THE TREATMENT OF PAH

requires novel disease-modifying approaches that are mechanistically distinct from current treatment options.

Emerging science reveals an important role of dysregulated peripheral serotonin in pathologies associated with tissue fibrosis and inflammation.

Over the last decade, the treatment of PAH has evolved considerably with the development of endothelin receptor antagonists (ERAs), phosphodiesterase-5 inhibitors (PDE5Is) or stimulators of soluble guanylate-cyclase, and prostacyclin-related vasodilators, sometimes used in combination. However, these therapeutic options do not halt or reverse the vascular remodeling that underlies the unabated disease progression characteristic of PAH. Indeed, as the disease progresses, patients may become refractory to their medications, while pulmonary vessels continue to degrade, resulting in considerable morbidity and mortality. Achieving further improvements in the treatment of PAH requires novel disease-modifying approaches that are mechanistically distinct from current treatment options.

Karos is developing a disease-modifying agent that operates through a distinct mode of action.

Karos’ product aims at providing a brand new therapeutic option to a $4B worldwide market and to patients still facing life expectancy of less than seven years after diagnosis. In preclinical studies, Karos’ lead candidate has demonstrated robust efficacy in two different PAH models. More importantly, the effects of the Karos compound were potentiated when administered in combination with drugs that represent the current standard of care. Karos has successfully submitted an IND and obtained Orphan Disease Status in October 2015. First in human clinical trials have started in November 2015 and are currently ongoing. In parallel, Karos is expanding this unique mode of action to other important therapeutic indications, while developing novel back-up compounds.

IP Position Protects Key Assets: Karos has an issued patent on its clinical candidate and other related compounds. Other patent applications have been filed on additional distinct chemotypes.

Significant Medical Need Remains in Treating PAH: Although the introduction over the last 20 years of a number of 11 new therapeutic agents to treat PAH has led to a pronounced improvement in one-year survival, five-year mortality for the disease remains stubbornly high at approximately 45-50%, on par with the long-term mortality seen with melanoma. Since many patients eventually become refractory to current treatments, Karos believes that the advent of a truly disease modifying therapy offers a real possibility to significantly improve long-term survival in PAH.