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Drug Discovery |
THE ACTELION ANNUAL REPORT 2003 |
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| Drug Discovery |
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Focused drug discovery has been the cornerstone of Actelion since it was founded in 1997. Starting with the first laboratories in biochemistry, pharmacology and chemistry, the company has steadily expanded to its current state-of-the-art research facility of nearly 5,000 square meters. The highly qualified team of 150 scientists is an expression of the deeply held conviction that innovation in new therapies is the basis of Actelion's long-term independence and success. There has been a steady increase in the capacity for additional drug discovery projects and a systematic addition of new expertise in critical areas. In 2003, new drug discovery projects were initiated in part with the help of carefully selected external research collaborations. The focus remains, however, on increasing in-house capabilities. The acquisition and integration of Axovan in October 2003 represents a significant development in this respect.
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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 and oncology 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. The recently announced global alliance with the pharmaceutical company Merck to discover, develop and market new classes of renin inhibitors is a visible affirmation of the caliber of Actelion’s drug discovery know-how.
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“The two driving forces of Actelion’s Drug Discovery
are the art of medicinal chemistry and the integration
of essential technologies. Their tight integration reduces complexity and shortens development time.” |
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By fully integrating Axovan's promising and highly productive preclinical efforts in the area of G-protein-coupled receptors (GPCR), Actelion expects to further increase the output of its drug discovery organization. Advanced projects to be integrated into preclinical efforts include programs in areas such as thrombosis and inflammation.
Actelion and Johnson & Johnson Pharmaceutical Research & Development, LLC reviewed the status of their collaboration and agreed that Actelion would be best placed to continue development of the collaboration compounds. The terms of the deal have therefore been adapted so that Actelion will be responsible for ongoing development and commercialization and will pay Johnson & Johnson Pharmaceutical Research & Development, LLC a small royalty on sales of any successfully commercialized product.
Today, Actelion has one of the most attractive pipelines in the industry. The following paragraphs summarize the substantial progress that has been made since 2003.
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| Project updates |
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The company currently has three compounds in full preclinical development, of which two have not been disclosed for competitive reasons. The third compound is an orexin receptor antagonist. 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, ACT-078573, has been selected for preclinical development based on its overall favorable profile.
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“Actelion’s criteria for selecting research projects are medical need, therapeutic novelty, predictive animalmodels and clinical feasibility.” |
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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 important drugs for treating cardiovascular and kidney disease. Inhibitors of the cascade are already very important drugs 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 therapies. 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.
Actelion has taken a new approach. Rather than continuing to try to make new derivatives of the known potent, large and complicated renin inhibitors, work began on smaller molecules, with good oral absorption, but weak renin inhibitory activity. After several years of chemical optimization work, the Actelion research team has now arrived at potent, orally active renin inhibitors, with high oral bioavailability. Several of these compounds have a profile suitable for preclinical development – a real breakthrough in this field. The Actelion renin inhibitors have been protected by at least 15 priority patent applications.
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“The fascination of Actelion’s Drug Discovery today is seeing that the approaches in screening and rational drug design are merging.” |
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Another area of research is identifying inhibitors of the enzyme beta-secretase (β-site amyloid precursor protein-cleaving enzyme, BACE), which target the enzymatic process believed to be at the core of Alzheimer’s disease. The structural biology group has been able to gain insight into the three-dimensional structure of this aspartyl protease, which will facilitate further optimization studies for an orally available BACE inhibitor.
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