Pharmacokinetics, Safety, and Tolerability of BI 685509 in Subjects With Severe Liver Impairment (Child-Pugh Classification C) as Compared to Healthy Subjects

This study is open to people with and without severe liver problems. People can join the study if they are 18 to 80 years of age and have a body mass index (BMI) between 18.5 and 42 kg/m2.
Avenciguat (BI 685509) is a medicine that is being developed to treat high blood pressure in the portal vein (main vessel going to the liver). The purpose of this study is to find out whether having liver problems influences how Avenciguat (BI 685509) is taken up in the body. All participants take Avenciguat (BI 685509) once as a tablet.
Participants are in the study for slightly longer than 1 month. Following the screening period of about 4 weeks, they stay at the study site for 4 nights. Afterwards, there are 2 visits to the study site. The site staff measures the amount of Avenciguat (BI 685509) in the blood. The doctors also regularly check participants' health and take note of any unwanted effects.

Start Date03 May 2024

Sponsor / Collaborator

Boehringer Ingelheim GmbH

CTR20234147

/ TerminatedPhase 2

在发生首次失代偿事件后病情稳定（CTP5-7）的失代偿期肝硬化伴临床显著性门静脉高压（CSPH）的患者中评估口服BI685509一种剂量（上调至固定剂量方案）治疗门静脉高压8周后临床疗效的随机、双盲、安慰剂对照、平行组试验。

[Translation] Evaluating oral BI685509 at one dose (up-titration to a fixed-dose regimen) for the treatment of the portal vein in patients with decompensated cirrhosis and clinically significant portal hypertension (CSPH) who are stable after a first decompensating event (CTP5-7) A randomized, double-blind, placebo-controlled, parallel-group trial of the clinical efficacy of hypertensive therapy after 8 weeks.

本试验将评估在标准治疗基础上，BI 685509在首次失代偿事件后失代偿期肝硬化伴临床显著性门静脉高压患者中用于治疗门静脉高压的安全性和耐受性。主要目的为估计失代偿期肝硬化患者治疗8周后HVPG较基线变化的百分比。

[Translation]

This trial will evaluate the safety and tolerability of BI 685509 for the treatment of portal hypertension in patients with decompensated cirrhosis and clinically significant portal hypertension after a first decompensation event, in addition to standard of care. The primary objective was to estimate the percentage change from baseline in HVPG after 8 weeks of treatment in patients with decompensated cirrhosis.

Start Date27 Feb 2024

Sponsor / Collaborator

Boehringer Ingelheim (China) Investment Co., Ltd.

[+2]

NCT06193811

/ CompletedPhase 1

Relative Bioavailability of Two Different Tablet Formulations of BI 685509 and Investigation of the Effects of Food and Esomeprazole on the Pharmacokinetics of BI 685509 Following Oral Administration in Healthy Male and Female Subjects (an Open-label, Randomised, Four-way Crossover Trial)

The main objective of this trial is to investigate:
the relative bioavailability of Avenciguat (BI 685509) TF2 (Reference, R) vs. Avenciguat (BI 685509) iCF (Test 1, T1) tablets under fasted conditions
the relative bioavailability of Avenciguat (BI 685509) iCF tablets under fasted (T1) and fed (Test 2, T2) conditions
the relative bioavailability of Avenciguat (BI 685509) iCF tablets given alone (T1) and together with esomeprazole (Test 3, T3) under fasted conditions

Start Date16 Jan 2024

Sponsor / Collaborator

Boehringer Ingelheim GmbH

100 Clinical Results associated with Avenciguat

100 Translational Medicine associated with Avenciguat

100 Patents (Medical) associated with Avenciguat

Literatures (Medical) associated with Avenciguat

01 Oct 2024·LIVER TRANSPLANTATION

Hepatic improvement within 27 days of avenciguat treatment in Child-Pugh A cirrhosis detected by an oral cholate challenge test

Article

Author: McRae, Michael P. ; Gashaw, Isabella ; Everson, Gregory T. ; Schoelch, Corinna ; Ertle, Judith ; Lawitz, Eric J. ; Helmke, Steve M.

New methods for measuring hepatic improvement in clinical trials and the clinic are needed. One new method, HepQuant SHUNT, detected dose-dependent improvements in hepatic function and portal physiology in the phase 1b study (NCT03842761) of avenciguat, an activator of soluble guanylyl cyclase that is being developed for the treatment of portal hypertension. Herein, we examined whether HepQuant Duo, an easy-to-administer test version, could similarly detect the effects of avenciguat. Twenty-three patients with Child-Pugh A cirrhosis and liver stiffness >15 kPa received either a placebo (n = 5) or a maximum twice-daily avenciguat dose of 1, 2, or 3 mg (n = 6 per group) for 28 days. The DuO test was performed at baseline and on days 11 and 27 in each subject. The test involved administering 40 mg of d4-cholate orally, measuring d4-cholate concentrations in serum at 20 and 60 minutes, and calculating portal hepatic filtration rate, disease severity index, portal-systemic shunting (SHUNT%), and hepatic reserve (HR%). Avenciguat demonstrated dose-dependent improvement in all test parameters. Changes from baseline in SHUNT% after 27 days’ treatment were 0.1 ± 9.0% for placebo, 1.7 ± 5.5% for 1 mg twice-daily, −3.2 ± 2.7% for 2 mg twice-daily, and −6.1 ± 5.0% for 3 mg twice-daily (paired t test for change from baseline p = 0.98, 0.48, 0.04, and 0.03, respectively). The changes detected by HepQuant DuO were similar to those previously observed and reported for HepQuant SHUNT. 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 the use of function testing to measure hepatic improvement in clinical trials and the clinic.

01 Oct 2024·NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY

Safety, tolerability, pharmacokinetics, and pharmacodynamics of BI 685509, a soluble guanylyl cyclase activator, in healthy volunteers: Results from two randomized controlled trials

Article

Author: Seitz, Friedeborg ; Bauer, Verena ; Schulze, Friedrich ; Wong, Diane ; Giessmann, Thomas

Abstract:

This study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of BI 685509 after oral single rising doses (SRDs) or multiple rising doses (MRDs) in healthy volunteers. In the SRD trial (NCT02694354; February 29, 2016), within each of the three dose groups (DGs), six subjects received BI 685509 (1.0, 2.5, or 5.0 mg) and two received placebo (N = 24). In the MRD trial (NCT03116906; April 17, 2017), within each of the five DGs, nine subjects received BI 685509 (uptitrated to 1 mg once daily [qd; DG1], 2.5 mg twice daily [DG2], 5.0 mg qd [DG3]; 3.0 mg three times daily [tid; DG4] or 4.0 mg tid [DG5]) and three received placebo, for 14–17 days (N = 60). In the SRD trial, 7/24 subjects (29.2%) had ≥ 1 adverse event (AE), most frequently orthostatic dysregulation (n = 4). In the MRD trial, 26/45 subjects (57.8%) receiving BI 685509 had ≥ 1 AE, most frequently orthostatic dysregulation and fatigue (each n = 12). Tolerance development led to a marked decrease in orthostatic dysregulation events (DG3). BI 685509 was rapidly absorbed after oral administration, and exposure increased in a dose-proportional manner after single doses. Multiple dosing resulted in near–dose-proportional increase in exposure and limited accumulation. BI 685509 pharmacokinetics appeared linear with time; steady state occurred 3–5 days after each multiple-dosing period. 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.

01 Sep 2024·JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY

Effect of Avenciguat on Albuminuria in Patients with CKD

Article

Author: Górriz, Jose Luis ; Tang, Sydney C W ; Gafor, Abdul Halim Abdul ; Desch, Marc ; Heerspink, Hiddo J L ; Iliev, Hristo ; Sun, Zhichao ; Steubl, Dominik ; Pergola, Pablo E ; Nangaku, Masaomi ; Cherney, David

Key Points:

Despite new treatments for CKD, kidney failure risk remains high, particularly where albuminuria remains.We report a prespecified pooled analysis of two randomized controlled trials assessing a soluble guanylate cyclase activator for CKD.Avenciguat led to improvements in albuminuria in patients with CKD with/without type 2 diabetes mellitus, with acceptable safety.

Background:

Avenciguat is a novel, potent soluble guanylate cyclase activator in development for CKD. Two trials investigated avenciguat in diabetic (NCT04750577) and non-diabetic (NCT04736628) CKD.

Methods:

A prespecified pooled analysis of two randomized, double-blind, placebo-controlled trials of identical design. Adults with CKD (eGFR ≥20 and <90 ml/min per 1.73 m2, urine albumin–creatinine ratio [UACR] ≥200 and <3500 mg/g) were randomized to 20 weeks of placebo or avenciguat 1, 2, or 3 mg three times daily (TID), adjunctive to angiotensin-converting enzyme inhibitor or angiotensin receptor blocker. The primary end point was change from baseline in UACR in 10-hour urine at week 20, analyzed per protocol. The secondary end point was UACR change from baseline in first morning void urine at week 20. Safety was monitored throughout.

Results:

Overall, 500 patients (mean age 62 years [SD 13]; mean eGFR 44 ml/min per 1.73 m2 [SD 18] and median 10-hour UACR 719 [interquartile range, 379–1285] mg/g) received placebo (n=122) or avenciguat 1 mg (n=125), 2 mg (n=126), or 3 mg (n=127) TID. All 243 patients in study one and 27 of 261 patients in study two had diabetes mellitus. Avenciguat 1, 2, and 3 mg TID reduced UACR in 10-hour and first morning void urine versus placebo throughout the treatment period. At week 20, placebo-corrected geometric mean changes (95% confidence interval) from baseline in UACR in 10-hour urine with avenciguat 1, 2, and 3 mg TID were −15.5% (−26.4 to −3.0), −13.2% (−24.6 to −0.1), and −21.5% (−31.7 to −9.8), respectively, analyzed per protocol. Corresponding changes in first morning void urine were −19.4% (−30.0 to −7.3), −15.5% (−26.9 to −2.5), and −23.4% (−33.5 to −11.8), respectively. Avenciguat was well tolerated; the overall frequency of adverse events was low and similar to placebo. The number of patients who discontinued the study drug because of adverse events with avenciguat 1, 2, and 3 mg TID were five (4%), 11 (9%), and 11 (9%), respectively, compared with four (3%) in the placebo group.

Conclusions:

Avenciguat lowered albuminuria and was well tolerated in patients with CKD.

Clinical Trial registry name and registration number::

A Study to Test the Effect of Different Doses of BI 685509 on Kidney Function in People With Diabetic Kidney Disease, NCT04750577, and A Study to Test the Effect of Different Doses of Avenciguat (BI 685509) on Kidney Function in People With Chronic Kidney Disease, NCT04736628.

Podcast:

This article contains a podcast at https://dts.podtrac.com/redirect.mp3/www.asn-online.org/media/podcast/JASN/2024_06_27_ASN0000000000000418.mp3

News (Medical) associated with Avenciguat

05 May 2023

·www.prnewswire.com

Chronic Kidney Disease Competitive Landscape Report 2023: Comprehensive Insights About 75+ Companies and 95+ Drugs

DUBLIN, May 5, 2023 /PRNewswire/ -- The "Chronic Kidney Disease - Competitive landscape, 2023" report has been added to ResearchAndMarkets.com's offering. This report provides comprehensive insights about 75+ companies and 95+ drugs in Chronic Kidney Disease Competitive landscape. It covers the therapeutics assessment by product type, stage, route of administration, and molecule type. It further highlights the inactive pipeline products in this space. In March 2023, POXEL SA, announced the publication of preclinical results in autosomal dominant polycystic kidney disease (ADPKD) for PXL770, a novel, first-in-class direct adenosine monophosphate-activated protein kinase (AMPK) activator. For the first time, POXEL SA showed beneficial effects of a direct and selective AMPK activator in preclinical ADPKD models from three species mouse, human, and dog. These results confirm the potential utility of AMPK activation for this disease and support the development of PXL770 in a Phase 2 clinical program for ADPKD. In February 2023, AstraZeneca announced the successful completion of the acquisition of CinCor Pharma, Inc. The acquisition bolsters AstraZeneca's cardiorenal pipeline by adding baxdrostat (CIN-107), an aldosterone synthase inhibitor (ASI) for blood pressure lowering in treatment-resistant hypertension, to its cardiorenal portfolio. In January 2023, The U.S. Food and Drug Administration (FDA) has accepted a supplemental New Drug Application (sNDA) for Jardiance (empagliflozin) tablets, which is being investigated as a potential treatment to reduce the risk of kidney disease progression and cardiovascular death in adults with chronic kidney disease (CKD), Boehringer Ingelheim and Eli Lilly and Company announced. In November 2022, The Medical Research Council Population Health Research Unit (MRC PHRU) at the University of Oxford, which designed, conducted and analyzed EMPA-KIDNEY in a scientific collaboration with Boehringer Ingelheim and Eli Lilly and Company, announced that EMPA-KIDNEY phase III clinical trial met its primary endpoint by demonstrating a significant kidney and cardiovascular benefit for adults living with chronic kidney disease (CKD). When treated with Jardiance (empagliflozin), the risk of kidney disease progression or cardiovascular death was significantly reduced by 28% vs. placebo (HR; 0.72; 95% CI 0.64 to 0.82; P< 0.0001). In October 2022, Revelation Biosciences Inc. announced positive results in a preclinical model of acute kidney injury (AKI), chronic kidney disease (CKD). Treatment with REVTx-300 significantly reduced renal cortical fibrosis in a dose dependent manner in the medium and high dose groups (21.7% reduction (p < 0.05) and 29.3% (p < 0.05), respectively) and was comparable to a known TGF inhibitor of fibrosis used as a positive control (38.1% reduction (P < 0.05)). In October 2022, French Biopharma Company, Poxel SA announced the U.S. Food and Drug Administration (FDA) has granted orphan drug designation (ODD) to PXL770 for the treatment of patients with autosomal-dominant polycystic kidney disease (ADPKD). PXL770 is a novel, first-in-class direct adenosine monophosphate-activated protein kinase (AMPK) activator - and is also a phase 2 ready ADPKD asset, subject to additional financing. In-depth Commercial Assessment: Chronic Kidney Disease Collaboration Analysis by Companies The Report provides in-depth commercial assessment of drugs that have been included, which comprises collaboration, agreement, licensing and acquisition - deals values trends. The sub-segmentation is described in the report which provide company-company collaboration (licensing/partnering), company academic collaboration and acquisition analysis in tabulated form. Current Treatment Scenario and Emerging Therapies: How many companies are developing Chronic Kidney Disease drugs? How many Chronic Kidney Disease drugs are developed by each company? How many emerging drugs are in mid-stage, and late-stage of development for the treatment of Chronic Kidney Disease? What are the key collaborations (Industry-Industry, Industry-Academia), Mergers and acquisitions, licensing activities related to the Chronic Kidney Disease therapeutics? What are the recent trends, drug types and novel technologies developed to overcome the limitation of existing therapies? What are the clinical studies going on for Chronic Kidney Disease and their status? What are the key designations that have been granted to the emerging and approved drugs? Key Players Boehringer Ingelheim Eli Lilly and Company Reata Pharmaceuticals Novo Nordisk KBP Biosciences AstraZeneca Allena Pharmaceuticals SCOHIA PHARMA DiaMedica Therapeutics CinCor Pharma Galapagos NV Sentien Biotechnologies, Inc. Regeneron Pharmaceuticals UnicoCell Biomed OccuRx Pharmicell Lisata Therapeutics Unicycive Therapeutics Senda Biosciences Sarfez Pharmaceuticals Rege Nephro Orgenesis GNI Group Algomedix Maze Therapeutics Chinook Therapeutics Angion Biomedica Corp Arch Biopartners Scohia Pharma Algernon Pharmaceuticals TICEBA GmbH Key Products Empagliflozin Bardoxolone methyl Ziltivekimab KBP-5074 AZD9977 ALLN-346 BI-685509 SCO-792 DM199 Baxdrostat GLPG2737 SBI-101 REGN5459 ELIXCYTE FT011 Cellgram-CKD CLBS201 UNI-494 Research Program SZ007 Renal progenitor cells MSCKD F351 Research programme: TRPC6 antagonist APOL1 Programme Research and discovery programs: severe chronic kidney disease ROCK2 Inhibitor LSALT peptide SCO-116 Repirinast Polycystic kidney disease (PKD) For more information about this report visit About ResearchAndMarkets.com ResearchAndMarkets.com is the world's leading source for international market research reports and market data. We provide you with the latest data on international and regional markets, key industries, the top companies, new products and the latest trends. Media Contact: Research and Markets Laura Wood, Senior Manager [email protected] For E.S.T Office Hours Call +1-917-300-0470 For U.S./CAN Toll Free Call +1-800-526-8630 For GMT Office Hours Call +353-1-416-8900 U.S. Fax: 646-607-1907 Fax (outside U.S.): +353-1-481-1716 Logo: SOURCE Research and Markets

Clinical ResultAcquisitionPhase 2Phase 3Orphan Drug

100 Deals associated with Avenciguat

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Liver Cirrhosis	Phase 2	AU	Boehringer Ingelheim Pharma GmbH & Co., KG	27 Feb 2024
Liver Cirrhosis	Phase 2	AU	Boehringer Ingelheim International GmbH	27 Feb 2024
Scleroderma, Systemic	Phase 2	US	Boehringer Ingelheim International GmbH	14 Dec 2022
Scleroderma, Systemic	Phase 2	US	Boehringer Ingelheim Pharma GmbH & Co., KG	14 Dec 2022
Scleroderma, Systemic	Phase 2	JP	Boehringer Ingelheim Pharma GmbH & Co., KG	14 Dec 2022
Scleroderma, Systemic	Phase 2	JP	Boehringer Ingelheim International GmbH	14 Dec 2022
Scleroderma, Systemic	Phase 2	AR	Boehringer Ingelheim Pharma GmbH & Co., KG	14 Dec 2022
Scleroderma, Systemic	Phase 2	AR	Boehringer Ingelheim International GmbH	14 Dec 2022
Scleroderma, Systemic	Phase 2	AU	Boehringer Ingelheim International GmbH	14 Dec 2022
Scleroderma, Systemic	Phase 2	AU	Boehringer Ingelheim Pharma GmbH & Co., KG	14 Dec 2022

Clinical Result

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT04736628 (CTgov)	Phase 2	Non-diabetic Chronic Kidney Disease	261	Avenciguat (Avenciguat 1 mg TID)	pgolkpgwzn(itasvgmjkm) = iabxwxagvm ylixlnplfr (inqzwjkesx, jverkptzdk - saefoeltds) View more	-	04 Sep 2024
				Avenciguat (Avenciguat 2 mg TID)	pgolkpgwzn(itasvgmjkm) = jnbikodzqa ylixlnplfr (inqzwjkesx, whvizmywbq - dpypsrmjdv) View more
NCT04750577 (CTgov)	Phase 2	Diabetic Nephropathies	243	BI 685509 (BI 685509 1 mg TID)	weralfqcvv(ldftgcadph) = dzqdkiytzy dkyweinuop (gkbklxzgwn, ecflqmgzhu - dilfgbdimt) View more	-	23 Jul 2024
				BI 685509 (BI 685509 3 mg TID)	weralfqcvv(ldftgcadph) = tjjwmsvdsv dkyweinuop (gkbklxzgwn, twtqvqrgdv - vspbjivomv) View more
NCT04750577 \| NCT04736628 (Pubmed \| J Am Soc Nephrol)	Phase 2	Non-diabetic Chronic Kidney Disease \| Diabetic Nephropathies	500	Avenciguat 1 mg TID	iqicjkksed(rsqekaxudt) = fvimwdxrbi qwsjhpvfuy (yjdjdeglxy, -26.4 to -3.0) View more	Positive	25 May 2024
				Avenciguat 2 mg TID	iqicjkksed(rsqekaxudt) = hdelyfrkxn qwsjhpvfuy (yjdjdeglxy, -24.6 to -0.1) View more
BI-685509 (ASN2022)	Phase 2	Diabetic Nephropathies	50	BI-685509 30 mpk/day	tbhknhjekk(lflvhxzuvg) = bejpzssvpi nfmlpopzuc (mfkrnwksdf ) View more	Positive	05 Nov 2022
				BI-685509 100 mpk/day	tbhknhjekk(lflvhxzuvg) = jkpjbwohsy nfmlpopzuc (mfkrnwksdf ) View more

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