- |||||||||| TRV027 / Trevena
Journal: Implications of ?-Arrestin biased signaling by angiotensin II type 1 receptor for cardiovascular drug discovery and therapeutics. (Pubmed Central) - Nov 13, 2024
Numerous experimental and animal studies have demonstrated that ?-arrestin biased AT1R-ligands (such as SII-AngII, S1I8, TRV023, and TRV027) offer cardiovascular benefits by blocking the G protein signaling while retaining the ?-arrestin signaling...Therefore, developing a small molecule ?-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.
- |||||||||| TRV027 / Trevena
Journal: Nanobody-mediated dualsteric engagement of the angiotensin receptor broadens biased ligand pharmacology. (Pubmed Central) - Feb 19, 2024
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 ?-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.
- |||||||||| TXA-127 / Constant Therap, TRV027 / Trevena, Tavalisse (fostamatinib) / Rigel
Trial completion: NECTAR: Novel Experimental COVID-19 Therapies Affecting Host Response (clinicaltrials.gov) - Jan 23, 2024
P2/3, N=871, Completed,
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. Active, not recruiting --> Completed
- |||||||||| TRV027 / Trevena
Journal: ?-arrestin pathway activation by selective ATR1 agonism promotes calcium influx in podocytes, leading to glomerular damage. (Pubmed Central) - Dec 22, 2023
Recently, a novel biased AT1R agonist, TRV120027 (TRV), which selectively activates the ?-arrestin cascade and blocks the G-protein-coupled receptor pathway has been proposed as a potential blood pressure medication...TRV-activated ?-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.
- |||||||||| TXA-127 / Constant Therap, TRV027 / Trevena, Tavalisse (fostamatinib) / Rigel
Enrollment closed, Enrollment change: NECTAR: Novel Experimental COVID-19 Therapies Affecting Host Response (clinicaltrials.gov) - Sep 30, 2023
P2/3, N=871, Active, not recruiting,
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. Recruiting --> Active, not recruiting | N=1600 --> 871
- |||||||||| TRV027 / Trevena
Review, Journal: The AT/AT Receptor Equilibrium Is a Cornerstone of the Regulation of the Renin Angiotensin System beyond the Cardiovascular System. (Pubmed Central) - Aug 2, 2023
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.
- |||||||||| TXA-127 / Constant Therap, TRV027 / Trevena, Tavalisse (fostamatinib) / Rigel
Trial completion date, Trial primary completion date: NECTAR: Novel Experimental COVID-19 Therapies Affecting Host Response (clinicaltrials.gov) - Feb 27, 2023
P2/3, N=1600, Recruiting,
A Bayesian analysis demonstrated there was a 92% probability that this change represented a true drug effect. Trial completion date: Apr 2023 --> Oct 2023 | Trial primary completion date: Feb 2023 --> Aug 2023
- |||||||||| TRV027 / Trevena
Downstream signaling of Angiotensin II type 1 receptors responsible for mammalian nephrogenesis (Poster Area - Exhibition Hall E) - Sep 20, 2022 - Abstract #IPNA2022IPNA_506;
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.
- |||||||||| TRV027 / Trevena, Reasanz (serelaxin) / Novartis
Biomarker, Journal: 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 Central) - Sep 10, 2022
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.
- |||||||||| FR900359 / Sidney Kimmel Cancer Center, Thomas Jefferson University, Icahn School of Medicine at Mount Sinai, TRV027 / Trevena
Journal: Myogenic Vasoconstriction Requires Canonical G Signaling of the Angiotensin II Type 1 Receptor. (Pubmed Central) - Apr 9, 2022
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.
- |||||||||| TXA-127 / Constant Therap, TRV027 / Trevena, Tavalisse (fostamatinib) / Rigel
Trial completion date, Trial primary completion date: NECTAR: Novel Experimental COVID-19 Therapies Affecting Host Response (clinicaltrials.gov) - Mar 9, 2022
P2/3, N=1600, Recruiting,
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. Trial completion date: Dec 2023 --> Apr 2023 | Trial primary completion date: May 2023 --> Feb 2023
- |||||||||| TRV027 / Trevena
Journal: Heterotrimeric Gq proteins act as a switch for GRK5/6 selectivity underlying β-arrestin transducer bias. (Pubmed Central) - Feb 17, 2022
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.
- |||||||||| TXA-127 / Constant Therap, TRV027 / Trevena, Tavalisse (fostamatinib) / Rigel
Trial completion date, Trial primary completion date: NECTAR: Novel Experimental COVID-19 Therapies Affecting Host Response (clinicaltrials.gov) - Dec 12, 2021
P2/3, N=1600, Recruiting,
These findings uncover a previously unappreciated Gq-regulated mechanism that encodes GRK-subtype selectivity and imparts distinct phosphorylation-barcodes directing downstream β-arrestin functions. Trial completion date: Dec 2022 --> Dec 2023 | Trial primary completion date: May 2022 --> May 2023
- |||||||||| TXA-127 / Constant Therap, TRV027 / Trevena, Tavalisse (fostamatinib) / Rigel
Enrollment open: NECTAR: Novel Experimental COVID-19 Therapies Affecting Host Response (clinicaltrials.gov) - Aug 8, 2021
P2/3, N=1600, Recruiting,
These data suggest that selective activation of ATR β-arrestin pathways may be exploitable therapeutically. Not yet recruiting --> Recruiting
- |||||||||| TRV027 / Trevena
Review, Journal: Targeting the Angiotensin II Type 1 Receptor in Cerebrovascular Diseases: Biased Signaling Raises New Hopes. (Pubmed Central) - Aug 6, 2021
In this paper, we review the involvement of AT in cerebrovascular diseases as well as recent advances in the understanding of its molecular dynamics and biased or non-biased signaling. We also describe why these alternative signaling pathways induced by β-arrestin biased AT agonists could be considered as new therapeutic avenues for cerebrovascular diseases.
- |||||||||| TRV027 / Trevena
Journal: Mapping Angiotensin II Type 1 Receptor-Biased Signaling Using Proximity Labeling and Proteomics Identifies Diverse Actions of Biased Agonists. (Pubmed Central) - Jun 22, 2021
To fully appreciate the diversity in cellular signaling profiles activated by AT1R transducer-biased ligands, we utilized peroxidase-catalyzed proximity labeling to capture proteins in close proximity to AT1Rs in response to six different ligands: angiotensin II (full agonist), S1I8 (partial agonist), TRV055 and TRV056 (G-protein-biased agonists), and TRV026 and TRV027 (β-arrestin-biased agonists) at 90 s, 10 min, and 60 min after stimulation (ProteomeXchange Identifier PXD023814)...A comparison between ligand classes revealed distinct signaling activation such as greater labeling by G-protein-biased ligands on ESCRT-0 complex proteins that act as the sorting machinery for ubiquitinated proteins. Our study provides a comprehensive analysis of AT1R receptor-trafficking kinetics and signaling activation profiles induced by distinct classes of ligands.
- |||||||||| TRV027 / Trevena
Trial completion, Enrollment change: RAS and Coagulopathy in COVID19 (clinicaltrials.gov) - May 27, 2021
P1, N=30, Completed,
Our study provides a comprehensive analysis of AT1R receptor-trafficking kinetics and signaling activation profiles induced by distinct classes of ligands. Recruiting --> Completed | N=60 --> 30
- |||||||||| TRV027 / Trevena
Trial primary completion date: RAS and Coagulopathy in COVID19 (clinicaltrials.gov) - Apr 29, 2021
P1, N=60, Recruiting,
Recruiting --> Completed | N=60 --> 30 Trial primary completion date: Apr 2021 --> Jul 2021
- |||||||||| TRV027 / Trevena
Trial primary completion date: RAS and Coagulopathy in COVID19 (clinicaltrials.gov) - Feb 11, 2021
P1, N=60, Recruiting,
Trial primary completion date: Apr 2021 --> Jul 2021 Trial primary completion date: Dec 2020 --> Apr 2021
- |||||||||| TRV027 / Trevena
Enrollment open, Trial primary completion date: RAS and Coagulopathy in COVID19 (clinicaltrials.gov) - Oct 14, 2020
P1, N=60, Recruiting,
No abstract available Not yet recruiting --> Recruiting | Trial primary completion date: Sep 2020 --> Dec 2020
- |||||||||| Biomarker, Review, Journal: Discontinued Drugs for the Treatment of Cardiovascular Disease from 2016 to 2018. (Pubmed Central) - Feb 7, 2020
Of these, six candidates (MDCO-216, TRV027, ubenimex, sodium nitrite, losmapimod, and bococizumab) were dropped for lack of clinical efficacy, the other six for strategic or unspecified reasons...Four candidate developments (OPC-108459, ONO-4232, GSK-2798745, and TAK-536TCH) were run without biomarkers, which could be used as surrogate endpoints in the 12 cardiovascular drugs discontinued from 2016 to 2018. This review will be useful for those involved in the field of drug discovery and development, and for those interested in the treatment of cardiovascular disease.
- |||||||||| TRV027 / Trevena
Journal: Biased Agonist TRV027 Determinants in AT1R by Molecular Dynamics Simulations. (Pubmed Central) - Jan 10, 2020
However, the biased ligand does not cause the rotamer toggle alternative positioning and displays an exclusive hydrogen bond pattern. Our work sheds light into biased agonism mechanism and will help future design of novel biased agonist for AT1R.
- |||||||||| Journal: Agents with vasodilator properties in acute heart failure. (Pubmed Central) - Jun 24, 2018
After diuretics, vasodilators are the most common intravenous therapy for AHF, but neither nitrates, nitroprusside, nor nesiritide have robust evidence supporting their ability to provide meaningful effects on clinical outcomes, except perhaps early symptom improvement...These agents include serelaxin, natriuretic peptides (ularitide, cenderitide), β-arrestin-biased angiotensin II type 1 receptor ligands (TRV120027), nitroxyl donors (CXL-1020, CXL-1427), soluble guanylate cyclase modulators (cinaciguat, vericiguat), short-acting calcium channel blockers (clevidipine), and potassium channel activators (nicorandil). No abstract available
- |||||||||| Journal: Potential new drug treatments for congestive heart failure. (Pubmed Central) - Mar 12, 2017
The mortality benefit associated with serelaxin treatment in the RELAX-HF trial is being tested in RELAX-AHF II, while two other drugs, ularitide and TRV027, are also being evaluated in ADHF patients. Two new agents for the treatment of chronic HFrEF, LCZ696 and ivabradine, have been recently been approved for use by the FDA and four novel agents which have shown considerable promise in early studies, omecamtiv mecarbil, vericiguat, finerenone, and neuregulin, are currently being evaluated in late-phase clinical trials.
- |||||||||| Journal: Novel Therapies for Heart Failure - Where Do They Stand? (Pubmed Central) - Feb 25, 2017
Omecamtiv mecarbil, an inotropic agent that improves myocardial contractility by a novel mechanism, and vericiguat, a drug that stimulates soluble guanylate cyclase, are both being developed to treat patients with chronic HF...Finally, despite the negative results of the CUPID study, gene transfer therapy continues to be explored as a means of improving the function of the failing heart. The basis for the use of these drugs and their current status in clinical trials are discussed.
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