– Study met primary endpoint demonstrating cebranopadol is significantly less abusable than oxycodone when taken intranasally (i.e., snorted) with majority of patients indicating no desire to take cebranopadol again –
– Results are similar to previously announced abusability data from oral administration of cebranopadol compared to oxycodone and tramadol –
– Results highlight novel mechanism of action of cebranopadol, a dual-NMR agonist, where NOP receptor activation minimizes the potential abusability associated with MOP receptor agonists, while still achieving significant pain management comparable to opioids –
MONMOUTH JUNCTION, N.J.--(BUSINESS WIRE)--Tris Pharma, Inc. (Tris), a commercial-stage biopharmaceutical company, today announced positive clinical data from its intranasal human abuse potential (HAP) study in subjects who are nondependent recreational opioid users, which demonstrate that cebranopadol, an investigational, first-in-class oral dual-nociceptin/orphanin FQ peptide (NOP) receptor and µ-opioid peptide (MOP) receptor (dual-NMR) agonist being developed for the treatment of moderate-to-severe pain, is significantly less likeable when crushed and taken intranasally (i.e., snorted) than oxycodone.
These results add to the growing body of data underscoring the promising safety profile, minimal abusability and potent efficacy of cebranopadol, which acts via dual-NMR agonism. Cebranopadol has the potential to deliver highly potent analgesia comparable to those of opioids with minimized risk of significant side effects, dependence and addiction by leveraging the body’s pain biology modulation processes, synergizing the well-understood analgesic properties of the MOP receptor with the novel analgesic and safety characteristics of the NOP receptor.
“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,” said Ketan Mehta, founder and CEO of Tris Pharma. “We are excited by these results, which coupled with our recent positive topline data from the pivotal Phase 3 ALLEVIATE-1 study, help to solidify cebranopadol’s potential to transform pain management.”
The results of this clinical study demonstrated statistically significant less drug liking for cebranopadol at a supratherapeutic dose of 1000 µg, which is 2.5 times higher than the proposed therapeutic dose for the treatment of pain. This was determined by measuring the maximum drug liking using a Visual Analog Scale (VAS Emax) compared to oxycodone 40 mg (difference of 24.8, P-value=<0.001, see Figure 1). In addition, secondary endpoints designed to measure positive subjective effects of the drugs were met, showing a large disparity between cebranopadol and oxycodone, including the key secondary endpoints of “take drug again” and “overall drug liking”.
These results show that cebranopadol is neither more rapidly absorbed, nor does it produce greater liking when taken via intranasal administration compared to oral administration.
A Comparison of Cebranopadol Oral HAP and Intranasal HAP Clinical Studies
A prior oral HAP study demonstrated the significantly lower oral abuse potential of cebranopadol compared to oxycodone (Schedule II opioid) and tramadol (Schedule IV opioid). In comparing both the oral HAP and intranasal HAP study results, the mean and median VAS Emax numerically decreased for cebranopadol between the two studies (69.2 to 67.3 and 68.0 to 60.5 for mean and median, respectively; see Table 1), and peak effects occurred hours after administration in both studies. This is in sharp contrast to oxycodone 40 mg, which saw an increase in drug liking when administered intranasally (83.9 to 92.1 and 85.0 to 100.0 for mean and median, respectively) and a rapid onset of effect. Additionally, the effects of cebranopadol were experienced at a slower rate when administered intranasally than orally, suggesting that cebranopadol is not absorbed significantly via the nasal mucosa, but is instead likely absorbed via the stomach when administered intranasally.
Table 1. Mean “Drug Liking” (At This Moment) VAS Scores for Both Intranasal and Oral HAP Studies
| INTRANASAL HAP | ORAL HAP | |||||
| Cebranopadol 1000 ug N= 36 | Oxycodone 40 mg N= 36 | Placebo N= 36 | Cebranopadol 1000 ug N= 33 | Oxycodone HCl 40 mg N= 33 | Tramadol HCl 600 mg N= 31 | Placebo N= 35 |
Mean (SD) | 67.3 (19.33) | 92.1 (11.37) | 53.8 (11.76) | 69.2 (15.72) | 83.9 (15.44) | 75.4 (18.99) | 51.3 (4.46) |
Median | 60.5 | 100.0 | 50.0 | 68.0 | 85.0 | 76.0 | 50.0 |
A comparison of the pharmacokinetic results from the two trials shows that intranasal administration of cebranopadol did not result in more rapid uptake into the bloodstream. In the intranasal study, peak plasma levels for cebranopadol occurred at approximately six hours after administration, compared to approximately five hours when administered orally. This contrasts with oxycodone, which reached peak levels after approximately 33 minutes when taken intranasally, and about one and a half hours when taken orally.
“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. This study’s findings demonstrate considerable promise of cebranopadol for treating moderate-to-severe acute pain, with markedly reduced addictive potential compared to classical opioids,” said Mark Greenwald, Ph.D., professor and associate chair for research, Wayne State University Department of Psychiatry and Behavioral Neurosciences, who conducts research in opioid addiction but was not involved in this trial. “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.”
Tris plans to submit full results from this trial for presentation at an upcoming medical congress. Tris recently shared positive topline results from the pivotal Phase 3 ALLEVIATE-1 clinical study for the treatment of pain in patients following abdominoplasty surgery. In Q1 2025, Tris also plans to share results evaluating cebranopadol in the pivotal Phase 3 ALLEVIATE-2 clinical study for the treatment of pain in patients following bunionectomy, with a New Drug Application (NDA) submission expected later this year. Tris plans to conduct cebranopadol studies in multiple chronic pain indications beginning in the second half of 2025.
Design of the Intranasal Human Abuse Study
The cebranopadol intranasal HAP study was a Phase 1 single-dose, randomized, double-blind, three-way crossover study designed to evaluate the intranasal pharmacokinetics and abuse potential of a supratherapeutic dose of cebranopadol in adult nondependent recreational opioid users versus placebo and the commonly used opioid, oxycodone, a Schedule II narcotic. Eligible participants randomly received a single intranasal dose of crushed placebo, cebranopadol 1000 μg, or oxycodone IR 40 mg. Abuse potential was determined based on participant-reported likeability using a 100-point VAS with 50 being neutral and numbers greater than 50 indicating liking.
About Cebranopadol (TRN-228)
Cebranopadol is a first-in-class investigational therapy that targets two key receptors, the nociceptin/orphanin FQ peptide (NOP) and µ-opioid peptide (MOP) receptors (a dual-NMR agonist), for the treatment of moderate-to-severe pain, as well as opioid use disorder (OUD). These receptors are partially homologous to each other, and they play both complementary and distinct roles in modulating pain biology pathways. Studied in over 32 clinical trials in over 2,200 patients, cebranopadol’s profile has been well-characterized in pain management studies. It has demonstrated positive clinical results in acute pain, chronic pain and diabetic neuropathic pain with a favorable safety profile. The FDA granted Fast Track Designation to cebranopadol for chronic low back pain, and if approved, it could become the first dual-NMR pain-relief therapy with the demonstrated ability to provide efficacy equivalent to opioids with less potential for misuse or risk of physical dependence, addiction or overdose.
Cebranopadol’s novel mechanism of action has potential in treating patients with substance use disorders. Tris plans to continue to evaluate cebranopadol’s potential to help patients break the cycle of opioid addiction. The National Institute on Drug Abuse (NIDA), part of the National Institutes of Health (NIH), has awarded Tris a five-year grant of up to $16.6 million to study cebranopadol’s potential to treat OUDs and SUDs.
About Tris Pharma
Tris Pharma is a privately held, innovation-driven biopharmaceutical company that is applying its drug development capabilities and proprietary technologies to transform the treatment of ADHD, pain, addiction and disorders of the central nervous system. Tris is an established commercial organization with a robust portfolio of best-in-class ADHD products and a promising pipeline of differentiated, near-term drug candidates. More information is available at www.trispharma.com and on LinkedIn @TrisPharma.
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