This presentation will discuss the design concepts of optimizing membrane affinity for inhaled GPCR targeted drug candidates, including novel NMR evidence that demonstrates the specific interaction of molecules with phospholipids, and the structure activity relationship related to these interactions. This has resulted in the discovery of QCC374, the first selective prostacyclin (IP) receptor agonist rationally designed for dry powder inhalation (DPI) for pulmonary arterial hypertension (PAH). Inhaled QCC374 offers high levels of lung exposure, a long duration of action (via optimized cell-membrane affinity) and low systemic exposure (high plasma protein binding, rapid clearance) and is currently in Ph2 trials.

Pulmonary arterial hypertension (PAH) is an orphan disease characterized by chronic elevation in pulmonary arterial pressure, progressive pulmonary remodeling, right heart failure, and mortality. Despite major advances with the development of marketed therapies targeting three pathways: the endothelin, nitric oxide (PDE5 and guanylate cyclase), and prostacyclin pathways, PAH remains a fatal disease with a median survival from diagnosis of 7 years (Benza et al, 2012).

Prostacyclin (IP) analogues confer antiproliferative, vasodilatory, and anti-inflammatory effects. Despite the precedent within this class of approved therapies (epoprostenol, iloprost, treprostinil, beraprost & recently approved oral selexipag), all these agents have significant dose-limiting adverse events (AEs), ranging from headache and jaw pain to nausea/vomiting/diarrhea and hypotension, that significantly impact the safety, tolerability and efficacy of this class. The initiation of prostacyclin therapy is therefore delayed in many PAH patients, with a subsequent negative effect on prognosis (Badagliacca et al 2012).
We believe with optimized membrane affinity and lung duration of action, QCC374 has the attributes to demonstrate a class-leading profile, differentiating from other marketed prostacyclin analogues, with the potential for earlier and broader use across PAH.

Badagliacca, R., et al (2012) Prognostic factors in severe pulmonary hypertension patients who need parenteral prostanoid therapy: the impact of late referral. J Heart Lung Transplant; 31:(4) 364-72.

Benza, R. L., et al (2012) An evaluation of long-term survival from time of diagnosis in pulmonary arterial hypertension from the REVEAL

















Emily Balskus(Harvard University) , Jennifer Prescher(University of California, Irvine) , Mark Healy(Novartis Institutes for Biomedical Research, Cambridge, MA, USA)