ataciguat (HMR1766) / Sanofi, Kardigan - LARVOL DELTA

DIRECT ACTIVATION OF OXIDIZED SOLUBLE GUANYLATE CYCLASE WITH ATACIGUAT BLUNTS OSTEOGENIC ACTIVATION AND NOTCH1 DOWNREGULATION IN 2D AND 3D MODELS OF MODERATE CALCIFIC AORTIC VALVE DISEASE (ACC 2026) - "Multi-dimensional VIC hydrogels recapitulated the activation and osteogenic remodeling of moderate CAVS, hallmarked by increased α-SMA expression, NOTCH1 downregulation, and calcium deposition. These effects were blunted by reactivation of oxidized sGC with ataciguat, highlighting restoration of local NO-signaling in the VICs as a potential therapeutic option in CAVS."

Cardiovascular • NOTCH1

KATALYST-AV: Ataciguat for Slowing the Progression of Moderate Calcific Aortic Valve Stenosis: A Randomized, Placebo Controlled Study (clinicaltrials.gov) - P2/3 | N=1276 | Recruiting | Sponsor: Kardigan, Inc. | Phase classification: P3 ➔ P2/3

Phase classification • Cardiovascular

Impact of Aortic Valve Calcification on Functional Valve Area and Cardiac Structure and Function in a Phase 2 Trial of Ataciguat (AHA 2025) - P2 | "ATA may have other favorable effects on ventricular, valvular, and/or vascular pathophysiology relevant to patients with CAVS.Hypothesis:We hypothesized that slowing the rate of AVC deposition is associated with improvements in valvular compliance and in measures of cardiac structure and function.A phase 2 study randomized patients with moderate CAVS 1:1 to receive ATA 200 mg/day or placebo for up to 12 months (NCT02481258). These data suggest that slowing the rate of AVC deposition with ATA may result in improvements in CO through improved myocardial function and valvular compliance. Larger controlled trials are needed to assess such favorable myocardial/valvular effects that may help to preserve functional capacity and slow progression to HF."

P2 data • Cardiovascular • Congestive Heart Failure • Heart Failure

KATALYST-AV: A Study to Investigate Ataciguat for Slowing the Progression of Moderate Calcific Aortic Valve Stenosis (clinicaltrials.gov) - P3 | N=1410 | Recruiting | Sponsor: Kardigan, Inc. | Not yet recruiting ➔ Recruiting

Enrollment open • Cardiovascular

KATALYST-AV: A Study to Investigate Ataciguat for Slowing the Progression of Moderate Calcific Aortic Valve Stenosis (clinicaltrials.gov) - P3 | N=1410 | Not yet recruiting | Sponsor: Kardigan, Inc.

New P3 trial • Cardiovascular

Reactivation of Oxidized Soluble Guanylate Cyclase as a Novel Treatment Strategy to Slow Progression of Calcific Aortic Valve Stenosis: Preclinical and Randomized Clinical Trials to Assess Safety and Efficacy. (PubMed, Circulation) - P1, P2 | "Here, we tested the hypothesis that reactivation of oxidized sGC (soluble guanylate cyclase), the primary receptor for nitric oxide, with ataciguat is a safe and efficacious strategy to slow progression of FCAVS...URL: https://www.clinicaltrials.gov; Unique identifier: NCT02049203. URL: https://www.clinicaltrials.gov; Unique identifier: NCT02481258."

Clinical • Journal • Preclinical • Cardiovascular • Fibrosis • Heart Failure • Immunology • BMP2

Discovery of the Soluble Guanylate Cyclase Activator Runcaciguat (BAY 1101042). (PubMed, J Med Chem) - "The first generation of sGC activators like cinaciguat or ataciguat exhibited limitations and were discontinued. This program resulted in the discovery of the oral sGC activator runcaciguat (compound 45, BAY 1101042). Runcaciguat is currently investigated in clinical phase 2 studies for the treatment of patients with chronic kidney disease and nonproliferative diabetic retinopathy."

Journal • Chronic Kidney Disease • Diabetic Retinopathy • Nephrology • Renal Disease • Retinal Disorders • sGC HDA+

Soluble guanylate cyclase stimulators and their potential use: a patent review. (PubMed, Expert Opin Ther Pat) - "After the first generation of sGC stimulators like riociguat or lificiguat, new compound classes with different physicochemical and kinetic profiles were identified, like the sGC stimulators vericiguat or praliciguat...Expert Opinion: With the recent advancements reported in the patent literature, sGC stimulators might be differentiated due to tissue selectivity or route of application although exhibiting the same molecular mode of action. The indication space of these compounds is potentially very broad and multiple indications in cardiovascular diseases and beyond are under investigation."

Journal • Review • Cardiovascular • sGC HDA+

CAVS: A Study Evaluating the Effects of Ataciguat (HMR1766) on Aortic Valve Calcification (clinicaltrials.gov) - P2; N=35; Active, not recruiting; Sponsor: Mayo Clinic; Trial primary completion date: Sep 2017 ➔ Jun 2018

Trial primary completion date • Biosimilar • Immunology

In Endothelial Cells, the Activation or Stimulation of Soluble Guanylyl Cyclase Induces the Nitric Oxide Production by a Mechanism Dependent of Nitric Oxide Synthase Activation. (PubMed, J Pharm Pharm Sci) - "Our results suggest that in aortic and coronary rings the endothelium potentiates the relaxation induced by activation or stimulation of sGC through a mechanism dependent of NOS activation. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page."

Journal • Preclinical

"Ataciguat failed his effect in phase IIA clinical trial although good outcome in animal model #ATVBLive19 #VascularDiscovery19 @AHAScience @escardio @atvbahajournals @yaqoub_lina @GiuseppeGalati_" (@HenryHa78520039)

P2a data