966 Targeting cAMP in ADPKD by small molecule activation of long form PDE4 enzymes

Abstract Background and Aims Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most common hereditary kidney disorder, affecting over 12 million people worldwide. ADPKD is characterized by the uncontrolled growth of fluid-filled cysts in the kidney that can lead to kidney enlargement, loss of function, and associated complications. Currently, there are limited treatment options for ADPKD patients. By activating long form PDE4 enzymes and increasing cAMP hydrolysis, Mironid®’s first-in-class small molecule LoAc® compounds [1] directly target the increased kidney cAMP levels that are known to drive cyst formation in ADPKD, resulting in decreased cyst growth in vitro and in vivo. Here we present translational data demonstrating that LoAc® compound MR-L22 lowers renal cAMP after single or multiple doses and delivers efficacy in the Pkd1RC/RC mouse model of ADPKD, alongside favourable differentiation from tolvaptan, the only therapy approved for ADPKD patients. Method To demonstrate cAMP lowering in urine, male Han Wistar rats (n = 6) were dosed p.o. with 100 mg/kg MR-L22 or vehicle (1% methylcellulose, 0.2% Tween 80) either once, or on 7 consecutive days. Urine was collected on Day 1 or Day 7. To assess the ability of MR-L22 to ameliorate disease progression alone, or in combination with tolvaptan, doses of MR-L22 (60 mg/kg) and tolvaptan (0.1% in chow), both expected to be individually sub-maximally efficacious, were administered singly, or in combination in F1 hybrid progeny Pkd1RC/RC mice (8 m and 8f/group), from 4-16 weeks of age. Urine measurements were taken after 8 weeks of dosing. Total kidney volume (TKV) was measured by MRI prior to randomisation and termination. cAMP in urine and kidney tissue were measured by ELISA. Results A 100 mg/kg oral dose of MR-L22 in rat resulted in a >40% decrease in cAMP in urine compared to vehicle. This effect was maintained over multiple days of dosing demonstrating that urinary cAMP can be used as a biomarker of LoAc® target engagement. Consistent with the mechanism of action, a small increase in urine production and commensurate decrease in urine osmolality was observed. To assess the ability of MR-L22 to ameliorate disease progression in an in vivo model of ADPKD, and to determine whether additive or synergistic effects might be seen in combination with tolvaptan, MR-L22 (60 mg/kg) and tolvaptan (0.1% in chow) were dosed individually and in combination in the Pkd1RC/RC mouse model of ADPKD. Alongside a red