cebranopadol (TRN-228) / Grunenthal, Tris Pharma - LARVOL DELTA

Respiratory and antinociceptive effects of NOP-MOP agonist cebranopadol versus full opioid receptor agonist oxycodone: a comparison in healthy volunteers. (PubMed, Anesthesiology) - "The primary endpoint showed separation between the respiratory effects of cebranopadol and oxycodone, with 25% less respiratory depression at equianalgesia, as observed in the pharmacokinetic/pharmacodynamic analysis."

Clinical • Journal • CNS Disorders • Depression • Pain • Psychiatry

Efficacy and safety cebranopadol, a first-in-class, dual NMR agonist in patients with pain due to diabetic peripheral neuropathy (NeuPSIG 2025) - "This study evaluates the analgesic efficacy and safety of once-daily oral cebranopadol at different doses compared to placebo and pregabalin in patients with moderate to severe chronic pain due to DPN. This was a randomized, multi-site, double-blind, placebo- and active-controlled, parallel-group, dose-ranging Phase 2 trial. Cebranopadol demonstrated clinically meaningful analgesic efficacy in patients with painful DPN. Cebranopadol's mechanism of action as a dual-NMR agonist highlights its potential as a promising potential treatment option for neuropathic pain. Additional studies with longer treatment durations and personalized titration protocols are warranted to maximize the therapeutic benefits of cebranopadol while minimizing adverse effects."

Clinical • Addiction (Opioid and Alcohol) • CNS Disorders • Pain • Peripheral Neuropathic Pain

Efficacy and safety cebranopadol, a first-in-class, dual NMR agonist in patients with pain due to diabetic peripheral neuropathy (NeuPSIG 2025) - "This study evaluates the analgesic efficacy and safety of once-daily oral cebranopadol at different doses compared to placebo and pregabalin in patients with moderate to severe chronic pain due to DPN. This was a randomized, multi-site, double-blind, placebo- and active-controlled, parallel-group, dose-ranging Phase 2 trial. Cebranopadol demonstrated clinically meaningful analgesic efficacy in patients with painful DPN. Cebranopadol's mechanism of action as a dual-NMR agonist highlights its potential as a promising potential treatment option for neuropathic pain. Additional studies with longer treatment durations and personalized titration protocols are warranted to maximize the therapeutic benefits of cebranopadol while minimizing adverse effects."

Clinical • Addiction (Opioid and Alcohol) • CNS Disorders • Pain • Peripheral Neuropathic Pain

Results of a Randomized, Placebo-Controlled, Phase 3 Trial of Cebranopadol for the Treatment of Acute Pain After Abdominoplasty (PAINWeek 2025) - "Rescue medications included IV morphine for the first 24 hours following study drug administration followed by oral oxycodone thereafter. A total of 300 subjects were included in the study (400µg/400µg: n=101; 400µg/200µg: n=98; placebo: n=101). Subjects were predominantly female (98.7%) ranging in age from 22 to 68 years. Baseline characteristics were generally comparable between groups."

Clinical • P3 data • Addiction (Opioid and Alcohol) • CNS Disorders • Depression • Pain • Psychiatry

A Study to Assess the Abuse Potential of Intranasal Cebranopadol (clinicaltrials.gov) - P1 | N=48 | Completed | Sponsor: Tris Pharma, Inc. | Active, not recruiting ➔ Completed | Trial completion date: Mar 2025 ➔ Nov 2024

Trial completion • Trial completion date • Addiction (Opioid and Alcohol)

(Scientific Abstract Presentation) Results of a Randomized, Placebo-Controlled, Phase 3 Trial of Cebranopadol for the Treatment of Acute Pain After Abdominoplasty (PAINWeek 2025) - "Sponsored By TRIS PHARAMA This presentation is sponsored by Tris Pharma and is not certified for credit."

Clinical • P3 data • CNS Disorders • Pain

Narcotics through time: exploring historical origins, synthetic advances, and clinical progress. (PubMed, Future Med Chem) - "Key transitions from traditional opioids to synthetic compounds such are explored, alongside novel clinical advancements like Oliceridine (TRV-130), NKTR-181, and Cebranopadol, which demonstrate promising analgesic efficacy with fewer adverse effects. Additionally, recent preclinical studies on synthetic mu-opioid receptor agonists and dual-receptor targeting compounds are discussed for their therapeutic potential. Overall, ongoing research into safer and more effective synthetic opioids offers a hopeful path forward in advancing analgesic therapy."

Journal • Review • Addiction (Opioid and Alcohol) • CNS Disorders • Pain • Psychiatry

A Double-Blind, Randomized, Crossover Study to Assess the Abuse Potential of Intranasal Cebranopadol Compared to Oxycodone and Placebo in Healthy, Nondependent Recreational Opioid Users (CPDD 2025) - "Crushed cebranopadol had significantly lower intranasal abuse potential compared with crushed oxycodone, a Schedule II opioid, in nondependent, recreational opioid users. The onset of drug liking and pharmacokinetics was notably delayed with intranasal cebranopadol vs. intranasal oxycodone."

Clinical • Late-breaking abstract • Addiction (Opioid and Alcohol) • CNS Disorders

Abuse Potential Assessment of Cebranopadol, a Novel Dual Nociceptin (NOP) and Mu Opioid (MOP) Receptor (NMR) Agonist: Implications for Scheduling (CPDD 2025) - " In the drug discrimination procedure, cebranopadol showed dose-dependent generalization to morphine; however, effects were antagonized by naloxone (MOP antagonist) and enhanced by J-11397 (NOP antagonist), indicating NOP activity reduces its MOP agonist properties...In recreational opioid users, cebranopadol at doses up to 2.5 times the anticipated maximum therapeutic dose showed lower abuse potential compared with Schedule II (hydromorphone, oxycodone) and Schedule IV (tramadol) opioids... The overall abuse potential of cebranopadol is less than Schedule II and IV full and partial MOP agonists, suggesting a less restrictive schedule than Schedule II is appropriate."

Addiction (Opioid and Alcohol) • CNS Disorders • Depression • Pain • Psychiatry

RESULTS OF A RANDOMIZED, PLACEBO-CONTROLLED, PHASE 3 TRIAL OF CEBRANOPADOL FOR THE TREATMENT OF ACUTE PAIN AFTER ABDOMINOPLASTY (ASRA-SPRING 2025) - "Ondansetron 4mg was administered for prophylaxis of nausea and vomiting with the possibility of a supplementary dose. Rescue medications included IV morphine for the first 24 hours following study drug administration followed by oral oxycodone thereafter...Cebranopadol, a novel analgesic with a unique dual mechanism of action as a nociceptin/orphanin FQ peptide (NOP) receptor and mu-opioid receptor agonist, demonstrates a more promising balance of efficacy and safety in treating moderate to severe acute pain. This study highlights cebranopadol’s potential to become a valuable new therapy for acute pain management."

Clinical • P3 data • Addiction (Opioid and Alcohol) • Aesthetic Medicine • Anesthesia • CNS Disorders • Constipation • Depression • Gastroenterology • Gastrointestinal Disorder • Pain • Psychiatry

LIMITED ABUSE POTENTIAL OF CEBRANOPADOL, A NOVEL POTENT ANALGESIC, COMPARED TO TRAMADOL AND OXYCODONE IN RECREATIONAL OPIOID USERS (ASRA-SPRING 2025) - "This study confirms what has previously been established while furthering the understanding of the abuse potential of cebranopadol. Cebranopadol may serve as a much-needed alternative treatment option for patients with moderate to severe pain."

Addiction (Opioid and Alcohol) • CNS Disorders • Epilepsy • Pain • Psychiatry

THE EFFECTS OF CEBRANOPADOL ON VENTILATORY DRIVE, CENTRAL NERVOUS SYSTEM, AND PAIN (ASRA-SPRING 2025) - "Taken together, the results of this and previous clinical studies, as well as results from preclinical models, provide evidence to support the likelihood a ceiling of respiratory depression exists in humans. However, these data lead us to conclude further studies are needed to fully characterize the ceiling of respiratory effects cebranopadol may exhibit."

Addiction (Opioid and Alcohol) • CNS Disorders • Depression • Pain • Psychiatry

Tris Pharma to Unveil Positive Phase 3 Results including a Strong Safety Profile Showcasing the Potential of Cebranopadol, an Investigational First-in-Class Dual-NMR Agonist for the Treatment of Pain, at the 2025 ASRA Annual Meeting (Businesswire) - "Tris Pharma...announced data from cebranopadol, the company’s investigational dual-NMR agonist for the treatment of moderate-to-severe pain, featured in three poster presentations during the 50th Annual Regional Anesthesiology and Acute Pain Medicine Meeting (ASRA), taking place May 1-3, 2025, in Orlando, Florida...The poster presentations will highlight clinical trial results demonstrating the efficacy and safety of cebranopadol, reinforcing its potential as a much-needed novel treatment option for patients with moderate-to-severe acute pain. Tris Pharma will also host a symposium focused on dual-NMR agonism, a promising new mechanism of action in treating pain. Dual-NMR agonists have the potential to treat moderate-to-severe pain as effectively as opioids, and due to its novel mechanism, it can potentially do so with significantly lower risks of abuse, addiction and overdose."

Clinical data • Addiction (Opioid and Alcohol) • Pain

ALLEVIATE-2 Phase 3 Results: Significant Pain Reduction in Cebranopadol-Treated Patients Following Bunionectomy Surgery (Businesswire) - P3 | N=240 | ALLEVIATE-2 (NCT06423703) | Sponsor: Tris Pharma, Inc | "Tris plans to submit New Drug Application to FDA in 2025..."The results of the ALLEVIATE-2 clinical study achieved its primary endpoint of demonstrating a statistically significant reduction in pain intensity as measured using the Pain Numeric Rating Scale (NRS) Area Under the Curve for two to 48 hours (AUC2-48) following dosing. Specifically, treatment with oral cebranopadol 400 µg once per day resulted in a statistically significant reduction in pain intensity compared to placebo...Additionally, cebranopadol was generally well tolerated and exhibited a favorable safety profile, with no serious adverse events observed. The most common adverse event was nausea."

FDA filing • P3 data • Pain

Additional Results From the ALLEVIATE-1 Phase 3 Trial in Patients Following Abdominoplasty Surgery (Businesswire) - P3 | N=300 | ALLEVIATE1 (NCT06545097) | Sponsor: Tris Pharma, Inc | "Furthermore, results from the ALLEVIATE-1 clinical trial demonstrated that cebranopadol-treated patients also required significantly fewer doses of rescue medication than patients receiving placebo (LS mean difference of 2.2; p<0.001)."

P3 data • Pain

In Q1 2025, Tris also plans to share results evaluating cebranopadol in two additional studies… (Businesswire) - "In Q1 2025, Tris also plans to share results evaluating cebranopadol in two additional studies, an intranasal human abuse potential study and ALLEVIATE-2, a Phase 3 clinical study in patients following bunionectomy, with an NDA submission expected later this year. Tris plans to conduct cebranopadol studies in multiple chronic pain indications beginning in the second half of 2025."

FDA filing • New trial • P1 data • Pain

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 Pain (Businesswire) - P3 | N=300 | ALLEVIATE1 (NCT06545097) | Sponsor: Tris Pharma, Inc. | "Specifically, treatment with cebranopadol 400 µg once per day for two days resulted in a statistically significant reduction in pain intensity compared to placebo (LS Mean difference [SE] of 59.2 [14.36]; p<0.001). Additionally, cebranopadol was generally well tolerated and exhibited a favorable safety profile that was comparable to placebo, with no serious adverse events related to cebranopadol...Tris plans to submit full results from the ALLEVIATE-1 abdominoplasty clinical trial for presentation at an upcoming medical congress."

P3 data • Pain

ALLEVIATE-1: A Study of Cebranopadol for the Treatment of Acute Pain After Abdominoplasty (clinicaltrials.gov) - P3 | N=300 | Active, not recruiting | Sponsor: Tris Pharma, Inc. | Not yet recruiting ➔ Active, not recruiting | Trial primary completion date: Apr 2025 ➔ Dec 2024

Enrollment closed • Trial primary completion date • Aesthetic Medicine • Pain

ALLEVIATE-2: A Study of Cebranopadol for the Treatment of Acute Pain After Bunionectomy (clinicaltrials.gov) - P3 | N=240 | Recruiting | Sponsor: Tris Pharma, Inc. | Not yet recruiting ➔ Recruiting | Trial completion date: Dec 2024 ➔ Mar 2025 | Trial primary completion date: Nov 2024 ➔ Feb 2025

Enrollment open • Trial completion date • Trial primary completion date • Pain

A Study to Assess the Abuse Potential of Intranasal Cebranopadol (clinicaltrials.gov) - P1 | N=45 | Active, not recruiting | Sponsor: Tris Pharma, Inc. | Not yet recruiting ➔ Active, not recruiting

Enrollment closed • Addiction (Opioid and Alcohol)

Drugs in Development to Manage Acute Pain. (PubMed, Drugs) - "These agents include VX-548 (Suzetrigine), Cebranopadol, AAT-076, Combogesic intravenous (IV), sublingual ketamine, XG004 (naproxen/pregabalin conjugate), and HTX-011 (Zynrelef). We analyze the pharmacodynamics, pharmacokinetics, development status, and clinical implications of these drugs, emphasizing the importance of finding an agent that provides both a strong safety profile and effective relief from acute pain. Our findings show promise but also highlight the need for further large-scale research to allow these drugs to be utilized in a clinical context for patients experiencing acute pain."

Journal • Review • Pain

The Effects of Cebranopadol on Ventilatory Drive, Central Nervous System, and Pain (PAINWeek 2024) - "Although all doses of cebranopadol administered in the study had a greater analgesic potency than either dose of oxycodone, the PK/PD results were able to establish a model to compare respiratory depression at equianalgesic doses. The extensive PK/PD analysis highlighted cebranopadol's advantages over oxycodone, showing approximately 25% less respiratory depression for equivalent analgesia, attributed to NOP activation. In addition, cebranopadol featured prolonged analgesic effects, with a gradual onset and offset, and a longer time to peak impact on respiratory and pain parameters compared to oxycodone.Special consideration was given to safety parameters related to respiratory function (e.g., apnea/decreased saturation), which were significantly more frequent after oxycodone 60mg than any other treatment, occurring approximately 2 to 3 times more often."

Addiction (Opioid and Alcohol) • CNS Disorders • Depression • Pain • Psychiatry

Cebranopadol effects on ventilatory drive, central nervous system, and pain (PAINWeek 2024) - "Sponsored By Tris Pharma This session is not certified for credit"

CNS Disorders • Pain

Findings Presented at PAINWeek 2024 Demonstrate Tris Pharma’s Investigational, First-in-Class Therapy Cebranopadol Provides Potent, Prolonged Pain Relief with Improved Safety Over Oxycodone (Businesswire) - "Tris Pharma, Inc...announced that data from a clinical study of cebranopadol suggest the investigational pain therapy produces potent and prolonged analgesia with 25% less respiratory depression than oxycodone....The findings will be shared in a poster presentation on September 4, 2024, at the 2024 PAINWeek conference in Las Vegas....At equianalgesic doses, cebranopadol produces 25% less respiratory depression compared to oxycodone. Treatment with cebranopadol presents a significantly longer time to impact on respiratory parameters compared to oxycodone, allowing for the gradual accumulation of arterial CO2 and mitigating the full manifestation of respiratory depression. Cebranopadol achieved prolonged analgesic effects with gradual onset and offset."

Clinical data • Back Pain • Immunology • Pain

Tris Pharma Initiates ALLEVIATE-1 and ALLEVIATE-2, Pivotal Phase 3 Trials Investigating Cebranopadol, a First-in-Class Compound with a Novel Mechanism of Action to Treat Pain (Businesswire) - "Tris Pharma, Inc...announced today the initiation of ALLEVIATE-1 and ALLEVIATE-2, pivotal Phase 3 trials evaluating the efficacy and safety of cebranopadol for the treatment of moderate-to-severe acute pain....Together, the studies will enroll more than 500 patients at clinical trial sites in the United States. The results of these registrational studies will be part of the New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) for the approval of cebranopadol."

Trial status • Pain