inc. is also leader in separation technology with a line of ultra-centrifuge equipment used by leading producers of influenza vaccine throughout the world and in other industrial and research applications. On the basis of its know-how in ultra-centrifuge technology, Alfa Wassermann, Inc. is designing an innovative instrument which will enable research laboratories to take great strides forward in the study of proteins and their interaction at a cellular level. The production facility is located at West Caldwell (New Jersey-USA) and international sales are coordinated by the associate company Alfa Wassermann B.V. based in the Netherlands, with a vast network of distributors. The globalization of the markets is also affecting strongly the pharmaceutical business. Since the beginning of the new millennium, Alfa Wassermann reacted to this trend by supplementing its traditional export activities with a drive to establish its own organization in a number of markets. This goal has been pursued by the acquisition of local companies or by setting up new subsidiaries. The new subsidiaries include Alfa Wassermann Polska sp.z o.o., Alfa Wassermann Tunisie s.a.r.l and Alfa Wassermann (Beijing)Market Research & Management Company Ltd. These are not, of course, random decisions, but selecting countries whose markets have interesting growth opportunities. Acquisitions include the Spanish company Bama-Geve S.L. and the Portuguese BioSade- Produtos Farmacuticos, Lda., both operating on the Iberian peninsula. BioSade is a relatively young company standing out for its rapid growth, while Bama-Geve is a company with a long tradition on the Spanish market. Founded in 1909, it has specialized in three areas, dermatology, cardiology and the hospitals market, with established products such as the historic Linitul (medicated gauze) and the more recent Mepentol, an innovative product for the prevention and treatment of bed sores. Bama-Geve also sells Alfa Wassermann products such as Tonocaltin, indicated for the treatment of osteoporosis and the well-known Rifaximin, which is also becoming established on the Spanish market under the name Spiraxin.
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At the beginning of 2004, Alfa Wasserman acquired a 35% stake in this company. Farmigea, founded in 1946, is a pharmaceutical company based in Pisa and specialized in Ophthalmology and Gynecology. The company manages and oversees all the various steps involved in the manufacture of its products: from research to production, from providing scientific information to physicians to marketing and distribution. The manufacturing process now is carried out in a new and state-of-theart plant. Farmigea and Alfa Wassermann made the same choice to put Research & Development at the top of their business strategies and therefore innovative products are being developed continuously.
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Offices and Plants Alfa Wassermann S.p.A. - Bologna The "historic" headquarters of Alfa Wassermann are situated in Bologna. Where the Head Offices, the Research Laboratories and two Divisions: - the Pharma Division - the OTC Division are located too.
Alfa Wassermann S.p.A. Milano Two Divisions: - the International Division - the Diagnostics Division.
Alfa Wassermann S.p.A. - Alanno The Alanno plant, recently expanded and renovated according to the latest standards, has a constructed area of over 16,000 sqm divided into 11 sections distributed over 7 blocks. The warehouse can store up to 3,000 pallets and is equipped with an air-conditioning system capable of ensuring an even temperature.
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BOUTY
Bouty has a strong hold in the Self Care (OTC) with different product dosage forms such as sedatives, eye drops, analgesics and others; Wound Care - a complete range which differs from the competitors for the presence of the most innovative haemostatic range on the market; Oral Care denture cleaners and adhesives and range of mouthwashes and toothpastes; Home Diagnostics early pregnancy and ovulation tests, and Cosmeceutical products classified as cosmetic and at the same time considered to have important attention to the curative functions. Bouty as a reliable distributor, can provide manufacturers without an adequate Italian sales network, or one of sufficient size, complete Italian market coverage. Bouty boasts of having a professional, effective sales force in the pharmacy and mass market channels that can function as the manufacturer's sales and marketing organization.
Products
ALLERGAN dermatological cream ASATEX HAIR CARE -anti-hair loss treatment ASPARTINA table sweetener BABY ZANZARA - biological anti mosquitos products CALMINE analgesic CEROXMED - medication and bandage range
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CERULISINA - otological solution CERULISINA FAST- otological spray CONFIDELLE PROGRESS pregnancy and ovulation test DAIGO- mineral supplement DAIGO ENERGY - energy bar DAIGO MAG- magnesium supplement DAIGO PROTEIN - proteic bar DAIGO SPORT - energetic supplement with mineral and antioxidant vitamins C and E DEOPED foot care products GRAN VISTA reading glasses NEO-EMOCICATROL oinment NOCTIS - supplement OCTILIA eyewash
ODONTOVAX dental prevention and treatment ORASIV denture care products Paolo Barbanti The Italian pharmaceutical industry: trends and business opportunities 26
PEARL DROPS Whitening toothpastes PEARL DROPS SMOKERS - 3 in 1 mouthwash PERILLACTIVE - cream dry and atopic skin PROPOCAINA - propocitral products RELAXAR oinment SINEGAS a natural remedy for intestinal gas VAXITIOL 2 biological lactobacillus supplement VAXITIOL COMB - probiotic + prebiotic supplement
VERELAIT - laxative
Mass Market CARE FOR YOU - daily hygiene products for all the family
CEROX EMOSTATICO - medication and bandage range
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CEROX ATHLETIC - products for prevention and treatment of home and sports small accidents CEROX AROMATHERAPIA - essential oils plasters CEROX BALSAMICO - essential oils plaster CEROX PROTECTION- essential oil patch FIRST RESPONSE - pregnancy and ovulation test MUDD clay cleansing masks PEARL DROPS Whitening toothpastes PEARL DROPS OZONE - self cleaning toothbrushes
RIGIDENT - complete range for denture THERMAE - thermal products range
Drug Delivery of Advanced Technologies The Drug Delivery System division, through the adoption of modern technologies, develops and produces different kinds of products: Trandsermal patches: Transdermal patch technology us away a way in which drugs are released constantly. Transdermal patches help reducing collateral effects and increase patients tolerability of drugs. The active principle is absorbed gradually, as it acts locally (in the case of topical patches) or enters body circulation directly (in the case of Transdermal patches with systemic action). Paolo Barbanti The Italian pharmaceutical industry: trends and business opportunities 28
Transdermal Drug Delivery System technology has a wide range of applications: it can be used, for example, to produce drugs for the treatment of cardio-circulatory diseases, anti-inflammatory, anti rheumatic, substitutive hormonal therapy and as pain therapy. Essential oils Patches: the technology adopted for essential oils patches allows patients to inhale decongestants or natural fragrances without using ointments or sprays. The active principle evaporates gradually and is inhaled easily by the application of the patch on clothes at the chest level. It doesnt stain, doesnt dirty and has a day-long action. Oral fast delivery: this kind of technology enables to produce highly bioavailability microfilms, and allows to immediate release a definite quantity of active principle orally. Oral fast delivery has a wide range of applications among drugs and medical devices.
Diagnostics Since 1975, Bouty has developed and manufactured diagnostic products for home and professional use. Currently, the company is the major player in the domestic diagnostics market for autoimmuno disease test reagents. In addition, Bouty is considered to be among the leading companies in the following IVD market sectors: ToRCH (Toxoplasma, Rubella, Cytomegalovirus, Herpes panel) Syphilis and other STD Rheumatology Endocrinology Bone metabolism markers Pancreatic hormones For some time now, Bouty has pioneered new diagnostic technologies. An example of which was the Bouty 1994 acquisition of Technogenetics, that brought know-how suitable for: development and production of special monoclonal antibodies implementation of DNA recombinant techniques molecular investigations.
29
The scientific challenges of the forthcoming era see the company involved in the development of new products, PCR is based, in the following areas: Virology Genetics Oncovirology Immunology
The
listed
products
are
the
state
of
the
art
ones
in
the
infectious
disease
testing,
30
31
32
33
34
ALFA WASSERMANN
35
CHIESI FARMACEUTICI
The company, founded in Parma in 1935, is today a dynamic reality in the pharmaceutical market with global operations consisting of: 21 direct affiliates 3 manufacturing sites 3 research centres. The Chiesi Group use over 2,700 employees, of whom 300 are involved in research and development activities. Chiesi Group has marketing and sales organisations in the majority of European countries: Italy, France, Spain, UK, Germany, Greece, Austria, Poland, Hungary, Czech Republic, Slovenia, Slovakia, Romania, Bulgaria and Russia. Italy is the largest market in terms of sales, followed by France, Spain, UK, and Germany. In addition to Europe, Chiesi is directly present in Brazil, Pakistan, Morocco, Algeria, Tunisia and Egypt. In the USA, a small subsidiary is involved in clinical research and regulatory submissions.
Chiesis technologies and products are available in over 50 countries through a strategic alliances network of international pharmaceutical groups developed both on a global and local scale. Group turnover reached 565 million Euros in 2005.
36
Chiesi's formula for success is based on a peculiar approach that allows to combine factors often thought of as opposites in the pharmaceutical industry such as research and ethics, technology and humanity, commitment to results and concern for individuals, reliability and empathy while encouraging innovation at all levels.
37
Research is the key to innovation, and according to a recent survey of the European Commission, Chiesi Farmaceutici is one of the Italian groups with the highest investments in R&D. With approximately 13-14% of the total turnover invested annually in R&D, Chiesi Farmaceutici is in line with the largest European pharmaceutical groups. Through these investments, Chiesi has generated more than 600 patents worldwide and 70% of sales have come from internal research and development efforts. The Company has currently collaborations with international research groups and academic centres producing synergies that can help ensure Chiesis future research success. Chiesi has 3 manufacturing facilities, located in: Parma (Italy) Blois-La Chausse Saint Victor (France) Santana de Parnaiba (Brazil) employing approximately 500 individuals.
38
The manufacturing plant in Parma is an international supply site providing products to over 50 countries. It has been inspected successfully by several Health Authorities, including the USA FDA. Chiesi Farmaceutici S.p.A. has been ISO 9001:2000 certified for Research, Development, Production and Sale of Medicinal Products. Specialised departments produce respiratory dosage forms, such as Metered-Dose Inhalers (MDI) and sterile Unit Dose Vials (UDV) for nebulisation, using the best available state-of-the-art technology, e.g. isolators and Blow Fill Seal aseptic techniques. The production and ancillary processes (Cleaning in Place, Sterilizing in Place) are driven and monitored through validated computer systems. The capacity of new sterile UDV production department is being increased to over 200 million doses per year. For MDIs, the current capacity is 13 million cans per year, using the HFA Modulite technology. While in the past decade, the Group has grown due to the establishment of new companies in key European countries, the contribution from Chiesis research and development to itsorganic growth has been highly significant. The number of corporate products is increasing mainly as a result of a number of successful Mutual Recognition Procedures (MRPs) in Europe and through the obtainement of market authorizations in several other countries worldwide. Three units: Parma in Italy Paris in France Rockville in Maryland (USA) employ over 300 people who work together on very focused drug discovery and development endeavours in conjunction with major international medical centres. In 2005, Chiesi invested 71 million Euros in R&D (12.6% of the Group revenues) plus 5 million Euros in R&D capital expenditures.
39
The goal of Chiesi is to become a recognised global player in pulmonology and to strengthen the leadership position in neonatology, both areas in which we have strong competencies and an established reputation. To achieve these strategic objectives, the company has focused R&D activities on these two key therapeutic areas, to maximise the value of internal resources and to reach a critical mass of approximately 550 million Euros in R&D expenditures from 2006 to 2010. Based on Chiesis proprietary Modulite, a unique and environmentally-friendly HFA solution technology for use in metered-dose inhalers - formoterol (Atimos, Forair) - was registered and launched in Europe, and partnered with Novartis. A fixed combination of formoterol and beclometasone was filed in Germany as Reference Member State for a following MRP. The anticipated successful launch of this new product (Foster)may drive and accelerate the current promising development of carmoterol, a novel potential once-daily beta-2 bronchodilator as well as its combinations with a steroid and a novel M3 antagonist for the treatment of asthma and Chronic Obstructive Pulmonary Disease (COPD). Chiesi also developed, together with Cambridge Consultants Ltd., a proprietary new-generation dry powder inhaler, NEXTTM DPI. This easy-to-use device may be suitable for all types of inhalation products and it may be used with a DPI formulation of Foster. The limited, but well focused and organised discovery program in the respiratory field, has successfully identified interesting new chemical entities for further development in clinically validated and new molecular targets as potential candidates in COPD, in collaboration with Italian academic centres. In an effort to focus R&D pipeline, two innovative CNS projects were out-licensed to Vernalis.
40
DOMPE
Domp is one of the most dynamic, flexible and innovative set-ups on the European scene. A successful in the traditional pharmaceutical market in the treatment of respiratory and osteoarticular pathologies, Domp has also developed its presence in the area of biotechnology with innovative drugs and services
DRUGS
Domp SpA Primary care

Arial (salmeterolo xinafoato) Artrosilene (ketoprofene sale di lisina) Fluifort (carbocisteina sale di lisina monoidrato) Frivent (teofillina anidra) Levotuss (levodropropizina) Miotens (tiocolchicoside) OKi (ketoprofene sale di lisina) Procef (cefprozil monoidrato) Prontinal (beclometasone dipropionato) Rexalgan (tenoxicam) decapinol (delmopinol) - Dispositivo Medico Ostenil (sodio ialuronato) - Dispositivo Medico
Aree Specialistiche

Tobi (tobramicina) Provigil (modafinil) Actiq (fentanil citrato) Remodulin (treprostinil sodio)
Domp Biotec SpA
41
Avonex (interferone 1a) Nespo (darbepoetina ) Neupogen (G-CSF) Neupopeg (pegfilgrastim) Parareg (cinacalcet) Gliadel (carmustina)
Biogen Domp

Avonex (interferone 1a) Tysabri (natalizumab)
Biogen Domp AG (Svizzera)
Avonex (interferone 1a)
42
RESULTS Annual sales summary
Draft subject to change. These values do not include intercompany sales
Research & Development The research & development departments are integrated within Domp. The core activities include early discovery, preclinical and clinical development, registration and support to marketing. R&D is mainly focusing on two major therapeutical fields: Immunology/Transplantation Oncology.
43
Immunological Diseases/Transplantation
The major focus of Domp research is to identify potent and specific inhibitors of pro-inflammatory chemokines. Chemokines are a large family of small, structurally related proteins that mediate a wide range of biological activities. Chemokines are essential mediators of normal leukocyte trafficking but their role is not restricted to cell recruitment but to intervene in a variety of pathophysiological processes including acute and chronic inflammation, angiogenesis, fibrosis, infectious diseases and immunological disorders such as rheumatoid arthritis, atherosclerosis, psoriasis and ulcerative colitis. Chemokines are multipotent cytokines that localize and enhance inflamation by inducing chemotaxis and cell activation of different types of inflammatory cells typically present at inflammatory sites. Chemokines and other mediators are secreted also by these cells. Chemokines exert their functions through the selective binding to one or more seventransmembrane spanning, G protein-coupled receptors through which various signals are transduced. Interleukin 8 (IL-8) is a chemokine that induces chemotaxis of neutrophils and is a potent angiogenic agent. IL-8 is produced by stimulated monocytes, macrophages, fibroblasts, endothelial cells, keratinocytes, melanocytes, hepatocytes, chondrocytes and a number of tumor cell lines. In humans, there are at least two different IL-8 receptor types (type-1 and type-2). The receptor is a dimeric glycoprotein consisting of 59 kDa and 67 kDa subunit and is expressed in many different cell types including those which don't respond to IL-8. The receptor density is approximately 20,000/cell in neutrophils and 300/cell in T-lymphocytes. IL-8 was reported to play a pathophysiological role in post-ischemia reperfusion injury occurring after kidney, liver, heart or lung transplantation or after myocardial ischemia or brain stroke. Reperfusion of ischemic tissues induces the local production of IL-8 which recruits and activates neutrophils that in turn release a number of tissue-damaging mediators. The discovery by Domp laboratories of potent inhibitors of the IL-8 activity has led to a potential innovative therapeutic approach for the treatment of reperfusional damage and other conditions in which IL-8 is involved. Chemical entities acting as dual inhibitors of IL-8 and C5a (a fraction of the complement cascade involved in the mechanism of inflammatory cells recruitment) have been also characterized and contributed to the creation of a molecular platform for inflammatory and immunological-related disorders. These chemical entities would broaden the inhibition of inflammation in several pathological conditions which include postischemic reperfusion injury and immunological-related disorders such as psoriasis, ulcerative colitis, rheumatoid arthritis.
44
Oncology
The main focus of Domp is to discover and characterize human recombinant antibodies as therapeutics mainly for treating neoplastic diseases but is also foreseen the cure of immunological disorders. This biotechnology platform represents a state of art technology for the characterization, purification and production of human recombinant antibodies which are gaining more and more importance in the treatment of neoplastic and immunological diseases as well as in the diagnostic field. The cloning and expression of human antibodies in E. coli presents numerous advantages over the cloning and expression in mammalian cells, e.g. no risk for biological contaminants and production costs are lower. Ovarian cancer has been identified as the principal therapeutic target of our antibody platform technology. Ovarian cancer cells highly express the -folate receptor (10100 folds the normal cells), thus this receptor represents an ideal therapeutic target. For therapeutic purposes, in collaboration with the National Institute of Tumors of Milan, a fragment of a human antibody (Fab) targeting the -folate receptor (-FR) present on the surface of most of the ovarian cancer cells was identified, cloned and expressed in E. coli. The anti -FR Fab is radiolabelled with Yttrium and directed against the tumor. A murine monoclonal antibody (MOv 18) directed against the same epitope and radiolabelled with Iodine has been successfully used in experimental models in nude mice as well as in patients. In patients, bone marrow toxicity and host immunoreactivity were the major concerns and represented limiting factors for radioimmunotherapy. A human antibody Fab fragment would not only markedly reduce the immunogenicity but would also facilitate the penetration of the radioconiugated antibody in the tumor. The shorter half life of Yttrium and its deep penetration in tissues represents another additional advantage to the traditional radiotherapy COMPETENCES Research profile Pharmacology
In vitro and in vivo models of inflammation, transplantation, respiratory and cancer diseases. Preclinical pharmacokinetics studies in rodents.
Biotechnology Paolo Barbanti The Italian pharmaceutical industry: trends and business opportunities 45
DNA cloning, phage display, identification and purification of fragments of human antibodies to be used as therapeutic tool.
Pharmaceutical Development

Structural, chemical and physical analysis. Preformulation and formulation studies (oral, injectable and topical formulations) stability, scale-up.
Chemistry
Molecular design, organic synthesis, peptide synthesis.
46
R & D PROJECTS Development Pipeline
Pharmaceutical manufacturing The pharmaceutical plant, designed and constructed by the Foster-Wheeler engineering company, was inaugurated in 1993 and constitutes the very latest evolution in company production knowhow, which took root at the beginning of the last century. The production facilities are validated internationally and have a production potential of many tens of millions of units per year of topical products, oral fluids and solids, combining the highest levels of quality with competitive costs. The level of supervision of the production activities and the environmental parameters is augmented by validated computerized systems which conform to the latest GMP standards in current use. The control of the environmental characteristics of the premises where the storage, dosed distribution and production activities take place, is carried out on a continuous basis by a DCS System which Paolo Barbanti The Italian pharmaceutical industry: trends and business opportunities 47
makes it possible to gain real time knowledge of differential levels in the pressure, humidity and temperature to which the processes are subjected. A natural consequence of Domps quest for total quality has been the certification, obtained in the last two years, relative to the management of the Quality System ISO 9001 and the Environmental Management System ISO 14001.
Domp SpA This Company draws up and provides services of updating and scientific assistance to doctors of General Medicine, Paediatrics, Pneumology, Otology, Orthopaedics, Rheumatology, Physiatrics, Odontology, Accident & Emergency and First Aid stations. It guarantees information to the Pharmacist, both within the hospital and outside, contributing to the development of the citizen's education in terms of health. It offers innovative solutions and efficient services to work alongside the National Health Service in the treatment of respiratory pathologies and osteoarticular disease for the sake of improving the patients quality of life. THERAPEUTIC AREAS

Physiatrics Cystic Fibrosis Sleep Medicine Geriatrics Infectious diseases Internal Medicine Sports Medicine Odontology Orthopaedics and Traumatology Otorhinolaryngology Paediatrics Pneumology Emergency
DRUGS
48
Primary Care

Arial Artrosilene Fluifort Frivent Levotuss Miotens OKi Procef Prontinal Rexalgan decapinol (device) Ostenil (device)
Specialist Care

Tobi Provigil Actiq Remodulin
Domp farmaceutici SpA Almost a century after its foundation, Domp Farmaceutici SpA has now moved into the field of rare pathologies, with the aim of providing the medical class and the patient with pharmaceutical products of high therapeutic value, often distinguished by their high technological content. Domp farmaceutici declares its express undertaking with regard to Cystic Fibrosis through the distribution of drugs with a high technological content, through its collaboration with specialist centres and in the creation of educational projects dedicated to the doctor and the patient. THERAPEUTIC AREAS
Palliative Care
49
Domp Biotec SpA Domp Biotec is exclusively concerned with biotechnological pharmaceuticals of high therapeutic value. It is the leading company in Italy both in terms of number of biotechnological drugs on the market and the number of patiets treated.All these drugs are used in specialist fields, mainly in the hospital setting. THERAPEUTIC AREAS

Haematology Infectious diseases Nephrology Oncology Transfusion units Neuro-Oncology
DRUGS

Nespo Neupogen Neupopeg Parareg Gliadel Domp pha.r.ma SpA
Domp pha.r.ma researches and develops innovative drugs for serious and debilitating pathologies; it produces medical specialities of its Group and of selected Partners. The goal of R&D is to improve the quality of life of patients suffering of life-threatening or debilitating diseases. To this aim, R&D is committed to the discovery and clinical development of innovative drugs. Domp International SA Domp International was founded in 1997 with the aim of internationalizing Domp activities by either boosting international and export sales and by increasing licensing contacts as well as developing technology exchange with other companies. Domp International monitors fast
50
developing markets in order to identify business opportunities in the core business therapeutic areas of the company.
PARTNERSHIPS Domp S.p.A.

Aziende Chimiche Riunite Angelini Francesco ACRAF S.p.A. - Levotuss F.I.R.M.A. S.p.A. - Levotuss Sigma-Tau Industrie Farmaceutiche Riunite S.p.A. - Levotuss Stada / Ciclum Farma S.A. - Levotuss, Fluifort Boehringer Ingelheim Ellas A.E. - Levotuss Boehringer Ingelheim Italia S.p.A. - Artrosilene Italfarmaco S.A. - Fluifort GlaxoSmithkline - Arial Bristol-Myers Squibb S.p.A. - Procef Roche S.p.A. - Rexalgan Schering-Plough Products Inc. - Frivent TRB Chemedica S.A. - Ostenil Chiron Corporation - Tobi Cephalon (UK) Limited - Actiq, Provigil United Therapeutics Europe Ltd - Remodulin
Domp pha.r.ma S.p.A. Ricerca e Sviluppo

Biofocus plc Bio-Quant Inc. Consorzio Interuniversitario Nazionale "Metodologie e Processi Innovativi di Sintesi" (C.I.N.M.P.I.S.) Consorzio per la Costituzione di Milano Ricerche Istituto Nazionale per lo Studio e la Cura dei Tumori Istituto di Ricerche Farmacologiche "Mario Negri" - Laboratori Negri Bergamo Istituto di Ricerche Farmacologiche "Mario Negri" - Milano 51
Consorzio Mario Negri Sud Universit degli Studi di Milano Universit degli Studi di Torino Rega Institute - University of Leuven Xoma Ireland Limited
Produzione

Boehringer Ingelheim Italia S.p.A. A. Menarini Manufacturing Logistics and Services S.r.l. Roche S.p.A.
Domp Biotec S.p.A.

Amgen (Europe) A.G. / Amgen Inc. - Nespo, Neupopeg, Neupogen, Parareg Guilford Pharmaceuticals Limited - Gliadel
Biogen Domp
Biogen B.V. - Avonex, Tysabri
Biogen Domp AG (Switzerland)
Biogen B.V. - Avonex
52
MENARINI
Menarini was established over a century ago (as many Italian pharmaceutical companies) in a small laboratory of the Farmacia Internazionale of Naples. In 1915, it transferred to Florence, where it its head office is still located. Since 1978 Menarini has established a series of agreements with some important Italian companies: the first agreement was with Malesci which was followed by agreements signed with Guidotti, Lusofarmaco, Lusochimica and Firma. The aim of these agreements has been a better organization of the strategic areas of Research and Development and of Internationalization, as well as reaching maximum efficiency in the chain of production and supply. In 1976, activity in the Diagnostics Division was added to the existing ethical drug production and in 1994 the OTC Division was started. Today the Menarini Group is the first Italian pharmaceutical group in the world and is present: in all countries of the European Union (except the Scandinavian countries) in Switzerland in Central and Eastern European countries in Central America where it ranks at the fifth position in the main developing countries such as India, Vietnam, People's Republic of China and Korea in South Africa in Argentina (opening of the affiliate from April 2001)
The Group is also present with its own products in over 100 countries in the world using agents and local distributors. EUROPE: in addition to Italy where Menarini is the leading pharmaceutical group, sales are mainly concentrated in Europe: Austria, Benelux, France, Germany, United Kingdom, Greece, Ireland, Portugal, Spain, Turkey and Switzerland. Paolo Barbanti The Italian pharmaceutical industry: trends and business opportunities 53
CENTRAL AMERICA / LATIN AMERICA: Menarini is present in all Central American countries and there it is ranked among the top five pharmaceutical companies. Menarini also has representative agents in Mexico, Colombia, Venezuela, Chile, Ecuador and Peru. The affiliate in Argentina has been opened in April 2001. ASIA: Menarini has created a Joint Venture in India and has a representative office in China. Currently, it is consolidating its presence in the People's Republic of China, in Vietnam and in South Korea. In other countries, Menarini is represented by agents and distributors mainly in Bangladesh, Indonesia, Hong Kong, Malaysia, Taiwan and Thailand. AFRICA and the MIDDLE EAST : In Africa and the Middle East, Menarini's products are managed by agents and distributors whose promotional activities are controlled by the Company.
RESULTS
2003 1,802 mill. Euros 51% of this abroad 2004 1,869 mill. Euros 55% of this abroad 2005 2,234 mill. Euros
The Research Activity of the Menarini Group centres on a single pole, Menarini Research, which deals with all R&D activities from the initial stage of new projects to the registration stage. Paolo Barbanti The Italian pharmaceutical industry: trends and business opportunities 54
The research programmes are divided up among the following centres:
Florence Pomezia (Rome) Milan Pisa Barcelona Berlin
and essentially address the following research areas: Cardiovascular diseases Oncology The pain/inflammation/asthma area
Products portfolio
The Menarini Group has a hold in the most important therapeutic fields. They are: cardiovascular gastro-intestinal antibiotics respiratory anti-diabetics anti-inflammatory/analgesics and many others.
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Menarini Diagnostics
The Company was founded in 1976 as a division of A. Menarini Industrie Farmaceutiche Riunite of Florence, Italy. The average annual growth of the Company turnover for the last four years is around 16%. In July 1997 A. Menarini Diagnostics was certified by the TV Product Service according to the ISO 9002 and EN 46002. In July 2003, the Company obtained by TV the certification ISO 9001:2000, ISO 13485:2000.. Now, A. Menarini Diagnostics employs approximately 700 people, 75% of whom are dedicated to marketing, sales, after-sales service and customer care activities. The 2005 consolidated turnover reached approximately 256 million Euros. Today, A. Menarini Diagnostics is an International Group and its headquarters are located in Florence. Additionally, there is an infrastructure made up of ten fully owned subsidiaries in: Austria Belgium France Germany Greece The Netherlands Portugal Spain United Kingdom Sweden. The strategic fields of A. Menarini Diagnostics are: Diabetes (self testing & laboratory systems) Clinical Chemistry (dry, wet and urinalysis) Haematology (blood typing, ESR, cell counting). Immunology (immunohistochemistry, autoimmunity, immunometric assays). Menarini Diagnostics has established a number of successful partnerships with leading producers including Arkray KDK Corporation (Japan), Inova (USA), Diesse (Italy), CLB (The Netherlands).
56
Main products and product lines are: Glucocard glucose self-testing potentiometric system GlucoMen glucose self-testing potentiometric system GlucoDay S continuous glucose monitoring system Menagent Easy ready-to-use multipurpose liquid reagents for clinical chemistry Spotchem easy-to-use dry chemistry analyser for Doctor Office and the veterinary diagnostics. Aution Orchestra fully automated urinalysis system Vesmatic System automatic system for ESR (Erytro Sedimentation Rate) measurement Ha 8160 fully automated haemoglobin analyser Inova a complete program of reagents for autoimmunity.
57
RECORDATI
Recordati, established in 1926, is a European pharmaceutical group, listed on the Italian Stock Exchange (Reuters RECI.MI, Bloomberg REC IM, ISIN IT 0003828271), dedicated to the research, development, manufacturing and marketing of pharmaceuticals, with headquarters in Milan, Italy. It operates in the main countries Of Europe with a total staff of over 2,000. A European field force of over 1,000 medical representatives promotes a wide range of innovative pharmaceuticals, both proprietary and licensed, in a number of therapeutic fields. Recordatis current and growing coverage of the European pharmaceutical market makes it a partner of choice for new product licenses of companies that do not have European marketing organizations. Recordati is committed to the research of new drug entities within the cardiovascular and urogenital therapeutic fielss in which its research team has proven scientific competence and a track record of discovery and development of original drugs. The most recent product is lercanidipine, a latest generation calcium channel blocker for the treatment of hypertension considered to be the companys leading product. Recordati operates directly in France, Germany, Greece, Ireland, Italy, Portugal, Spain and United Kingdom. In these countries, it does not only market original pharmaceutical specialties, but it also promotes innovative in-licensed pharmaceuticals. Thanks to numerous licensing agreements with international pharmaceutical companies, Recordati's innovative proprietary pharmaceuticals (lercanidipine, flavoxate, fenticonazole) are distributed in approximately 100 countries.
Consolidated revenue for 2006 was 576.2 million Euros, operating income was 120.3 million Euros and the net income was 74.0 million Euros.
58
Economic & Financial Data

Key Data
(m ) 2002 Net Sales 492.7 2003 487.5 2004 488.3 2005 576.1 2006 576.2
(100%) (100%) (100%) (100%) (100%) Operating Income 89.2 81.0 90.4 111.1 120.3
(18.1%) (16.6%) (18,5%) (19.3%) (20.9%) Net Income 50.2 23.7 54.0 64.5 74.0
(10.2%) (4.9%)
(11.1%) (11.2%) (12.8%)
Net Sales
Sales by Business
59
Pharmaceuticals: Net Sales
60
Key P&L and Cash Flow (m ) 2002 Net Sales Gross profit as % of Sales Operating Income (EBIT) as % of Sales Pretax Income Net Income CASH FLOW 2003 2004 2005 2006
492.7 487.5 488.3 576.1 576.2 289.1 287.8 309.0 375.5 384.2 58.7% 59.0% 63.3% 65.2% 66.7% 89.2 81.0 90.4 111.1 120.3
18.1% 16.6% 18.5% 19.3% 20.9% 80.7 50.2 84.2 38.4 23.7 80.5 86.7 107.0 118.2 54.0 76.9 64.5 89.0 74.0 97.3
Per Share Data
2002 Earnings per share (EPS) Cash flow per share
2003 2004 2005 2006
0.2525 0.1225 0.270 0.326 0.370 0.4225 0.4125 0.387 0.45 0.487
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Balance Sheet Structure
62
Corporate Structure
63
RESEARCH AND DEVELOPMENT
Drugs are sourced either internally through original research activities or externally through partnerships with other pharmaceutical companies. Recordati conducts development activities in the field of cardiovascular diseases; the related hypertension Recordatis efforts in this area, led to the discovery of lercanidipine, a latest generation drug belonging to the widely used calcium channel blocker class. Zanitek, a fixed combination of lercanidipine and enalapril and by Recordati, is a new specialty indicated for the treatment of hypertension developed. Recordatis original research is primarily focused on the search for treatments for micturition disorders. In this field, the researchers at Recordati are working on projects for innovative drugs that act through new mechanisms of action or on various combinations.
Pipeline
NAME
ORIGINATOR
INDICATION
PHASE
Project S
Recordati
Chronic Heart Failure (CHF)
Discovery
2 new projects Recordati
Overactive bladder and Incontinence
Discovery
REC 0035
Recordati
Benign prostatic hyperplasia
Preclinical
REC 2615
Recordati
Sexual dysfunction, female
Reformulation
new lercanidipine
Recordati
Hypertension
Formulation
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combinations lercanidipine MR pitavastatin Stanate Different technology platforms Kowa Hyperlipidemia, general Hypertension, general Formulation / Phase II Phase III Phase II / III
Rockefeller U. / InfaCare Neonatal jaundice, hyperbilirubinemia
silodosin
Kissei
Benign prostatic hyperplasia
Phase III
prulifloxacin
Nippon Shinyaku / Angelini
Infection, respiratory tract, urinary tract Calf derived surfactant Moderate to severe chronic pain
Phase III
Infasurf
Ony
Pre-filing Filed in the RMS (UK) Approved
fentanyl patch Lavipharm
rupatadine
Uriach
Rhinitis, allergic, seasonal / perennial urticaria
Zanipress / Zanitek
Recordati
Hypertension (lercanidipine + enalapril)
Launched in the RMS (Germany)
RMS - Reference Member State
Manufacturing Facilities Milan (Italy) The Group's principal pharmaceutical manufacturing site is in Milan. The premises measure 25,000 square metres, and the plant has a production capacity of 45 million units per year. It specializes in the manufacturing and packaging of oral solid, drops, injectables and topical formulations. Situated Paolo Barbanti The Italian pharmaceutical industry: trends and business opportunities 65
in Milan and licensed to produce pharmaceutical specialties for the major international markets, the plant is designed to ensure the highest manufacturing standards in compliance with CGMP (Current Good Manufacturing Practices) standards; it operates in conformity with the most stringent international environmental regulations.
Campoverde di Aprilia (Latina, Italy) The high-tech facility covering an area of over 360,000 square metres, has an installed capacity of 800 cubic metres. In this site, by employing chemical syntheses, active ingredients are produced for Recordati pharmaceutical brands, and large-scale active ingredients and active ingredients are manufactured for international markets. The plant operates in accordance with the cGMP (current Good Manufacturing Practices) and in conformity with the most stringent international environmental regulations. It is regularly inspected by the FDA, by other national and international authorities as well as our customers. The Plant Environmental Management System, has gotten the certification in 2003, according to the UNI EN ISO 14001: 1996 norm, subsequently confirmed according to UNI EN ISO 14001: 2004 norm. The certification was been released by the International Accredited Unit DNV (Det Norske Veritas, Italy). Montluon (France) Montlucon in France is the pharmaceutical manufacturing facility of Bouchara Recordati. Covering an area of approximately 3,500 square metres, the plant is licensed to produce and package oral liquid, solid formulations and sprays. It has a manufacturing capacity of 20 million units per year. The plant is designed to ensure the highest manufacturing standards in compliance with GMP (Good Manufacturing Practices) standards; it operates in conformity with the most stringent international environmental regulations. Ringaskiddy, Cork (Ireland) The site, which covers the area of 4.21 hectares, is located in the pharmaceutical industrial area of Ringaskiddy, approximately 15km from Cork, the second largest city in Ireland. The lercanidipine
66
manufacturing facility became operational at the end of 2005. A GMP (Good Manufacturing Practices) certificate was issued by The Irish Medicines Board in December 2005.
Raw materials The pharmaceutical chemicals business accounts for 6% of Recordatis total revenue. Recordati produces both active ingredients for its own proprietary pharmaceuticals, and active ingredients and intermediates for the generic drugs market. Recordati exports around 90% of its production of APIs and intermediates by selling its products directly to over 50 countries.
67
SIGMA TAU
Sigma Tau is one of the most important Italian pharmaceutical groups, it employs 2,366 people and its corporate turnover in 2005 amounted to 674 million.
The drive towards internationalization is best testified by the constant development of new cooperation agreements with many scientific institutes in Europe and North America. Paolo Barbanti The Italian pharmaceutical industry: trends and business opportunities 68
Sigma - Tau is a company whose main objective is to help improve health and the quality of life for everybody. To achieve these goals, the company operates in all the clinically important therapeutic sectors and the huge investments devoted to research - 16% of corporate turnover - are at the basis of its business Sigma-Tau employs over 400 researchers, providing them with the means and resources to develop therapeutic breakthroughs that can better guarantee health conditions for everyone. All this requires considerable investments. The Company has opened branches in France, Switzerland, the Netherlands, Portugal, Germany and other countries in Europe
69
R & D PROJECTS
ACTIVITIES AND PROJECTS Cardiovascular disease, metabolism, oncology, immunology, central and peripheral nervous system. 50 projects, 33 clinical indications studied with 18 molecules of property of Sigma Tau, and most of which (15) are new and original. This is the scope and the dimension of internal research, which is carried out in the following facilities: Sigma-Tau Research Centre (Pomezia, RM) Prassis Research Institute (Settimo Milanese, MI) Tecnogen S.p.A. (Piana di Monte Verna, CE) Kenton srl (Pomezia, RM) Sigma-Tau Research Inc. (Gaithersburg, MD).
70
R & D PROJECTS
Therapeutic Area
Drug 4 Thymosin
Indication Rip. stasis related venous wounds and ulcers
State of Progress Stage 2 study in programme* Stage 2** Stage 2 Pre-registration (U.S.A.)
Cardiovascular disease
Istaroxime Rostafuroxin Propionyl-L-carnitine
Heart failure Hypertension Intermittent Claudication
L-carnitine L-carnitine Teglicar Propionyl-L-carnitine
Transplant medicine Peritoneal dialysis Type 2 diabetes Dialysis
Stage 2 study in programme Stage 2 Stage 2 Stage 2; Stage 3 study in programme
Metabolism
ST 1968 Vaccine ST 1926 Oncology Gimatecan Acetyl-L-carnitine Defibrotide
Misc. tumours Misc. tumours Misc. tumours Misc. tumours (solid) Chemotherapeutic neuropathy Occlusive venous disease
Preclinical development Start of clinical trials in programme Stage 1 Stage 2# Stage 3 Stage 3 (USA)##
Immunology
ST 1959 PTX 3 Radioimmunotherapy antibody-guided (PAGRIT) Intraoperative avidination
Autoimmune diseases Immunotherapy Glioma and misc. tumours Misc. tumours
Preclinical development Preclinical development Stage 1 Stage 1
71
for radiotherapy (IART) Propionyl-L-carnitine 1 Thymosin 1 Thymosin DHA/PPQ (Dihydroartemisinin/Piperaquine) Patch Ibuprofene Soft tissue inflammation Central Nervous System ST 2472 ST 1535 ST 1859 ST 983 Other ST 1898 Schizophrenia Preclinical development Registration Intestinal inflammatory disease Melanoma, Liver cancer Hepatitis C, Hepatitis B Malaria Stage 3^^ Stage 3^ Stage 2 study in programme Stage 2/3^
Parkinson's Disease Preclinical development Alzheimer's Disease Preclinical development Liposomial preparations Acne Preclinical development Preclinical development
Cardiovascular disease - Sigma-Tau has discovered and patented Istaroxamine, an innovative agent (drug) for the treatment of Heart Failure, which is currently in State 2 clinical studies and object of a research development and in terms of marketing agreement with Debiopharm SA (Switzerland). Moreover, currently clinical studies are ongoing for a new hypertension treatment (Rostafuroxime). Metabolism - Research on type 2 diabetes is currently focussed on developing drugs that can control glucose levels without causing serious secondary metabolic changes.
Immunology and inflammation - Research on non-steroid anti-inflammatory drugs and molecules that control the activity of inflammation mediators.
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Oncology and immunology - A multiple approach to tumour therapy, recognizing the importance of research in tumour therapy, and, believing in the importance of trying different therapeutic approaches, developing research programmes on new antitumour drugs that act by means of different mechanisms (cytotoxic, antiangiogenetic, cytodifferentiated), on somatic cell therapy (cancer vaccine) and on a radioimmunotherapy kit. This cutting-edge programme is unique in placing different approaches and techniques side by side and has produced a wealth of important data. Of special significance is the work on biotechnologies, and particularly the development of PAGRIT (Pretargeted Antibody-Guided RadioImmuno Therapy), based on original tumourspecific monocloned antibodies which are selectively carried to the tumour. The project, which originated at the European Institute of Oncology, is being carried out with the participation of Tecnogen. Among the other projects, a special mention must be reserved for Gimatecan, an oral antitumor drug belonging to the family of topoisomerase-1 inhibitors, which has been developed in Italy (University of Milan, Istituto dei Tumori in Milan and Sigma Tau). Gimatecan has been licensed for co-development by Novartis, a leading concern in oncology research, which has acquired the worldwide selling rights for the product. The drug is currently in Stage 2. Central and Peripheral Nervous System In neuropharmacology, research at Sigma-Tau follows three main lines: - the study of molecules that show potential applicability against neurovegetative diseases, such as Alzheimer's disease, multiple sclerosis or encephalomyielitis; - the study of new atypical anti-psychotic drugs for the treatment of schizophrenia with fewer side effects; - the study of drugs for the treatment of Parkinson's disease which work by a new action mechanism (A2a antagonists). An area in which Sigma-Tau is especially proud of its results is the field of rare diseases, the commitment to rare diseases is underlined by the fact that Sigma-Tau was the fourth company in the world to obtain the United States Orphan Drug Designation, in 1984, after which it received seven more; five new designations have been requested from European authorities. Sigma Tau has recently established cooperation relationships with China which are fully in line with the Company's approach to the study of natural molecules of particular interest for research. . Together with the Chinese company Chongqing Holley, the Company has launched a project directed at internationally registering an anti-malaria drug, in which Sigma-Tau makes its industrial Paolo Barbanti The Italian pharmaceutical industry: trends and business opportunities 73
know-how available in order to guarantee the distribution of the drug in those countries where malaria still culls millions of victims. In addition, still with Chongqing Holley, as well as with other Chinese partners, opportunities are being explored to investigate new compounds for the development in important therapeutic areas, including oncology, making use of the millenary experience of traditional Chinese medicine. Another important field of research made by Sigma-Tau is the development of drugs designed for the treatment of individual patients rather than the disease in general. Hence the study of vaccines for specific forms of cancer in individual patients, or the development of antihypertensive drugs for groups of hypertensive patients who share particular genetic features.
FACILITIES: - Research Centre - Pomezia (RM) - The Research Centre is located at the centre of Pomezia's industrial estate, marking the importance that Sigma-Tau assigns to the relations between research and corporate activities. The Research Centre covers 24,000 square metres and hosts approximately 300 researchers. This is where all drug synthesizing, discovery and preclinical development activities (Pharmacology, Toxicology, Analytic, etc.) are carried out. The complex also houses the Medical Supervision and Regulation Affairs offices, which are the divisions involved in coordinating clinical activities and drug registration worldwide. - Prassis Research Institute - Settimo Milanese (MI) - The Prassis Research Institute was created by the Sigma-Tau Group at Settimo Milanese in 1989. The Institute is divided into two scientific divisions (Chemistry & Analysis, Cardiovascular Pharmacology) and an Administration Division. The complex was restored during 1996-1999 to comply with the new legislation on environmental safety. Research is carried out by a staff of 50 people and is performed in close coordination with Sigma-Tau's corporate Research and Development structure, of which the Prassis Institute represents the sector specialised in cardiovascular diseases. - Tecnogen - Piana di Monte Verna (CE) - Located in Piana di Monte Verna, in the province of Caserta, Tecnogen carries out biotechnology research for pharmaceutical applications, and has acquired specific experience in peptide combinatorial libraries and pharmaceutical proteins. Tecnogen has recently been authorized to produce monoclonal antibodies and recombinant proteins for use in clinical experiments. Paolo Barbanti The Italian pharmaceutical industry: trends and business opportunities 74
- Kenton srl - Pomezia (RM) - Kenton is specifically qualified in biotechnologies applied to the development of methods for the early diagnosis of tumours and of infections caused by the hepatitis C virus in humans. - Sigma-Tau Research Inc. - Gaithersburg, MD - The Group's R&S activities are completed by Sigma-Tau Research Inc., which follows the clinical development of Sigma-Tau products in the United States. These facilities cover an area of 36,500 square metres. Research activities are often carried out together with the collaboration of leading academic institutes, many of which are in Italy, such as the Istituto dei Tumori in Milan, the European Institute of Oncology, and various universities, including Rome, Milan, Parma, Siena, Brescia and Bari.
PRODUCTS
THERAPEUTIC AREAS Sigma Tau products include a wide range of products in important
therapeutic areas:
the cardiovascular and metabolic area includes drugs for the treatment of hypertension, ischemic heart disease, rhythm disorders, hyperlipoproteinemia and thrombosis. Cardiovascular drugs include: nitro derivatives, calcium antagonists, ACE-inhibitors, angiotensin II antagonists, statins, an antiplatelet drug, omega-3 polyunsaturated fatty acids and bemiparin, a second-generation low molecular weight heparin. In addition, a new drug is being studied for the treatment of heart failure which is currently in Stage 2 of the clinical trials; it is a completely new drug that combines lusitropic action with a strong inotropic effect without increasing oxygen consumption. A new drug is in the development phase for the treatment of hypertension (Rostafuroxin) which normalizes changes in the tubular reabsorption of sodium associated with hypertension without interfering with other receptors involved in regulating arterial pressure or hormonal homeostasis and without inducing the effects typically caused by diuretics; 75
SIGMA-TAU PHARMACEUTICALS FOR CARDIOLOGY ACESISTEM AMIODAR DILZENE ESKIM ESRADIN IVOR LIBRADIN LOSAPREX LOSAZID NAPRILENE NEOPREX NITRO-DUR SIVASTIN TICLODONE Enalapril + Hydrochlorothiazide Amiodarone Diltiazem Polyunsaturated fatty acid ethyl esters Isradipine Bemiparin Barnidipine Losartan Losartan + Hydrochlorothiazide Enalapril Enalapril + Hydrochlorothiazide Nitroglycerine Simvastatin Ticlopidine
the gastroenterology area includes antiulcer drugs, H2 receptor antagonists and proton pump inhibitors, modulators of intestinal motility and probiotics;
SIGMA-TAU PHARMACEUTICALS FOR GASTROENTEROLOGY FAMODIL LIMPIDEX VSL#3 YOVIS Famotidine Lansoprazol Milk enzymes Milk enzymes
76
the respiratory area presents innovative products, for the treatment of asthma and obstructive syndromes of the respiratory tracts, such as an antileukotriene and the association between beta-2 adrenergic receptor agonists and a corticosteroid;
SIGMA-TAU PHARMACEUTICALS FOR PNEUMOLOGY LUKASM SINESTIC Montelukast Budesonide + Formoterol
the infectious disease area includes oral and injectable antibiotics, either on their own or in predetermined associations, that can inhibit the activity of a number of pathogens, and antiviral drugs for systemic applications; SIGMA-TAU PHARMACEUTICALS FOR INFECTIOUS DISEASES ACTIRA AMPLIUM LORICIN SPECTRUM TALAVIR TENACID TROZOCINA VIRUXAN Moxifloxacin Ampicillin + Cloxacillin Ampicillin + Sulbactam Ceftazidime Valacyclovir Imipenem + Cilastatin Azithromycin Metisoprinol
the urologic area offers a drug for the treatment of benign prostatic hypertrophy based on finasteride, an inhibitor of the enzyme 5-alpha-reductase;
77
SIGMA-TAU PHARMACEUTICALS FOR UROLOGY PROSTIDE Finasteride
the rheumatologic area is represented by etoricoxib, a second-generation COX-2 inhibitor, a Tenoxicam based Fans, a transdermic preparation (patch) based on Ketoprofene and a local Felbinac based gel base for symptomatic treatment of osteoarticular and muscle-tendon pathologies;
SIGMA-TAU PHARMACEUTICALS FOR RHEUMATOLOGY DOLMEN KEPLAT TAUXIB TRAXAM GEL Tenoxican Ketoprofene Etoricoxib Felbinac
in the area of bone metabolism and osteoporosis, we have alendronate, of the biphosphonates family, a molecule that finds application in the treatment of osteoporosis; SIGMA-TAU PHARMACEUTICALS FOR OSTEOPOROSIS DRONAL Alendronate
the neurological area, offers a combination for the symptomatic treatment of migraine, as well as l-acetylcarnitine for use in peripheral neuropathies;
SIGMA-TAU PHARMACEUTICALS FOR Paolo Barbanti The Italian pharmaceutical industry: trends and business opportunities 78
NEUROLOGY MIGRAPRIM ZIBREN Lysine acetylsalicylate + Metoclopramide Acetylcarnitine
Sigma-Tau recognizes the importance of research in tumour therapy, and, believing in the importance of trying different therapeutic approaches, has developed research programmes on new antitumor drugs with different action mechanisms (cytotoxic, antiangiogenic, cytodifferentiated), on somatic cell therapy (cancer vaccine) and on a radioimmunotherapy kit. SIGMA-TAU PHARMACEUTICALS FOR ONCOLOGY GELCLAIR NATULAN TARGRETIN Polyvinylpirrolidone + Ialuronic acid + Glycyrrhetinic acid Procarbazine Bexarotene
This cutting-edge programme is unique in putting different approaches and techniques side by side and has produced a wealth of important data. Of special significance is the work on biotechnologies, and particularly the development of PAGRIT (Pretargeted Antibody-Guided RadioImmuno Therapy), based on original tumour-specific monoclonal antibodies which are selectively carried to the tumour. The project, which originated at the European Institute of Oncology, is being performed by the participation of Tecnogen. Among the other projects, Gimatecan merits a special mention; this is an oral antitumor drug belonging to the family of topoisomerase-1 inhibitors which has been developed in Italy (University of Milan, Istituto dei Tumori in Milan). Gimatecan has been licensed for co-development by Novartis, a leading concern in oncology research, which has acquired the worldwide selling rights for the product. The drug is
79
currently in Stage 2.
LIST OF PRODUCTS BY BRAND NAMES
LIST OF PRODUCTS BY BRAND NAME

ACESISTEM ACTIRA AMIODAR AMPLIUM DILZENE DOLMEN DRONAL ESKIM ESRADIN FAMODIL GELCLAIR CONCENTRATED ORAL GEL IVOR KEPLAT LIBRADIN LIMPIDEX LORICIN LOSAPREX LOSAZID LUKASM MIGRAPRIM NAPRILENE NATULAN NEOPREX NITRO-DUR PROSTIDE Enalapril + Hydrochlorothiazide Moxifloxacin Amiodarone Ampicillin + Cloxacillin Diltiazem Tenoxicam Alendronate Polyunsaturated fatty acid ethyl esters Isradipine Famotidine Polyvinylpirrolidone + Hyaluronic acid + Glycyrrhetinic acid Bemiparin Ketoprofene Barnidipine Lansoprazol Ampicillin + Sulbactam Losartan Losartan + Hydrochlorothiazide Montelukast Lysine acetylsalicylate + Metoclopramide Enalapril Procarbazine Enalapril + Hydrochlorothiazide Nitroglycerine Finasteride 80
SINESTIC SIVASTIN SPECTRUM TALAVIR TARGRETIN TAUXIB TENACID TICLODONE TRAXAM GEL TROZOCINA VIRUXAN VSL#3 YOVIS ZIBREN
Budesonite + Formoterol fumarate Simvastatin Ceftazidime Valacyclovir Bexarotene Etoricoxib Imipenem + Cilastatin Ticlopidine Felbinac Azithromycin Metisoprinol Milk enzymes Milk enzymes Acetylcarnitine
LIST OF PRODUCTS BY ACTIVE INGREDIENT
LIST OF PRODUCTS BY ACTIVE INGREDIENT

Acetylcarnitine Lysine acetylsalicylate + Metoclopramide Alendronate Amiodarone Ampicillin + Cloxacillin Ampicillin + Sulbactam Azithromycin Barnidipine Bemiparin Bexarotene Budesonite + Formoterol ZIBREN MIGRAPRIM DRONAL AMIODAR AMPLIUM LORICIN TROZOCINA LIBRADIN IVOR TARGRETIN SINESTIC 81
fumarate Ceftazidime Diltiazem Enalapril Enalapril + Hydrochlorothiazide Enalapril + Hydrochlorothiazide Etoricoxib Polyunsaturated fatty acid ethyl esters Famotidine Felbinac Milk enzymes Milk enzymes Finasteride Imipenem + Cilastatin Isradipine Ketoprofene Lansoprazol Losartan Losartan + Hydrochlorothiazide Metisoprinol Montelukast Moxifloxacin Nitroglycerine Polyvinylpirrolidone + Hyaluronic acid + Glycyrrhetinic acid Procarbazine Rivastigmine Tenoxicam Simvastatin Ticlopidine Valacyclovir SPECTRUM DILZENE NAPRILENE ACESISTEM NEOPREX TAUXIB ESKIM FAMODIL TRAXAM GEL VSL#3 YOVIS PROSTIDE TENACID ESRADIN KEPLAT LIMPIDEX LOSAPREX LOSAZID VIRUXAN LUKASM ACTIRA NITRO-DUR GELCLAIR CONCENTRATED ORAL GEL NATULAN PROMETAX DOLMEN SIVASTIN TICLODONE TALAVIR
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Via Placido Riccardi 19 20132 Milano Italy Tel. ++39-02-45409122 / 27203492 Fax ++39-02-27203492 barbanti@pharmaebiotech.com
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The Italian Pharmaceutical Industry

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The Italian Pharmaceutical Industry

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Via Placido Riccardi 19 20132 Milano Italy Tel. ++39-02-45409122 / 27203492 Fax ++39-02-27203492 barbanti@pharmaebiotech.

The Italian Pharmaceutical Industry Table of Contents

2. A SELECTED TARGET OF ITALIAN COMPANIES

Netherlands Sweden Spain China Denmark Austria Israel Australia India

7.7 2.2 2.3 1.0 1.2 0.3 1.8 0.1 0.1

Types of packages prevailing in Italy

Pharmaceuticals in liquid form

Pharmaceuticals in Solid Form

Various Pharmaceutical Products

Comments and Market Situation:

Trends and demographics

1. USA 2. JAPAN 3. FRANCE 4. GERMANY 5. UK 6. ITALY Pharma-products spending / Person

Dealing with Demographics

Implications for Research

Selected Priority Research Areas

New price-setting Models

Changes in Distribution Margins

The Introduction of Generics

Attempts to influence General Practitioner Prescribing

A selected target of Italian Companies

CEROX EMOSTATICO - medication and bandage range

RIGIDENT - complete range for denture THERMAE - thermal products range

Domp Biotec SpA

Avonex (interferone 1a) Tysabri (natalizumab)

Biogen Domp AG (Svizzera)

Avonex (interferone 1a)

RESULTS Annual sales summary

Draft subject to change. These values do not include intercompany sales

Molecular design, organic synthesis, peptide synthesis.

R & D PROJECTS Development Pipeline

Tobi Provigil Actiq Remodulin

Haematology Infectious diseases Nephrology Oncology Transfusion units Neuro-Oncology

Nespo Neupogen Neupopeg Parareg Gliadel Domp pha.r.ma SpA

PARTNERSHIPS Domp S.p.A.

Domp pha.r.ma S.p.A. Ricerca e Sviluppo

Domp Biotec S.p.A.

Biogen B.V. - Avonex, Tysabri

Biogen Domp AG (Switzerland)

Biogen B.V. - Avonex

The research programmes are divided up among the following centres:

Florence Pomezia (Rome) Milan Pisa Barcelona Berlin

Economic & Financial Data

(11.1%) (11.2%) (12.8%)

Pharmaceuticals: Net Sales

Per Share Data

2002 Earnings per share (EPS) Cash flow per share

2003 2004 2005 2006

Balance Sheet Structure

RESEARCH AND DEVELOPMENT

Chronic Heart Failure (CHF)

2 new projects Recordati

Overactive bladder and Incontinence

Benign prostatic hyperplasia

Sexual dysfunction, female

Rockefeller U. / InfaCare Neonatal jaundice, hyperbilirubinemia

Benign prostatic hyperplasia

Nippon Shinyaku / Angelini

Pre-filing Filed in the RMS (UK) Approved

fentanyl patch Lavipharm

Rhinitis, allergic, seasonal / perennial urticaria

Hypertension (lercanidipine + enalapril)

Launched in the RMS (Germany)

RMS - Reference Member State