Tris Pharma's Cebranopadol Shows Low Potential for Misuse in Intranasal Human Abuse Potential Study

Tris Pharma, Inc. announced positive results from an intranasal human abuse potential (HAP) study demonstrating that cebranopadol, an investigational first-in-class dual-NMR agonist for the treatment of moderate-to-severe pain, is significantly less “likeable” when crushed and taken intranasally than oxycodone, an outcome suggesting low potential for abuse, the company said.1

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The study met its primary endpoint, with participants indicating a significantly lower preference for cebranopadol compared to oxycodone (likability difference of 24.8, P <.001), and the majority of participants expressed no desire to take cebranopadol again.1 These findings are consistent with previously announced data on the lower abuse potential of cebranopadol when taken orally compared to oxycodone and tramadol.2

Cebranopadol is an investigational therapy targeting both the nociceptin/ orphanin FQ peptide (NOP) and µ-opioid peptide (MOP) receptors, a mechanism designed to provide potent pain relief while minimizing the abuse potential and side effects typically associated with opioid analgesics, according to the Tris announcement. The activation of the NOP receptor has been shown to counteract the addictive properties of MOP receptor activation, offering a potentially safer alternative to opioid analgesics for individuals with moderate-to-severe pain.1

Intranasal Route and Likability

The intranasal HAP study was a Phase 1, single-dose, randomized, double-blind, 3-way crossover trial conducted in nondependent recreational opioid users. The primary objective was to evaluate the intranasal pharmacokinetics (PK) and abuse potential of the dual NMR agonist.1

Participants received a single intranasal dose of crushed cebranopadol 1000 μg, oxycodone immediate release 40 mg, or placebo. The supratherapeutic dose of cebranopadol is 2.5 times higher than the therapeutic dose being proposed for treatment of pain, according to Tris. Drug likeability was measured using maximum drug liking on a 100-point Visual Analog Scale (VAS Emax), where 50 is neutral and higher scores indicate increased preference. The mean VAS Emax score for cebranopadol was significantly lower than that for oxycodone (67.3 vs 92.1, respectively), with a median score of 60.5 for cebranopadol compared to 100.0 for oxycodone.1

Additionally, when researchers compared the PK results from this intranasal HAP study with findings from a previous oral HAP trial, intranasal administration did not lead to more rapid absorption than oral administration, with peak plasma levels occurring approximately 6 hours and 5 hours post-administration, respectively. In contrast, oxycodone reached peak levels after approximately 33 minutes when administered intranasally. When taken orally, oxycodone reaches peak plasma levels in about 90 minutes, according to the Tris announcement.1

“These extremely encouraging results validate the novel profile of cebranopadol, a dual-NMR agonist, whereby NOP receptor agonism minimizes side effects of MOP receptor agonism without interfering with pain relief,” Mark Greenwald, PhD, professor and associate chair for research at Wayne State University Department of Psychiatry and Behavioral Neurosciences, said in the news release.

“Some people misuse opioids intranasally to generate a faster and more intense high compared to the oral route, which can be a precursor to using other opioids such as heroin or fentanyl, or the injection route. These results suggest that opioid misusers would be unlikely to do that with cebranopadol.” Greenwald conducts research in opioid addiction but was not involved in the current study.1

Oral vs Intranasal Abuse Potential

Results from the intranasal HAP study align with prior findings from an oral HAP study, which demonstrated significantly lower abuse potential with cebranopadol compared to oxycodone (schedule II) and tramadol (schedule IV).2 In that study, mean and median VAS Emax scores for cebranopadol were 69.2 and 68.0, respectively, compared to 83.9 and 85.0 for oxycodone and 75.4 and 76.0 for tramadol. Unlike oxycodone, which showed an increase in likeability when administered intranasally vs orally, cebranopadol’s effects were experienced more slowly via the intranasal route, suggesting low absorption through the nasal mucosa using this delivery method and potentially reducing further its appeal for misuse, the company said.1,2

“Together with prior human abuse potential studies, these results provide strong support for the significantly lower abusability of cebranopadol compared to existing therapies that treat moderate-to-severe pain, including opioids,” Ketan Mehta, founder and CEO of Tris Pharma, stated in the release. “Coupled with our recent positive topline data from the pivotal Phase 3 ALLEVIATE-1 study, [these results] help to solidify cebranopadol’s potential to transform pain management.”1

Cebranopadol has been studied in over 32 clinical trials involving more than 2200 participants and has demonstrated efficacy in acute pain, chronic pain, and diabetic neuropathic pain. It has received FDA Fast Track Designation for chronic low back pain and, if approved, could become the first dual-NMR therapy with comparable efficacy to opioids but with a reduced risk of misuse, dependence, and overdose.

Tris Pharma plans to present full results from this study at an upcoming medical congress and anticipates releasing topline results from the phase 3 ALLEVIATE-2 study in the first quarter of 2025, with a New Drug Application submission expected later this year.1

References
1. Tris Pharma announces positive clinical results of intranasal human abuse potential study indicating low abusability of cebranopadol, an investigational, first-in-class oral dual-NMR agonist for the treatment of moderate-to-severe pain. News release. Tris Pharma. January 28, 2025. Accessed January 29, 2025.https://www.businesswire.com/news/home/20250128250701/en/Tris-Pharma-Reports-Positive-Clinical-Results-of-Intranasal-Human-Abuse-Potential-Study-Indicating-Low-Abusability-of-Cebranopadol-an-Investigational-First-in-Class-Oral-Dual-NMR-Agonist-for-the-Treatment-of-Moderate-to-Severe-Pain
2. Jennings S. Topline data suggest novel pain therapy cebranopadol has significantly less potential for abuse compared to tramadol, oxycodone. Patient Care Online. December 19, 2022. https://www.patientcareonline.com/view/topline-data-suggests-novel-pain-therapy-cebranopadol-has-significantly-less-potential-for-abuse-compared-to-tramadol-oxycodone