PALI-2108, A COLON SPECIFC PDE4B INHIBITOR PRODRUG IS ACTIVATED IN THE COLON AND REDUCES ULCERATIVE COLITIS SYMPTOMS IN AN ACUTE COLITIS DSS MOUSE MODEL

Abstract Ulcerative Colitis is a devastating inflammatory disease of the lower GI tract with an estimated incidence of 900,000 patients and an estimated prevalence of 5 million patients. Phosphodiesterase-4 (PDE4) inhibition leads to downregulation of inflammatory cytokines. Systemic PDE4 inhibitors exposure has resulted in Central Nervous System (CNS) toxicity such as nausea or vomiting, often leading to discontinuation of therapy and thereby limited efficacy. We developed PALI-2108, an orally-delivered, colon-activated PDE4 inhibitor prodrug. PALI-2108 gets converted by colonic bacterium enzyme β-glucuronidase to the active drug PALI-0008 and minimizes its systemic exposure, thereby reducing CNS toxicity as demonstrated in mice and dogs. Here we show that oral administration of PALI-2108 in mice leads to effective conversion of the prodrug PALI-2108 to the active PDE4 inhibitor PALI-0008 in the colon in a dose dependent manner. To demonstrate the absence of side effects of PALI-2108, single ascending doses of prodrug PALI-2108 and active PALI-0008 were administered to dogs and toxicity was assessed. Prodrug PALI-2108 was well tolerated, while oral delivery of the active drug PALI-0008 resulted in emesis only at the higher doses, suggesting that systemic toxicity might not be observed in patients exposed to PALI- 2108. We have shown that mice, dogs and human possess similar levels of β-glucuronidase. We have demonstrated effective conversion of PALI-2108 prodrug into active PDE4 inhibitor PALI-0008 in humans using routine stool samples from 6 healthy patients and 6 patients with UC. Prodrug-to-drug conversion percentage at 24 hours of 90.1% was observed across samples. All samples had conversion of greater than 30% and conversion increased steadily over time. We utilized an acute DSS-induced colitis model of disease induction in mice. In this model, disease activity index (DAI) score was based on a scoring system including body weight loss, stool consistency and the presence of blood in feces. PALI-2108 reduced the mean DAI score over time compared to the vehicle group and in a dose dependent manner. Additionally, body weight loss over time was attenuated in the higher dose groups. Tissue distribution showed colon preference of PALI-2108 with limited plasma levels. Here we demonstrated the effectiveness of PALI-2108 in reducing colitis symptoms in this standard colitis mouse model. Better-tolerated oral PDE4 inhibitors remain an unmet need in IBD and we show that PALI-2108 is a colon specific PDE4 inhibitor that reduces colitis symptoms in the DSS mouse model in a dose-dependent manner in the absence of CNS toxicity seen in systemic exposure with PDE4 inhibitors. This should present a novel alternative for UC patients and we have initiated a phase 1 study to test the safety of PALI-2108 in healthy volunteers and Ulcerative Colitis patients.