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During the fourth day of the 2017 European Society of Cardiology (ESC) Congress in Barcelona, Dr. Jigisha Patel of University College London (UCL) presented her lab’s results featuring a preclinical study regarding the potent anti-proliferative and vasorelaxant properties in the human pulmonary artery of Arena Pharmaceuticals’ ralinepag.

Ralinepag is a Phase II prostacyclin (IP) receptor agonist that boasts a long half-life of 24 hours and is in clinical development for pulmonary arterial hypertension (PAH).

PAH is a fatal cardiopulmonary disease with a global annual mortality rate of 15%. The pathology of PAH has been attributed mainly to endothelial dysfunction and vascular remodeling, although increasing evidence indicates that the disease has more of an inflammatory proliferative nature.

The current five classes of drugs indicated for PAH are endothelin receptor antagonists (ERA), phosphodiesterase type 5 (PDE5) inhibitors, soluble guanylate cyclase (sGC) stimulators, IP derivatives, and IP receptor agonists.

The only marketed IP receptor agonist is Actelion’s Uptravi (selexipag).

The aim of Dr. Patel’s study was to compare the functional effects of ralinepag with other prostacyclin mimetics already licensed for PAH.

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By GlobalData

The study utilised distal pulmonary arterial smooth muscle cells (PASMC) isolated from the lungs of PAH patients who were either idiopathic or associated with small cardiac defects and human pulmonary arteries derived from the histologically normal tissue of cancer patients undergoing lobectomy.

Dr. Patel first showed data comparing the effects that selexipag metabolite, ralinepag, and iloprost each had on cyclic adenosine monophosphate (cAMP) generation in distal PASMCs from PAH patients. According to Dr. Patel, ralinepag had a better effect than selexipag in generating cAMP. However, the effects of cAMP generation were completely reversed once an IP receptor antagonist was introduced to the sample. However, Iloprost demonstrated the best cAMP generation in the distal PASMCs and was still able to produce cAMP when an IP receptor antagonist was introduced.

Dr. Patel’s lab also assessed the remodelling of ralinepag versus selexipag, finding that ralinepag had a tenfold superior effect in anti-proliferation compared to selexipag. In addition, Dr. Patel noted: “the effects on proliferation of both drugs [ralinepag and selexipag] were completely reversed by the IP receptor antagonist.”

Dr. Patel concluded her presentation by stating that the vascular relaxation properties induced by ralinepag, selexipag, treprostinil, and iloprost, were accessed via wire myography. She stated: “Ralinepag produced almost 100% relaxation on human pulmonary arteries and was significantly better than selexipag in these assays. Iloprost, on the other hand, was also good at relaxing human pulmonary arteries, but in this particular assay, ralinepag was able to produce better results than…both agents.”

The results she referred to were from the Emax, a metric used to measure vessel relaxation induced by each of the drugs. Ralinepag produced a significantly greater relaxation (p<0.001, Emax 98%) compared to selexipag (Emax 59%), treprostinil (Emax 71%), and iloprost (Emax 84%).

These preclinical results of the study show the potential superiority ralinepag has over Actelion’s Uptravi, the lone IP receptor agonist currently marketed for PAH. While showing some superiority over ralinepag in Dr. Patel’s study, Iloprost is an inhaled therapy and ralinepag and selexipag are both oral therapies.

According to key opinion leaders interviewed by GlobalData, not only are more efficacious therapies needed for the treatment of PAH patients, but also therapies that improve ease of administration.

At the end of her presentation, Dr. Patel noted that Arena Pharmaceuticals will pursue a Phase III trial to obtain more efficacy and safety evidence for ralinepag. Specific details of the trial have yet to be announced.