# Clinical Evaluation of C4X3256, a Non-Opioid, Highly-Selective Orexin-1 Receptor Antagonist for the Treatment of Opioid Use Disorder

> **NIH NIH UG3** · INDIVIOR, INC. · 2020 · $2,763,621

## Abstract

Opioid use disorder (OUD) and its consequences are a major public health concern and have
recently been declared a national public health emergency. Despite the availability of medications
to treat OUD, there is a need for improved treatment modalities that involve other mechanisms of
action. Current pharmacologic treatment options all target the mu-opioid receptor, either as a full
agonist (methadone), partial agonist (buprenorphine), or antagonist (naltrexone). While these
medications have demonstrated efficacy and safety, they also have limitations. Full and partial
agonists have abuse liability, and significant levels of misuse, abuse, and diversion have been
observed in the US and internationally (Lofwall 2014; Yokell 2012). This has resulted in
restrictions on access due to a lack of waivered prescribers and patient limits on prescribing for
buprenorphine and dispensing through federally regulated opioid treatment programs requiring
daily observed buprenorphine. In addition, there are concerns about methadone overdose.
Naltrexone requires abstinence from opioids prior to initiation of treatment, which is a barrier to
treatment for many patients. Of the 2.1 million people suffering from OUD in the US, only 20%
seem to receive any form of treatment and many of those who are treated with these medications
do not achieve abstinence from opioid use and fail to achieve recovery (Saloner 2015). Thus,
there is a need for additional pharmacologic treatment options, particularly for medications without
abuse liability and that do not require completion of withdrawal from opioids prior to treatment.
Nonclinical studies support a role for the orexin system in drug seeking, as compounds that
selectively block signaling at the orexin-1 receptor (OX1R) reduce seeking of multiple drugs of
abuse (James 2017). C4X3256, a Non-Opioid, Highly-Selective OX1R Antagonist has been
shown to have a long residence time at the OX1R, and also reduce intravenous self-
administration and cue-induced reinstatement in animal models of nicotine addiction, suggesting
it could be a treatment for a range of addiction related behaviors. Studies proposed in the
application will move C4X3256 from preclinical development through Phase I testing, including
up to 7 days dosing in healthy volunteers and up to 28 days dosing in subjects with OUD. The
current toxicology studies will support the administration of C4X3256 to human volunteers for 4
weeks. Additional toxicology studies are proposed to allow for extended dosing duration in phase
II and for women of childbearing potential to participate in Phase II outpatient trials. Thus, the
clinical, preclinical and supporting pharmaceutical development studies proposed will allow
C4X3256 to move to Phase II studies.

## Key facts

- **NIH application ID:** 10023930
- **Project number:** 5UG3DA050308-02
- **Recipient organization:** INDIVIOR, INC.
- **Principal Investigator:** Christian Arthur Heidbreder
- **Activity code:** UG3 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $2,763,621
- **Award type:** 5
- **Project period:** 2019-09-30 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10023930

## Citation

> US National Institutes of Health, RePORTER application 10023930, Clinical Evaluation of C4X3256, a Non-Opioid, Highly-Selective Orexin-1 Receptor Antagonist for the Treatment of Opioid Use Disorder (5UG3DA050308-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10023930. Licensed CC0.

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