CLINAPAI

Hypertension (HTN) remains still difficult to control: In France, only 50% of the hypertensive population is at the blood pressure (BP) target, more than 25% of the hypertensive patients more than 3 antihypertensive treatments and 10% of the hypertensive patients are resistant to at least 3 antihypertensive drugs (including a diuretic). Consequently, there is a need to develop new classes of antihypertensive agents acting on new targets with different mechanisms of action to improve blood pressure (BP) control and the associated cardiovascular risks. Evidences support that hyperactivity of the brain renin-angiotensin system (RAS) participates to the development and maintenance of HTN. Research programs carried out by the laboratory of Dr. C.Llorens-Cortes (Partner 2) have allowed to demonstrate in hypertensive rats, that in the brain RAS, angiotensin III (AngIII) is one of the main effector peptides exerting a tonic stimulatory action on the control of BP. Using specific and selective APA inhibitors developped by the laboratory of Pr. BP. Roques, EC33 and its prodrug RB150, Partner 2 demonstrated the key role of aminopeptidase A (APA), in the formation of brain AngIII from AngII. Thus, blockade of brain APA activity by these compounds normalizes BP in hypertensive rats. This highlights that brain APA constitutes a novel potential therapeutic target for the treatment of HTN. In 2007, Quantum Genomics (Partner 1) signed an exclusive license agreement for the patents that protect EC33, RB150 and the use of APA inhibitors as antihypertensive agents in human and animals. RB150 was selected by Quantum Genomics as an investigational medicinal product for clinical development and renamed QGC001. In the framework of the BiotecS-2008 program (BAPAI), RB150/QGC001, administered by oral route in two experimental rat models of HTN (the DOCA-salt rat and the spontaneous hypertensive rat (SHR)), was found to cross the intestinal, hepatic and blood brain barriers, to inhibit brain APA activity, to block brain AngIII formation and to normalize BP for several hours. Moreover, in SHR, combining RB150/QGC001 with a systemic RAS blocker potentiates the RB150-induced BP decrease. Non clinical toxicology, genotoxicity, safety pharmacology and pharmacokinetics studies performed in animals have demonstrated that RB150/QGC001 is safe and well tolerated both in rats and dogs at doses significantly superior to the dose showing anti-hypertensive activity in rats. Phase I clinical studies confirmed that RB150/QGC001 is clinically and biologically well-tolerated in healthy volunteers after single oral administrations up to 2000 mg. Like in animal experiments, in normotensive male human volunteers, RB150/QGC001 has no effect on BP and heart rate (HR) and the activity of the systemic RAS. The work proposed with the “CLINAPAI” project will aim (1) at assessing the tolerability, the pharmacokinetics and the clinical efficacy of RB150/QGC001 in a “Proof of Concept” exploratory study in hypertensive patients, (2) at identifying new chemical families of centrally-acting APA inhibitors with higher affinity and selectivity and improved pharmacodynamics and pharmacokinetics properties compared to those of RB150/QGC001. These inhibitors could lead ultimately to the selection of “Best-in-Class” drug-candidates.