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

– Study achieved primary endpoint with cebranopadol demonstrating a statistically significant and high level of pain reduction compared to placebo –

– Cebranopadol demonstrated a larger magnitude of effect than the opioid comparator, oxycodone, in post hoc analysis of the results –

– The need for additional rescue medication to adequately manage pain was significantly reduced in cebranopadol-treated patients as compared to placebo in both the ALLEVIATE-2 study and the previously announced ALLEVIATE-1 Phase 3 study –

– Cebranopadol was well tolerated and demonstrated a favorable safety profile with no serious adverse events observed in both studies –

– The positive results from ALLEVIATE-2 and ALLEVIATE-1 trials, and human abuse potential (HAP) studies comparing against various opioids, constitute the full Phase 3 program for cebranopadol in the treatment of moderate-to-severe acute pain; Tris plans to submit New Drug Application to FDA in 2025 –

MONMOUTH JUNCTION, N.J.--(BUSINESS WIRE)--Tris Pharma, Inc. (Tris), a commercial-stage biopharmaceutical company, today announced positive topline results from its ALLEVIATE-2 Phase 3 pivotal clinical trial evaluating cebranopadol, an investigational therapy, for the treatment of moderate-to-severe acute pain in patients following bunionectomy surgery. The company also detailed additional positive data from the ALLEVIATE-1 Phase 3 pivotal clinical trial in patients following abdominoplasty surgery from which topline data were recently announced.

These results add to the growing body of data underscoring the promising efficacy and safety profile of cebranopadol, a first-in-class pain therapy involving dual-nociceptin/orphanin FQ peptide (NOP) receptor and µ-opioid peptide (MOP) receptor (dual-NMR) agonism. This dual-NMR agonist has the potential to deliver significant pain relief comparable to opioids with minimized risk of significant side effects, dependence and addiction by leveraging the body’s pain biology modulation processes, synergizing the analgesic and safety characteristics of the NOP receptor with the analgesic advantages of the MOP receptor.

“We are in desperate need of effective medications that provide opioid-level analgesia while minimizing the risk of misuse and abuse,” said Jeff Gudin, M.D., anesthesiologist at the University of Miami, Miller School of Medicine. “Both the ALLEVIATE-1 and -2 trials, as well as promising results from the previous human abuse potential studies, demonstrate cebranopadol’s potential to fill this unmet need for patients suffering from moderate-to-severe acute pain. 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.”

“With our Phase 3 program for cebranopadol in the treatment of moderate-to-severe acute pain complete, we now have a comprehensive data package that will be submitted to the FDA as the basis for potential approval,” said Ketan Mehta, CEO and founder of Tris. “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.”

ALLEVIATE-2 Phase 3 Results: Significant Pain Reduction in Cebranopadol-Treated Patients Following Bunionectomy Surgery

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 (AUC_2-48) following dosing. Specifically, treatment with oral cebranopadol 400 µg once per day resulted in a statistically significant reduction in pain intensity compared to placebo (LS Mean difference [SE] of 56.1 [13.49]; p<0.001; see Table 1, Figure 1). In a separate arm of the study, oxycodone immediate release (IR) 10 mg was administered orally, four times per day. While as expected, oxycodone demonstrated more pain relief compared to placebo, its mean activity was lower than the mean activity observed by cebranopadol as measured via NRS score. 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.

Table 1

Patients were allowed the use of additional analgesic options, or “rescue medication,” if analgesia was not sufficient; first line rescue was ibuprofen, and second line was oxycodone IR 5 mg. The use of rescue medication was a secondary endpoint in the ALLEVIATE-2 trial.

The results demonstrated that over the course of the seven-day study period, the proportion of patients receiving cebranopadol who did not require opioid rescue was significantly higher than patients receiving placebo (57.5% versus 28.4%; p<0.001). In addition, total doses of rescue medication were lower for cebranopadol compared to placebo (LS mean difference [SE] of 7.8 [2.68]; p=0.004).

“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,” said Todd Bertoch, M.D., chief medical officer for pain research at CenExel and lead investigator for the ALLEVIATE-2 study. “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.”

Additional Results From the ALLEVIATE-1 Phase 3 Trial in Patients Following Abdominoplasty Surgery

Positive topline results from the ALLEVIATE-1 Phase 3 pivotal study of cebranopadol in patients for the treatment of moderate-to-severe pain following abdominoplasty surgery were announced in January 2025. These results demonstrated a large analgesic effect in the cebranopadol-treated patients compared to patients receiving placebo (see Figure 2).

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).

The ALLEVIATE-1 and ALLEVIATE-2 clinical studies, combined with strong safety data from several human abuse potential (HAP) studies, will be submitted to the U.S. Food and Drug Administration (FDA) as the basis for potential approval. Tris plans to submit full results from the ALLEVIATE-1 abdominoplasty and ALLEVIATE-2 bunionectomy clinical trials for presentation at an upcoming medical congress.

About ALLEVIATE-1

The ALLEVIATE-1 clinical trial (NCT06545097) was a Phase 3 multicenter, randomized, double-blind, placebo-controlled study. The primary objective of ALLEVIATE-1 was to evaluate the analgesic efficacy of cebranopadol compared with placebo for the management of moderate-to-severe acute pain following full abdominoplasty as measured by pain intensity (11-point numeric rating scale) assessments. Secondary objectives included assessing the analgesic efficacy of cebranopadol through use of rescue medication, early discontinuations and subject’s overall assessment of study medication.

About ALLEVIATE-2

The ALLEVIATE-2 clinical trial (NCT06423703) was a Phase 3 multicenter, randomized, double-blind, placebo-and active-controlled study. The primary objective of ALLEVIATE-2 was to evaluate the analgesic efficacy of cebranopadol compared with placebo for the management of moderate-to-severe acute pain following bunionectomy as measured by pain intensity (11-point numeric rating scale) assessments. Secondary objectives included assessing the analgesic efficacy of cebranopadol through use of rescue medication, including the need for opioid rescue medication, early discontinuations and subject’s overall assessment of study medication.

About Acute Pain

Acute pain affects millions of patients each year and is caused by injury, surgery, illness, trauma, burns or painful medical procedures, which can last up to three months, and typically resolves once the underlying cause is treated or healed. Moderate-to-severe acute pain can often only be effectively treated with opioid analgesics such as oxycodone, especially following joint replacements and other orthopedic procedures, invasive surgeries, and major traumas and burns.

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 to modulate pain biology pathways. Studied in over 33 clinical trials in more than 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 (SUDs). 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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