avenciguat (BI 685509) / Boehringer Ingelheim - LARVOL DELTA

Nephrology: What You May Have Missed in 2024. (PubMed, Ann Intern Med) - "Three studies examined treatments to improve specific aspects of CKD management, including mineralocorticoid receptor agonists to address heart failure, avenciguat to address albuminuria, and oral phosphate binders to address fracture risk. One study demonstrated that inorganic nitrate reduced the risk for contrast-induced nephropathy. Finally, a trial of cefepime-taniborbactam showed benefit for treating complicated urinary tract infection."

Journal • Cardiovascular • Chronic Kidney Disease • Congestive Heart Failure • Heart Failure • Infectious Disease • Musculoskeletal Diseases • Nephrology • Orthopedics • Renal Calculi • Renal Disease

Registry Clinical Trials on Treatment of Cirrhotic Portal Hypertension Evaluated by Hepatic Venous Pressure Gradient: A Systematic Review (APASL 2025) - " Drug Classification by Pharmacological Mechanism: Beta-blockers (30%): Including carvedilol and propranolol, targeting portal pressure reduction. Vasodilators (15%): Agents like doxazosin and nitrates targeting vascular resistance. Anti-metabolic agents (10%): Metformin targeting hepatic insulin sensitivity. Gut microbiota modulators (10%): Rifaximin and probiotics improving gut-liver interactions. Experimental agents (15%): Emerging therapies such as BI 685509... This systematic review underscores the diversity in therapeutic strategies for CPH, with beta-blockers as the mainstay of treatment and promising new directions from emerging agents. Despite progress, variability in trial phases and limited long-term follow-up necessitate larger, harmonized trials across all phases to refine HVPG-guided therapies for CPH. Table and Figure:Figure 1.Regional Distribution of Clinical Trials Figure 2.Focus Areas of Primary Outcomes in Clinical Trials"

Clinical • Review • Cardiovascular • Hepatology • Portal Hypertension

Avenciguat: a novel soluble guanylate cyclase activator that affects multiple cell types to inhibit IFN-1 signalling and fibrosis. (PubMed, Rheumatology (Oxford)) - P2 | "In preclinical studies, avenciguat shows the potential to influence vascular, fibrotic and immune-related processes in murine models of SSc. These studies suggest that it may offer therapeutic benefit across multiple aspects of SSc pathophysiology and support the rationale for further investigation in a Phase II clinical trial (VITALISScE™; NCT05559580) of avenciguat in SSc."

Journal • Cardiovascular • Fibrosis • Hypertension • Immunology • Inflammation • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases • Scleroderma • Systemic Sclerosis • TGFB1

A novel soluble guanylate cyclase activator, avenciguat, in combination with empagliflozin, protects against renal and hepatic injury in diabetic db/db mice. (PubMed, Am J Physiol Endocrinol Metab) - "These results suggested that either avenciguat alone or in combination with Empa is therapeutic. Avenciguat in combination with Empa shows promise in halting the progression of diabetic complications."

Journal • Preclinical • Diabetes • Diabetic Nephropathy • Fibrosis • Genetic Disorders • Glomerulonephritis • Hepatology • Immunology • Liver Cirrhosis • Liver Failure • Metabolic Disorders • Metabolic Dysfunction-Associated Steatotic Liver Disease • Nephrology • Obesity • Renal Disease • Type 2 Diabetes Mellitus

A Study in People With Systemic Sclerosis to Test Whether Avenciguat (BI 685509) Has an Effect on Lung Function and Other Systemic Sclerosis Symptoms (clinicaltrials.gov) - P2 | N=188 | Active, not recruiting | Sponsor: Boehringer Ingelheim | Recruiting ➔ Active, not recruiting

Enrollment closed • Immunology • Scleroderma • Systemic Sclerosis • CRP

A Phase II study of avenciguat, a novel soluble guanylate cyclase activator, in patients with systemic sclerosis: Study design and rationale of the VITALISScE™ study. (PubMed, J Scleroderma Relat Disord) - P2 | "VITALISScE™; EU CT No. 2022-500332-11-00; Clinicaltrials.gov: NCT05559580 (https://www.clinicaltrials.gov/study/NCT05559580)."

Journal • P2 data • Cardiovascular • Fibrosis • Immunology • Rheumatology • Scleroderma • Systemic Sclerosis

A Study to Test How Avenciguat (BI 685509) is Taken up in the Body of People With and Without Liver Problems (clinicaltrials.gov) - P1 | N=4 | Terminated | Sponsor: Boehringer Ingelheim | N=16 ➔ 4 | Recruiting ➔ Terminated; Sponsor decision

Enrollment change • Trial termination • Hepatology

Avenciguat reduces albuminuria in patients with chronic kidney disease. (PubMed, Nat Rev Nephrol) - No abstract available

Journal • Chronic Kidney Disease • Nephrology • Renal Disease

A Study to Test Whether BI 685509 Alone or in Combination With Empagliflozin Helps People With Liver Cirrhosis Caused by Viral Hepatitis or Non-alcoholic Steatohepatitis (NASH) Who Have High Blood Pressure in the Portal Vein (Main Vessel Going to the Liver) (clinicaltrials.gov) - P2 | N=90 | Terminated | Sponsor: Boehringer Ingelheim | Active, not recruiting ➔ Terminated; Company decision

Combination therapy • Trial termination • Cardiovascular • Fibrosis • Gastroenterology • Hepatology • Hypertension • Immunology • Infectious Disease • Inflammation • Liver Cirrhosis • Metabolic Dysfunction-Associated Steatohepatitis • Portal Hypertension

A Study to Test Whether Two Different Doses of Avenciguat Help People With Liver Cirrhosis and High Blood Pressure in the Portal Vein (Main Vessel Going to the Live (clinicaltrials.gov) - P2 | N=80 | Terminated | Sponsor: Boehringer Ingelheim | Active, not recruiting ➔ Terminated; Company decision

Trial termination • Cardiovascular • Fibrosis • Gastroenterology • Hepatology • Hypertension • Immunology • Liver Cirrhosis • Portal Hypertension

A Study to Test Whether Avenciguat Helps People With Liver Cirrhosis and High Blood Pressure in the Portal Vein (Main Vessel Going to the Liver) Who Had Bleeding in the Esophagus or Fluid Accumulation in the Belly (clinicaltrials.gov) - P2 | N=22 | Terminated | Sponsor: Boehringer Ingelheim | Active, not recruiting ➔ Terminated; Company decision

Trial termination • Cardiovascular • Fibrosis • Gastroenterology • Hepatology • Hypertension • Immunology • Liver Cirrhosis • Portal Hypertension

Hepatic improvement within 27 days of avenciguat treatment in Child-Pugh a cirrhosis detected by an oral cholate challenge test. (PubMed, Liver Transpl) - P1 | "The results support further study of avenciguat in treating portal hypertension and spotlight the utility of HepQuant DuO in the development of drug therapy for liver disease. HepQuant DuO facilitates use of function testing to measure hepatic improvement in clinical trials and the clinic."

Journal • Cardiovascular • Fibrosis • Hepatology • Hypertension • Immunology • Liver Cirrhosis • Portal Hypertension

A Study to Test Whether Two Different Doses of Avenciguat Help People With Liver Cirrhosis and High Blood Pressure in the Portal Vein (Main Vessel Going to the Live (clinicaltrials.gov) - P2 | N=80 | Active, not recruiting | Sponsor: Boehringer Ingelheim | Trial completion date: Oct 2024 ➔ Jun 2024 | Trial primary completion date: Sep 2024 ➔ Jun 2024

Trial completion date • Trial primary completion date • Cardiovascular • Fibrosis • Gastroenterology • Hepatology • Hypertension • Immunology • Liver Cirrhosis • Portal Hypertension

Efficacy and safety of avenciguat in diabetic and non-diabetic kidney disease: Pooled analysis from two Phase II randomised controlled clinical trials (ERA-EDTA 2024) - P2 | "Avenciguat was effective in lowering albuminuria and was well tolerated in patients with diabetic and non-diabetic CKD. These results will support avenciguat dose selection for future trials."

Late-breaking abstract • P2 data • Retrospective data • Chronic Kidney Disease • Diabetic Nephropathy • Hypotension • Nephrology • Renal Disease

Effect of Avenciguat on Albuminuria in Patients with CKD: Two Randomized Placebo-Controlled Trials. (PubMed, J Am Soc Nephrol) - P2 | "Avenciguat lowered albuminuria, and was well tolerated in patients with CKD."

Clinical • Journal • Chronic Kidney Disease • Metabolic Disorders • Renal Disease

Safety, tolerability, pharmacokinetics, and pharmacodynamics of BI 685509, a soluble guanylyl cyclase activator, in healthy volunteers: Results from two randomized controlled trials. (PubMed, Naunyn Schmiedebergs Arch Pharmacol) - P1 | "Increased plasma cyclic guanosine monophosphate and decreased blood pressure followed by a compensatory increase in heart rate indicated target engagement. BI 685509 was generally well tolerated; orthostatic dysregulation may be appropriately countered by careful uptitration."

Journal • PK/PD data • Fatigue

A Study to Test Whether Avenciguat Helps People With Liver Cirrhosis and High Blood Pressure in the Portal Vein (Main Vessel Going to the Liver) Who Had Bleeding in the Esophagus or Fluid Accumulation in the Belly (clinicaltrials.gov) - P2 | N=22 | Active, not recruiting | Sponsor: Boehringer Ingelheim | Recruiting ➔ Active, not recruiting | N=40 ➔ 22

Enrollment change • Enrollment closed • Cardiovascular • Fibrosis • Gastroenterology • Hepatology • Hypertension • Immunology • Liver Cirrhosis • Portal Hypertension

A Study to Test How Avenciguat (BI 685509) is Taken up in the Body of People With and Without Liver Problems (clinicaltrials.gov) - P1 | N=16 | Recruiting | Sponsor: Boehringer Ingelheim | Not yet recruiting ➔ Recruiting

Enrollment open • Hepatology

A Study in Healthy People to Compare Two Different Tablets of BI 685509 and to Test How Food and Esomeprazole Influence the Amount of BI 685509 in the Blood (clinicaltrials.gov) - P1 | N=16 | Completed | Sponsor: Boehringer Ingelheim | Active, not recruiting ➔ Completed

Trial completion

VITALISSCE™: A PHASE II STUDY OF BI 685509, A NOVEL SOLUBLE GUANYLATE CYCLASE ACTIVATOR, IN PATIENTS WITH SYSTEMIC SCLEROSIS (SSWC 2024) - P2 | "The VITALISScE™ study is assessing the efficacy, safety and tolerability of BI 685509 in patients with early progressive SSc and vasculopathy. Results from this trial will inform further development of BI 685509 and future trial designs. The VITALISScE™ study (NCT05559580) is due to complete November 2025."

Clinical • P2 data • Cardiovascular • Fibrosis • Immunology • Respiratory Diseases • Rheumatology • Scleroderma • Systemic Sclerosis • CRP

A Study to Test Whether BI 685509 Alone or in Combination With Empagliflozin Helps People With Liver Cirrhosis Caused by Viral Hepatitis or Non-alcoholic Steatohepatitis (NASH) Who Have High Blood Pressure in the Portal Vein (Main Vessel Going to the Liver) (clinicaltrials.gov) - P2 | N=80 | Active, not recruiting | Sponsor: Boehringer Ingelheim | Recruiting ➔ Active, not recruiting

Combination therapy • Enrollment closed • Cardiovascular • Fibrosis • Gastroenterology • Hepatology • Hypertension • Immunology • Infectious Disease • Inflammation • Liver Cirrhosis • Metabolic Dysfunction-Associated Steatohepatitis • Portal Hypertension

A Study to Test Whether Two Different Doses of Avenciguat Help People With Liver Cirrhosis and High Blood Pressure in the Portal Vein (Main Vessel Going to the Live (clinicaltrials.gov) - P2 | N=78 | Active, not recruiting | Sponsor: Boehringer Ingelheim | Recruiting ➔ Active, not recruiting

Enrollment closed • Cardiovascular • Fibrosis • Gastroenterology • Hepatology • Hypertension • Immunology • Liver Cirrhosis • Portal Hypertension

A Study to Test How Avenciguat (BI 685509) is Taken up in the Body of People With and Without Liver Problems (clinicaltrials.gov) - P1 | N=16 | Not yet recruiting | Sponsor: Boehringer Ingelheim

New P1 trial • Hepatology

Bi 685509: a Potent Activator of Soluble Guanylate Cyclase as a Novel Treatment of Vasculopathy and Fibrosis in Systemic Sclerosis (CRA-AHPA 2024) - "In the mouse model of bleomycin-induced skin and lung fibrosis, sGC activation via BI 685509 resulted in significant improvement in skin thickness and lung fibrosis, comparable to mice treated with Nintedanib (60mg/kg) or Riociguat (1 mg/kg). Collectively, these results point to the use of the sGC activator BI 685509 as a novel treatment for SSc and suggests potential superior effects vs. sGC stimulators like Riociguat in this autoimmune disease."

Fibrosis • Immunology • Inflammation • Respiratory Diseases • Scleroderma • Systemic Sclerosis • TGFB1 • TGFB2

A Study in Healthy People to Compare Two Different Tablets of BI 685509 and to Test How Food and Esomeprazole Influence the Amount of BI 685509 in the Blood (clinicaltrials.gov) - P1 | N=16 | Active, not recruiting | Sponsor: Boehringer Ingelheim | Recruiting ➔ Active, not recruiting

Enrollment closed