Indivior Announces Publication Demonstrating that OPVEE® (nalmefene) Nasal Spray Rapidly Reverses Effects of Opioid-Induced Respiratory Depression in Head-to-Head Study Against Intranasal Naloxone

• 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 (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 www.opvee.com.

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 www.indivior.com to learn more. Connect with Indivior on LinkedIn by visiting www.linkedin.com/company/indivior.

References

1. 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 https://www.cdc.gov/nchs/nvss/vsrr/drug-overdose-data.htm
2. Palkovic B, Marchenko V, Stuth EA, Stucke AG. Multi-level regulation of opioid-induced respiratory depression. Physiology. 2020; 35(6):391-404.
3.  Rawat, D., Modi, P., & Sharma, S. (2023). Hypercapnea. In StatPearls. StatPearls Publishing. Accessed February 15, 2024, from https://pubmed.ncbi.nlm.nih.gov/29763188/ 
4. 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.
5. 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.
6. 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.
7. Dahan A, Aarts L, Smith T. Incidence, reversal and prevention of opioid-induced respiratory depression. Anesthes. 2010; 112(1):226-238.
8. Glass, P, Jhaveri, R, Smith, L. Comparison of potency and duration of action of nalmefene and naloxone. Anesth. Analg., 1994; 78(3):536-541.
9. 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.

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