(370) Overview of Nonclinical Studies of LIB-01, a Novel Promising Oral Drug Under Development for Treatment of Erectile Dysfunction

Abstract

Abstract Introduction LIB-01 is a novel molecule being developed as an oral drug for the treatment of erectile dysfunction (ED). It is a semi-synthetic analog, developed based on research on active compounds identified in root bark that had been used for treatment of male sexual disability since time immemorial. Objective In preparation for clinical development, a number of nonclinical studies on erectile function were conducted in normal and diabetic rats with ED. Studies to investigate the mechanism supporting the pro-erectile effect of LIB-01 were also conducted. A summary of the results from the nonclinical research program is presented. Methods Erectile response elicited by electrical stimulation of the cavernous nerve (ES CN) in anaesthetized rats was assessed. Intracavernous and arterial blood pressures were monitored according to a standardized experimental procedure. Mechanism of action studies were conducted with rat cavernosal tissue samples using immunohistochemistry and in ex vivo/organ chamber experiments. The isometric tension studies were conducted on cavernosal strips from LIB-01 treated and untreated Wistar rats. Cavernosal strips from untreated rats were incubated with either LIB-01 or DMSO (control) and then pre-contracted by phenylephrine (PHE). Concentration- or frequency response curves were performed on PHE pre-contracted strips in 3 consecutive steps: (i) cumulative addition of increasing acetylcholine (ACh) concentrations, (ii) electrical field stimulation (EFS) with increasing frequencies, and (iii), cumulative addition of increasing sodium nitroprusside (SNP) concentrations. Results A statistically significant pro-erectile facilitatory effect of LIB-01 has been repeatedly evidenced in all the studies conducted in anaesthetized control Wistar rats, by oral or subcutaneous administration of LIB-01 at 15 mg/kg/d, with an effect in the similar range as iv sildenafil 0.3mg/kg, when compared. The pro-erectile effect of LIB-01 was not acute, instead, the effect gradually increased and remained for at least 7 days post treatment. In addition, LIB-01 significantly improved erectile responses in anaesthetized diabetic Goto-Kakizaki ED rats compared to vehicle-treated rats, demonstrating the pro-erectile effect of LIB-01 in a robust validated pathophysiological rat model of type 2 diabetes. Immunohistochemistry experiments on cavernosal tissue from LIB-01 treated normal rats showed that neither CD31 nor nNOS expression was altered, thus likely ruling out any effect of LIB-01 on cavernosal micro-vascularization or cavernosal nNOS. Furthermore, only at a high concentration (10-5 M) was there a slight increase in the endothelium dependent relaxations induced by ACh compared to vehicle while LIB-01 did not exert any effect neither on endothelium-independent relaxations induced by SNP nor on nitrergic relaxation induced by EFS of untreated cavernosal strips exposed ex-vivo to different concentrations of LIB-01. Conclusions LIB-01 is a novel molecule which displays a significant pro-erectile effect in anesthetized normal rats as well as in diabetic rats with ED. The pro-erectile effect of LIB-01 is not acute, instead, the effect gradually increases and remains for at least 7 days post-treatment. Results from several mechanistic studies lead to postulate that the mechanism of LIB-01 does not recruit the NO-cGMP pathway thereby differing from phosphodiesterase type 5 inhibitors. A first-in-human clinical trial with LIB-01 is planned to start in 2023. Disclosure Yes, this is sponsored by industry/sponsor: Dicot AB. Clarification: Industry initiated, executed and funded study. Any of the authors act as a consultant, employee or shareholder of an industry for: Dicot AB.