Annual Report 2009 In Detail

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(1)WorldReginfo - 60e0ae8d-cd84-4435-bdcf-3e8de072d25b. Annual Report 2009 In Detail.

(2) Introduction. "The level of commitment and excitement about what we do is contagious. It makes you want to come to work each day". 02. WorldReginfo - 60e0ae8d-cd84-4435-bdcf-3e8de072d25b. Administrative assistant, Clinical Development.

(3) Business overview 2009 In 2009, Actelion became an even stronger company in many respects. Total net revenues grew to more than CHF 1.7 billion. We added new indications or formulations for all three marketed products. In 2010, as well as informing physicians about these developments, our marketing and sales forces will start detailing a fourth product, acquired in the year under review. With 11 compounds in clinical development at the end of 2009, we have a strong pipeline. We are continuing to investigate novel approaches in 25 drug discovery projects. We have strengthened our management capabilities, welcoming a new Head of Clinical Development and creating the positions of Chief Medical Officer and Chief Scientific Officer. We have reinforced our Board of Directors, with three new members contributing specific expertise in finance, pharmaceuticals and science. We have invested in the training and development of our staff, now comprising more than 2,260 people. The 314 new employees hired in 2009 have been familiarized with our corporate values.. Strong financial performance The excellent performance of our products in the marketplace resulted in strong top line growth in 2009. Total net revenues increased by 20 percent to CHF 1,772.6 million. Growth in local currencies (LC) – masked by the appreciation of the Swiss franc – was even more pronounced, at 23 percent year on year.. The resulting operating profit in 2009 was CHF 339.4 million, with net profit of CHF 311.3 million. Non-GAAP (cash) EBIT – a better indicator of the company’s ongoing performance – reached CHF 567.9 million, an increase of 19 percent year on year (LC growth: 25 percent).. An expanding PAH franchise Actelion has continued to expand its core business in pulmonary arterial hypertension (PAH), both with marketed products and with development projects focused on this devastating disease. Our PAH franchise includes several treatment options for patients, with different routes of administration. New developments, the potent tissue-targeting endothelin receptor antagonist macitentan and an orally available therapy targeting the prostacyclin system, have the potential to further expand our portfolio and optimize treatment for patients.. 03. WorldReginfo - 60e0ae8d-cd84-4435-bdcf-3e8de072d25b. In 2009, operating costs increased by 331 million, as we continued to support marketed products in existing and new markets, as well as investing in our maturing R&D pipeline. Taking into account a one-time charge relating to the arbitration award of CHF 93.7 million payable by the Actelion subsidiary CoTherix, Inc., total operating costs amounted to CHF 1,433.2 million..

(4) In 2009, Tracleer ® (bosentan) was additionally approved in the US for use in patients with mildly symptomatic WHO Functional Class II PAH. This milestone now allows physicians not only in the EU but also in the US, to start therapy at an earlier stage, potentially slowing disease progression. 2009 also saw EU approval being granted for the specially designed pediatric formulation of Tracleer ®. This new dispersible tablet is the result of a long process, conducted in parallel with the development of the original formulation. We are proud to be the first company offering a PAH therapy fully tailored to children’s needs from appropriate and convenient dosing to flavor. In the US market, Actelion gained approval in 2009 for an increased-strength formulation of the inhaled prostacyclin Ventavis® (iloprost). This improvement will allow patients to receive the same dose in half the volume, which is expected to reduce inhalation time, enhancing convenience and patient compliance. With the acquisition of a new formulation of intravenous epoprostenol with improved thermal stability from the US-based company GeneraMedix, Inc. Actelion will add an additional treatment option to its PAH portfolio. This formulation addresses several limitations of conventional epoprostenol, offering patients with PAH clear benefits over the existing therapy. It is expected to reach the US market in 2010. As well as expanding the product portfolio, Actelion has made significant progress with two late-stage development compounds, which should help to maintain the company’s leading position in the field of PAH. Firstly, extended enrollment has been completed for the Phase III study of macitentan, with final results expected to be reported before the end of 2012. Secondly, following positive data from a Phase IIa study of the first-in-class, orally active non-prostanoid IP receptor agonist, this innovative compound has advanced directly into Phase III. With this significant progress of our compounds in the pipeline, Actelion will be in a position to further its leading role in the field of PAH.. We have also made progress in offering patients new treatment options for previously unmet medical needs. In the EU, Zavesca® (miglustat) was approved for the treatment of Niemann-Pick type C (NP-C) disease, a progressive and ultimately fatal neurodegenerative genetic disorder. Zavesca®, which has been demonstrated to reduce the progression of neurological symptoms, is the first treatment approved for NP-C. In 2009, positive results were reported for the first Phase III study of almorexant, although certain safety observations necessitate further evaluation. Our S1P1 receptor agonist developed for multiple sclerosis and psoriasis has advanced in Phase II clinical development. Actelion remains fully committed to this compound after the discontinuation of the S1P1 alliance with Roche, which followed a review of our former partner’s R&D portfolio. We are also awaiting final study results both for bosentan in idiopathic pulmonary fibrosis (IPF) – expected in the first months of 2010 – and, later this year, for clazosentan in non-traumatic subarachnoid hemorrhage stabilized with surgical clipping.. 04. WorldReginfo - 60e0ae8d-cd84-4435-bdcf-3e8de072d25b. Focus on unmet patients’ needs.

(5) A strong company ready for continued value creation With 3 (soon to be 4) products on the market, 11 compounds in clinical development and around 25 drug discovery projects, Actelion is ready to meet the challenges ahead. We remain well placed to expand and grow our existing business. We are also well prepared for accelerated growth and additional value creation once our innovative compounds reach the marketplace. At Actelion, we believe that improving patients’ lives by developing innovative products that address unmet medical needs is the key to creating value for our shareholders.. 05. Robert E. Crawthorn Chairman of the Board of Directors. WorldReginfo - 60e0ae8d-cd84-4435-bdcf-3e8de072d25b. Jean-Paul Clozel Chief Executive Officer .

(6) 06. WorldReginfo - 60e0ae8d-cd84-4435-bdcf-3e8de072d25b. Contents.

(7) Please click on the desired chapter. Our purpose. 09. Our future. 10. 02 Research & Development. 11. Research at Actelion. 12. Therapeutic areas. 14. Development pipeline. 17. 03 Partnerships & Collaborations. 30. Partnerships. 31. In-licensing. 32. Acquisitions. 33. 04 Marketed Products. 34. Business Strategic Operations. 35. About Tracleer®. 36. About Ventavis®. 41. Zavesca®. 42. About. 05 Financial Report. 07. 08. 46. Financial summary. 47. Corporate Governance. 49. Consolidated Financial Statements. 63. Notes to Consolidated Financial Statements. 67. Holding Company Statements. 100. Notes to the Financial Statements 2009. 101. Actelion Management, Board and Scientific Advisory Board. 112. Shareholder Information. 113. WorldReginfo - 60e0ae8d-cd84-4435-bdcf-3e8de072d25b. 01 Company strategy.

(8) "I enjoy working for Actelion because of the goal and future oriented atmosphere". 01 Company Strategy Back to Contents. 8 08. WorldReginfo - 60e0ae8d-cd84-4435-bdcf-3e8de072d25b. Sales Representative, Germany.

(9) “I believe we can only really turn innovation into value when all our desires and drive are focused on being among the best – in everything we do.” Jean-Paul Clozel, Chief Executive Officer. Actelion is executing a long-term strategic plan to leverage its potential to become one of the world’s leading biopharmaceutical companies. Actelion’s founders shared a vision: to create a unique type of biopharmaceutical company – an organization with experienced, motivated people and a working environment that encourages innovation and creativity, making it possible to discover, develop and deliver novel medicines which fundamentally improve patients’ lives.. “We’ve kept to everything that was written in our first business plan, and it’s worked – innovation, science, and focusing on new drugs which would make a difference, not doing ‘me-too’s’. A lot of failures happen because people lose their strategic focus.” Jean-Paul Clozel, Chief Executive Officer. Actelion’s business momentum is reflected by the growing number of employees. Our staff represent the best professional attributes, combining the innovation of biotech with pharmaceutical discipline and the highest ethical standards.. “I try to maintain a corporate culture that encourages innovation, and to make sure that our people are happy. This approach seems to contradict a number of management theories which subordinate personal happiness to the company’s performance. But I think it works the other way round: the success of a business is a result of employees’ well-being.” Jean-Paul Clozel, Chief Executive Officer. As part of our strategy, we are giving high priority to attracting, developing and retaining highly talented people. Employees who identify with the goals and values of our company have transformed the vision of Actelion’s founders into reality. People with passion and expertise are laying the foundations for our future success.. 09. Our purpose To improve people’s lives by creating innovative medicines that make a real difference.. “Severe diseases affect many people beyond the patient. Providing a therapeutic option in areas of unmet medical need touches the lives of patients, caregivers, family and friends. It’s a real motivator for our people.” Isaac Kobrin, Chief Medical Officer. Core values Actelion’s core values of innovation, trust & teamwork, open communication, and a results-driven approach make the company unique.. They are central to our success and have high priority in the company to make them part of our daily culture. These values form the backbone of our working environment and serve to guide us in daily interactions with internal and external stakeholders.. “A good corporate culture facilitates long-term value creation. Therefore, Actelion attaches great importance to its core values and supports initiatives aimed at fostering our culture.” Simon Buckingham, President, Global Corporate and Business Development. Strategic principles Actelion’s four strategic principles describe the fundamental priorities required to reach its long�term business objective; to become one of the world’s leading innovative biopharmaceutical companies.. “Having a very good drug is essential but just the beginning. You need to execute smart market shaping and development strategies and find an effective way to communicate the science and medical utility of your product. Educating all stakeholders about the disease and our products is our part in enhancing medical practice and ensuring patients have access to therapy. This is especially critical when you deal with a rare disease – as was the case with our first drug Tracleer® for pulmonary arterial hypertension.” Otto Schwarz, President, Business Strategy & Operations. 01 Company Strategy. WorldReginfo - 60e0ae8d-cd84-4435-bdcf-3e8de072d25b. Company strategy.

(10) 1. Follow innovation where it leads. 4. Drive core values together. Pursue top-quality science, internally and externally, balanced with medical need and commercial potential.. Foster a culture of innovation, trust & teamwork, open communication, and a results-driven approach.. “We’re discoverers. Sometimes we dig something out that is not what we expected. But if you dig for gold and find diamonds, you certainly wouldn’t throw them away.”. “Our culture is more valuable than anything that’s on the balance sheet. It’s the only thing you cannot buy.” Jean-Paul Clozel, Chief Executive Officer. Jean-Paul Clozel, Chief Executive Officer. 2. Retain the value of innovation. Our future. Develop projects ourselves and seek partners when necessary to maximize value. Control our destiny and retain our independence.. We will build a global biopharmaceutical leader, blending biotech’s innovation, speed and flexibility with Big Pharma’s operating discipline and excellence in execution.. Simon Buckingham, President, Global Corporate and Business Development. 3. Excel in sales and marketing Expand innovative commercial capabilities to new customers and regions. Manage alliances, putting the product first.. Our innovative R&D is at the heart of our growth and will deliver medicines that make a real difference for people. We will be a strong, well-respected partner in strategic alliances.. “Discovering and developing drugs for diseases with a high medical need is the most fascinating endeavor I can imagine. It is a fantastic experience to provide a new drug to patients and observe how their condition improves.” Martine Clozel, Chief Scientific Officer. Over the next decade and beyond, Actelion will multiply revenues and R&D projects, yielding strong value creation. People will work in an inspiring environment, generating high levels of employee satisfaction. Our continued improvement and success will deliver superior shareholder returns.. “Since the first launch of Tracleer®, we have invested our time and resources to increase awareness of PAH and the science behind endothelin receptor antagonism. We hire the best people in sales and marketing to ensure our physicians have all the information they need to prescribe the best therapy. Even if you achieve a breakthrough, you still need to invest a lot of energy to communicate it.” Jean-Paul Clozel, Chief Executive Officer. Back to Contents. 10. WorldReginfo - 60e0ae8d-cd84-4435-bdcf-3e8de072d25b. “For Actelion, maximizing value means accelerating the delivery to patients! In some cases, the combined knowledge, capabilities and experience of two companies allow us to realize the full potential of a given compound. As Actelion grows, we are able to move further and further through the development and marketing process alone. Indeed, we can now offer an established platform to partners with innovative technologies or products, creating a win-win situation for both parties.”.

(11) "One day, the results of my work could help patients who currently have no treatment of their disease". 02 Research and. Development. 11. WorldReginfo - 60e0ae8d-cd84-4435-bdcf-3e8de072d25b. Lab Technician, Drug Discovery.

(12) Scientists at Actelion use an inquisitive drug hunting approach 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 flourish. By removing the barriers to innovation, such as bureaucracy and hierarchy, the founders set out to empower “their” people. In turn, Actelion’s people take ownership of their projects and grasp opportunities. There are many barriers to overcome when guiding a compound that addresses an unmet medical need from the bench to the market. To maximize success, the Research and Development teams must know which projects are most promising, 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 integrated approach. This sharing of knowledge stimulates and builds scientific intuition. 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 345 professionals at the end of 2009, combines technology with human expertise and teamwork in a single research center based in Allschwil to make the best use of Actelion's toolbox. Actelion has over 120 medicinal and process chemists creating low molecular weight compounds which go through a cyclic drug discovery process for optimization.. molecular drug targets. The characterization includes the development of a variety of assays and execution of activity screens. The vast quantities of assay result data generated, more than 2.8 million data points in 2009, are managed and analyzed by data-management programs developed inhouse. 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 toxicologists. At the end of 2009, the platform approach, combined with our technological capabilities and in-house expertise, resulted in two novel compounds progressing into clinical development and four compounds undergoing preclinical investigation, with the potential selection of several other preclinical candidates during 2010. The final outcome is a robust clinical development pipeline of compounds discovered and optimized in Actelion’s laboratories.. Platform approach Actelion’s efforts in drug discovery have focused on developing 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 unmet medical needs. The first focus is the design, synthesis and optimization of low molecular weight drug-like molecules. The productivity of Actelion’s drug discovery endeavors is demonstrated by the more than 1,800 pending patent applications and/or granted patents currently in Actelion’s portfolio. In 2009, the company filed 17 priority patent applications and 37 foreign filing patent applications, an indication of 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 a specific enzyme family known as aspartic proteinases. As the company’s capabilities have expanded, so too have the target platforms to include anti-infectives, ion channels and a broad range of soluble enzymes.. These innovative compounds are then characterized by molecular biologists and biochemists in relation to the chosen. Back to Contents. 12. WorldReginfo - 60e0ae8d-cd84-4435-bdcf-3e8de072d25b. Research at Actelion.

(13) Actelion's research focuses on the design and synthesis of novel low molecular weight drug-like molecules. Experience 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 structurally diverse molecules, process research chemists prepare the quantities of selected compounds needed for further studies.. G-Protein coupled receptors G-Protein coupled receptors (GPCRs), also known as seven transmembrane domain receptors (7TMs), are integral membrane proteins. They can be activated by external signals, such as hormones, neurotransmitters, or odors. This activation 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-phosphate receptor S1P1.. Enzymes Enzymes are proteins that catalyze chemical reactions and are involved in almost all metabolic pathways in a living cell. They speed up the conversion of a substrate into a new product. Enzymes are specific for a given molecular substrate and are classified by the mechanism by which they act on the substrate. Actelion currently works on several different enzyme targets in its research programs, most of them being soluble intracellular proteins. One such class is the aspartic proteinases. This class of enzyme promotes chemical reactions inside and outside cells. There are more than 50 known aspartic proteinases, of which at least nine are currently known to exist in humans. Although knowledge of their precise physiological roles is still emerging, they have been implicated in cancer, as well as in inflammatory, degenerative, and cardiovascular diseases. In. 13. addition, aspartic proteinases play a vital role in organisms that cause infections, including parasites, fungi, and retroviruses such as HIV.. Ion channels Ion channels are transmembrane pores that allow the passage 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 fluctuations, acidity changes, temperature variations, or mechanical stimuli (e.g. touch or sound). Initially, Actelion established an in-house in-vitro electrophysiology group to provide internal support for early preclinical evaluation of drug safety in the area of cardiac electrophysiology. Since the scientific knowledge and technical capabilities required in this area are very similar to those in the area of cardiovascular ion channel therapies, research programs were soon initiated looking for modulators of selected ion channels to treat cardiovascular diseases. Expansion of the electrophysiology group and integration of new expertise and technologies led to the initiation of research projects targeting ion channels to treat neurological and immunological diseases.. Anti-infectives Antibiotics have saved millions of lives since their introduction 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 (e.g., point mutations within the active site). Increasingly, infections that were once treatable with antibiotics are becoming difficult or impossible to treat. 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 frameworks 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.. 02 Research and Development. WorldReginfo - 60e0ae8d-cd84-4435-bdcf-3e8de072d25b. New chemical entities.

(14) Actelion selects its molecular drug targets on the basis of the established platforms of expertise, capabilities, technologies and the professionals at its research center. Actelion’s drug hunters 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 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, infectious diseases and oncology. For more information on our therapeutic areas, target diseases and how our compounds act, please visit the corporate website at www.actelion.com.. 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 focuses its efforts in cardiovascular disorders on key target diseases such as pulmonary arterial hypertension, digital ulcers in systemic sclerosis, idiopathic pulmonary fibrosis and cerebral vasospasm as a consequence of aneurysmal subarachnoid hemorrhage.. Central nervous system Central nervous system (CNS) disorders (psychiatric, neurological, and neurosurgical disorders) figure among the leading causes of disease and disability. Recent WHO data suggest that CNS disorders cause 35% of the burden of all diseases. Back to Contents. in Europe. Of patients in primary care, 25% are affected by a neuropsychiatric disease; such as mood disorders (depression, anxiety), psychotic conditions (schizophrenia, mania), declined cognitive function (Alzheimer and neurodegenerative diseases) or brain trauma (stroke, brain or spine lesion). CNS 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 focuses its efforts in central nervous system disorders on key target diseases such as sleep disorders and 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 disorders call for a global approach to special and combined efforts to prevent significant morbidity or avoidable premature mortality, and to improve the quality of life of those affected. Actelion focuses its efforts in genetic disorders on key target diseases such as type 1 Gaucher disease, Niemann-Pick type C disease and cystic fibrosis.. 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 affecting 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-. 14. WorldReginfo - 60e0ae8d-cd84-4435-bdcf-3e8de072d25b. Project selection.

(15) Actelion focuses its efforts in immunological disorders on key target diseases such as allergy, asthma, multiple sclerosis and psoriasis.. 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 introduction 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 (e.g., point mutations within the active site). Increasingly, infections that were once treatable with antibiotics are becoming difficult or impossible to treat. The Infectious Diseases Society of America (ISDA) estimated that in 2004, two million people acquired bacterial infections 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.. 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 as well as the selection and testing of new treatments. The recent identification 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. Actelion’s research programs to identify and develop compounds for cardiovascular and other diseases have provided compounds which can be of potential use in oncology. For instance, endothelin receptors and endothelin are over-expressed 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. 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 inflammatory cells). Besides exploiting compounds in our pipeline from other indication areas, we are using our discovery platform and experience with certain target classes to select novel oncology approaches.. Actelion focuses its efforts in infectious diseases on developing antibiotics with the following characteristics: • • • • • •. 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 pathophysiology of cancer has improved significantly over the last 25 years. This has led to the testing of a large number of new. 15. 02 Research and Development. WorldReginfo - 60e0ae8d-cd84-4435-bdcf-3e8de072d25b. 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 profiles superior to currently available therapies..

(16) Development process. Progress in Clinical Development. 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.. At the end of 2009, Actelion’s clinical development group was working on a total of 76 different clinical trials enrolling more than 10,000 patients or healthy volunteers. This represents a significant increase compared to 2008, with almost 8,300 patients.. 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 different 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 development of a product to its full potential, from entryinto-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.. Our S1P1 receptor agonist program in multiple sclerosis and psoriasis has advanced in Phase II clinical development. Actelion remains fully committed to this compound after the discontinuation of the S1P1 alliance with Roche, which followed a review of our former partner’s R&D portfolio. Actelion also saw a successful proof-of-mechanism study of its CRTH2 receptor antagonist in asthma, with further clinical studies in this and other indications planned for 2010, once additional preclinical studies have concluded. A pilot study with macitentan in idiopathic pulmonary fibrosis was initiated during 2009. A first Phase IIa study with miglustat in cystic fibrosis was concluded in mid-2009. Following further preclinical and clinical analysis, a newly designed proofof-concept study has been decided upon to be initiated in 2010. Based on the results of several clinical studies, the renin alliance with Merck & Co., Inc. (through an affiliate), has discontinued the clinical development of the lead clinical candidates. The alliance is continuing to evaluate more renin inhibitors currently in the drug discovery phase. The company also entered two novel compounds in the field of antibiotics and cardiovascular care into the first Phase of clinical development.. Back to Contents. 16. WorldReginfo - 60e0ae8d-cd84-4435-bdcf-3e8de072d25b. The process is achieved through creative and targeted clinical and pharmacological research that is supported by high performance strategic clinical development, biometry, drug safety, drug regulatory, life cycle, and operations functions.. In 2009, Actelion’s innovative pipeline made substantial progress in many areas of unmet medical need. Almorexant reported positive results of the first Phase III study, although certain safety observations necessitate further evaluation. The Phase III BUILD-3 study with bosentan in idiopathic pulmonary fibrosis was closed upon reaching the target of 202 confirmed events and consequently, Actelion expects top-line results to become available in early 2010. Clazosentan continued enrolling patients with non-traumatic subarachnoid hemorrhage stabilized with surgical clipping into the Phase III CONSCIOUS-2 study as well as initiating a second Phase III study in patients treated by endovascular coiling. Macitentan completed enrollment into the Phase III SERAPHIN study and is on track to report final study result before the end of 2012. Following a successful proof-of-concept study, Actelion’s IP receptor agonist, selexipag, progressed into a Phase III morbidity/mortality study enrolling the first patient before the end of 2009..

(17) Development pipeline. Phase. IV IV. Product/ Compound EpoprostenolActelion Bosentan Iloprost. IV. Miglustat. III III III. Almorexant Bosentan Clazosentan. III III II II II II I I. Macitentan Selexipag CRTH2 antagonist S1P1 agonist S1P1 agonist Macitentan Antibiotic Cardiovascular. Registered. 17. Indication. Study. Pulmonary arterial hypertension. n/a. Results expected n/a. Combination bosentan & sildenafil in PAH Pulmonary arterial hypertension (improved delivery system) Type 1 Gaucher disease patients switched from ERT to miglustat Insomnia Idiopathic pulmonary fibrosis Prevention of vasospasm-related morbidity/mortality post a subarachnoid hemorrhage (SAH) Pulmonary arterial hypertension Pulmonary arterial hypertension Asthma Multiple Sclerosis Psoriasis Idiopathic pulmonary fibrosis Anti-infective Cardiovascular. COMPASS-2 PROWESS-15. n/a H1 2010. MAINTENANCE. 2010. RESTORA BUILD-3 CONSCIOUS-2 CONSCIOUS-3 SERAPHIN GRIPHON n/a n/a n/a MUSIC n/a n/a. n/a H1 2010 H1 2010 2011 H2 2012 n/a n/a n/a n/a n/a n/a n/a. 02 Research and Development. WorldReginfo - 60e0ae8d-cd84-4435-bdcf-3e8de072d25b. Actelion's focus on high unmet medical needs.

(18) Registered. Phase IV. Epoprostenol-Actelion. Phase IV trials are normally conducted in order to build data on the long-term safety and efficacy of compounds which have marketing approval, or to provide technical support for an approved therapy. Actelion’s strategy is to maximize the value created with its products by providing additional evidence in specific patient groups to assist physicians in their treatment approach.. In June 2008, the U.S. Food and Drug Administration approved this new formulation of epoprostenol for injection, developed by GeneraMedix Inc., for the long-term intravenous treatment of primary pulmonary hypertension and pulmonary hypertension associated with the scleroderma spectrum of disease in NYHA Class III and Class IV patients who do not respond adequately to conventional therapy.. Progress in 2009 In February 2009, Actelion acquired EpoprostenolActelion thereby strengthening its PAH franchise.. Milestones 2009 2008. Actelion acquired Epoprostenol-Actelion FDA approved the Epoprostenol-Actelion for treatment of primary pulmonary hypertension (PH) and PH associated with the scleroderma spectrum of disease in NYHA Class III and Class IV patients who do not respond adequately to conventional therapy.. Key scientific literature Barst RJ, Rubin LJ, Long WA, et al. A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. The Primary Pulmonary Hypertension Study Group. N Engl J Med 1996;334:296–302.. Back to Contents. Bosentan Bosentan (Tracleer ®), is an oral dual endothelin receptor antagonist, which is currently approved for the treatment of pulmonary arterial hypertension (PAH), a chronic, life-threatening disorder which severely compromises the function of the lungs and heart. In the United States, Tracleer ® is approved for the treatment of PAH Functional Class II - IV to improve exercise capacity and decrease the rate of clinical worsening. Patients with class II symptoms showed reduction in the rate of clinical deterioration and a trend for improvement in walk distance. Physicians should consider whether these benefits are sufficient to offset the risk of liver injury in class II patients, which may preclude future use as their disease progresses. In Europe, 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. 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 potential 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. For patients with IPF outside of Japan, there are currently no approved therapies available.. 18. WorldReginfo - 60e0ae8d-cd84-4435-bdcf-3e8de072d25b. Epoprostenol-Actelion is a new formulation of intravenous epoprostenol with improved thermal stability for the treatment of pulmonary arterial hypertension (PAH). Epoprostenol is synthetic prostacyclin with potent vasodilatory activity and inhibitory activity of platelet aggregation like the naturally occurring molecule. The mechanism of action of EpoprostenolActelion influences all the main pathological mechanisms involved in pulmonary hypertension..

(19) Bosentan in development for PAH. Progress in 2009 The COMPASS program specifically evaluates the 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 pathological 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. At the end of 2009, the COMPASS-2 study is ongoing to investigate the effect on morbidity and mortality of a combination of bosentan with sildenafil compared to sildenafil monotherapy.. Available clinical data COMPASS-1 demonstrated that adding sildenafil to patients on long-term bosentan therapy produced significant hemodynamic 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 decrease in the mean total pulmonary resistance (-13.3% [95% CI: –17.0 to –9.6]; p < 0.0001).. Iloprost Iloprost (Ventavis®) is an inhaled formulation of a synthetic compound that possesses high affinity for the prostacyclin receptor (IP receptor). Iloprost has a similar pharmacological profile to endogenous prostacyclin (natural PGI2) but with greater chemical stability and longer half-life. The mechanism of action of iloprost influences all the main pathological mechanisms involved in pulmonary hypertension (potent vasodilation, and antithrombotic, antiproliferative, anti-inflammatory and antifibrotic activity). In December 2004, the US Food and Drug Administration approved Ventavis® (iloprost) inhalation solution, developed by Bayer Schering Pharma for the treatment of pulmonary arterial hypertension (PAH) (WHO Group I) in patients with Functional Class III or IV. CoTherix, Inc., a biopharmaceutical company 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 Europe and other countries outside the US. In January 2007, Actelion announced the successful completion 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.. Iloprost in development for PAH. Milestones 2007 2006. COMPASS-1 study results presented at ESC COMPASS program initiated. The PROWESS 15 study is ongoing to demonstrate that a single dose of iloprost (delivered by the Power 15 disc) versus placebo, improves exercise capacity in patients with PAH.. Key scientific literature Available clinical data Gruenig E. et al. Acute administration of sildenafil in patients with pulmonary arterial hypertension (PAH) treated with bosentan produced a significant hemodynamic response: results of the COMPASS-1 study. European Society of Cardiology (ESC) Congress 2007 Abstract 1012. Ventavis® is indicated for the treatment of PAH (WHO Group I) in patients with NYHA Class III or IV symptoms. In controlled trials, it improved a composite endpoint consisting of exercise tolerance, symptoms (NYHA Class), and lack of deterioration. In December 2006, data from the Phase II/III clinical trial STEP, evaluating the safety and added benefit of using Ventavis®. 19. 02 Research and Development. WorldReginfo - 60e0ae8d-cd84-4435-bdcf-3e8de072d25b. Progress in 2009.

(20) (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.. Milestones 2009 2007 2004. FDA approved increased 20 mcg/ml strength formulation for treatment of PAH in US Actelion acquired CoTherix Inc, adding Ventavis to its product offerings FDA approved inhaled iloprost for treatment of PAH in US. Miglustat in development for type 1 Gaucher disease. Progress in 2009 The MAINTENANCE study 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 patients with stable disease. With enrollment completed during the second quarter of 2008, the results of this study are expected to become available in 2010.. 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.. Zavesca® (miglustat) 100 mg is the only oral drug available for the treatment of type 1 Gaucher disease, and was approved 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 glucosylceramide 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 miglustat 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 patients with longitudinal bone density measurements. There were no events of bone crisis, avascular necrosis or fracture during the treatment period.. Olschewski et al. Inhaled iloprost for severe pulmonary hypertension. N Engl J Med. 1;347(5):322-9; 2002.. Milestones. Key scientific literature Ivy et al. Short- and long-term effects of inhaled iloprost therapy in children with pulmonary arterial hypertension. J Am Coll Cardiol. 51(2):161-9; 2008. McLaughlin et al. Randomized study of adding inhaled iloprost 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.. Miglustat Miglustat (Zavesca®) is a low molecular weight inhibitor of glucosylceramide synthase and α-glucosidase. Zavesca® is approved 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 unsuitable. It is approved for this indication in 39 countries including the US and EU since 2003. Zavesca® is also approved in the EU for the treatment of progressive neurological manifestations in adult and pediatric patients with Niemann-Pick type C disease.. Back to Contents. 2009. 2008 2004 2003 2002. EU approval for the treatment of progressive neurological manifestations in patients with Niemann-Pick type C disease EU approval for a type II variation for miglustat and bone disease in type 1 Gaucher disease Zavesca® launched in the US and Switzerland 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. 20. WorldReginfo - 60e0ae8d-cd84-4435-bdcf-3e8de072d25b. Available clinical data.

(21) 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.. 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 inhouse research program.. 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.. Actelion and GSK entered into an exclusive worldwide (excluding Japan) collaboration in July 2008 to jointly develop and commercialize Actelion’s first-in-class orexin receptor antagonist almorexant.. Elstein D. et al. Sustained therapeutic effects of oral miglustat (Zavesca, N-butyldeoxynojirimycin, OGT 918) in type 1 Gaucher disease. J Inherit Metab Dis 27: 757-66; 2004.. Almorexant in development for insomnia. Phase III Phase III studies aim to be the definitive assessment of the drug under investigation, providing additional safety data, confirming efficacy, and providing the necessary comparative data where an approved therapy is available. These studies are randomized, controlled, multicenter trials enrolling large numbers of patients. The actual number of patients studied can be as large as 3,000 to 5,000, but is also dependent on the number of patients who suffer from the disease or condition. Once the comprehensive Phase III studies have been completed, all available evidence, including all preclinical and clinical data collected before and during the clinical trials, is compiled to form the registration dossier. This dossier (e.g., the New Drug Application [NDA] in the US, or the Marketing Authorisation Application [MAA] in the EU) is then submitted to the relevant regulatory authorities in order to obtain approval to market the drug in the respective jurisdictions. If the regulatory authorities are satisfied that the information provided in the dossier shows that the drug has fulfilled the relevant safety and efficacy criteria, approval to market the drug is granted.. Almorexant. Progress in 2009 Throughout 2009, Almorexant continued to be investigated in the comprehensive Phase III program RESTORA (REstore physiological Sleep with The Orexin Receptor antagonist Almorexant). The first Phase III study, RESTORA 1 has met its primary endpoint, superiority of the dual orexin receptor antagonist almorexant compared to placebo on objective and subjective wake after sleep onset (WASO). The finding was highly significant (p<0.001). In addition, several secondary endpoints of the study were met with statistical significance. In RESTORA 1, the use of almorexant was well-tolerated. However, in this study as well as in the ongoing non-pivotal program, certain safety observations were made that will require further evaluation and assessment in longer-term Phase III studies. The Phase III studies are currently in preparation - in both adults and elderly patients suffering from primary insomnia - and will evaluate long-term efficacy and safety. Additional studies are being planned to further establish the clinical profile of almorexant. The Actelion/ GSK collaboration will explore aspects of sleep quality, absence of addiction and improved next-day performance. Chronic use studies in both adults and elderly will further evaluate the safety profile of this innovative agent.. Almorexant is a first-in-class, dual orexin receptor antagonist which has the potential to shift the paradigm for treating sleep disorders. It is an oral therapy that penetrates the. 21. 02 Research and Development. WorldReginfo - 60e0ae8d-cd84-4435-bdcf-3e8de072d25b. adult patients with type 1 Gaucher disease: a pooled analysis of three multinational Open-label studies. Clinical Therapeutics. 29: 1645-53; 2007..

(22) Available clinical data RESTORA 1 was a multi-center, double-blind, randomized, placebo-controlled, active reference (zolpidem), parallelgroup polysomnography study to evaluate efficacy and safety of 16-day oral administration of almorexant 200mg and 100mg in 709 adult patients with chronic primary insomnia. Enrollment took place in 90 clinical study centers in Australia, Europe and Israel. A proof-of-concept/dose-ranging study in patients with primary insomnia indicated that almorexant significantly improved the primary parameter of sleep efficiency (the time asleep during the night divided by the time spent in bed), as measured by polysomnography (PSG), in a dose-dependent manner.. and Sleep Medicine Societies, Cairns, Australia, 2–6 September 2007; PO444. Hoever P, et al. Entry-into-humans study with almorexant (ACT-078573), a dual orexin receptor antagonist: pharmacodynamics. Poster presentation at the 5th World Congress of the World Federation of Sleep Research and Sleep Medicine Societies, Cairns, Australia, 2–6 September 2007; P0443.. Bosentan Related Links Compound description Bosentan in development for IPF. Milestones. 2008 2007 2005 1998. RESTORA 1 meets primary end-point in two week Phase III study Exclusive world-wide (excluding Japan) collaboration with GlaxoSmithKline initiated Phase III RESTORA study initiated Entry-into-man study initiated Project initiated in-house in 1998. Key scientific literature Hoever P, et al. Multiple-dose pharmacokinetics, pharmacodynamics, safety and tolerability of the orexin receptor antagonist almorexant in healthy subjects. Poster presentation at SLEEP 2008 22nd Annual Meeting of the Associated Professional Sleep Societies, LLC (APSS) June 7-12, 2008. Dingemanse J et al. Proof-of-concept study in primary insomnia patients with almorexant (ACT-078573), a dual orexin receptor antagonist. Poster and oral presentation at the 5th World Congress of the World Federation of Sleep Research and Sleep Medicine Societies, Cairns, Australia, 2–6 September 2007; P0653-J.. Progress in 2009 In May 2006, data presented from the BUILD program (Bosentan Use in Interstitial Lung Disease) at the American Thoracic Society (ATS) conference provided a strong rationale to further evaluate the safety and efficacy of bosentan in a morbidity/mortality-driven Phase III study in the idiopathic form of pulmonary fibrosis (IPF). Actelion is conducting this trial (BUILD-3) in patients suffering from lung biopsy-proven IPF, with the objective of confirming the BUILD-1 results. BUILD-3 enrollment was completed in November 2008 with 616 patients. The second interim analysis for BUILD-3 (i.e., 75 % of the events) took place on the 07 May 2009, with the independent Data and Safety Monitoring Board (DSMB) recommending continuation of the study. The BUILD-3 study closed upon reaching the target of 202 confirmed events at the end of 2009. Consequently, Actelion expects top-line results to become available in early 2010.. Brisbare-Roch C. et al. Promotion of sleep by targeting the orexin system in rats, dogs and humans. Nat Med. 13(2):150-5; 2007.. Available clinical data. Hoever P, et al. Entry-into-humans study with almorexant (ACT-078573), a dual orexin receptor antagonist: tolerability, safety and pharmacokinetics. Poster presentation at the 5th World Congress of the World Federation of Sleep Research. In November of 2005, Actelion reported results of BUILD-1, a clinical study in IPF. Although not statistically significant for the primary end point, positive trends were observed for predefined secondary endpoints, such as the combined inci-. Back to Contents. 22. WorldReginfo - 60e0ae8d-cd84-4435-bdcf-3e8de072d25b. 2009.

(23) dence of death or treatment failure at twelve months (36.1% in the placebo group versus 22.5% in the bosentan group; p=0.076; 95% CL 0.37, 1.05), representing a relative risk reduction of 38%.. ed morbidity and mortality following aneurysmal subarachnoid hemorrhage (aSAH). The product was granted orphan medicinal product status in Europe in 2003, and in the US in 2006.. Also in November of 2005, Actelion reported the results of BUILD-2, a clinical study in patients suffering from pulmonary fibrosis related to Systemic Sclerosis. No effect was observed on either primary or secondary endpoints.. Clazosentan in development for the prevention of vasospasm related morbidity/mortality post aneurysmal subarachnoid hemorrhage. Milestones. Progress in 2009. 2009. In 2009, Clazosentan continued to be investigated in the pivotal Phase III study CONSCIOUS-2 (Clazosentan to Overcome Neurological iSChemia and Infarct OccUrring after Subarachnoid hemorrhage). The study will measure the clinical benefits of clazosentan through the primary endpoint of vasospasm-related morbidity and all-cause mortality, which includes neurological deterioration, new brain infarcts, introduction of vasospasm rescue therapy, or death from any cause.. Key scientific literature King T.E. et al. BUILD-1: A Randomized Placebo-controlled Trial of Bosentan in Idiopathic Pulmonary Fibrosis. Am J Respir Crit Care Med Vol 177. 75–81, 2008. Noth I., Martinez F. Recent Advances in Idiopathic Pulmonary Fibrosis. Chest. 132;637-650; 2007. Raghu G. et al. Bosentan in idiopathic pulmonary fibrosis (IPF): quality of life results of the placebo-controlled BUILD 1 study [abstract]. Annual Congress of the European Respiratory Society. 28(Suppl 50):571s; 2006. Swigris J.J. et al. Longitudinal trends in dyspnea in patients with idiopathic pulmonary fibrosis (IPF): the BUILD 1 study [abstract]. Chest.130:282S; 2006. Brown K.K. et al. Effects of bosentan on oxygen pulse oximetry (SpO2) during exercise in idiopathic pulmonary fibrosis (IPF): the BUILD 1 study [abstract]. Chest. 130:151S; 2006. Clozel M. & Salloukh H. Role of endothelin in fibrosis and anti-fibrotic potential of bosentan. Annals of Medicine 37, 2-12; 2005.. Clazosentan Clazosentan (Pivlaz ®) is an intravenous endothelin receptor antagonist added to Actelion’s pipeline through the acquisition of Axovan in 2003. It is currently being evaluated in a Phase III program looking at its impact on vasospasm-relat-. 23. CONSCIOUS-2 is a global study which will include over 1,100 patients with aSAH and aneurysmal surgical clipping, from more than 100 centers, randomized 2:1 to receive either 5 mg/h of clazosentan, or placebo. The centers are in over 25 countries in the EU, North America and region. CONSCIOUS-2 results are expected to become available by mid 2010. If successful, Actelion will approach health authorities for filing. Also in 2009, ongoing enrollment in another Phase III study with Clazosentan, CONSCIOUS-3 commenced. This 1500 patient study evaluates the efficacy and safety of two doses (5 or 15 mg/h) of clazosentan versus placebo in patients post-aSAH treated by endovascular coiling. The primary endpoint is identical to that of CONSCIOUS-2.. Available clinical data Clazosentan has been studied in a Phase II program consisting of two studies. The first was a proof-of-concept Phase IIa placebo-controlled study of prevention of vasospasm after clipping for aSAH, published in 2005. Fewer cases of vasospasm and less severe vasospasm were observed in the clazosentan group compared with the placebo group. There were also. 02 Research and Development. WorldReginfo - 60e0ae8d-cd84-4435-bdcf-3e8de072d25b. 2007 2006. BUILD-3 second interim analysis: DSMB recommends study continuation BUILD-3 Phase III study initiated BUILD-1 & BUILD-2 study results presented at ATS.

(24) fewer patients with new cerebral infarcts in the clazosentantreated group. CONSCIOUS-1 was a multi-center, international, doubleblind, randomized, placebo-controlled, parallel-group, dosefinding study to evaluate the efficacy of three dose levels of clazosentan (15, 5 and 1mg/hour) in preventing the occurrence of cerebral vasospasm following aSAH in patients who underwent either clipping or coiling to stop the initial bleed, assessed by angiography. CONSCIOUS-1 showed a strong treatment effect on the primary endpoint. Clazosentan significantly reduced moderate/severe vasospasm at all tested doses, with a relative risk reduction compared to placebo of 65% at the highest dose. A post-hoc analysis showed a trend in favor of reducing morbidity/mortality related to vasospasm using central assessment.. Macitentan Macitentan is a highly potent, tissue-targeting endothelin receptor antagonist discovered in an in-house research program. Through complete blockade of tissular endothelin, macitentan is expected to protect tissue from the damaging effect of elevated endothelin, specifically in the cardiovascular system. In preclinical studies, macitentan also exhibited effects suggesting that it maintains the integrity of the vascular wall and improves long-term outcome. Accordingly, macitentan may provide therapeutic benefit in a wide range of cardiovascular indications.. Macitentan in development for PAH. Progress in 2009 Milestones 2009 2007 2006 2005 2003 2003. Phase III CONSCIOUS-3 study initiation Phase III CONSCIOUS-2 study initiation Orphan status granted in US Proof-of-concept published Orphan status granted in Europe Axovan acquisition. In 2009, Macitentan was investigated in the Phase III study SERAPHIN (Study with an Endothelin Receptor Antagonist in Pulmonary arterial Hypertension to Improve cliNical outcome). This study is designed to evaluate the safety and efficacy of this highly potent tissuetargeting endothelin receptor antagonist through the primary endpoint of morbidity and all-cause mortality in patients with symptomatic PAH. Global enrollment was completed in December 2009 with a total of 742 patients.. Macdonald R L, Kassell N F, Mayer S et al. Clazosentan to Overcome Neurological Ischemia and Infarction Occuring After Subarachnoid Hemorrhage (CONSCIOUS-1). Stroke 39: 3015 – 3021; 2008. Vajkoczy P, Meyer B, Weidauer S et al. Clazosentan (AXV034343), a selective endothelin A receptor antagonist, in the prevention of cerebral vasospasm following severe aneurysmal subarachnoid hemorrhage: a randomized, double-blind, placebo-controlled, multicenter, Phase IIa study. Journal of Neurosurgery 103, 9-17; 2005. Roux S. et al. Ro-61-1790, a new hydrosoluble endothelin antagonist: general pharmacology and effects on experimental cerebral vasospasm. J Pharmacol Exp Ther 283, 1110-1118; 1997.. Back to Contents. Patients are randomized 1:1:1 to receive two different doses of macitentan (3 mg and 10 mg once daily) or placebo. With around 180 centers participating, in over 40 countries in North and South America, Europe, Asia-Pacific and Africa, this is the largest study in PAH patients and the first to include, from the beginning, a clearly defined morbidity/mortality primary end-point. Study results could become available before the end of 2012.. Available clinical data In a Phase II study with 379 hypertensive patients, macitentan was significantly better than placebo and better than enalapril in reducing blood pressure 24 hours after drug intake. In this patient population, macitentan was generally well tolerated. The overall frequency of adverse events was similar to those observed in the placebo group. Similar to other endothelin receptor antagonists, macitentan may potentially exhibit known class effects such as a propensity for elevated liver. 24. WorldReginfo - 60e0ae8d-cd84-4435-bdcf-3e8de072d25b. Key scientific literature.

(25) enzymes, which will be monitored in the SERAPHIN study. Additional interaction studies concluded prior to the start of the SERAPHIN study have shown no clinically relevant interaction with warfarin, sildenafil, or ketoconazole (CYP 3A4 inhibitors).. Milestones 2007 2005 2004 2003. Initiation of Phase III SERAPHIN study in PAH patients Initiation of Phase II dose ranging study Entry-into-man Selection of macitentan for initiation of preclinical studies. tolerability of this compound in 43 patients suffering from PAH and already receiving standard care with oral PAH medications. The primary endpoint of pulmonary vascular resistance (PVR) change from baseline was met with high statistical significance (p < 0.01). The compound was well tolerated. Based on these results, Actelion has progressed selexipag into a Phase III morbidity/mortality study in pulmonary arterial hypertension, enrolling the first patient in late 2009.. Available clinical data Key scientific literature Iglarz M. et al. Pharmacology of macitentan, an orally active tissue targeting dual endothelin receptor antagonist. J Pharmacol Exp Ther. 2008 Sep 9.. Selexipag*. Data from the Phase I study indicated that multiple doses up to 600 μg bid were well tolerated. There was no clinically relevant pharmacokinetic or pharmacodynamic interaction with warfarin.. Milestones 2009. Selexipag (previously known as ACT-293987 or NS-304), originally discovered and synthesized by Nippon Shinyaku, is a long-lasting orally-available drug that is converted to the active principle, a potent non-prostanoid IP receptor agonist which exerts vasodilating effects. Selexipag has major potential as a novel treatment of pulmonary arterial hypertension.. 2009 2008 2007. First patient enrolled in Phase III morbidity / mortality study Positive Phase IIa data obtained – primary endpoint met with statistical significance Actelion in-licensed selexipag Phase II study initiated. * proposed INN Selexipag in development for PAH. Kuwano et al (2007). NS-304, an orally available and longacting prostacyclin receptor agonist prodrug. J Pharmacol Exp Ther 322: 1181-1188. Kuwano et al (2008). A long-acting and highly selective prostacyclin receptor agonist prodrug, NS-304, ameliorates rat pulmonary hypertension with unique relaxant responses of its active form MRE-269 on rat pulmonary artery. J Pharmacol Exp Ther 326: 691-699.. Progress in 2009 Actelion’s first-in-class, orally active, non-prostanoid IP receptor agonist successfully completed a Phase IIa, placebo-controlled study to assess efficacy, safety and. 25. 02 Research and Development. WorldReginfo - 60e0ae8d-cd84-4435-bdcf-3e8de072d25b. Key scientific literature In April 2008, Actelion and Nippon Shinyaku signed a licensing agreement, under which Actelion will be responsible for the global development and commercialization of selexipag outside Japan, and the two companies will co-develop and co-commercialize the drug in Japan..

(26) Phase II. Available clinical data. Phase II trials investigate a drug in patients, rather than in the healthy subjects tested in Phase I trials. This phase continues to provide safety data as the number of people receiving the drug increases. However the focus of these studies is the efficacy of the drug, and the intention is to prove the hypothesis of how the drug works.. In Phase I studies, the compound was well tolerated and showed an appropriate pharmacological profile.. Milestones 2009. Actelion’s CRTH2 receptor antagonist Actelion's CRTH2 receptor antagonist blocks the effects of prostaglandin D2 (PGD2) on inflammation and, as a consequence, the amplification and maintenance of allergic reactions. It targets allergic inflammation at the beginning of the cascade, with potential to be used as controller therapy in both asthma and/or allergic rhinitis, as well as in multiple potential indications that are based on allergic inflammation.. Actelion’s CRTH2 receptor antagonist in development for asthma. Progress in 2009 Positive data was obtained in 2009 in a proof-of-mechanism study with Actelion’s orally active CRTH2 receptor antagonist in mild asthma. In preclinical studies, this compound inhibited migration and activation of fundamental cell types involved in allergic inflammation. In the 18-patient crossover double-blind placebocontrolled study, the primary endpoint (FEV1) was met, and the compound was well tolerated. Plans for initiating a Phase II dose-finding study in asthma are ongoing. Back to Contents. 2008 2007 2006. Positive proof-of-mechanism study – primary endpoint met with statistical significance Phase II proof-of-mechanism study initiated Entry-into-humans study initiated Preclinical development initiated. Key scientific literature Pettipher R. Review: The roles of the prostaglandin D2 receptors DP1 and CRTH2 in promoting allergic responses. Brit. J. Pharmacol. 1-9; 2007. Tanaka K., et al. Effects of prostaglandin D2 on helper T cell functions. Biochem & Biophys Res Coms. 316, 1009-14; 2004. Iwasaki M., et al. Association of a new-type prostaglandin D2 receptor CRTH2 with circulating T helper cells in patients with atopic dermatitis. J. Invest. Dermatol. 119:609-16; 2002. Hirai H., et al. Prostaglandin D2 selectivity induces chemotaxis in T helper type 2 cells, eosinophils, and basophils via seven-transmembrane receptor CRTH2. J. Exp. Med 193(2) 255-261; 2001. Gervais F., et al. Selective modulation of chemokinesis, degranulation, and apoptosis in eosinophils through the PGD2 receptors CRTH2 and DP. J allergy clin immunol 108 (6), 9828; 2001.. Actelion’s S1P1 receptor agonist Actelion has identified novel small molecules for clinical development on the basis of their S1P1 receptor selectivity. These molecules also have high potency and a favorable pharmacokinetic profile after oral dosing, resulting in a substantial and rapidly reversible depletion of circulating lymphocytes. They are effective in animal models of T cell mediated inflammation. Actelion's selective S1P1 receptor agonists are potential therapeutic agents for immune disorders in which activated T cells play a critical role. In these pathological situ-. 26. WorldReginfo - 60e0ae8d-cd84-4435-bdcf-3e8de072d25b. Phase II trials can be further divided into Phase IIa and Phase IIb studies. Phase IIa studies focus on proving the hypothesized mechanism of action – often called ‘proof-of-concept’ or ‘proof-of-mechanism’ studies – and tend to be with fewer numbers of patients than Phase IIb studies. Having confirmed the hypothesis, Phase IIb studies look to find the optimum dose at which the drug shows biological activity with minimal side-effects – often called ‘dose-ranging’ studies..

(27) ations, traditional immunosuppressants have a high potential for toxicity, slow reversibility, and may increase the risk of infection or malignancy. Actelion’s selective S1P1 receptor agonist is currently in development, as an immunomodulator with the potential for once-a-day oral dosing, for multiple autoimmune disorders.. Actelion’s S1P1 receptor agonist in development for multiple sclerosis. Milestones 2009 2008 2006 2004. Initiation of dose-finding study in multiple sclerosis Initiation of proof of concept study in psoriasis Entry-into-humans Preclinical development initiated. Key scientific literature Waubant E. Emerging therapies for MS. Rev Neurol (Paris). 163(6-7):688-96; 2007.. Following a successful Phase I program, Actelion’s first-in-class selective S1P1 receptor agonist moved forward to a Phase IIb dose-finding study in patients with multiple sclerosis.. Actelion’s S1P1 receptor agonist in development for psoriasis. Progress in 2009 Actelion has advanced its selective S1P1 receptor agonist for the treatment of psoriasis based on a Phase IIa proof-of-concept study. While this short term study did not reach statistical significance, sufficient information was obtained to proceed with a first pivotal study in psoriasis. The Phase IIa study also extended the safety information of Actelion’s selective S1P1 receptor agonist, previously established in healthy volunteers, to a larger group of psoriasis patients for up to six weeks of treatment. Full study results will become available through future presentation at major scientific meetings and subsequent scientific publication.. Brinkmann V. Sphingosine 1-phosphate receptors in health and disease: mechanistic insights from gene deletion studies and reverse pharmacology. Pharmacol Ther. 115(1):84105; 2007. Rosen H. et al. Tipping the gatekeeper: S1P regulation of endothelial barrier function. Trends Immunol. 28(3):102-7; 2007. Doggrell SA. Is fingolimod an advancement in the treatment of multiple sclerosis? Expert Opin Pharmacother. 8(3):383-6; 2007. Kappos L. et al. Oral fingolimod (FTY720) for relapsing multiple sclerosis. N Engl J Med 355(11):1124-40; 2006.. Macitentan Related Links Compound description Macitentan in development for IPF. Progress in 2009 In 2009, a double-blind, randomized, multicenter study evaluating efficacy and safety of macitentan in patients with IPF was initiated.. Available clinical data Given the marked lymphocyte lowering effects, the Phase I data support further exploration of Actelion’s S1P1 receptor agonist in patients.. Available clinical data In a Phase II study with 379 hypertensive patients, macitentan was significantly better than placebo and better than enalapril. 27. 02 Research and Development. WorldReginfo - 60e0ae8d-cd84-4435-bdcf-3e8de072d25b. Progress in 2009.