FDA Submission Planned for Nonopioid Cebranopadol Following Positive Phase 3 Results: Tris Pharma Update

The investigational nonopioid analgesic cebranopadol was associated with a statistically significant and high level of pain reduction compared to placebo in adults undergoing bunionectomy, satisfying the primary endpoint of the pivotal ALLEVIATE-2 phase 3 clinical trial, according to developer Tris Pharma. In a post-hoc analysis of the results, cebranopadol showed greater analgesic efficacy than the opioid comparator, oxycodone immediate release (IR) 10 mg, widely used for moderate-to-severe acute pain.

The positive ALLEVIATE-2 findings add to similarly promising data from the ALLEVIATE-1 phase 3 trial announced in January and complete the full phase 3 development program for cebranopadol, a first-in-class oral dual nociceptin/orphanin FQ peptide (NOP) receptor and µ-opioid peptide (MOP) receptor agonist (dual-NMR agonist). Cebranopadol shows promise to offer opioid-level analgesia with a reduced risk of adverse effects, misuse, and dependence, the company said in a statement. Tris plans to submit a New Drug Application to FDA in 2025.

“Both the ALLEVIATE-1 and -2 trials, as well as promising results from previous human abuse potential studies, demonstrate cebranopadol’s potential to fill this unmet need for patients suffering from moderate-to-severe acute pain,” Jeff Gudin, MD, anesthesiologist at the University of Miami, Miller School of Medicine, said in the Tris statement. “The strong analgesic effect, exceeding that observed with oxycodone in the bunionectomy study, coupled with low abuse potential, demonstrates the power of agonizing the NOP/MOP receptor system, which represents a breakthrough in our understanding of pain biology.”

In the multicenter randomized double-blind and active-controlled ALLEVIATE-2 study, postoperative pain was assessed using the Pain Numeric Rating Scale (NRS) Area Under the Curve for 2 to 48 hours (AUC2-48) after dosing. Study participants who received cebranopadol 400 µg once daily experienced a statistically significant reduction in pain intensity compared to placebo (LS Mean difference 56.1; P <.001). Oxycodone IR 10 mg, given 4 times daily in a separate arm of the study, also reduced pain compared to placebo but exhibited a lower magnitude of pain relief than cebranopadol (LS Mean Difference -27.0; P =.054).

“The strong analgesic effect, exceeding that observed with oxycodone in the bunionectomy study, coupled with low abuse potential, demonstrates the power of agonizing the NOP/MOP receptor system, which represents a breakthrough in our understanding of pain biology.”

Over the 7-day study period, more than half (57.7%) of cebranopadol-treated participants did not require use of rescue medication compared to approximately one-quarter (28.4%) of those treated with placebo (P <.001). When rescue medication was required, total doses were also lower in the cebranopadol group (LS mean difference 7.8; P =.004), Tris Pharma reported.

Cebranopadol was well tolerated, with the most common adverse event reported being nausea. There were no serious adverse events reported.

“These are extremely encouraging results that emphasize the important role dual-NMR drugs could play in treating moderate-to-severe acute pain with much lower risk of the misuse, physical dependence, addiction or overdose seen with opioids while still being able to provide a comparable level of analgesia,” Todd Bertoch, MD, chief medical officer for pain research at CenExel and lead investigator for the ALLEVIATE-2 study, said in the statement. “The biggest challenge in the search for new drugs for pain has been finding something safe that can treat more severe pain that today requires use of an opioid. The level of analgesia seen across both ALLEVIATE-1 and ALLEVIATE-2 as well as the safety data that has been generated suggest that cebranopadol could fulfill this urgent need.”

ALLEVIATE-1. The ALLEVIATE-1 study, which evaluated cebranopadol in adults following abdominoplasty, also met its primary endpoint, demonstrating a significant reduction in pain intensity compared to placebo. Participants treated with cebranopadol in this study also required fewer doses of rescue medication than those receiving placebo (LS mean difference 2.2; P <.001).

Rounding out the phase 3 development program alongside ALLEVIATE-1 and ALLEVIATE-2 are strong data from several human abuse potential studies showing low potential for misuse.2,3

“If approved, cebranopadol has the potential to redefine the standard of care for acute pain management, offering a first-in-kind treatment option for patients in need,” Ketan Mehta, CEO and founder of Tris Pharma, said.

Over the course of more than 32 clinical trials involving more than 2200 participants, cebranopadol has shown efficacy in acute pain, chronic pain, and diabetic neuropathic pain, and has received FDA Fast Track Designation for chronic low back pain. In addition, the investigational dual-NMR agonist has shown efficacy in treating opioid use disorder (OUD), leading to a $16.6 million grant from the National Institute on Drug Abuse to further explore its potential in substance use disorders.

References
1. Tris Pharma announces positive results from ALLEVIATE-2 phase 3 pivotal trial for cebranopadol, an investigational first-in-class oral dual-NMR agonist, for the treatment of moderate-to-severe acute pain. News release. Tris Pharma. March 6, 2025. Accessed March 12, 2025. https://www.trispharma.com/tris-pharma-announces-positive-results-from-alleviate-2-phase-3-pivotal-trial-for-cebranopadol-an-investigational-first-in-class-oral-dual-nmr-agonist-for-the-treatment-of-moderate-to-severe-acute-p/
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
3. Halsey G. Tris Pharma's cebranopadol shows low potential for misuse in intranasal human abuse potential study. Patient Care Online. January 29, 2025. https://www.patientcareonline.com/view/cebranopadol-shows-low-potential-for-misuse-in-intranasal-human-abuse-potential-study