THE NEXT STEP IN MEETING PATIENTS’ NEEDS IN PAH. Actelion has made a new breakthrough in the treatment of pulmonary arterial hypertension (PAH). Patients and physicians wanted a drug capable of providing more long term benefit. With its extensive expertise in endothelin science, Actelion established a tailored program to discover a new endothelin receptor antagonist (ERA) with optimized efficacy and safety. Actelion researchers synthesized and characterized approximately 2,500 novel compounds before selecting macitentan – a dual ERA with unique sustained endothelin receptor-binding properties and enhanced tissue penetration.

REsEARCH

Actelion Annual Report 2012

Actelion Annual Report 2012

understanding of PAH – and of the still unmet medical needs in this se-vere life-threatening condition.

The initial discovery of bosentan, an ERA indicated for the treatment of pulmonary arterial hypertension (PAH), inspired the vision to seek an ERA which would be able to impact long-term morbidity and mortality, with a good tolerability profile.

A TAILORED DISCOVERY PROCESSThe goal of Actelion’s drug discovery program was to find a potent and efficacious dual ERA which could be given at dosages not limited by safety signals. Actelion’s medicinal chemists synthesized approximately 2,500 novel chemical structures, which were all tested for affinity to both endothelin receptors. The most potent compounds were then tested in a selection cascade that included functional inhibition assays and in vivo models. A total of 380 compounds were assessed for oral efficacy in pathological models of hypertension or pulmonary hypertension, and 40 compounds were also tested in a model relevant for hepatic safety. At

the end of this process, one compound with the required characteristics was selected for progression toward clinical development – macitentan.

UNIqUE FEATURESEndothelin is produced and acts in tissues, not in the blood. In PAH, the expression of endothelin and of ETA and ETB receptors, which mediate the detrimental effects of endothelin, is enhanced in the pulmonary arteries and in the heart. Actelion’s discovery program was designed to address these peculiar features of the en-dothelin system in pathology: the novel ERA had to penetrate well into the tissue, bind to the receptors with high affinity and durability and exert beneficial structural effects, which would be fundamental to impact mor-bidity/mortality in PAH.

Macitentan was ideally suited to meet these requirements, as it displays enhanced tissue penetration and sus-tained receptor binding, independent of local endothelin concentrations. As a result, macitentan showed in-creased in vivo preclinical efficacy compared to other ERAs in several

The discovery of the endothelin sys-tem in the late 1980s was the spark that ignited the comprehensive sci-ence Actelion is known for today. At Hoffmann-La Roche, the future founders of Actelion were among the world leaders in the science of the endothelin system, discovering the first oral endothelin receptor antago-nist (ERA), bosentan. Within a year after its foundation, Actelion had in-licensed bosentan from Hoffmann-La Roche, initiated a clinical develop-ment program for the treatment of pulmonary arterial hypertension (PAH), and established a tailored drug discovery program to find novel ERAs with improved efficacy and safety. In 2001, Tracleer® (bosentan) became the first oral drug to be approved for the treatment of PAH. In 2002, macitentan was discovered.

A SCIENTIFIC VISION Actelion’s knowledge in the field of endothelin and ERAs continued to ex-pand, thanks to its founders’ exten-sive 25-year research experience and their academic collaborations, and to the company’s clinical programs. In parallel, Actelion developed a deeper

COMPREHENSIVE SCIENCE SHAPES A TAILORED DISCOVERY PROCESS

Actelion Annual Report 2012

In addition, these preclinical models have shown a favorable safety profile for macitentan. Macitentan is well absorbed, with a pharmacokinetic profile allowing for once-daily treat-ment in PAH, and with a low propen-sity for drug-drug interactions and therefore a potential for combination therapy.

The unique properties of macitentan should allow Actelion to exploit its full therapeutic potential, opening the door for new indications beyond the PAH field.

preclinical models of hypertension and pulmonary hypertension. Follow-ing recognition of these results by the European Medicines Agency’s Com-mittee for Orphan Medicinal Prod-ucts, macitentan was granted orphan drug status in 2011. Two years earlier, macitentan had also been granted orphan drug designation in the US.

Actelion Annual Report 2012