A discovery pipeline filled by innovative science

Actelion began in late 1997 with a vision to discover and develop truly innovative medicines to address unmet medical needs. Building on the success of the first marketed drug, Tracleer®, a breakthrough treatment for pulmonary arterial hypertension (PAH), the company’s researchers have made tremendous progress in other therapeutic areas.

A closer look at the current drug discovery pipeline shows that Actelion can be compared favorably to companies many times its size – both in terms of the innovative science and the commercial potential of the products.

Since its inception, Actelion has concentrated on two platforms of molecular targets, G-protein-coupled receptors and aspartyl proteases. A third platform was added in 2004 in antibacterial research to find novel approaches in the battle against antibiotic resistant bacteria (see Inside story).

Aspartyl proteases: Renin inhibitors and BACE-1 antagonists

Renin is a critical enzyme at the beginning of a biochemical cascade involved in a number of widespread cardiovascular and kidney diseases. Drugs developed to act on targets further down the cascade, angiotensin-coverting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs), have become multi-billion-dollar blockbusters. Convinced that the best medical results can be achieved by attacking this problem at the source, Actelion’s researchers have succeeded in developing the first orally highly available renin inhibitors, which are protected by over 30 priority patent applications. This led to an exclusive worldwide alliance in December 2003 with Merck, based on milestone payments and future royalties to Actelion. In 2005, a second milestone in this project was achieved when a highly bioavailable renin inhibitor was selected for full preclinical development, which is currently ongoing. An entry into man is planned by mid-2006.

Alzheimer’s disease affects about 25 million people worldwide, with an increasing incidence as the global population ages. The beta-secretase (BACE) enzyme, essential in the formation of the amyloid beta peptide, is thought to be the trigger for the formation of cerebral plaques found in Alzheimer’s patients. Actelion’s scientists are working intensively to develop BACE-1 inhibitors as a possible treatment for Alzheimer’s. Substantial progress has been made in solving the molecular structure of beta-secretase and developing novel in-silico screening methods. However, no compound candidate has been indentified to date.

G-protein-coupled receptors: S1P₁ agonists

The sphingosine-1 phosphate receptor 1 (S1P₁), which modulates the immune system, is located on endothelial cells – an area of core expertise at Actelion. The company’s researchers have developed a selective S1P₁ agonist, protected by seven priority patent applications, that shows promise for treatment of autoimmune diseases. In animal models, Actelion’s selective S1P₁ agonist has shown potential advantages over competitor compound FTY720 from Novartis, now in late stage clinical development as the first orally available therapy for multiple sclerosis. Potential advantages include a better side-effect profile and a very rapid onset of action combined with very rapid reversibility upon cessation of treatment – a critical concern when dealing with the immune system. The S1P₁ agonist is another drug discovery project that has reached full preclinical development with potential for multiple applications, including multiple sclerosis and rheumatoid arthritis. An entry into man is planned for early 2006.

In addition to the drug discovery programs already mentioned, an additional nine unnamed projects (Actelion-3 to Actelion-11) are in various phases of drug discovery. These projects target indications in immunology, cardiovascular diseases, infectious diseases and central nervous system disorders.

Customized infrastructure supports drug discovery efforts

The vast amount of data generated by biopharmaceutical research means that informatics plays a vital role in drug discovery. Unlike most companies, which purchase off-the-shelf software, Actelion has developed in-house programs such as a 3-D Ligand Docking Simulator that are tailor-made and constantly updated on the basis of feedback from the scientists. This gives Actelion a competitive edge in the race to develop new drugs.

At the beginning of 2006, a new Research Center was completed at Actelion’s headquarters in Allschwil. From its inception, the building was constructed in close collaboration with the scientific staff – built by researchers for researchers. The new facility provides state-of-the-art technology and workspace for 300 scientists. It is a symbol of the company’s faith in its future and the ability of its scientists to transform innovative thinking into successful drugs.