The Novel, Clinical-Stage Soluble Guanylate Cyclase Activator BI 685509 Protects from Disease Progression in Models of Renal Injury and Disease

Abstract

Activation of soluble guanylate cyclase (sGC) to restore cyclic guanosine monophosphate (cGMP) and improve functionality of nitric oxide (NO) pathways impaired by oxidative stress is a potential treatment for diabetic and chronic kidney disease. We report the pharmacology of BI 685509, a novel, orally active small molecule sGC activator with disease modifying potential. BI 685509 and human sGC α1/β1 heterodimer containing a reduced heme group, produced concentration-dependent increases in cGMP that were elevated modestly by NO whereas hemefree sGC and BI 685509 greatly enhanced cGMP with no effect of NO. BI 685509 increased cGMP in human and rat platelet-rich plasma treated with the heme-oxidant ODQ; respective EC 50 values were 467 nM and 304 nM. In conscious telemetry-instrumented rats, BI 685509 did not effect mean arterial pressure (MAP) or heart rate (HR) at 3 and 10 mg/kg (p.o.) whereas 30 mg/kg decreased MAP and increased HR. Ten-days of BI 685509 at supratherapeutic doses (60 or 100 mg/kg po, qd) attenuated MAP and HR responses to a single 100 mg/kg challenge. In the ZSF1 rat model, BI 685509 (1, 3, 10, 30 mg/kg/day qd) co-administered with enalapril (3 mg/kg/day) dose-dependently reduced proteinuria and incidence of glomerular sclerosis; MAP was modestly reduced at the higher doses vs. enalapril. In the 7-day rat UUO model, BI 685509 dose-dependently reduced tubulointerstitial fibrosis (p<0.05 at 30 mg/kg). In conclusion, BI 685509 is a potent, orally bioavailable sGC activator with clear renal protection and anti-fibrotic activity in preclinical models of kidney injury and disease.

Soluble Guanylyl Cyclase Activator BI 685509 Reduces Portal Hypertension and Portosystemic Shunting in a Rat Thioacetamide-Induced Cirrhosis Model

“…We have previously shown that sGC activator monotherapy inhibits the progression of diabetic nephropathy in ZSF1 rats, a disease also characterized by oxidative stress (Boustany-Kari et al, 2016). Additionally, BI 685509 has been shown to be a potent activator of heme-free sGC and to demonstrate a low nM potency for the activation of the human and mammalian sGC α1β1 heterodimer (Reinhart et al, 2022). This was contrasted against the sGC stimulator praliciguat (Tobin et al, 2018), which had no effect on heme-free sGC activity (Reinhart et al, 2022).…”

“…The small molecule BI 685509 is a potent, NO-independent sGC activator (Reinhart et al, 2022) shown to be well tolerated in Phase I studies in patients with portal hypertension in compensated cirrhosis (Lawitz et al, 2021) and with chronic kidney disease (Cherney et al, 2021) and has progressed to Phase II trials for CSPH (NCT05161481), chronic kidney disease (NCT04736628), and diabetic kidney disease (NCT04750577). In previous preclinical studies, BI 685509 was shown to be a potent activator of heme-free human sGC and was orally bioavailable with rapid absorption in mouse and rat models (Reinhart et al, 2022).…”

“…The small molecule BI 685509 is a potent, NO-independent sGC activator (Reinhart et al, 2022) shown to be well tolerated in Phase I studies in patients with portal hypertension in compensated cirrhosis (Lawitz et al, 2021) and with chronic kidney disease (Cherney et al, 2021) and has progressed to Phase II trials for CSPH (NCT05161481), chronic kidney disease (NCT04736628), and diabetic kidney disease (NCT04750577). In previous preclinical studies, BI 685509 was shown to be a potent activator of heme-free human sGC and was orally bioavailable with rapid absorption in mouse and rat models (Reinhart et al, 2022). Given that the pathophysiology of cirrhosis and portal hypertension involves endothelial cell dysfunction, our goal was to test the therapeutic benefit of the sGC activator BI 685509 on progression of liver fibrosis and extrahepatic complications in a preclinical rat model of thioacetamide (TAA)induced endothelial damage.…”

Safety, tolerability, pharmacodynamics and pharmacokinetics of the soluble guanylyl cyclase activator BI 685509 in patients with diabetic kidney disease: A randomized trial

“…22,24 Targeting the NO-sGC-cGMP axis, therefore, is an area of therapeutic interest, especially because sGC activation is associated with kidney protection in experimental models. 22,24 Our aim was to examine the safety, tolerability, pharmacodynamic (PD), and pharmacokinetic (PK) characteristics of BI 685509-a potent, NO-independent activator of sGC 25 -in patients with DKD. Furthermore, given the strong association between albuminuria lowering and protection against DKD, 26 we also explored the impact of BI 685509 on urinary albumin:creatinine ratio (UACR) in the trial cohort.…”

A Homogeneous Bioluminescent System to Monitor Cyclic Guanosine Monophosphate

“…The most notable commercial success by targeting cGMP metabolism is the development of PDE5 inhibitors such as sildenafil (Viagra), vardenafil (Levitra), and tadalafil (Cialis) to treat erectile dysfunction . cGMP signaling has also been targeted in other disease states including pulmonary hypertension, , retinal disease, diabetes, heart failure, kidney dysfunction, , and neurological disorders. , Due to the importance of cGMP in human health and the need for further drug development, it will be necessary to establish robust and reliable assays to accurately determine cGMP levels.…”