TRV027 / Trevena - LARVOL DELTA

Development of a Novel Therapeutic for Pediatric Heart Failure Targeting Angiotensin II Receptor (PubMed, Yakugaku Zasshi) - "Furthermore, chronic administration of TRV027 improved the survival rate of mice with dilated cardiomyopathy during the preweaning period. These results demonstrate that TRV027 has the potential to be a safe and effective drug for treating pediatric heart failure."

Journal • Cardiomyopathy • Cardiovascular • Congestive Heart Failure • Heart Failure • Pediatrics

Synthesis and Pharmacological Characterization of Fluorescent Ligands Targeting the Angiotensin II Receptors Derived from Agonists, β-Arrestin-Biased Agonists, and Antagonists. (PubMed, J Med Chem) - "We designed and synthesized new fluorescent derivatives based on AngII, TRV027, or the AT1 antagonist losartan. Fluorescent derivatives of TRV027 become AT2-selective and lose their AT1 β-arrestin bias. These new ligands can be applied to trace AT1 or AT2 receptors in vitro and ex vivo."

Journal

Implications of β-Arrestin biased signaling by angiotensin II type 1 receptor for cardiovascular drug discovery and therapeutics. (PubMed, Cell Signal) - "Numerous experimental and animal studies have demonstrated that β-arrestin biased AT1R-ligands (such as SII-AngII, S1I8, TRV023, and TRV027) offer cardiovascular benefits by blocking the G protein signaling while retaining the β-arrestin signaling...Therefore, developing a small molecule β-arrestin biased AT1R-ligand with a longer half-life and specificity to AT1R could be more effective in treating heart failure. This approach has the potential to revolutionize the treatment of cardiovascular diseases by offering more sustained and targeted therapeutic effects."

Journal • Cardiovascular • Congestive Heart Failure • Heart Failure • Myocardial Infarction

The Association of Circulating Renin Angiotensin System Components With Clinical Outcomes and Treatment Responses in COVID-19: A Mechanistic Substudy of the ACTIV-4 Host Tissue Trials (ATS 2024) - "In this nested, multicenter, mechanistic study within the ACTIV-4 Host Tissue Platform trial, we evaluated the association of the circulating RAS with clinical outcomes and treatment responses to the RAS modulators TXA-127 [Angiotensin-(1-7)], TRV-027 (a biased AT1R agonist) or placebo. 60)]. Conclusions Baseline levels of key RAS peptides and enzymes may be useful for outcome risk prediction or RAS-directed treatment responsiveness in COVID-19 or other pathologies."

Clinical • Clinical data • Late-breaking abstract • Infectious Disease • Inflammation • Novel Coronavirus Disease • Respiratory Diseases

EFFECTS OF A BIASED ANGIOTENSIN II TYPE 1 RECEPTOR AGONIST IN AN EXPERIMENTAL STROKE MODEL (ESOC 2024) - "TRV120027 treatment reduced the size of the ischemic lesion without a direct improvement of the CBF in the dMCAO mouse model. The impact of TRV1200027 treatment on neuroinflammation is being assessed."

Cardiovascular • Ischemic stroke

Investigation of Strategies to Block Downstream Effectors of AT1R-Mediated Signalling to Prevent Aneurysm Formation in Marfan Syndrome. (PubMed, Int J Mol Sci) - "TRV027, the combination of barbadin with losartan (25 mg/kg/day), and DMX-200 (90 mg/kg/day) with a low dose of losartan (5 mg/kg/day) did not show a significant beneficial effect. Our results confirm that while losartan effectively halts aneurysm formation in Fbn1C1041G/+ MFS mice, neither TRV027 alone nor any of the other compounds combined with lower doses of losartan demonstrate a notable impact on aneurysm advancement. It appears that complete blockade of AT1R function, achieved by administrating a high dosage of losartan, may be necessary for inhibiting aneurysm progression in MFS."

Journal • Cardiovascular • Genetic Disorders • Inflammation • CCL2 • CCR2

NECTAR: Novel Experimental COVID-19 Therapies Affecting Host Response (clinicaltrials.gov) - P2/3 | N=871 | Completed | Sponsor: Sean Collins | Active, not recruiting ➔ Completed

Trial completion • Cardiovascular • Hematological Disorders • Infectious Disease • Inflammation • Novel Coronavirus Disease • Respiratory Diseases • Thrombosis

Nanobody-mediated dualsteric engagement of the angiotensin receptor broadens biased ligand pharmacology. (PubMed, Mol Pharmacol) - "To explore the signaling profiles that dualsteric ligands of the angiotensin II type 1 receptor (AT1R) can access, we ligated a 6e epitope tag-specific nanobody (single-domain antibody fragment) to angiotensin II (AngII) and analogs that show preferential allosteric coupling to Gq (TRV055, TRV056) or β‑arrestin (TRV027)...Significance Statement Here we engineer bitopic (dualsteric) ligands for epitope-tagged angiotensin II type 1 receptor by conjugating angiotensin II or its biased analogs to an epitope-specific nanobody (antibody fragment). Our data demonstrate that nanobody-mediated interactions with the receptor N‑terminus endow angiotensin analogs with properties of allosteric modulators and provide a novel mechanism to increase the potency, modulate the maximal effect, or alter the bias of ligands."

Journal

β-arrestin pathway activation by selective ATR1 agonism promotes calcium influx in podocytes, leading to glomerular damage. (PubMed, Clin Sci (Lond)) - "Recently, a novel biased AT1R agonist, TRV120027 (TRV), that selectively activates the β-arrestin cascade and blocks the G-protein-coupled receptor pathway has been proposed as a potential blood pressure medication...TRV-activated β-arrestin signaling in podocytes may promote TRPC6 channel-mediated Ca2+ influx, foot process effacement, and apoptosis, possibly leading to severe defects in glomerular filtration barrier integrity and kidney health. Under these circumstances, the potential therapeutic application of TRV for hypertension treatment requires further investigation to assess the balance of the benefits versus possible deleterious effects and off-target damage."

Journal • Cardiovascular • Hypertension • TRPC6

NECTAR: Novel Experimental COVID-19 Therapies Affecting Host Response (clinicaltrials.gov) - P2/3 | N=871 | Active, not recruiting | Sponsor: Sean Collins | Recruiting ➔ Active, not recruiting | N=1600 ➔ 871

Enrollment change • Enrollment closed • Cardiovascular • Hematological Disorders • Infectious Disease • Inflammation • Novel Coronavirus Disease • Respiratory Diseases • Thrombosis

The AT/AT Receptor Equilibrium Is a Cornerstone of the Regulation of the Renin Angiotensin System beyond the Cardiovascular System. (PubMed, Molecules) - "Other mechanisms still largely unexplored, such as S-nitrosation of the AT receptor, homo- and heterodimerization, and the use of AT receptor-biased agonists, may significantly contribute to and/or interfere with the settings of this AT/AT equilibrium. This review will detail, through several examples (the brain, wound healing, and the cellular cycle), the importance of the functional balance between AT and AT receptors, and how new molecular pharmacological approaches may act on its regulation to open up new therapeutic perspectives."

Journal • Review • Cardiovascular • Hypertension • Nephrology • Renal Disease • RAS

G protein-biased ligand of angiotensin II type 1 receptor mediates myofibroblast differentiation through TGF-β1/ERK axis in human cardiac fibroblasts. (PubMed, Eur J Pharmacol) - "Stimulation of AT receptors by their G-biased ligand (TRV120055), but not β-arrestin-biased ligand (TRV120027), substantially exerted fibrogenic effects at a level similar to that of Ang II, suggesting that AT receptor induced cardiac fibrosis in a G-dependent and β-arrestin-independent manner. Valsartan prevents TRV120055-mediated fibroblast activation...In addition, G protein and TGF-β1 were necessary for ERK1/2 activation induced by Ang II and TRV120055. Collectively, TGF-β1 and ERK1/2 are downstream effectors of the G-biased ligand of AT receptor for the induction of cardiac fibrosis."

Journal • Fibrosis • Immunology • TGFB1

Renin-Angiotensin System Modulation With Synthetic Angiotensin (1-7) and Angiotensin II Type 1 Receptor-Biased Ligand in Adults With COVID-19: Two Randomized Clinical Trials. (PubMed, JAMA) - P2/3 | "To evaluate the efficacy and safety of RAS modulation using 2 investigational RAS agents, TXA-127 (synthetic angiotensin [1-7]) and TRV-027 (an angiotensin II type 1 receptor-biased ligand), that are hypothesized to potentiate the action of angiotensin (1-7) and mitigate the action of the angiotensin II. These results do not support the hypotheses that pharmacological interventions that selectively block the angiotensin II type 1 receptor or increase angiotensin (1-7) improve outcomes for patients with severe COVID-19. ClinicalTrials.gov Identifier: NCT04924660."

Clinical • Journal • Allergy • Hypotension • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

NECTAR: Novel Experimental COVID-19 Therapies Affecting Host Response (clinicaltrials.gov) - P2/3 | N=1600 | Recruiting | Sponsor: Sean Collins | Trial completion date: Apr 2023 ➔ Oct 2023 | Trial primary completion date: Feb 2023 ➔ Aug 2023

Trial completion date • Trial primary completion date • Cardiovascular • Hematological Disorders • Immunology • Infectious Disease • Inflammation • Novel Coronavirus Disease • Respiratory Diseases • Thrombosis

Comparative evaluation of biased agonists Sarcosine , d-Alanine -Angiotensin (Ang) II (SD Ang II) and Sarcosine , Isoleucine -Ang II (SI Ang II) and their radioiodinated congeners binding to rat liver membrane AT receptors. (PubMed, Pharmacol Res Perspect) - "Even though Trevena®'s biased agonist peptide TRV027 offered greater stability and potency compared to earlier AT R biased agonists, it failed its phase II clinical trial in 2016. Further refinements to AT R biased agonist peptides to improve affinity, as seen with SI Ang II, with better stability and bioavailability, has the potential to achieve the anticipated biased agonism."

Journal • Preclinical • Review • Cardiovascular

Distinct Mechanisms of β-Arrestin-Biased Agonist and Blocker of AT1R in Preventing Aortic Aneurysm and Associated Mortality. (PubMed, Hypertension) - "TRV027-engaged AT1R prevented AA and associated mortality by distinct molecular mechanisms compared with the AT1R blocker, Olmesartan. Developing novel β-arrestin-biased AT1R ligands may yield promising drugs to combat AA."

Journal • Cardiovascular • Fibrosis • Immunology • APOE

The effect of TRV027 on coagulation in COVID 19: A pilot randomized, placebo-controlled controlled trial. (PubMed, Br J Clin Pharmacol) - P1 | "There was a numerical decrease in D-dimer in the TRV027 group and increase in D-dimer in the placebo group, however, this did not reach statistical significance (p=0.15). A Bayesian analysis demonstrated there was a 92% probability that this change represented a true drug effect."

Journal • Cardiovascular • Hematological Disorders • Infectious Disease • Novel Coronavirus Disease • Thrombosis

Efficacy of pharmacologic therapies in patients with acute heart failure: A network meta-analysis. (PubMed, Front Pharmacol) - " After screening 14,888 citations, 23 RCTs (17,097 patients) were included, focusing on nesiritide, placebo, serelaxin, rhANP, omecamtiv mecarbil, tezosentan, KW-3902, conivaptan, tolvaptan, TRV027, chlorothiazide, metolazone, ularitide, relaxin, and rolofylline. No drug was superior to the other drugs for the secondary outcomes and safety outcomes. Current drugs for AHF show similar efficacy and safety."

Journal • Retrospective data • Review • Cardiovascular • Congestive Heart Failure • Heart Failure

NECTAR: Novel Experimental COVID-19 Therapies Affecting Host Response (clinicaltrials.gov) - P2/3 | N=1600 | Recruiting | Sponsor: Vanderbilt University Medical Center | Trial completion date: Dec 2023 ➔ Apr 2023 | Trial primary completion date: May 2023 ➔ Feb 2023

Trial completion date • Trial primary completion date • Cardiovascular • Hematological Disorders • Immunology • Infectious Disease • Inflammation • Novel Coronavirus Disease • Respiratory Diseases • Thrombosis

Downstream signaling of Angiotensin II type 1 receptors responsible for mammalian nephrogenesis (IPNA 2022) - "We investigated how the two pathways affect renal development in juvenile mice. Wild-type BALB c mice subcutaneously received ARB, candesartan (3 mg/kg/day), the BBA, TRV027 (3 mg/kg/day), or saline daily from the postnatal day 1 (P1) to P15. Renal pathology showed a decreased in the glomerular number, cortical thinning, thickened vascular wall mainly in interlobular arteries, and disorganized cell arrangement of vascular smooth muscles. However, these abnormalities were not observed in BBA or saline groups. These observations indicate that β-arrestin pathway that is differentially regulated by ARB and BBA is responsible for the postrenal kidney development."

Nephrology • Renal Disease

Neutrophil-to-Lymphocyte Ratio and Outcomes in Patients Admitted for Acute Heart Failure (As Seen in the BLAST-AHF, Pre-RELAX-AHF, and RELAX-AHF Studies). (PubMed, Am J Cardiol) - "Individual patient data from the BLAST-AHF (phase 2b study of the biased ligand of the angiotensin 2 type 1 receptor, TRV027), Pre-RELAX-AHF (phase 2b study of recombinant human relaxin-2, serelaxin), and RELAX-AHF (phase 3 study of serelaxin) randomized, placebo-controlled studies for patients with acute HF were pooled for analysis. NLR was an independent predictor of 30-day all-cause mortality (adjusted hazard ratio [HR] per log NLR increment: 1.66 [1.22 to 2.25], p = 0.001), 60-day HF/renal failure rehospitalizations or CV death: 1.33 [1.12 to 1.57], p = 0.001), 180-day all-cause mortality (adjusted HR 1.27 [1.08 to 1.50], p = 0.003), and 180-day CV death (adjusted HR 1.24 [1.04 to 1.49], p = 0.018). NLR, a readily available inflammatory biomarker, was associated with independent risk for short- and long-term adverse outcomes in acute HF, surpassing traditional markers, such as natriuretic peptides."

Journal • Cardiovascular • Chronic Kidney Disease • Congestive Heart Failure • Heart Failure • Pulmonary Disease • Renal Disease

Myogenic Vasoconstriction Requires Canonical G Signaling of the Angiotensin II Type 1 Receptor. (PubMed, J Am Heart Assoc) - "Methods and Results We tested the mechanosensitive function of AT1R using tamoxifen-inducible smooth muscle-specific AT1aR knockout (smooth muscle-Agtr1a) mice and studied downstream signaling cascades mediated by G and/or β-arrestins. FR900359, Sar1Ile4Ile8-angiotensin II (SII), TRV120027 and TRV120055 were used as selective G inhibitor and biased agonists to activate noncanonical β-arrestin and canonical G signaling of the AT1R, respectively...FR900359 decreased myogenic tone and angiotensin II-induced constrictions whereas selective biased targeting of AT1R-β-arrestin signaling pathways had no effects. Conclusions This study demonstrates that myogenic arterial constriction requires G-dependent signaling pathways of mechanoactivated AT1R but not G protein-independent, noncanonical pathways in smooth muscle cells."

Journal

Heterotrimeric Gq proteins act as a switch for GRK5/6 selectivity underlying β-arrestin transducer bias. (PubMed, Nat Commun) - "Using the angiotensin II (Ang II) type-1 receptor (AT1R), we show that β-arrestin recruitment depends on both GRK2/3 and GRK5/6 upon binding of Ang II, but solely on GRK5/6 upon binding of the β-arrestin-biased ligand TRV027...Single-molecule imaging identifies relocation of AT1R and GRK5, but not GRK2, to an immobile phase under the Gq-inactive, AT1R-stimulated conditions. These findings uncover a previously unappreciated Gq-regulated mechanism that encodes GRK-subtype selectivity and imparts distinct phosphorylation-barcodes directing downstream β-arrestin functions."

Journal

NECTAR: Novel Experimental COVID-19 Therapies Affecting Host Response (clinicaltrials.gov) - P2/3; N=1600; Recruiting; Sponsor: Vanderbilt University Medical Center; Trial completion date: Dec 2022 ➔ Dec 2023; Trial primary completion date: May 2022 ➔ May 2023

Clinical • Trial completion date • Trial primary completion date • Cardiovascular • Hematological Disorders • Immunology • Infectious Disease • Inflammation • Novel Coronavirus Disease • Respiratory Diseases • Thrombosis

A novel way of modification of AT angiotensin receptors to alleviate neonatal and infantile heart failure (PubMed, Nihon Yakurigaku Zasshi) - "TRV027 did not cause any obvious adverse effects on their preweaning wildtype littermates. Thus, we reason in this review that BBA can be important therapeutics for preweaning heart failure."

Journal • Atrial Fibrillation • Cardiomyopathy • Cardiovascular • Congestive Heart Failure • Heart Failure