Remifentanil Hydrochloride

Double-blind, placebo-controlled study aims to measure safety and efficacy of INDV-2000 over 3 months in participants with moderate to severe Opioid Use Disorder. INDV-2000 is an investigational non-opioid treatment that acts through the orexin pathway, shown to play a key role in the neurobiology of substance use disorder in animals. Recent animal studies have demonstrated that selective Orexin-1 receptor antagonism can reduce self-administration of opioids and synthetic opioids such as fentanyl and remifentanil. RICHMOND, Va., June 10, 2024 /PRNewswire/ -- Indivior PLC (LSE/Nasdaq: INDV) today announced the dosing of the first subject with INDV-2000 in a Phase 2 double-blind, placebo controlled, randomized, dose-ranging study to assess the safety and efficacy of INDV-2000 over 3 months in treatment-seeking individuals with Opioid Use Disorder (OUD) (NCT06384157). The purpose of this proof-of-concept study is to measure safety and efficacy and to determine the dose-response relationship for INDV-2000 in participants with moderate to severe OUD who are treatment-naïve, have recently initiated or completed short-term medically supervised opioid withdrawal with transmucosal (TM) buprenorphine, and are interested in transitioning to a non-opioid treatment. This milestone is another step in Indivior's mission to develop new treatment options for patients with OUD and other substance use disorders. With the support of an NIH-HEAL grant (1R01DA043898-01A1) titled "Clinical Evaluation of INDV-2000 (C4X3256), a Non-Opioid, Highly Selective Orexin-1 Receptor Antagonist for the Treatment of Opioid Use Disorder" the study was initiated for the clinical development of INDV-2000, a potent and selective oral orexin-1 receptor (OX1R) antagonist, with demonstrated activity in rodent models of addiction and a safety profile suitable for therapeutic administration in clinical studies.1 More recently, animal studies also have shown that selective antagonism of the OX1R can reduce heroin intake and oxycodone self-administration2 and reduce the consumption of synthetic opioids including remifentanil3 and fentanyl.4 "INDV-2000 provides Indivior with a unique opportunity to further address unmet patient needs in the treatment of OUD with potentially the first non-opioid orexin-targeted therapy," said Christian Heidbreder, Chief Scientific Officer. "By providing a potential therapeutic option for patients who might benefit from a non-opioid alternative, INDV-2000 may broaden the spectrum of care for OUD treatment." The orexin-A and orexin-B neuropeptides are agonists of the orexin-1 receptor (OX1R) and orexin-2 receptor (OX2R), respectively. The OX1R and OX2R are thought to play differential physiological roles with the OX1R mainly involved in motivation and reward and the OX2R in the modulation of the sleep/wake cycle and energy homeostasis.3 The completion of clinical Phase 1 Single Ascending Dose (NCT04413552) and Multiple Ascending Dose (NCT04976855) studies happened after an end-of-Phase 1 meeting with the FDA on November 3, 2023, paving the way for the preparation and initiation of this clinical Phase 2 proof-of-concept (PoC) study. Opioid use disorder (OUD) involves disruption of brain circuits engaged in reward, decision-making, learning, and self-control. The magnitude of OUD worldwide highlights the need for novel molecular entities ultimately translating into new medications for the treatment of OUD. In the United States, among people aged 12 or older in 2022, 3.2% (or 8.9 million people) misused opioids in the past year.5 "As the opioid epidemic continues to escalate, it is important to develop more treatment options," said Dr. Heidbreder. "This milestone highlights Indivior's commitment to developing a wider range of therapeutics in both the opioid and non-opioid treatment category, ultimately providing more choices for the patient." About the Study The purpose of this Phase 2 study is to measure safety and efficacy and to determine the dose-response relationship for INDV-2000 in participants with moderate to severe Opioid Use Disorder (OUD) who are new to treatment, have recently initiated or completed short-term medically supervised opioid withdrawal with TM buprenorphine, and are interested in transitioning to a non-opioid treatment. On Day 1, trial participants will be randomized to the INDV-2000 or placebo group and receive the treatment in conjunction with TM buprenorphine until Day 7. From Day 8 onward, INDV-2000 or placebo will be administered as a standalone. The randomized treatment period starts when the participant receives randomized treatment (at Day 1) and ends at his/her last study visit after 3 months on INDV-2000 or placebo. Alternatively, the treatment period ends when participants initiate buprenorphine rescue therapy due to a relapse in illicit opioid use. About Indivior Indivior is a global pharmaceutical company working to help change patients' lives by developing medicines to treat substance use disorders (SUD), opioid overdose and serious mental illnesses. Our vision is that all patients around the world will have access to evidence-based treatment for the chronic conditions and co-occurring disorders of SUD. Indivior is dedicated to transforming SUD from a global human crisis to a recognized and treated chronic disease. Building on its global portfolio of opioid use disorder treatments, Indivior has a pipeline of product candidates designed to both expand on its heritage in this category and potentially address other chronic conditions and cooccurring disorders of SUD. Headquartered in the United States in Richmond, VA, Indivior employs more than 1,100 individuals globally and its portfolio of products is available in 37 countries worldwide. Visit to learn more. Connect with Indivior on LinkedIn by visiting . Important Cautionary Note Regarding Forward-Looking Statements This news release contains certain statements that are forward-looking. Forward-looking statements include, among other things, statements regarding potential new productor or therapies, express or implied statements about their safety and efficacy, and other statements containing the words "believe", "anticipate", "plan", "expect", "intend", "estimate", "forecast," "strategy," "target," "guidance," "outlook," "potential", "project", "priority," "may", "will", "should", "would", "could", "can", "outlook," "guidance", the negatives thereof, and variations thereon and similar expressions. By their nature, forward-looking statements involve risks and uncertainties as they relate to events or circumstances that may or may not occur in the future. Actual results may differ materially from those expressed or implied in such statements because they relate to future events. Various factors may cause differences between Indivior's expectations and actual results, including, among others, the risk that the clinical trial may fail to demonstrate the safety or efficacy of the treatment; that the FDA will require one or more Phase 3 trials before approving INDV-2000 for individuals with opioid use disorder; that the FDA may decline to approve INDV-2000 for individuals with opioid use disorder for many other reasons; and the material risks described in the most recent Indivior PLC Annual Report and in subsequent releases. Forward-looking statements speak only as of the date that they are made and should be regarded solely as our current plans, estimates and beliefs. Except as required by law, we do not undertake and specifically decline any obligation to update, republish or revise forward-looking statements to reflect future events or circumstances or to reflect the occurrences of unanticipated events. References Murray CM, Fox JC, Heidbreder C, Young M. A Novel, Non-Opioid, Selective Orexin-1 Receptor Antagonist for the Treatment of Substance Use Disorders. Neuroscience Applied, Volume 3, 2024, 104053. . Epub ahead of print. Smith, R.J., Aston-Jones, G., 2012. Orexin / hypocretin 1 receptor antagonist reduces heroin self-administration and cue-induced heroin seeking. Eur. J. Neurosci. 35, 798–804. Mohammadkhani, A., James, M.H., Pantazis, C.B., Aston-Jones, G., 2020. Persistent effects of the orexin-1 receptor antagonist SB-334867 on motivation for the fast-acting opioid remifentanil. Brain Res. 1731:146461. Fragale, J E., Pantazis, C.B., James, M.H., and Aston-Jones, G., 2019. The role of orexin-1 receptor signaling in demand for the opioid fentanyl. Neuropsychopharmacology. 44, 1690–1697. Substance Abuse and Mental Health Services Administration. (2022) Highlights for the 2022 National Survey on Drug Use and Health1. Retrieved from Highlights for the 2022 National Survey on Drug Use and Health (samhsa.gov) SOURCE Indivior PLC

This head-to-head pharmacodynamic study in healthy volunteers examined the ability of both OPVEE and intranasal naloxone to reverse opioid-induced respiratory depression, which is the shallow and slow breathing associated with an opioid overdose In this model, OPVEE 2.7mg reversed respiratory depression to 95% of pre-opioid baseline within 5 minutes; a similar reversal following a 4 mg dose of intranasal naloxone required 20 minutes RICHMOND, Va., March 11, 2024 /PRNewswire/ -- Indivior PLC (LSE/Nasdaq: INDV) today announced results from a pharmacodynamic study demonstrating that OPVEE® rapidly reverses opioid-induced respiratory depression, which is the major cause of deaths due to opioid overdose. The study, "Reversal of opioid-induced respiratory depression in healthy volunteers: comparison of intranasal nalmefene and intranasal naloxone", was published in the Journal of Clinical Pharmacology (Reversal of Opioid‐Induced Respiratory Depression in Healthy Volunteers: Comparison of Intranasal Nalmefene and Intranasal Naloxone - Ellison - The Journal of Clinical Pharmacology - Wiley Online Library) and is the first head-to-head comparison examining the effects of 2.7 mg intranasal (IN) nalmefene (OPVEE) and 4 mg IN naloxone on opioid-induced respiratory depression. This study was a part of the OPVEE development program and reviewed by the FDA as part of the approval process. This study met the primary endpoint by demonstrating that OPVEE reversed the respiratory depression produced by remifentanil, a potent synthetic opioid related to fentanyl, within the first 5 minutes following administration. Both OPVEE and IN naloxone produced a time-dependent reversal of the opioid-induced respiratory depression 2.5 to 20 minutes post administration. Point estimates favored OPVEE, demonstrating non-inferiority and superiority to naloxone. After OPVEE administration, subjects' minute ventilation (a measure of the amount of air that enters the lungs per minute) reached approximately 95% of the pre-opioid baseline within 5 minutes and maintained this robust reversal through the initial 20-minute monitoring period. By contrast, naloxone required 20 minutes to restore respiration to levels equaling those observed 5 minutes after OPVEE. There is an urgent need for rapid acting reversal agents because synthetic opioids, like fentanyl, impair breathing and reduce oxygen levels to vital organs like the brain more rapidly than other opioids such as morphine and heroin. "This study provides the first head-to-head comparison of IN OPVEE and IN naloxone in a clinical model of opioid-induced respiratory depression. While both reverse the effects of remifentanil induced respiratory depression, this pharmacodynamic study provides important insights about the time course of reversal for both drugs," said Christian Heidbreder, Ph.D. and Chief Scientific Officer of Indivior. "The first few minutes following an overdose – particularly with very potent and fast acting synthetic opioids like fentanyl – are critical for a successful rescue. OPVEE reverses the respiratory depression rapidly in this model, making it a valuable tool for combating the synthetic opioid overdose crisis we're facing as a nation." Following administration of OPVEE, subjects' minute ventilation (MV), a measure of how much a person is breathing, increased by an average of 5.75 L/min at 5 minutes, the study's primary endpoint. Intranasal naloxone produced a mean increase of 3.01 L/min at 5 minutes post-administration, and 20 minutes was required to produce an increase in MV similar to that observed 5 minutes after OPVEE. Adverse events (AEs) occurred in 91.8% of subjects following OPVEE and 86.7% of subjects following IN naloxone. The authors conclude that the AEs observed in this study are most likely related to remifentanil and hypercapnic experimental conditions used and not the drugs under investigation. The most common adverse events were headache (59.0% following OPVEE and 58.3% following intranasal naloxone), nausea (39.3% and 41.7%), vomiting (11.5% and 23.3%), and dizziness (18.0% and 21.7%). Adverse events were mild or moderate, with no subjects reporting a serious adverse event. In the United States, the provisional number of reported opioid overdose deaths reached 80,318 in the 12 months ending in September 2023.1 The reported overdose deaths linked to synthetic opioids, such as fentanyl, during the same period was 73,686, representing more than 90% of all opioid overdose fatalities. About the Study This study was an open-label, head-to-head, randomized, 2-period, 2-treatment crossover noninferiority study designed to model the pharmacodynamic effects of intranasal OPVEE® (nalmefene) and intranasal naloxone. A total of 69 opioid-experienced, non -dependent healthy male and female volunteers were randomized to receive study drugs. Subjects breathed a hypercapnic gas mixture containing 7% carbon dioxide and their minute ventilation (MV) was monitored. Minute ventilation is a measure of how deeply and rapidly a patient is breathing and is reduced by opioid exposure.2 Previous work has demonstrated that opioids blunt the increase in MV that normally occurs with hypercapnia (excessive carbon dioxide in the bloodstream) and that opioid antagonists can reverse this effect.3-7 After 10 minutes of breathing the hypercapnic gas mixture, subjects were administered a loading dose of remifentanil followed by a continuous infusion of remifentanil to maintain steady state plasma concentrations. After 25 minutes, the subjects were administered a single dose of either intranasal OPVEE 2.7 mg or intranasal naloxone 4 mg and MV was monitored. The primary objectives were to demonstrate noninferiority at the primary endpoint of 5 minutes after antagonist exposure of IN nalmefene to reverse remifentanil-induced reductions in MV and to determine the tolerability of IN nalmefene during remifentanil infusion. Of the 69 subjects who received a single dose of either IN nalmefene or IN naloxone, a total of 52 subjects received both treatments and data was collected at the primary endpoint in 50 subjects. About OPVEE ® OPVEE (nalmefene) nasal spray INDICATION OPVEE nasal spray is an opioid antagonist indicated for the emergency treatment of known or suspected overdose induced by natural or synthetic opioids in adults and pediatric patients aged 12 years and older, as manifested by respiratory and/or central nervous system depression. OPVEE nasal spray is intended for immediate administration as emergency therapy in settings where opioids may be present. OPVEE nasal spray is not a substitute for emergency medical care. HIGHLIGHTED SAFETY INFORMATION CONTRAINDICATIONS Hypersensitivity to nalmefene or to any of the other ingredients. WARNINGS AND PRECAUTIONS Risk of Recurrent Respiratory and Central Nervous System Depression: While the duration of action of nalmefene is as long as most opioids, a recurrence of respiratory depression is possible, therefore, keep patient under continued surveillance and administer repeat doses of OPVEE using a new nasal spray with each dose, as necessary, while awaiting emergency medical assistance. Limited Efficacy with Partial Agonists or Mixed Agonist/Antagonists: Reversal of respiratory depression caused by partial agonists or mixed agonists/antagonists, such as buprenorphine and pentazocine, may be incomplete. Larger or repeat doses may be required. Precipitation of Severe Opioid Withdrawal: Use in patients who are opioid dependent may precipitate opioid withdrawal. In neonates, opioid withdrawal may be life-threatening if not recognized and properly treated. Monitor for the development of opioid withdrawal. Risk of Cardiovascular (CV) Effects: Abrupt postoperative reversal of opioid depression may result in adverse CV effects. These events have primarily occurred in patients who had preexisting CV disorders or received other drugs that may have similar adverse CV effects. Monitor these patients closely in an appropriate healthcare setting after use of nalmefene hydrochloride. Risk of Opioid Overdose from Attempts to Overcome the Blockade: Attempts to overcome opioid withdrawal symptoms caused by opioid antagonists with high or repeated doses of exogenous opioids may lead to opioid intoxication and death. ADVERSE REACTIONS Most common adverse reactions (incidence at least 2%) are nasal discomfort, headache, nausea, dizziness, hot flush, vomiting, anxiety, fatigue, nasal congestion, throat irritation, rhinalgia, decreased appetite, dysgeusia, erythema, and hyperhidrosis. For more information about OPVEE and the full Prescribing Information visit . About Indivior Indivior is a global pharmaceutical company working to help change patients' lives by developing medicines to treat substance use disorders (SUD) and serious mental illnesses. Our vision is that all patients around the world will have access to evidence-based treatment for the chronic conditions and co-occurring disorders of SUD. Indivior is dedicated to transforming SUD from a global human crisis to a recognized and treated chronic disease. Building on its global portfolio of opioid use disorder treatments, Indivior has a pipeline of product candidates designed to both expand on its heritage in this category and potentially address other chronic conditions and co-occurring disorders of SUD, including alcohol use disorder and cannabis use disorder. Headquartered in the United States in Richmond, VA, Indivior employs more than 1,100 individuals globally and its portfolio of products is available in 37 countries worldwide. Visit to learn more. Connect with Indivior on LinkedIn by visiting . References Ahmad FB, Cisewski JA, Rossen LM, Sutton P. Provisional drug overdose death counts. National Center for Health Statistics. July 2023. Accessed February 8, 2024, from Palkovic B, Marchenko V, Stuth EA, Stucke AG. Multi-level regulation of opioid-induced respiratory depression. Physiology. 2020; 35(6):391-404. Rawat, D., Modi, P., & Sharma, S. (2023). Hypercapnea. In StatPearls. StatPearls Publishing. Accessed February 15, 2024, from Gelberg J, Jonmarker C, Stenqvist O, Werner O. Intravenous boluses of fentanyl, 1 μg kg-1, and remifentanil, 0.5 μg kg-1, give maximum ventilatory depression in awake volunteers. Brit. J. Anaes. 2012; 108(6):1028-34. Webster L, Hansen E, Stoddard G, Rynders A, Ostler D, Lennon H. Ventilatory response to hypercapnia as experimental model to study effects of oxycodone on respiratory depression. Curr. Rev. Clin. Exper. Pharmacol. 2021; 16:1-9. Glass PS, Iselin-Chaves IA, Goodman D, Delong E, Hermann DJ. Determination of the potency of remifentanil compared with alfentail using ventilatory depression as the measure of opioid effect. Anesthesiol. 1999; 90(6):1556-1563. Dahan A, Aarts L, Smith T. Incidence, reversal and prevention of opioid-induced respiratory depression. Anesthes. 2010; 112(1):226-238. Glass, P, Jhaveri, R, Smith, L. Comparison of potency and duration of action of nalmefene and naloxone. Anesth. Analg., 1994; 78(3):536-541. Konieczko K, Jones J, Barrowcliffe M, Jordan C, Altman, D. Antagonism of morphine-induced respiratory depression with nalmefene. Br. J. Anaesth. 1988; 61(3):318-323. SOURCE Indivior PLC