Annual Report 2007 In Detail WorldReginfo - 954f6161-6bac-48a4-873f-6ee9f4f1d49c Content WorldReginfo - 954f6161-6bac-48a4-873f-6ee9f4f1d49c 01 Marketed Products 04 Summary of Achievements 05 Tracleer® 06 Ventavis® 08 Zavesca® 08 02 Research & Development 10 Drug Discovery 11 Drug Discovery Platforms 11 Therapeutic Areas 12 Clinical Development 18 03 Our Strategy 27 04 Business Development 29 05 Financial Report 32 Corporate Governance 37 Consolidated Financial Statements 49 Holding Company Statements 78 03 WorldReginfo - 954f6161-6bac-48a4-873f-6ee9f4f1d49c 01 Marketed Products WorldReginfo - 954f6161-6bac-48a4-873f-6ee9f4f1d49c Summary of achievements Actelion’s strong commitment to expand Tracleer® into new indications is demonstrated by the comprehensive clini- Actelion continued its strong performance in 2007 and further cal trial program, including the COMPASS trials (combina- built its leadership position in pulmonary arterial hypertension tion therapy), BUILD 3 (idiopathic pulmonary fibrosis) and (PAH) with Tracleer® (bosentan) sales of CHF 1,18 billion, a FUTURE (pediatric indication). growth of 31% compared to the previous year (+32% in lo- cal currencies). This strong performance was seen in all re- Several marketing and life cycle activities were initiated for gions worldwide, including the United States, Europe, and Ventavis® in 2007 to enhance its profile and set it up for con- Japan in particular. It was also the first full year of marketing tinued success in 2008. Ventavis® (iloprost) after the acquisition of CoTherix in the United States. In an increasingly competitive PAH market, Zavesca® (miglustat), Actelion’s second global brand, gener- Ventavis® was able to contribute CHF 78.2 million to our PAH ated sales of CHF 35.3 million, a growth of 39% compared franchise revenues. to the previous year. Increased awareness and acceptance of the value of Zavesca® for patients suffering from Type 1 These excellent results are particularly remarkable consider- Gaucher disease are the basis for future market share growth. ing that new competition entered the market in 2007 within New data published in 2007 confirmed the positive effects the class of endothelin receptor antagonists (sitaxentan in of Zavesca® on Gaucher disease related bone manifestations, the European Union and ambrisentan in the United States). and bone pain in particular, strengthening the competitive Actelion’s in-depth knowledge of the PAH market, together profile of the brand. with our highly professional and determined worldwide mar- keting and sales force, continued medical education activities, The submission for an expansion of the indication to patients and further geographical expansion, were the basis for main- suffering from Niemann-Pick Type C disease is still under re- taining leadership and further growth. view by the European regulatory authorities. Actelion further strengthened the profile of its flagship brand, Tracleer®. In 2007, we submitted an application in the US and Europe to expand the indication of Tracleer® for patients with Actelion currently markets the following products: PAH in WHO Functional Class II* (FC II), based on the conclu- sive results of the EARLY study – the only study investigating Product Indication(s) Status Commerciali- the effects of a PAH therapy specifically in a FC II patient zation rights ® group. With EARLY, Tracleer has shown a significant effect Tracleer® Pulmonary arterial hyper- marketed Actelion on delaying time to clinical worsening, a measure of disease tension progression, in three separate randomized controlled trials. Prevention of digital registered(1) Actelion ulcers in patients with The positive results of the double-blind, placebo-controlled, systemic sclerosis multi-national BENEFIT trial – which investigated the effects Prevention of digital in Actelion (2) ® ulcers in patients with registration of Tracleer in a patient population outside of WHO group systemic sclerosis I*, namely patients with chronic thromboembolic pulmo- Ventavis® Pulmonary arterial hyper- marketed Actelion(3) nary hypertension (CTEPH) – further proved to the value of tension ® Tracleer for patients. In June 2007, the EMEA granted ap- Zavesca® Type 1 Gaucher disease marketed Actelion(4) proval in the European Union for an expansion of the indi- cation of Tracleer® for reducing the number of new digital ulcers in patients suffering from systemic sclerosis and ongo- (1) Only in the EU (2) A product is said to be "in registration" when it has completed Phase III clinical trials and ing digital ulcer disease. Digital ulcers are a serious and very its developer is in discussion with the relevant regulatory authorities relating to the filing of debilitating consequence of this disease. a new drug application for the product. (3) Only in the USA. (4) Except Israel, the West Bank and Gaza Strip. * WHO clinical classification of pulmonary hypertension group diseases sharing similarities. PAH is WHO group 1. Group 1 comprises the following classifications: I. Patients with pulmonary hypertension in whom there is no limitation of usual physical activity II. Patients with pulmonary hypertension who have mild limitation of physical activity III. Patients with pulmonary hypertension who have a marked limitation of physical activity IV. Patients with pulmonary hypertension who are unable to perform any physical activity at rest and who may have signs of right ventricular failure. Annual Report 2007 - Marketed Products 05 WorldReginfo - 954f6161-6bac-48a4-873f-6ee9f4f1d49c Tracleer® sels – makes the vessels stiffer and thicker, and some may become completely blocked. This increased stress causes Actelion’s lead product is Tracleer®, the first and only dual en- the heart to enlarge and become less flexible. As the cycle dothelin receptor antagonist. Tracleer® was the first oral treat- continues, less and less blood is able to flow out of the heart, ment approved for pulmonary arterial hypertension (PAH), a through the lungs and into the body, which causes additional rare, chronic, life-threatening disorder that severely compro- severe symptoms to appear. Heart and lung functions are mises the functions of the lungs and heart. Today, Tracleer® severely compromised in PAH patients, resulting in limited has been approved for the treatment of PAH in more than exercise capacity and, ultimately, a reduced life expectancy. 30 countries, including the United States in November 2001, the European Union in May 2002, and Japan in April 2005. The first signs of PAH – such as dyspnea (shortness of breath), We currently market Tracleer® in all major markets worldwide fatigue and difficulty exercising – are subtle. As a result, the – including the United States, the European Union, Japan, disease is often either misdiagnosed or not diagnosed at all Switzerland, Canada, Australia, and China. until a patient's condition is advanced. According to a 1991 study by D'Alonzo (et al) in the Annals of Internal Medicine, if Actelion received an orphan drug designation for Tracleer® in the disease is left untreated, 45 to 60% of PAH patients die PAH for jurisdictions including the European Union, the Unit- within two years of diagnosis. ed States, Japan, and Australia. Prior to the availability of Tracleer®, the main treatment alter- In addition to the indication in PAH, based on compelling natives for early-stage PAH were vasodilators – such as cal- clinical data, Tracleer® received approval from the European cium channel blockers, which cause blood vessels to expand, regulatory authorities in 2007 for the reduction in the number and oral anti-coagulants, which reduce blood clotting. These of new digital ulcers in patients suffering from systemic scle- therapies are able to relieve some of the symptoms of PAH, rosis and ongoing digital ulcer disease. but do not work in all patients. As the disease progressed, many patients were forced to turn to prostacyclin therapy, which required a 24-hour infusion pump and an intravenous Indications line implanted through the chest to deliver the drug directly into the patient's pulmonary vein. Tracleer® in pulmonary arterial hypertension Pulmonary hypertension, or high blood pressure in the cardio- This treatment is associated with a number of quality-of-life pulmonary system, is a simplified name for a complex health and safety limitations. Ultimately, many patients would re- problem. Pulmonary hypertension is a disease affecting peo- quire lung or heart-lung transplantation; this is costly and se- ple of all ages and ethnic background, seriously impacting verely limited due to the lack of suitable donor organs. the quality of life and life expectancy of patients. Pulmonary hypertension may result from any of a number of primary Tracleer® was approved on the basis of two Phase III clinical diseases. It can also arise idiopathically, that is, without a trials and is a twice-a-day oral formulation offering effective medically understood cause. The World Health Organization treatment for most moderate to severe PAH patients. It has (WHO) classifies five different forms of pulmonary hyperten- been shown to significantly delay disease progression, im- sion. These five forms differ in both their causes and their prove exercise capacity and increases the patient's ability to precise effects. Tracleer® is currently indicated for the WHO perform daily activities without shortness of breath. It also group 1 classification of pulmonary arterial hypertension improves quality of life, in some cases placing the patient (PAH).