Actelion's Drug Discovery Pipeline 

(February 2007)

Focused drug discovery has been the cornerstone of Actelion since it was founded in 1997. Our highly qualified research team is an expression of the deeply held conviction that innovation in new therapies is the basis of Actelion's long-term independence and success.

Several of Actelion’s drug discovery projects are in an advanced stage and have the potential to satisfy important unmet medical needs in: cardiovascular, central nervous system, oncology and immunology as well as anti-infective indications. In addition to the urotensin-II receptor antagonist, for which clinical investigations have been initiated in diabetic nephropathy, Actelion’s drug discovery efforts have generated several advanced projects in areas such as orexin antagonists and renin inhibitors. Actelion's global alliances with the pharmaceutical companies Merck and Roche to discover, develop and market innovative drugs, are a visible affirmation of the calibre of Actelion’s drug discovery know-how. In addition, yet unnamed compounds (Actelion-3 to -11) are in full preclinical development for cardiovascular, onco/immuno, cns and anti-infective indications. Actelion has currently more than 25 active drug discovery programs under investigation, focusing both on new molecular entities (NCE) as well as follow-up compounds for new chemical entities already in either full pre-clinical or clinical development. Since its foundation in 1997, Actelion has filed more than 146 priority patent applications. Actelion's patent portfolio currently encompasses more than 1040 pending patent applications and granted patents.
At the current size and speed, Actelion expects that its discovery efforts could lead to two or more compounds to enter full-preclinical testing every year.

Orexin Receptor Antagonists

The orexins are peptide hormones produced in the brain that are implicated in the regulation of wakefulness and feeding behavior. Substances that block the G-protein-coupled orexin receptors hold promise as novel sleep and appetite regulators. Although work was well in progress on potent orexin receptor antagonists in 2002, a major breakthrough came about during 2003 when the first orally active compounds were discovered. One particular substance, had been selected for preclinical development based on its overall favorable profile. In 2005, Actelion has initiated a clinical program evaluating an orexin receptor antagonist in sleep disorders (see Clinical Development).

S1P₁ Receptor Agonist
S1P is a phospholipid released by platelets, mast and other cells. S1P stimulates five G-protein coupled (GPC) receptors: S1P_1,2,3,4,5. The different receptors induce a variety of biological responses. It has been shown that S1P receptor modulators inhibit the egress and recirculation of lymphocytes in lymph nodes, thereby potentially preventing immuno-reactions. There is a high medical need in several common autoimmune diseases such as psoriasis, rheumatoid arthritis, multiple sclerosis and other diseases (e.g. transplantation).

Actelion has commenced full pre-clinical development of a novel, orally available immunomodulator. In pre-clinical models, the Actelion S1P₁ agonist has shown to substantially decrease the number of circulating lymphocytes. In rat A ctelion’s S1P₁ agonist showed to prevent arthritis. In July 2006, Actelion and Roche entered into an exclusive worldwide collaboration to jointly develop and commercialize Actelion’s selective S1P1 receptor agonist, as immunomodulator with the potential for once-a-day oral dosing for multiple autoimmune disorders. Currently, additional discovery and early pre-clinical development efforts in the field of selective S1P1 receptor agonists are underway at Actelion’s resear ch facilities (see Clinical Development).

Renin Inhibitors
Renin is the critical enzyme at the beginning of the biochemical cascade that produces the peptide hormone angiotensin II. Inhibitors of the cascade are already very impo rtant d r ugs for treating cardiovascular and kidney disease. Inhibitors of renin are expected to provide more complete and more specific inhibition of this biochemical cascade, with better efficacy and tolerability compared to existing th erapies. While major pharmaceutical companies have succeeded in finding prototypical renin inhibitors, all have suffered from the same critical disadvantage: only a small fraction of the drug was absorbed after oral administration. As these were large complicated molecules, also expensive to make, the poor oral bioavailability proved to be a fatal flaw. Most major pharmaceutical companies abandoned their efforts in this field in the mid-1990s.

Renin inhibition is the most recent pharmacological approach for the treatment of hypertension and, potentially, renal failure, and vascular diseases. Actelion has made substantial progress in identifying potent renin inhibitors. Actelion and Merck & Co., Inc. formed an exclusive worldwide alliance in December 2003 to discover, develop and market new classes of orally available renin inhibitors for patients suffering from cardio-renal diseases.Through a joint committee, the parties are collaborating on the development of products. A first milestone was achieved in March 2004 with the completion of the technology transfer, which provided Merck with unrestricted access to Actelion's multiple renin inhibitor classes. A second milestone was achieved in March 2005 when the first compound was selected for full preclinical development. In July 2006, the renin alliance achieved its third milestone: The alliance entered into man its first compound, a new renin inhibitor (see Clinical Development).

BACE Inhibitors
Another area of research is identifying inhibitors of the enzyme beta-secretase (ß-site amyloid precursor protein-cleaving enzyme, BACE), which targets the enzymatic process believed to be at the core of Alzheimer’s disease. The structural biology group has been able to gain insight in to the t hree-dimensional structure of this aspartyl protease , which will facilitate further optimization studies for an orally available BACE-1 inhibitor. No final compound was selected yet. Step by step, new tools and approaches improve Actelion’s continuing drug discovery efforts in Alzheimer’s disease.

Antibacterials
Existing antibiotics are about to lose their therapeutic value due to the ever-increasing resistance development. Big pharma companies have discontinued research efforts for new anti-bacterial compounds. The pharmaceutical pipeline for new antibiotics is drying-up.

Actelion is searching for highly potent antibacterials, covering clinically relevant resistance patterns of Gram- positive (e.g. Staphylococcus epidermidis, Streptococcus pneumoniae) and Gram-negative (e.g. Enterobacteriaceae, Acinetobacter, Pseudomonas) bacteria. Additionally of importance is, a lack of cross-resistance with existing mechanisms, a low propensity to develop resistance, and a bactericidal mode of action. Actelion‘s strategy to develop new c ompounds with novel mechanisms of action has paid off in providing molecules with excellent spectrum and potency, cov eri ng clinically relevant resistance mechanisms.