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

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

1. 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. https://doi.org/10.1016/j.nsa.2024.104053. Epub ahead of print.
2. 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. https://doi.org/10.1111/j.1460-9568.2012.08013.x    
3. 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. https://doi.org/10.1016/j.brainres.2019.146461 
4. 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. https://doi.org/10.1038/s41386-019-0420-x
5. 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)

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SOURCE Indivior PLC