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Type | Public |
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Nasdaq: TRVN Russell Microcap Index component | |
Industry | Biotechnology / Pharmaceutical |
Headquarters | , United States |
Key people | Carrie L. Bourdow (President and CEO) |
Website | www |
Trevena Inc is a clinical stage biopharmaceutical company, headquartered in Chesterbrook, Pennsylvania, USA, and is involved in the discovery and development of G-protein coupled receptors (GPCR) biased ligands. Trevena was founded in 2007 with technology licensed from Duke University, which originated in the labs of company founders Robert Lefkowitz winner of the 2012 Nobel Prize in Chemistry [1] and Howard Rockman. Trevena's approach to drug discovery is based on utilizing ligand bias, or functional selectivity, at GPCR targets to produce drugs with improved efficacy and reduced side effect profiles. [2] Trevena was named one of the top 15 US startups of 2008 by Business Week. [3]
Trevena's expertise lies in engineering "biased ligands" that activate only the beneficial signaling pathways downstream of a GPCR to unlock new biology and avoid drug adverse effects. [4] Trevena's pipeline currently includes a clinical stage mu-opioid biased ligand for post-operative pain, and discovery-stage programs for chronic pain, migraine, and Parkinson's disease. [5]
In 2008, the company raised $25 Million in a Series A[ clarification needed ] financing round led by Alta Partners, Polaris Ventures, New Enterprise Associates, Healthcare Ventures, and Yasuda Economic Development Corporation. [6]
In early 2009, Trevena entered into a collaborative agreement with Ligand Pharmaceuticals to identify biased ligands at numerous GPCRs from a large, diverse chemical library. [7] Later that year, Trevena received a competitively awarded American Recovery and Reinvestment Act Grand Opportunities Grant, spanning two years and funding US$7.65 million of research. [8] The company has disclosed specific interests in the mu Opioid receptor and kappa Opioid receptor. [9] The company raised an additional US$35 million in a B round of venture financing in the summer of 2010. [10] In 2011, Treveva received another NIH grant as part of the NIH Blueprint Neurotherapeutics Network, potentially worth up to $10M USD, to support preclinical development of a delta opioid receptor biased ligand for major depressive disorder. [11] Trevena has received funding from the Michael J. Fox Foundation to explore the potential for delta opioid receptor biased ligands to treat Parkinson's disease. [12]
Trevena's initial public offering was on January 30, 2014. [13]
Trevena's leading drug candidate is Oliceridine (TRV130), a G protein-biased ligand binding to the mu opioid receptor [14] for the intravenous treatment of acute moderate-to-severe post-operative pain. Phase I and II clinical trials of TRV130 for postoperative pain are complete. Phase II trials showed effectiveness is analgesia and a wider therapeutic window than morphine. [15] In February 2016, the FDA granted Breakthrough Therapy status to olicerdine. [16] In January 2017, Trevena announced that enrollment for its phase III trials, APOLLO-1 and APOLLO-2 are complete. In November 2018, Trevena received a Complete Response Letter (CRL) from FDA regarding Oliceridine and the need for additional safety data. As of late December 2018, the company has yet to release the meeting minutes from FDA on how to move forward with Oliceridine approval in 2019.
Trevena announced FDA approval of oliceridine on August 7, 2020. [17]
Trevena announced DEA scheduling, Schedule II controlled substance, of oliceridine on October 30, 2020 [18]
https://finance.yahoo.com/news/trevena-announces-publication-comprehensive-review-110010409.html
Trevena's developed TRV027 for acute heart failure, targets the angiotensin receptor utilizing beta-arrestin bias, an approach that has shown numerous beneficial cardiovascular and renal actions in preclinical species. [19] [20] Trevena completed Phase I clinical trials in 2010. [21] Phase 2 clinical trials on TRV027 began in the spring of 2011. [22] In May 2016, Trevena announced that the TRV027 phase II trial failed to meet its primary endpoints and they were no longer developing the drug. [23]
Trevena announced it has entered into a collaboration with Imperial College London to evaluate the potential of TRV027, a novel AT1 receptor selective agonist, to treat acute lung injury contributing to acute respiratory distress syndrome (ARDS) in COVID-19 patients. ARDS is a major complication leading to mortality associated with COVID-19. Imperial College London will be sponsoring and funding this study, with additional support through the British Heart Foundation Centre for Research Excellence Award.
TRV250 is a pre-clinical drug candidate for migraine binding to the delta opioid receptor. This avoids the addiction potential of drugs that activate the mu opioid receptor. Other delta opioid-targeting drugs are known to cause seizures, [24] but Trevena hopes to avoid this with TRV250 by bypassing the β-arrestin pathway. [25]
TRV734 is an oral follow-up to the injected TRV130 mu-opioid biased ligand program. While it binds to the same receptors as opioid analgesics, TRV734 has very weak β-arrestin recruitment, unlike other available opioids, and produced fewer off-target effects. [26] Phase I clinical trials were completed in 2014. [27]
G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily-related proteins that are cell surface receptors that detect molecules outside the cell and activate cellular responses. Coupling with G proteins, they are called seven-transmembrane receptors because they pass through the cell membrane seven times. Ligands can bind either to extracellular N-terminus and loops or to the binding site within transmembrane helices. They are all activated by agonists although a spontaneous auto-activation of an empty receptor can also be observed.
An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the agonist, while an inverse agonist causes an action opposite to that of the agonist.
Functional selectivity is the ligand-dependent selectivity for certain signal transduction pathways relative to a reference ligand at the same receptor. Functional selectivity can be present when a receptor has several possible signal transduction pathways. To which degree each pathway is activated thus depends on which ligand binds to the receptor. Functional selectivity, or biased signaling, is most extensively characterized at G protein coupled receptors (GPCRs). A number of biased agonists, such as those at muscarinic M2 receptors tested as analgesics or antiproliferative drugs, or those at opioid receptors that mediate pain, show potential at various receptor families to increase beneficial properties while reducing side effects. For example, pre-clinical studies with G protein biased agonists at the μ-opioid receptor show equivalent efficacy for treating pain with reduced risk for addictive potential and respiratory depression. Studies within the chemokine receptor system also suggest that GPCR biased agonism is physiologically relevant. For example, a beta-arrestin biased agonist of the chemokine receptor CXCR3 induced greater chemotaxis of T cells relative to a G protein biased agonist.
The κ-opioid receptor or kappa opioid receptor, abbreviated KOR or KOP for its ligand ketazocine, is a G protein-coupled receptor that in humans is encoded by the OPRK1 gene. The KOR is coupled to the G protein Gi/G0 and is one of four related receptors that bind opioid-like compounds in the brain and are responsible for mediating the effects of these compounds. These effects include altering nociception, consciousness, motor control, and mood. Dysregulation of this receptor system has been implicated in alcohol and drug addiction.
G-protein-coupled receptor kinase 2 (GRK2) is an enzyme that in humans is encoded by the ADRBK1 gene. GRK2 was initially called Beta-adrenergic receptor kinase, and is a member of the G protein-coupled receptor kinase subfamily of the Ser/Thr protein kinases that is most highly similar to GRK3(βARK2).
The μ-opioid receptors (MOR) are a class of opioid receptors with a high affinity for enkephalins and beta-endorphin, but a low affinity for dynorphins. They are also referred to as μ(mu)-opioid peptide (MOP) receptors. The prototypical μ-opioid receptor agonist is morphine, the primary psychoactive alkaloid in opium and for which the receptor was named, with mu being the Greek letter m. It is an inhibitory G-protein coupled receptor that activates the Gi alpha subunit, inhibiting adenylate cyclase activity, lowering cAMP levels.
The δ-opioid receptor, also known as delta opioid receptor or simply delta receptor, abbreviated DOR or DOP, is an inhibitory 7-transmembrane G-protein coupled receptor coupled to the G protein Gi/G0 and has enkephalins as its endogenous ligands. The regions of the brain where the δ-opioid receptor is largely expressed vary from species model to species model. In humans, the δ-opioid receptor is most heavily expressed in the basal ganglia and neocortical regions of the brain.
Nalfurafine is an antipruritic that is marketed in Japan for the treatment of uremic pruritus in individuals with chronic kidney disease undergoing hemodialysis. It acts as a potent, selective, centrally-penetrant κ-opioid receptor (KOR) agonist, and is the first and currently the only selective KOR agonist to have been approved for clinical use. It has also been dubiously referred to as the "first non-narcotic opioid drug" in history.
Noribogaine, or 12-hydroxyibogamine, is the principal psychoactive metabolite of the oneirogen ibogaine. It is thought to be involved in the antiaddictive effects of ibogaine-containing plant extracts, such as Tabernanthe iboga.
G-protein-coupled receptor kinase 3 (GRK3) is an enzyme that in humans is encoded by the ADRBK2 gene. GRK3 was initially called Beta-adrenergic receptor kinase 2 (βARK-2), and is a member of the G protein-coupled receptor kinase subfamily of the Ser/Thr protein kinases that is most highly similar to GRK2.
Sacubitril/valsartan, sold under the brand name Entresto, is a fixed-dose combination medication for use in heart failure. It consists of the neprilysin inhibitor sacubitril and the angiotensin receptor blocker valsartan. It is recommended for use as a replacement for an ACE inhibitor or an angiotensin receptor blocker in people with heart failure with reduced ejection fraction.
Mitragynine pseudoindoxyl is a rearrangement product of 7-hydroxymitragynine. It is an analgesic being more potent than morphine.
Oliceridine, sold under the brand name Olinvyk, is an opioid medication that is used for the treatment of moderate to severe acute pain in adults. It is given by intravenous (IV) injection.
N-2′-Indolylnaltrexamine (INTA) is an opioid and derivative of β-naltrexamine. This molecule is loosely derived from the classical opioid morphine. This experimental drug candidate is under development as a κ-opioid receptor agonist for pain management with fewer adverse side effects. Preclinical study in mice showed potent analgesic effects with no tolerance or dependence. The mice also showed no adverse effects in the conditioned place aversion assay.
PZM21 is an experimental opioid analgesic drug that is being researched for the treatment of pain. It is claimed to be a functionally selective μ-opioid receptor agonist which produces μ-opioid receptor mediated G protein signaling, with potency and efficacy similar to morphine, but with less β-arrestin 2 recruitment. However, recent reports highlight that this might be due to its low intrinsic efficacy, rather than functional selectivity or 'G protein bias' as initially reported. In tests on mice, PZM21 was slightly less potent than morphine or TRV130 as an analgesic, but also had significantly reduced adverse effects, with less constipation than morphine, and very little respiratory depression, even at high doses. This research was described as a compelling example of how modern high-throughput screening techniques can be used to discover new chemotypes with specific activity profiles, even at targets such as the μ-opioid receptor which have already been thoroughly investigated. More recent research has suggested however that at higher doses, PZM21 is capable of producing classic opioid side effects such as respiratory depression and development of tolerance and may have only limited functional selectivity.
Mitragynine is an indole-based alkaloid and the most abundant active alkaloid in the Southeast Asian plant Mitragyna speciosa, commonly known as kratom. The total alkaloid concentration in dried leaves ranges from 0.5 to 1.5%. In Thai varieties, mitragynine is the most abundant component while 7-hydroxymitragynine is a minor constituent. In Malaysian kratom varieties, mitragynine is present at lower concentration. Such preparations are orally consumed and typically involve dried kratom leaves which are brewed into tea or ground and placed into capsules. Mitragynine consumption for medicinal and recreation purposes dates back centuries, although early use was primarily limited to Southeast Asian countries such as Indonesia and Thailand where the plant grows indigenously. Recently, mitragynine use has spread throughout Europe and the Americas as both a recreational and medicinal drug. While research into the effects of kratom have begun to emerge, investigations on the active compound mitragynine are less common.
Sadashiva "Sadu" Karnik is an Indian-born American molecular biologist who is a Professor in the Molecular Medicine Department of Cleveland Clinic Lerner College of Medicine at Case Western Reserve University. He is also head of the Karnik-lab at the Lerner Research Institute of Cleveland Clinic.
SR-17018 is a drug which acts as a biased agonist at the μ-opioid receptor, selective for activation of the G-protein signalling pathway over β-arrestin 2 recruitment. In animal studies it produces analgesic effects but with less respiratory depression and development of tolerance than conventional opioids.
TRV734 is a drug developed by Trevena Inc which acts as a biased agonist at the μ-opioid receptor, selective for activation of the G-protein signalling pathway over β-arrestin 2 recruitment. It is closely related to oliceridine and has a similar pharmacological profile, but unlike oliceridine which has to be injected, TRV734 is suitable to be administered orally.
SHR9352 is a drug which acts as a potent and selective biased agonist at the μ-opioid receptor, selective for activation of the G-protein signalling pathway over β-arrestin 2 recruitment. It was structurally derived from oliceridine by replacing the benzylic side chain with a cyclised group, although only some compounds in the series retained the desired biased agonist profile, with some derivatives such as compound 12 being potent, unbiased μ-opioid full agonists.