Annual Report 2008 In Detail

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(1)WorldReginfo - 347f5acf-d29f-4cfe-9635-5f104be92861. Annual Report 2008 In Detail.

(2) WorldReginfo - 347f5acf-d29f-4cfe-9635-5f104be92861. Introduction.

(3) Progress in 2008. In an effort to optimize geographic reach, Actelion has ex panded and enhanced its commercial infrastructure. At the end of 2008, the company had 26 sales and marketing orga nizations, including the expansion to Mexico, and 25 other countries serviced through partners. This global reach – with future expansion to markets such as Russia, as well as re alignment in the key Japanese market – means that Actelion is equipped to shape markets for future launches. We have also been putting processes and infrastructure in place to transform novel chemical entities, currently in late stage development, into innovative medicines for patients. Our global headcount expanded by more than 300 employ ees in 2008 taking Actelion over 1900 professionals. With higher levels of growth expected in the future, office and laboratory space, IT infrastructure and the coordination of corporate services will be key efficiency factors. Actelion’s business center, founded at the end of 2007, has already made great progress in addressing these future needs, and we have started work on our second R&D building. With a broad dataset and experience in over 60,000 patients, Tracleer ® is the best described treatment for PAH. In 2008 Tracleer ® saw the successful market introduction for digital ulcers in systemic sclerosis and WHO Functional Class II pa tients added to the label in the EU. Having secured the ex panded label, Actelion intends to continue its commitment to patients with PAH by building a product franchise led by the global availability of Tracleer ® and our commercialization of Ventavis® (iloprost) in the US. In addition, our Phase III com pound macitentan is continuing to progress rapidly through development. Thanks to Actelion’s partnership with Nippon Shinyaku, announced in the first quarter of 2008, an orally active non-prostanoid PGI2 receptor agonist has also been added to the development pipeline. We also continued our commitment to Zavesca® in 2008, not only in the market place but also with clinical support resulting in the CHMP positive opinion in December to extend the use of this treatment to include patients with a very rare neurodegenerative genetic disease, Niemann-Pick type C.. 03. The Zavesca® sales force is now making the necessary preparations to immediately bring this product to patients after obtaining approval in the EU in January 2009. Our clinical development pipeline holds great promise for pa tients with many other unmet medical needs. Results from the current Phase III study with bosentan (Tracleer ®) as a treatment for idiopathic pulmonary fibrosis are expected to become available toward the end of 2009. A positive out come would allow patients to benefit from this compound’s antifibrotic properties. Also expected for the second half of 2009 are results from two other Phase III projects, inves tigating clazosentan in the prevention of vasospasm as a consequence of aneurysmal subarachnoid hemorrhage and almorexant in primary insomnia. Almorexant shows potential in the treatment of insomnia and beyond. To optimize the value of this discovery, Actelion sought a partner who understood this potential. The partnership with GlaxoSmithKline, announced in July 2008, has proved to be a good choice, with rapid and committed implementation. The two companies’ combined knowledge, capabilities and experience will allow us to realize the transformational potential of almorexant and other orexin receptor antagonists, creating value above and beyond what each company could achieve alone. The alliance also allows Actelion to potentially build a primary care presence in key pharmaceutical markets, driving almorexant's value creation and helping to maximize leverage for our substantial pipeline. As data is reported from our early-stage development pro grams, we will learn more about the potential of our CRTH2 receptor antagonist in allergic asthma and the initiation of Phase II studies for the S1P1 receptor agonist (in partnership with Roche). We also hope to benefit from a drug discovery approach in which compound identification is followed by a patient-oriented search for therapeutic applications. Our corporate culture – combining the innovation, entrepre neurial spirit and flexibility of biotech with the risk manage ment and regulatory and commercial discipline of big pharma – will continue to drive our success in 2009. By focusing on our values and fostering an enthusiastic, stimulating environ ment for employee development and company growth, we will attract and retain the best people in the industry.. WorldReginfo - 347f5acf-d29f-4cfe-9635-5f104be92861. In 2008, strong financial performance – with a keen eye on the bottom line – enabled Actelion to continue its unprec edented growth in the biopharmaceutical sector. Once again, this was largely driven by sales of our flagship product Tracleer ® (bosentan), the undisputed cornerstone therapy for pulmonary arterial hypertension (PAH)..

(4) WorldReginfo - 347f5acf-d29f-4cfe-9635-5f104be92861. Contents.

(5) 06. 02 Our people and values. 08. 03 Research. 10. Research strategy Project selection Therapeutic areas Cardiovascular disorders Central nervous system Genetic disorders Immunology Infectious diseases Oncology. 04 Development Development pipeline Phase IV Bosentan (Tracleer®) Iloprost (Ventavis®) Miglustat (Zavesca®) Phase III Almorexant Bosentan in IPF Clazosentan Macitentan Phase II CRTH2 receptor antagonist Miglustat in cystic fibrosis PGI2 receptor agonist S1P1 receptor agonist Phase I Renin inhibitor. 05. 11 13 13 13 15 16 17 19 19 21 22 23 23 24 24 26 26 28 29 30 30 30 31 32 32 33 33. 05 Partnerships & Collaborations Partnerships In-licensing Acquisitions. 06 Marketed Products Actelion’s products in the marketplace About Tracleer® About Ventavis® About Zavesca®. 07 Financial Report Financial summary Corporate Governance Consolidated Financial Statements Notes to the Consolidated Financial Statements Holding Company Statements Notes to the Financial Statements 2008 Actelion Management, Board and Scientific Advisory Board Shareholder Information. 35 36 37 38 39 40 41 45 46 49 50 53 65 69 97 98 109 110. WorldReginfo - 347f5acf-d29f-4cfe-9635-5f104be92861. 01 Our strategy.

(6) WorldReginfo - 347f5acf-d29f-4cfe-9635-5f104be92861. 01 Our strategy.

(7) Since its founding more than a decade ago, Actelion has be come a new kind of biopharmaceutical company: one that blends biotech‘s innovation, speed and flexibility with big pharma‘s operating discipline and excellence in execution. With the intrinsic belief that innovation in all domains is the key to growth, Actelion has built a global biopharmaceuti cal leader with a robust pipeline, three approved products, and commercial operations in more than 25 countries. Our over 1’900 employees have a common purpose: to improve patients’ lives by creating innovative medicines that make a real difference.. Four key principles strengthen Actelion’s strategy: 1. Follow innovation where it leads We pursue innovation - internal and external - balancing scien tific merit, unmet medical needs and commercial potential. 2. Retain the value of innovation We develop projects within the company, consider partner ships for strategic or financial benefit; if appropriate to maxi mize long-term value creation and to strengthen company infrastructure and reach. 3. Excel in sales and marketing We aim to continue to expand our highly experienced com mercial team into new territories as well as new markets when we have suitable products.. 3. Seek licensing deals or acquisitions that are synergetic to existing businesses or to provide an infrastructure plat form for pipeline products. 4. Focus on people: It takes professionals from many areas of expertise, working together over a sustained period of time, to create an innovative medicine. We know that products don’t discover or sell themselves and so con tinue to grow our innovative team of creative minds.. The Future for Actelion Actelion is on the verge of transforming itself into an orga nization with a much larger footprint. The success of any of the four ongoing major Phase III programs – bosentan for Idiopathic Pulmonary Fibrosis (IPF), clazosentan for vasos pasm after aneurysmal subarachnoid hemorrhage (aSAH), almorexant for insomnia and macitentan for pulmonary arte rial hypertension – could accelerate Actelion’s growth over the next decade. While pursuing the key components of our strategy, we must carefully plan for success and anticipate the needs of a much larger organization. Even if only two of these programs are ultimately successful, Actelion will undoubtedly become one of the world’s leading and largest biopharmaceutical companies. It is my belief that only when all of our desire and drive is focused on being number one, in everything we do, can we really turn innovation into value. Jean-Paul Clozel, CEO. 4. Retain core values, culture and independence We constantly strive to strengthen our culture of Innovation, Trust and Teamwork and Open Communication to foster an enthusiastic and stimulating environment for employees. At the same time we maintain our Results Driven orientation.. The key components of Actelion’s strategy are: 1. Build our existing businesses in PAH and lipid storage dis orders whilst developing or licensing additional synergetic products. 2. Pursue an R&D-focused growth strategy by pursuing in ternal projects, especially those which would accelerate value creation. Selectively form partnerships for these products to optimize risk, investment and return.. 07. 01 Our strategy. WorldReginfo - 347f5acf-d29f-4cfe-9635-5f104be92861. Securing a successful future.

(8) WorldReginfo - 347f5acf-d29f-4cfe-9635-5f104be92861. 02 Our people and values.

(9) Our employees - Together we innovate. At Actelion, people make the difference. Actelion’s business momentum is mirrored in the growing number of employees. Our staff represents the best profes sional attributes and the highest ethical standards. We place high priority on attracting, developing and retaining highly tal ented people. Employees identify with the goals and values of our company and turn the vision of Actelion’s founders into reality: People with passion and expertise are paving the way to our future success.. Throughout its years of rapid growth, Actelion has always been highly conscious of the fact that it’s people who make the difference. In turn, we have made sure our employees understand that we expect each of them to make a signifi cant contribution.. Our values A culture focused on innovation, trust and teamwork enables Actelion to flourish in the biopharmaceutical sector by at tracting and retaining the best people in the industry. Our open communication and a results-driven approach fosters an enthusiastic, stimulating environment for both employee and company development. Innovation Actelion has a keen understanding of the entrepreneurial spirit. We know the importance of enabling freedom to im prove people’s lives by creating medicines that make a real difference. This shared “patients-first” mindset drives us to achieve our goals.. Actelion acknowledges that people come to us from diverse backgrounds, both culturally and professionally. We strive to provide our employees with the best environment in which they can fulfill their individual aspirations and contribute to innovative medicines that positively affect patients’ lives. Actelion's CEO, Jean-Paul Clozel, spends a considerable amount of his time working to foster a corporate culture in which innovation is the focus. As a company, we have de fined the professional development of our employees as a strategic priority. On a day-to-day basis, we undertake sub stantial improvements in infrastructure and the services pro vided to our rapidly expanding workforce. In this way, we can ensure a well-resourced environment conducive to optimal productivity.. Open Communication To rapidly advance our projects, we need to make sound de cisions based on facts. We identified open communication as a vital way to share information and knowledge in order to recognize risks as well as opportunities early on. This en sures efficiency and the effective use of our resources. Results Driven Actelion strives to improve patients’ lives and is therefore committed to rapidly advance its pipeline. We are consistent and clear in decision-making and focus on simple, practical approaches to provide innovative life-changing drugs to pa tients.. 09. 02 Our people and values. WorldReginfo - 347f5acf-d29f-4cfe-9635-5f104be92861. Trust & Teamwork Trust and teamwork is key to everything we have accom plished. Through sharing ideas and responsibilities, we en hance our expertise and skills – because working together yields greater results..

(10) WorldReginfo - 347f5acf-d29f-4cfe-9635-5f104be92861. 03 Research.

(11) Scientists at Actelion use an inquisitive drug hunting ap proach to discover and develop novel medicines to improve patients' lives. From the outset, Actelion's founders wanted to create a company with a bold, pioneering spirit, one that understands the true nature of innovation. The founders understood that innovation could not be taught, but the right environment to allow innovation can be fostered. Actelion’s productivity is evidence that from creative freedom, innovative ideas flour ish. By removing the barriers to innovation, such as bureaucracy and hierarchy, the founders set out to empower “their” peo ple. In turn, Actelion’s people take ownership of their proj ects and grasp opportunities. There are many barriers to overcome when guiding a com pound that addresses an unmet medical need from the bench to the market. To maximize success, the Research and De velopment teams must know which projects are most prom ising, which compounds should be promoted, and where to focus their efforts. The only way to make the correct choices is to base these decisions on all facts available. This means open, effective communication within teams and across functions in an in tegrated approach. This sharing of knowledge stimulates and builds scientific in tuition. By using this approach, innovation can be translated into evidence-based medicine.. Drug discovery process To maximize output from its focus on target families, Actelion implements appropriate state-of-the-art technologies. The Drug Discovery group, comprising of 310 professionals at the end of 2008, combines technology with human expertise and teamwork in a single research center based in Allschwil to make the best use of Actelion's toolbox.. molecular drug targets. The characterization includes the development of a variety of assays and execution of activ ity screens. The vast quantities of assay result data gener ated, more than 3.8 million data points in 2008, are managed and analyzed by data-management programs developed in house. A lead compound is then passed to our pharmacologists, neurobiologists, immunologists and electrophysiologists to further characterize the compounds. These lead compounds are then passed back through this cycle until an optimized compound is available for preclinical development by our pharmacokineticists, formulation specialists, and toxicolo gists. At the end of 2008 the platform approach, combined with our technological capabilities and in-house expertise, resulted in three compounds undergoing preclinical investigation, with the potential selection of several other preclinical candidates during 2009. The final outcome is a robust clinical develop ment pipeline of compounds discovered and optimized in Actelion’s laboratories.. Platform approach Actelion’s efforts in drug discovery have focused on develop ing platforms of expertise based on its core capabilities. This focus allows high productivity in the generation of innovative compounds potentially addressing a wide range of highly un met medical needs. The first focus is the design, synthesis and optimization of low molecular weight drug-like molecules. The productiv ity of the drug discovery endeavors is demonstrated by the more than 1,300 pending patent applications and/or granted patents currently in Actelion’s portfolio. In 2008, the com pany filed 52 priority patent applications, an indication of very high research productivity. Actelion also focuses on the choice of its molecular target families. Initially, the company looked solely at G-protein coupled receptors (GPCRs) and aspartic proteinases. As the company’s capabilities have expanded so too have the target platforms to include anti-infectives and ion channels.. Actelion has over 100 medicinal and process chemists creat ing low molecular weight compounds which go through a cyclic drug discovery process for optimization.. New chemical entities. These innovative compounds are then characterized by mo lecular biologists and biochemists in relation to the chosen. Actelion's research focuses on the design and synthesis of novel low molecular weight drug-like molecules. Experience. 11. 03 Research. WorldReginfo - 347f5acf-d29f-4cfe-9635-5f104be92861. Research strategy.

(12) G-Protein coupled receptors G-Protein coupled receptors (GPCRs), also known as seven transmembrane domain receptors (7TMs), are integral mem brane proteins. They can be activated by external signals, such as hormones, neurotransmitters, or odors. This activa tion induces a conformational change of the receptor which in turn causes activation of G-proteins and the subsequent transmission of biochemical signals within the cell. There are more than a hundred known GPCRs in humans, and many of them are involved in a broad range of diseases. Some of these receptors are the subject of our development programs, such as the endothelin receptors ETA and ETB, orexin receptors OX1 and OX 2, or the sphingosine-1-phos phate receptor S1P1.. Aspartic proteinases Aspartic proteinases are a class of enzymes that promote chemical reactions inside and outside cells. To perform their function, aspartic proteinases use an arrangement of two as partic acids in order to activate a water molecule that acts as a chemical “scissor”. There are more than 50 known aspartic proteinases, of which at least nine are currently known to exist in humans. Al though knowledge of their precise physiological roles is still emerging, they have been implicated in cancer, as well as in inflammatory, degenerative, and cardiovascular diseases.. Ion channels Ion channels are transmembrane pores that allow the pas sage of ions (charged molecules) into or out of a cell. There are hundreds of different ion channels, distinguished by ion selectivity, opening mechanism, and protein sequence. Ion channels can be opened by chemical ligands, voltage fluctua tions, acidity changes, temperature variations, or mechanical stimuli (e.g. touch or sound). In mid-2004, Actelion established an in-house in-vitro elec trophysiology group. This was primarily to provide internal support for early preclinical evaluation of drug safety in the area of cardiac electrophysiology. Since the scientific knowledge and technical capabilities re quired in this area are very similar to those in the area of car diovascular ion channel therapies, research programs were soon initiated looking for modulators of selected ion chan nels to treat cardiovascular diseases. Expansion of the electrophysiology group and integration of new expertise and technologies led to the initiation of re search projects targeting ion channels to treat neurological and immunological diseases.. Anti-infectives Due to the development of resistance to currently available antibiotics and the emergence of new pathogens, the medi cal need for new antibiotic compounds is high. In order to address this high unmet medical need, Actelion initiated, in 2004, a research program in the field of antibiotics. Actelion’s focus is on the discovery of novel classes of antibiotics that may offer improved properties, such as in creased potency, coverage of multi-resistant pathogens, and a decreased inherent liability for resistance development. A portfolio of projects has been established focusing on both antibiotics for intravenous treatment of severe hospital infec tions, and oral antibiotics for community acquired infections.. In addition, aspartic proteinases play a vital role in organisms that cause infections, including parasites, fungi, and retrovi ruses such as HIV. Members of the aspartic proteinase family are the subject of our research and development programs, such as the renin inhibitor program.. 12. WorldReginfo - 347f5acf-d29f-4cfe-9635-5f104be92861. has shown that small molecules generally lend themselves to easier formulation, have a broader array of dosage forms, have greater potential for bioavailability, in particular after oral administration, and are more efficiently manufactured. While Actelion’s medicinal chemistry and high-throughput chemistry groups synthesize smaller quantities of structur ally diverse molecules, process research chemists prepare the quantities of selected compounds needed for further studies..

(13) Actelion selects its molecular drug targets on the basis of the established platforms of expertise, capabilities, technol ogies and the professionals at its research center. Actelion’s inquisitive researchers all have the opportunity to suggest a new target and follow the evaluation process. Additional selection criteria which the proposed projects are required to demonstrate include: • • • •. medical need therapeutic novelty predictive animal models clinical feasibility. Therapeutic areas. Endothelial cells produce several vasoactive chemical fac tors including endothelin, nitric oxide and prostacyclin. Endothelin system Endothelin Endothelial cells produce several vasoactive chemical fac tors, among them endothelin and nitric oxide, which work in opposition. Nitric oxide dilates blood vessels, prevents plate let adhesion, and inhibits cell proliferation. Endothelin, however, is a powerful blood vessel constrictor that also promotes cell proliferation. In a normal healthy state, the body maintains a balance between nitric oxide and en dothelin. In contrast, in certain disease states endothelin is produced in excess. In addition to causing vasoconstriction – the narrowing of blood vessels – excessive endothelin can: •. Actelion endeavors to follow innovation where it leads, as evidenced by the fact that from a few target platforms, Actelion’s compounds have found, or might find, applications in multiple disease areas, such as cardiovascular diseases, central nervous system disorders, immunological disorders and infectious diseases. In 2007, Actelion expanded its re search efforts by adding a dedicated oncology unit to evalu ate all ongoing efforts for further potential applications in the field of cancer.. Cardiovascular disorders Cardiovascular disorders encompass all conditions where there is a disturbance in the function of the heart or blood vessels. Cardiovascular disease accounts for more than one death in three in industrialized countries, and accounts for an increasing proportion of death in the developing world.. Actelion's focus The endothelium The endothelium is an organ consisting of a single layer of cells between the blood stream and the blood vessel wall. The main functions of the endothelium include: • •. 13. maintenance of blood vessel tone, which is critical for regulating blood pressure levels prevention of blood clots forming on the vessel wall by providing a non-adhesive surface. •. •. stiffen blood vessels and tissues by promoting fibrosis, the accumulation of connective tissue cause vascular remodeling (a change in the vessels' structure), vascular hypertrophy (an increase in the thick ness of blood vessel walls), and cardiac hypertrophy predispose the vessels to inflammation. Endothelin receptors Endothelin binds to two types of receptors found on the blood vessel walls and in tissues: ETA receptors, which are found predominantly in smooth muscle cells in the blood vessels, and ETB receptors, which are also found in fibroblasts, neu ronal cells, endothelial cells, and hormone-producing cells. The activation of the endothelin system plays a critical role in chronic cardiovascular diseases, such as pulmonary hy pertension, and in acute cardiovascular conditions, such as right heart failure and cerebral vasospasm – a constriction of blood vessels in the brain following subarachnoid hem orrhage. It is also implicated in connective tissue diseases such as scleroderma and pulmonary fibrosis. Endothelin levels have been shown to correlate with disease severity. Among Actelion's endothelin receptor antagonists are oral dual ETA -ETB antagonists, and an intravenous selective ETA antagonist for cerebral vasospasm, which block the conse quences of excessive endothelin. Prostacyclin system Prostacyclin Endothelial cells produce several vasoactive chemical fac tors, among them prostacyclin (PGI2), which induce vasodi latation of blood vessels and inhibit smooth muscle cell pro liferation and platelet aggregation. The peptide endothelin is. 03 Research. WorldReginfo - 347f5acf-d29f-4cfe-9635-5f104be92861. Project selection.

(14) Prostacyclin receptor (IP) Prostacyclin binds the prostacyclin receptor (IP) located on the surface of platelets and vascular smooth muscle cells. The IP receptor is a G-protein coupled receptor that, upon activation by prostacyclin, stimulates the formation of cyclic adenosine monophosphate (cAMP). Dysfunction of the pros tacyclin system occurs in several cardiovascular disorders, including thrombosis, myocardial infarction, stroke, myo cardial ischemia, atherosclerosis and pulmonary arterial hy pertension (PAH). Restoration of prostacyclin function using prostacyclin analogues that activate IP receptors improves prognosis for patients with PAH. Prostacyclin counteracts the vasoconstrictor and pro-thrombotic activity of endothe lin. Actelion is developing an orally available and long-acting non-prostanoid IP receptor agonist that mimics the actions of endogenous prostacyclin for the treatment of PAH.. Disorders of the endothelium Pulmonary arterial hypertension Pulmonary arterial hypertension (PAH) is a serious disease of the pulmonary arteries connecting the right side of the heart to the lungs. Under normal conditions, the lower right chamber of the heart (the right ventricle) pumps venous blood through the lungs, so the blood can pick up oxygen. PAH develops as a consequence of increasingly restricted blood flow through the pulmonary arteries. Pressure increas es within the pulmonary arteries, which puts the right side of the heart under increased strain to pump blood through to the lungs. Right ventricular failure may ultimately result. PAH may be idiopathic (no known cause) or secondary to other diseases such as scleroderma, congenital heart disease and HIV. Digital ulcers in systemic sclerosis Systemic sclerosis (SSc) is a chronic autoimmune connective tissue disease characterized by excessive collagen deposi tion in the skin and internal organs, such as the gastrointes tinal tract, kidney, heart, and lungs. Symptoms result from vascular dysfunction, inflammation, and progressive fibrosis, which lead to occlusion of the microvasculature.. As a result of the vascular injury, complications such as pulmonary arterial hypertension (approximately 100,000 to 200,000 PAH patients worldwide) and digital ulcers (approxi mately 5,000 severe cases every year worldwide) can occur. Around 40% - 50% of systemic sclerosis patients suffer from digital ulcers (DUs) at least once in their disease history. DUs are very painful and result in difficult-to-heal open sores that occur on fingers and toes. They leave depressed scars and adversely impact the ability to perform work and daily activi ties, particularly those associated with fingertip functions. In severe cases, infection can become a complication leading to osteomyelitis and gangrene, for which surgery and even amputation may be required. DUs are caused by a reduction in the lumen of small blood vessels (obliterative vasculopathy as observed in the lung in PAH) that diminishes the blood flow to the fingers and toes. Endothelin, a pathogenic mediator, is implicated in vascular damage in SSc. In addition to causing vasoconstriction, en dothelin also has direct deleterious effects, which cause fi brosis, vascular hypertrophy, and inflammation. Idiopathic pulmonary fibrosis Pulmonary fibrosis is a progressive and usually fatal disease which may arise idiopathically or in association with underly ing diseases like systemic sclerosis. It is estimated that there are around 60,000 patients worldwide with idiopathic pulmo nary fibrosis (IPF). In IPF, fibrosis destroys both the structure and function of the respiratory system. Endothelin has direct pro-fibrotic and pro-inflammatory effects. Since endothelin concentrations are strongly elevated in interstitial lung disease, there is also evidence implicating endothelin in these diseases. For pa tients with IPF outside of Japan, there are currently no ap proved therapies available. Cerebral vasospasm as a consequence of aneurysmal subarachnoid hemorrhage Aneurysmal subarachnoid hemorrhage (aSAH) is a life threatening condition affecting over 100,000 people in the EU, US and Japan every year. This condition occurs when the rupture of an aneurysm on the cerebral vessels leads to release of blood into the subarachnoid space of the brain. Endovascular coiling or microsurgical clipping is usually re quired to stop the bleeding and prevent further episodes. Cerebral vasospasm following SAH causes the intracranial arteries to constrict thus diminishing blood flow to the brain. It is a significant predictor of poor outcome and the leading. 14. WorldReginfo - 347f5acf-d29f-4cfe-9635-5f104be92861. also produced by the endothelium, and is a potent constrictor of blood vessels and promotes cell proliferation. In a normal healthy state, prostacyclin helps counter-balance the ac tions of endothelin. In certain disease conditions, however, production of prostacyclin by the endothelium is impaired, allowing the deleterious effects of excessive levels of en dothelin to predominate..

(15) Endothelial system related oncology Endothelin receptors and endothelin are over-expressed on tumor cells and stromal cells in several tumor types, such as melanoma. They also contribute to invasion and metas tasis. Actelion's endothelin antagonists are therefore being explored for application in cancer therapy.. Renin angiotensin system The key enzyme renin is produced in the kidney, where it serves as gatekeeper to the biochemical cascade that ulti mately results in production of the hormone angiotensin II. Under normal conditions, the kidney controls blood volume, blood pressure, and the electrolyte composition of body fluids, through the tightly regulated production of renin and therefore of angiotensin II. The overproduction of angiotensin II produces a range of del eterious effects. Disorders of this system are a major fac tor in high blood pressure, heart disease and kidney failure. Drugs that block the renin-angiotensin II system comprise an important category of cardiovascular drugs used today. These drugs – angiotensin II converting enzyme (ACE) inhibi tors, and angiotensin II receptor blockers, or ARBs – are ap proved medicines for high blood pressure, kidney disease and heart failure, and are among the most commercially suc cessful classes of pharmaceuticals. A compensatory increase in other enzymes, such as chy mase, can bypass the effects of an ACE inhibitor; further more, ARBs do not block all angiotensin II receptors. There fore, it is predicted that an orally active renin inhibitor may provide a more specific and a more complete inhibition of the renin-angiotensin II system than either an ACE inhibitor or an ARB alone.. Central nervous system Central nervous system (CNS) or brain diseases (psychiat ric, neurological, and neurosurgical disorders) figure among the leading causes of disease and disability. Recent WHO data suggest that brain disorders cause 35% of the burden of all diseases in Europe. Of patients in primary care, 25% are affected by a neuropsychiatric disease – such as mood disorders (depression, anxiety), psychotic conditions (schizo phrenia, mania), declined cognitive function (Alzheimer and neurodegenerative diseases) or brain trauma (stroke, brain or spine lesion). Brain disorders are substantially more costly to society than other important fields in medicine such as heart disease, cancer, and diabetes. The brain, a very sophisticated and complex organ, cannot easily be investigated in isolation, and this has impacted the development of neurological and psychiatric treatments. However, dramatic advances in CNS research over the last two decades, enable the development of truly innovative treatments today.. Actelion's focus Sleep & sleep disorders It is widely acknowledged that a lack of sleep can have a significant negative impact on daily functioning, and physical and mental health. There are four main categories of sleep disorder: hypersomnia, circadian rhythm disorders, parasom nias, and insomnia. Insomnia is, worldwide, the most com monly reported sleep disorder, and is estimated to affect up to one third of the adult population. Most sleep disorder products on the market enhance the ef fects of gamma-aminobutyric acid (GABA), the major inhibi tory neurotransmitter in the central nervous system. Such medications suffer from a major trade-off: the greater the efficacy, the greater the "hangover" effect the next day in terms of impaired mental and physical performance. Usually, sedatives decrease the length of the REM (rapid eye move ment) sleep phase, which – together with non-REM sleep – is hypothesized to be important for memory consolidation. Normal physiological sleep Overall, the structure of sleep is described as "sleep archi tecture". Sleep is composed of non-rapid eye movement (NREM) and rapid eye movement (REM) sleep. REM is the stage of sleep during which most dreams occur,. 15. 03 Research. WorldReginfo - 347f5acf-d29f-4cfe-9635-5f104be92861. potentially treatable cause of mortality and morbidity in these patients. Vasospasm is unpredictable in nature and seen in over 67% of untreated patients with angiography at the time of maximum spasm, around the end of the first week. It becomes symptomatic in about half of these patients. Cur rently, there is no effective treatment for the prevention and treatment of the severe complications following vasospasm..

(16) NREM is divided into four further stages: stages one and two are light sleep, while stages three and four are deep or "slow wave" sleep. The total time of REM sleep per night is about 90–120 min utes. Over the course of the night, time spent in REM sleep increases in length, while deep sleep decreases. By morning, people spend the majority of their sleep time in stages one and two, and REM sleep. Seven to eight hours of sleep a night is considered to be a healthy level for most adults over the age of 25, although people over the age of 65 gener ally tend to sleep less, and spend less time in deep or REM sleep. Neurotransmitters and neuromodulators involved in the reg ulation of the sleep-wake cycles include: dopamine, orexin (hypocretin), histamine, acetylcholine, norepinephrine, gluta mate, GABA, adenosine and serotonin. Orexin system Actelion's research team is targeting the G-Protein coupled receptors (GPCRs) that mediate the actions of orexins. Orex ins are neuropeptide modulators produced in the brain to regulate alertness and reward seeking. For example, genetic defects of the orexin peptides, or their receptors, are asso ciated with certain inherited sleep disorders. Orexins have been further associated with food consumption, physical ac tivity, and metabolism in experimental animals. Orexins may also play a role in other conditions.. Alzheimer's disease Alzheimer’s disease is a form of senile dementia, a progres sive neurodegenerative disease. Each patient might expe rience the symptoms and disease progression very differ ently. Early symptoms can be missed easily because they resemble the natural signs of aging, or can result from fa tigue, grief, depression, illness or alcohol. Since the preva lence of neurodegenerative diseases, such as Alzheimer’s disease, increases with age, these diseases are likely to be come commonplace due to the aging population, and will therefore become a greater burden on family and care-givers, and on health care services in general.. BACE-1 inhibition BACE-1 (beta amyloid converting enzyme, or beta-secretase) a member of the aspartic proteinase family, is an important target for development of a drug therapy for Alzheimer's dis ease. It is hypothesized that inhibition of BACE-1 will prevent the formation of amyloid plaques, which are protein frag ments that accumulate in the brains of Alzheimer's disease patients. If so, a BACE-1 inhibitor may prove effective in pre venting and treating Alzheimer's disease.. Genetic disorders Genetic disorders are caused by abnormalities in genes or chromosomes. They are chronically debilitating, sometimes life-threatening, diseases with a low prevalence and a high level of complexity and heterogeneity. There are many high unmet medical needs in the field of genetic disorders, with only few disease-modifying drugs available. These rare dis orders call for a global approach to special and combined efforts to prevent significant morbidity or avoidable prema ture mortality, and to improve the quality of life of those af fected.. Actelion's focus Type 1 Gaucher disease Gaucher disease is the most common disease among all inherited glycosphingolipid storage disorders, affecting ap proximately 7,000 patients worldwide. It is an inherited autosomal recessive disorder caused by the accumulation of glucosylceramide in the lysosomes of monocyte-derived macrophages (Gaucher cells), in tissues of the reticuloendothelial system, due to the reduced activity of lysosomal ß-glucocerebrosidase. Accumulation of gluco sylceramide in Kuppfer cells in the liver and in splenic mac rophages is associated with enlargement of the correspond ing organs. Splenomegaly and bone marrow infiltration by Gaucher cells lead to progressive anemia and thrombocy topenia. Accumulation of glucosylceramide in bone marrow is associated with osteopenia, lytic lesions, chronic pain, acute episodes of "bone crisis”, bone infarcts, and osteone crosis. Overall, Gaucher disease is a multi-system disease with under-diagnosed bone manifestations – in particular, re duced bone mineral density and bone pain, resulting in long term disability.. 16. WorldReginfo - 347f5acf-d29f-4cfe-9635-5f104be92861. and is thought to play an important role in the consolidation of certain types of memories – this is key for a person’s abil ity to store and process information. During this stage, the eyes move rapidly behind the eyelids, and the activity of the brain’s neurons is similar to that which occurs during wake fulness..

(17) Niemann-Pick type C disease Niemann-Pick type C (NPC) disease is a rare, fatal, degenera tive, genetic condition primarily affecting children and teenag ers, but which can strike at any age. There are approximately 900 NPC patients worldwide. The neurological symptoms of NPC are caused by the accumulation of glycosphingolipids in neurons, secondary to abnormal lipid trafficking. NPC is re lentlessly progressive. Neurological deterioration is a key fea ture of the disease, and can manifest itself as clumsy body movements, balance problems, slow and slurred speech, swallowing difficulty, eye movement problems, and seizures. Intellectual decline is common. In the final stages of the dis ease, the child or young adult is frequently bedridden, has little muscle control, and is intellectually impaired.. Cystic fibrosis Cystic fibrosis (CF) is an autosomal recessive, genetic disor der that leads to a multi-system organ dysfunction. CF is the most common fatal genetic disorder in the Caucasian popu lation, affecting approximately 80,000 patients in the US and EU. Cystic fibrosis involves all epithelial cells, and classically impacts the lungs, sinuses, pancreas, liver/bile ducts, intes tines, reproductive tract, bones, and sweat glands. The most serious consequence of CF is respiratory disease. Due to mucus hyperviscosity, individuals with CF develop chronic lung infections, leading to chronic inflammation and lung scarring. Progressive lung dysfunction is the most significant cause of morbidity and mortality. CF is caused by functional defects of the cystic fibrosis trans membrane conductance regulator (CFTR) protein, a chloride channel that controls ion and water content in epithelial cells. A large number of mutations can affect the CFTR protein, the most frequent being delF508. The delF508 mutation gives rise to a CFTR protein that retains some function, but which is not transported properly to the plasma membrane. As a result, ion and water movements through the epithelial cell membrane are abnormal, causing mucus hyperviscosity. Current therapies for CF involve mucolytics, antibiotics to prevent bacterial colonization and lung infection, and nutri tional management. There is currently no disease-modifying drug approved for CF.. 17. Immunology Autoimmune diseases and allergies are characterized by an inappropriate response of the immune system to either the body's own tissue or to environmental antigens. An estimated five to eight percent of the North American population is affected by autoimmune diseases, underscoring their importance in the public health sector. The prevalence of allergic diseases has increased over the past decades af fecting up to 20% of the population in developed countries. In parallel the economic burden by direct (e.g. medical) and indirect (e.g. work days lost) costs has been growing sub stantially. Across these indications, there is (in the absence of a cure) a high medical need for therapies which provide adequate efficacy combined with safety and tolerability pro files superior to currently available therapies.. Actelion's focus Allergy An allergy is a unique type of an immune reaction. Normally, the immune system responds to foreign microorganisms or particles by producing specific proteins called antibodies. These antibodies are capable of binding to specific sites, or antigens, on the foreign particle. The recognition between antibody and antigen sets off a series of chemical reactions designed to protect the body. Sometimes, the production of antibodies is triggered by harmless, everyday substances such as pollen, dust, and animal dander. When this occurs, an allergy may develop against the offending substance (which is then called an allergen). Not all patients respond to current therapies, and the majori ty of patients do not achieve disease control. This, combined with inconvenient administration forms and side effects, amounts to a high unmet medical need, requiring a new ap proach. Actelion’s research targets allergy-specific process es with a focus on regulation of specific immune cells. Allergic response Initiation The first time an allergy-prone person encounters an innocu ous substance misidentified as harmful, the immune system produces antibodies called immunoglobulins, or Igs. The Ig responsible for allergic reactions is IgE. These IgE molecules attach themselves to mast cells (a type of cell containing histamine and other allergy mediators instrumental in the al. 03 Research. WorldReginfo - 347f5acf-d29f-4cfe-9635-5f104be92861. Current treatments for type 1 Gaucher disease include en zyme replacement therapy (imiglucerase, Cerezyme®) and substrate reduction therapy (miglustat, Zavesca®). Palliative treatments include analgesics, antibiotics and bisphospho nates..

(18) lergic response).. Actelion believes that based on this information:. The second time the person encounters the substance, the IgE antibodies bound to the mast cells recognize surface markers of the allergen (antigens). As a consequence, the mast cells become activated.. •. CRTH2 antagonism has the potential to influence the al lergic response at a high hierarchical level (Th2 cell).. •. CRTH2 antagonism could have the potential to affect the LAR, as well as phases of the allergy borne inflam mation and its consequences beyond LAR.. Amplification The released mediators activate other leukocytes, including eosinophils and Th2 lymphocytes and recruit them to the site of inflammation. These cells promote downstream effects including eosino philia and further IgE production. This late response can eas ily convert into a chronic inflammatory response. CRTH2 receptor antagonism CRTH2 (Chemoattractant Receptor-homologous molecule expressed on Th2 cells) is a G-protein coupled receptor ex pressed by Th2 lymphocytes, eosinophils, and basophils. The receptor mediates the activation and chemotaxis of these cell types in response to prostaglandin D2 (PGD2), the major prostanoid produced by mast cells. PGD2 is released through mast cell degranulation in the initial phase of IgE-mediated reactions. This process is considered to occur also at the site of inflammation such as the nasal and bronchial mucosa. Through interaction with CRTH2, PGD2 is thought to mediate recruitment and activation of CRTH2-bearing cell types to the site of the allergic reaction, in consequence amplifying and maintaining the allergic inflammation. In the nasal and bronchial mucosa this pro-inflammatory cascade is thought to start already during the so-called late allergic response (LAR) occurring three to nine hours after allergen challenge. The interaction between PGD2 and CRTH2 would therefore contribute to the so-called “Th2 polarization”, with conse quent Th2 cytokine production and the typical eosinophilic and basophilic characteristics of the inflammation.. S1P system The adaptive immune system relies on constant circulation of lymphocytes between lymphoid organs and other tissues of the body. After maturation, lymphocytes leave the bone marrow or thymus, enter the circulation, and travel via the blood and the lymphatic system, surveying for antigens they recognize. In the secondary lymphoid organs, which include lymph nodes, Peyer's patches, and the spleen, naïve lymphocytes encounter antigen-presenting cells and may be activated. Once activated, T cells must leave the lymph node to reach target tissues, whereas B cells can secrete antibodies with out leaving the secondary lymphoid organs. Circulation of lymphocytes between blood, lymphatic system, and non-lymphoid tissues is tightly regulated, and it has recently been shown that the lysophospholipid sphingosine 1-phosphate (S1P) plays a central role in lymphocyte trafficking. Sphingosine-1-phospate (S1P) is a phospholipid released by platelets, mast and other cells. It is now known that S1P stimulates at least five different G-protein coupled recep tors (GPCRs): S1P1, S1P 2, S1P 3, S1P4, and S1P5. Activation of these GPCRs mediates a complex variety of biological responses, such as lymphocyte migration, endothelial cell proliferation, blood vessel constriction, heart rate modula tion and others. The concentration of S1P is low within the lymph node interior, but very high in the adjacent draining lymphatic vessels. These two compartments are separated by lymphatic endothelium. Lymphocytes are able to sense a concentration gradient of S1P and migrate towards the higher S1P concentration. The migration of lymphocytes out of secondary lymphoid organs is dependent on the S1P1 receptor. Actelion's efforts in the field of selective S1P1 receptor ago nists started in 1999 by focusing on receptors found on the endothelium, the inner lining of blood vessels.. 18. WorldReginfo - 347f5acf-d29f-4cfe-9635-5f104be92861. Activated mast cells release powerful chemical mediators such as histamines, prostanoids, leukotrienes, chemokines, and cytokines from preformed granules. In addition, the ac tivation of mast cells leads to the continued production of these mediators promoting long term effects..

(19) S1P1 agonism. Actelion's focus. In the presence of a selective S1P1 receptor agonist, lym phocytes lose their ability to sense S1P concentration gra dients. As a consequence, selective S1P1 receptor agonists block lymphocyte migration out of lymphoid tissue into the lymphatic and blood circulation, thereby reducing peripheral lymphocyte counts and preventing lymphocyte recruitment to sites of inflammation.. • •. Infectious diseases Infectious diseases are the second leading cause of mortality, causing about 20% of global deaths according to the World Health Report 2003. Among these, respiratory and other bacterial infections account for four million deaths each year; tuberculosis is responsible for another 1.5 million fatalities. Antibiotics have saved millions of lives since their introduc tion in the 1940s, and have contributed much to the increase of life expectancy around the world in the past century. Yet drug-resistant pathogens have been on the rise in recent decades. Resistance may be due to exclusion (stopping the drug from entering the bacteria), efflux (pumping the drug out of the bacteria), inactivation of the drug (breakdown or chemical modification), or modification of the cellular target (eg. point mutations within the active site). Increasingly, in fections that were once treatable with antibiotics are becom ing difficult or impossible to treat. The Infectious Diseases Society of America (ISDA) estimat ed that in 2004, two million people acquired bacterial infec tions while in hospital, and about 90,000 patients died as a result. About 70% of these infections were due to resistant or multiple-resistant pathogens.. 19. Infectious diseases strategy Actelion’s research focuses on new targets with proven antibacterial activity, and new chemical scaffolds with new mechanisms of action. It aims to combine two pharmacophores - molecular framework with biological activity - into one molecule, thus addressing multiple targets in parallel. Actelion believes that this strategy offers the potential benefits of no cross-resistance with established classes, a low propensity to developing resistance, and a broad spectrum. Characteristics of Actelion's anti-bacterials • • • • • •. Novel chemical classes with new modes of action Addressing multiple targets Broad coverage of indication-specific spectrums No cross-resistance with established classes Low propensity to developing resistance Bactericidal effect. Oncology Knowledge and understanding of the molecular pathophysi ology of cancer has improved significantly over the last 25 years. This has led to the testing of a large number of new approaches to treating cancer patients. Some of these target oriented approaches have led to impressive benefits for the patients with certain cancers, such as Hodgkin lymphoma or chronic myelogenous leukemia. However, the majority of cancers respond only initially, or become resistant to current targeted therapies or drug combinations. Fortunately, the technologies available today allow rapid progress in further understanding the mechanistic basis of cancer, and the se lection and testing of new treatments. The recent identifica tion of tumor stem cells, the importance of the tumor stroma – such as angiogenesis and the dissection of the process of tumor metastasis – and the process leading to cancer spread, all offer many new targets and target combinations. Taken together, the result is a promise for improved treatments for cancer patients in the future.. 03 Research. WorldReginfo - 347f5acf-d29f-4cfe-9635-5f104be92861. This new strategy for therapeutic immunomodulation offers potential advantages over existing therapies. Sequestration of T cells in lymphoid organs is expected to prevent the pro cesses that contribute to inflammatory diseases – such as tissue invasion, local cytokine release, macrophage recruit ment, and direct cell killing – while sparing functions that do not rely on homing mechanisms. These include antibody gen eration by B lymphocytes, first line immunological protection by neutrophils and monocytes, and antigen-dependent T cell activation and expansion.. New targets with proven antibacterial activity New chemical scaffolds with new mechanism of action.

(20) Actelion's focus Actelion’s research programs to identify and develop com pounds for cardiovascular and other diseases have provided compounds which can be of potential use in oncology. For instance, endothelin receptors and endothelin are over-ex pressed on tumor cells and stromal cells in several tumor types, such as melanoma, and contribute to invasion and metastasis. Our endothelin antagonists are therefore being explored for application in cancer therapy.. 20. WorldReginfo - 347f5acf-d29f-4cfe-9635-5f104be92861. The test systems we use will not only analyze effects on the cancer cells, but study the interaction between cancer cells and the tumor stromal elements (vascular cells and inflam matory cells). Besides exploiting compounds in our pipeline from other indication areas, we are using our discovery plat form and experience with certain target classes to select novel oncology approaches..

(21) WorldReginfo - 347f5acf-d29f-4cfe-9635-5f104be92861. 04 Development.

(22) Development process Actelion’s mission to bring innovative medicines to patients can only be realized when vigorous testing of the compounds in its pipeline has been performed, and the resulting data analyzed. Actelion’s clinical development department aims to fully explore and describe both the benefits for patients and any potential risks of the compounds. The group works to efficiently develop and bring to the market, on a global scale, innovative pharmaceutical products. The process is achieved through creative and targeted clinical and pharmacological research – supported by high performance strategic clinical development, biometry, drug safety, drug regulatory, life cycle, and operations functions. Through life cycle project teams, strategic clinical development initiates and consolidates the processes, from defining the target profile to submission to regulatory authorities. These processes are required to advance innovative compounds through the dif ferent phases of clinical development in a rapid and cost-effective manner. Actelion’s clinical science function ensures that all clinical programs adhere to the highest standards of science and medicine, while also ensuring the appropriate generation of all the information required by health care authorities worldwide. Through global, cross-functional life cycle teams organized by the development function, Actelion ensures the timely develop ment of a product to its full potential – from entry-into-humans through to introduction to the market – and that all appropriate measures are undertaken to maximize the full value creation potential of each product until the patent expires. The Biometry function with its expertise in the field of statistics and data management supports the development of Actelion's compounds and, together with Drug Safety, the safety monitoring of marketed products. At the end of 2008, Actelion’s clinical development group was working on a total of 75 different clinical trials enrolling close to 8,300 patients or healthy volunteers. This represents a significant increase compared to 2007, with 42 trials and almost 4,900 patients.. Development pipeline. Phase. Product/Compound. Indication. Study. Results expected. IV. Bosentan. Combination bosentan & sildenafil in PAH. COMPASS-2. n/a. IV. Iloprost. Pulmonary arterial hypertension (improved delivery system). PROWESS-15. H1 2009. IV. Miglustat. Type 1 Gaucher disease patients switched from ERT to miglustat. MAINTENANCE. 2010. III. Almorexant. Sleep disorders. RESTORA. n/a. III. Bosentan. Idiopathic pulmonary fibrosis. BUILD-3. H2 2009. III. Clazosentan. Prevention of vasospasm-related morbidity/mortality post a subarachnoid hemorrhage (SAH). CONSCIOUS-2. H2 2009. III. Macitentan. Pulmonary arterial hypertension. SERAPHIN. n/a. II. CRTH2 antagonist. Asthma. n/a. H1 2009. II. Miglustat. Cystic fibrosis. n/a. H1 2009. II. PGI2 agonist. Pulmonary arterial hypertension. n/a. n/a. II. S1P1 agonist. Immunology. n/a. n/a. I. Renin inhibitor. Cardiovascular. n/a. n/a. 22. WorldReginfo - 347f5acf-d29f-4cfe-9635-5f104be92861. Actelion's focus on high unmet medical needs.

(23) Phase IV Bosentan (Tracleer®). which were presented at the European Society of Cardiol ogy (ESC) in early September 2007. The longer-term safety and efficacy of this pediatric formulation of bosentan con tinue to be studied in the FUTURE-2 extension study.. About Bosentan in clinical development. Milestones. Bosentan (Tracleer ®), is an oral dual endothelin receptor antagonist, which is currently approved for the treatment of PAH, a chronic, life-threatening disorder which severely compromises the function of the lungs and heart. In the United States, Tracleer is approved for treatment of PAH Functional Class III and IV to improve exercise capacity and decrease the rate of clinical worsening, and in the European Union (EU) it is approved for treatment of PAH Functional Class III to improve exercise capacity and symptoms, as well as PAH Functional Class II where some improvements have also been shown. In the EU, Tracleer ® is also indicated to reduce the number of new digital ulcers in patients with systemic sclerosis and ongoing digital ulcer disease.. 2007 2005. FUTURE-1 study results presented at ESC 2007 FUTURE program initiated.. Key scientific literature Beghetti M. et al. Pharmacokinetics and safety profile of a novel formulation of bosentan in children with pulmonary arterial hypertension (PAH): FUTURE-1 study. European So ciety of Cardiology (ESC) Congress 2007 Abstract 1090 Bosentan in combination with sildenafil. Progress in 2008 Actelion’s development efforts for bosentan concentrate on compiling evidence in PAH sub-populations to assist doctors in their treatment approach. In addition, Actelion’s development team is actively investigating bosentan’s po tential in other endothelin-related diseases. Building on our knowledge about the effects of elevated endothelin levels, we are developing bosentan beyond PAH and digital ulcers as a treatment for idiopathic pulmonary fibrosis (IPF). IPF is a progressive and usually fatal disease of the lungs which, for patients outside of Japan, there is currently no approved therapy. Bosentan in Pediatric PAH. The COMPASS program specifically evaluates safety and efficacy of the use of bosentan in combination with sildenafil. Sildenafil is an approved treatment for PAH but one which works by its effect on another pathologi cal pathway of the disease. Actelion has concluded COMPASS 1, the first clinical trial to provide detailed hemodynamic information on the combination of sildenafil and bosentan. As of the end of 2008, the COMPASS 2 study was ongoing and investigates the effect on morbidity and mortality of a combination of bosentan with sildenafil compared to sildenafil monotherapy.. In the second quarter of 2008, Actelion initiated the regulatory review process for a dedicated pediatric for mulation of Tracleer ® and the extension of the indica tion to include the pediatric patient population, with a first submission to the European Health Authorities.. Available clinical data The Phase III open-label, single-arm FUTURE-1 (pediatric FormUlation of bosenTan in pUlmonary arterial hyperten sion) study evaluated the safety and pharmacokinetics of a unique, specially designed, pediatric formulation of bosen tan. This study provided important pharmacokinetic data. 23. Available clinical data COMPASS-1 demonstrated that adding sildenafil to patients on long-term bosentan therapy produced significant hemo dynamic improvements, including a significant reduction in mean pulmonary vascular resistance (PVR) observed 60 minutes after administration of a single dose of sildenafil 25 mg (-15.2% [95% CI: –20.8 to –9.6]; p < 0.0001), and a de crease in the mean total pulmonary resistance (-13.3% [95% CI: –17.0 to –9.6]; p < 0.0001).. 04 Development. WorldReginfo - 347f5acf-d29f-4cfe-9635-5f104be92861. Progress in 2008.

(24) Milestones. Available clinical data. 2007 2006. Ventavis is indicated for the treatment of PAH (WHO Group I) in patients with NYHA Class III or IV symptoms. In con trolled trials, it improved a composite endpoint consisting of exercise tolerance, symptoms (NYHA Class), and lack of deterioration.. Key scientific literature. Iloprost (Ventavis®). In December 2006, data from the Phase II/III clinical trial STEP, evaluating the safety and added benefit of using Ventavis® (iloprost) Inhalation Solution therapy in patients with PAH already undergoing treatment with bosentan, were published. The analysis of this study showed that the combination of Ventavis® added to bosentan therapy was well tolerated, consistent with the safety profile observed in patients receiving only iloprost.. About iloprost in clinical development. Milestones. Iloprost (Ventavis®) is an inhaled formulation of a synthetic compound that possesses high affinity for the prostacyclin receptor (IP receptor). Iloprost has a similar pharmacologi cal profile to endogenous prostacyclin (natural PGI2) but with greater chemical stability and longer half-life. The mecha nism of action of iloprost influences all the main pathological mechanisms involved in pulmonary hypertension (potent va sodilation, and antithrombotic, antiproliferative, anti-inflam matory and antifibrotic activity).. 2007. Gruenig E. et al. Acute administration of sildenafil in patients with pulmonary arterial hypertension (PAH) treated with bosentan produced a significant hemodynamic response: re sults of the COMPASS-1 study. European Society of Cardiol ogy (ESC) Congress 2007 Abstract 1012. In December 2004, the U.S. Food and Drug Administration approved Ventavis® (iloprost) inhalation solution, developed by Bayer Schering Pharma for the treatment of pulmonary arterial hypertension (WHO Group I) in patients with Func tional Class III or IV. CoTherix, Inc., a biopharmaceutical com pany based in San Francisco, USA, licensed the exclusive rights to develop and commercialize Ventavis® in the United States from Bayer Schering Pharma. Ventavis® is marketed by Bayer Schering Pharma as first inhaled prostacyclin in Eu rope and other countries outside the US. In January 2007, Actelion announced the successful com pletion of its cash tender offer for shares of CoTherix, Inc., thereby strengthening its PAH franchise by adding Ventavis® to its product offerings in the United States.. 2004. Actelion acquired CoTherix Inc, adding Ventavis to its product offerings FDA approved inhaled iloprost for treatment of PAH in US. Key scientific literature Ivy et al. Short- and long-term effects of inhaled iloprost ther apy in children with pulmonary arterial hypertension. J Am Coll Cardiol. 51(2):161-9; 2008. McLaughlin et al. Randomized study of adding inhaled ilo prost to existing bosentan in pulmonary arterial hypertension. Am J Respir Crit Care Med. 174(11):1257-63; 2006. Hoeper et al. Goal-oriented treatment and combination therapy for pulmonary arterial hypertension. Eur Respir J. 26(5):858-63; 2005. Hossein A. et al. Oral sildenafil as long-term adjunct therapy to inhaled iloprost in severe pulmonary arterial hypertension. J Am Coll Card. 42 (1): 158-64; 2003. Olschewski et al. Inhaled iloprost for severe pulmonary hy pertension. N Engl J Med. 1;347(5):322-9; 2002.. Progress in 2008. Miglustat (Zavesca®). In the second quarter of 2008, Actelion started the clinical evaluation of a reprogrammed Ventavis® (Iloprost) delivery device to potentially reduce inhalation time and increase patient compliance.. About miglustat in clinical development Miglustat is a low-molecular-weight inhibitor of glucosylcer amide synthase and α-glucosidase. With its unique physico. 24. WorldReginfo - 347f5acf-d29f-4cfe-9635-5f104be92861. COMPASS-1 study results presented at ESC COMPASS program initiated.

(25) chemical properties, miglustat exhibits a large volume of dis tribution and has the capacity to access deep organs such as bone, brain and lung. Miglustat (Zavesca®) 100 mg is indicated for the oral treatment of adult patients with mild to moderate type 1 Gaucher disease, and may only be used in those patients for whom enzyme replacement therapy is un suitable. It is approved in the European Union, United States, Canada, Switzerland, Turkey, Brazil, Australia, and Israel. Miglustat in type 1 Gaucher disease. Progress in 2008 The MAINTENANCE trial is evaluating the long term safety and efficacy of miglustat as maintenance therapy after a switch from enzyme replacement therapy (ERT) in mild to moderate adult type 1 Gaucher disease pa tients with stable disease. Enrollment in the MAINTE NANCE trial was completed during the second quarter of 2008. Results of this study are expected to become available in 2010.. 2003 2002. Zavesca® launched in the EU Zavesca® in-licensed; marketing authorization granted by European Commission. Key scientific literature Pastores G.M. et al. Effect of miglustat on bone disease in adult patients with type 1 Gaucher disease: a pooled analysis of three multinational Open-label studies. Clinical Therapeu tics. 29: 1645-53; 2007. Elstein D. et al. Oral maintenance clinical trial with miglustat for type 1 Gaucher disease: switch from or combination with intravenous enzyme replacement. Blood. 110: 2296-2301; 2007. Giraldo P. et al. Short-term effect of miglustat in every day clinical use in treatment-naïve or previously treated patients with type 1 Gaucher’s disease. Haematologica. 91:125-8; 2006. Elstein D. et al. Sustained therapeutic effects of oral miglus tat (Zavesca, N-butyldeoxynojirimycin, OGT 918) in type 1 Gaucher disease. J Inherit Metab Dis 27: 757-66; 2004.. Available clinical data Miglustat in Niemann-Pick disease type C. Milestones 2008 2008 2007 2005 2004. 25. EU approval for a type II variation for miglustat and bone disease in type 1 Gaucher disease Zavesca® launched in Turkey and Brazil Zavesca® approved in Australia Zavesca® launched in Canada Zavesca® launched in the US and Switzerland. Progress in 2008 In December 2008, Actelion announced that the Com mittee for Medicinal Products for Human Use (CHMP) had adopted a positive opinion for an extension of in dication for the use of miglustat (Zavesca®) in patients suffering from Niemann Pick type C disease. In late January 2009 Zavesca® (miglustat) received EU approval for the treatment of progressive neurological manifestations in patients with Niemann Pick type C disease. Actelion is currently evaluating the possibility for sub mission for miglustat (Zavesca®) in Niemann Pick type C disease in other countries outside the European Union.. Available clinical data Miglustat is able to cross the blood-brain barrier and, in an NPC mouse model, substrate reduction therapy with miglus tat was shown to reduce glycosphingolipid accumulation in. 04 Development. WorldReginfo - 347f5acf-d29f-4cfe-9635-5f104be92861. Zavesca® (miglustat) 100 mg is the only oral drug available for the treatment of type 1 Gaucher disease, and was ap proved on the basis of three international open-label clinical trials. The rationale for the use of miglustat in type 1 Gaucher disease is to help balance the overall level of glucosylcer amide by reducing its production to a level compatible with breakdown by residual glucocerebrosidase activity, a unique mode of action known as "substrate reduction therapy". Bone manifestations of type 1 Gaucher disease were evaluated in three open-label clinical studies in patients treated with mi glustat 100 mg t.i.d. for up to two years (n = 72). In a pooled analysis of uncontrolled data, bone mineral density Z-scores at the lumbar spine and femoral neck increased by more than 0.1 units from baseline in 27 (57%) and 28 (65%) of the pa tients with longitudinal bone density measurements. There were no events of bone crisis, avascular necrosis or fracture during the treatment period..

(26) the brain, improve neuromotor performance and increase survival. This data served as the basis for conducting the randomized controlled clinical trial OGT 918-007, and an in ternational retrospective survey in patients receiving miglus tat outside the clinical trial.. patients with Niemann-Pick disease type C. The data from this survey are consistent with results from the clinical trial OGT918-007 in the same patient population.. Key scientific literature. At twelve months, HSEM velocity had improved in patients treated with miglustat versus those receiving standard care; results were significant when patients taking benzodiaz epines were excluded (p=0.028). Children showed an im provement in HSEM velocity of similar magnitude. Improve ment in swallowing capacity, stable auditory acuity, and a slower deterioration in ambulatory index were also seen in treated patients of twelve years or older. Although the ex tension phase of the trial was not controlled, the data at 24 months confirmed that treatment with miglustat can provide disease stabilization for important markers of neurological dysfunction in NPC disease, both in the juvenile/adult and pediatric groups. The 24 month results further strengthen the interpretation of a treatment effect of miglustat indicated by the twelve month, controlled clinical trial phase previously reported. The safety and tolerability of miglustat 200mg, three times daily in NPC patients was consistent with previous trials in type 1 Gaucher disease patients, where 100 mg three times daily was used. The international survey was performed in 25 centers in twelve countries to assess retrospectively data on changes of neurological status and overall utility of treatment with mi glustat in 66 NPC patients receiving miglustat outside of the clinical trial OGT918-007 for a mean duration of 1.5 years. A disease-specific disability scale was used to evaluate the severity of dysphagia (swallowing), dystonia (manipulation), ataxia (ambulation) and dysarthria (language articulation) at diagnosis, treatment initiation and last visit. A majority of patients remained at least stable after treatment as regards to the four parameters. Miglustat appears to provide clini cally relevant benefits on neurological disease progression in. Patterson M.C., Vecchio D., Prady H., Abel L., Wraith J.E. Miglustat for treatment of Niemann-Pick C disease: a ran domised controlled study. Lancet Neurol 6,765-772; 2007. Patterson M.C., Vecchio D., Prady H., Abel L., Wraith J.E. Mi glustat for treatment of Niemann-Pick C disease: results of 24 month's treatment. Proceedings of 57th Annual meeting of the American Society of Human Genetics, 2007; abstract # 2253. Pineda M, Wraith JE, Sedel F, et al. Miglustat in patients with Niemann-Pick type C disease (NPC): a multicentre retrospec tive survey. Journal of Inherited Metabolic Disease 31(Suppl 1) 98; 2008.. Phase III Almorexant About almorexant in clinical development Almorexant is a first-in-class orexin receptor antagonist which has the potential to shift the paradigm for treating sleep dis orders. It is an oral therapy that penetrates the blood-brain barrier and is capable of inducing a transient and reversible blockade of the orexin receptors. Orexins are neuropeptides produced in the brain, or more specifically, by a very small number of specialized neurons located in the hypothalamus. Orexins play an important role in maintaining wakefulness, and therefore regulate the sleep-wake-cycle. Almorexant was discovered by Actelion scientists in an in-house re search program.. 26. WorldReginfo - 347f5acf-d29f-4cfe-9635-5f104be92861. In the clinical trial OGT 918-007, NPC patients aged twelve years or older (n=29) were randomly assigned to receive either miglustat 200 mg three times a day (n=20), or stan dard care (n=9) for twelve months. Twelve children under twelve years of age were included in an additional group; all received miglustat at a dose adjusted for body surface area. After twelve months, all participants were then treated with miglustat for an additional year in an extension study. The primary endpoint was horizontal saccadic eye movement (HSEM) velocity, based on its correlation with disease pro gression..