Investigational Nonopioid Cebranopadol Meets Primary Endpoint in Pivotal Phase 3 ALLEVIATE-1 Clinical Trial

Cebranopadol developer Tris Pharma expects to submit an NDA to the FDA for the dual-NMR agonist to treat moderate-to-severe acute pain later this year.

Cebranopadol, an investigational first-in-class dual-NMR agonist for the treatment of moderate-to-severe acute pain, was associated with a statistically significant reduction in pain intensity compared to placebo following abdominoplasty surgery, according to developer Tris Pharma.1

Topline results from the pivotal phase 3 ALLEVIATE-1 clinical trial showed that participants treated with cebranopadol 400 µg once daily for 44 hours following surgery experienced a least squares mean difference of 59.2 (SE 14.36; P <.001) in pain intensity, as measured by the Pain Numeric Rating Scale (NRS) Area Under the Curve (AUC4-48), satisfying the study’s primary endpoint. Trist reported a favorable safety profile for the novel nonopioid analgesic, with tolerability comparable to placebo and no serious adverse events related to the drug. The most common adverse event was nausea.1

“These are extremely encouraging results, emphasizing the important role cebranopadol could play in effectively and safely alleviating moderate-to-severe acute pain for patients,” Harold Minkowitz, MD, primary investigator in the ALLEVIATE-1 study and president of analgesics, perioperative, and hospital-based research at Evolution Research Group, said in the Trist announcement.1

“Our team was impressed by the magnitude of analgesia seen, suggesting that cebranopadol’s novel mechanism of dual-NMR agonism has the potential to be as effective as opioids in the post-surgical setting,” he added. Combined with evidence from earlier clinical studies demonstrating low drug likability2 and the reduced potential for respiratory events, the analgesic efficacy seen in the study “demonstrate that cebranopadol could help address a critical unmet medical need for the millions of people who experience acute pain,” Minkowitz stressed.1

Secondary objectives of ALLEVIATE-1, not reported in the company press release, include assessing the analgesic efficacy of cebranopadol through use of rescue medication, early discontinuations and subject overall assessment of study medication.1

Cebranopadol, an investigational therapy with potential to be a first-in-class analgesic, targets both the nociceptin/orphanin FQ peptide (NOP) and µ-opioid peptide (MOP) receptors, described by Trist as a unique approach to pain relief. The dual-NMR mechanism combines the analgesic effects of the MOP receptor with the safety characteristics of NOP receptor activation, providing “potent” pain reduction while mitigating the risk of abuse and dependence associated with traditional opioid analgesics. The mechanism of action also reduces the risk of respiratory depression and the potential for abuse, the company stated.1

“The opioid crisis has highlighted the urgent need for pain management options that treat moderate-to-severe pain as effectively as opioids but do not carry similar risk of addiction and detrimental side effects. We believe cebranopadol has the potential to transform the treatment landscape for patients suffering from acute pain.”

“We are excited by the results from the ALLEVIATE-1 trial demonstrating a strong level of pain relief,” Ketan Mehta, founder and chief executive officer at Tris Pharma, said in the announcement. “The opioid crisis has highlighted the urgent need for pain management options that treat moderate-to-severe pain as effectively as opioids but do not carry similar risk of addiction and detrimental side effects. We believe cebranopadol has the potential to transform the treatment landscape for patients suffering from acute pain.”1

Tris Pharma intends to submit the full results from ALLEVIATE-1 for presentation at an upcoming medical congress. In the first quarter of 2025, the company plans to release data from 2 additional studies: an intranasal human abuse potential study2 and the ALLEVIATE-2 phase 3 trial, which is evaluating cebranopadol in bunionectomy patients. A New Drug Application submission is expected later this year, with additional studies planned for chronic pain indications beginning in the second half of 2025.

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, according to Trist. The therapy has received FDA Fast Track Designation for chronic low back pain, and if approved, it could become the first dual-NMR therapy to offer opioid-equivalent analgesia with a significantly lower potential for misuse, dependence, and overdose.

References
1. Tris Pharma announces positive results from ALLEVIATE-1 phase 3 clinical trial of cebranopadol, an investigational first in class oral dual-NRM agonist, for the treatment of moderate-to-severe acute pain. News release. Tris Pharma. January 22, 2025. Accessed January 29, 2025. https://www.trispharma.com/tris-pharma-announces-positive-results-from-alleviate-1-phase-3-clinical-trial-of-cebranopadol-an-investigational-first-in-class-oral-dual-nmr-agonist-for-the-treatment-of-moderate-to-severe-acute-p/
2. 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