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AACHEN, Germany I October 22, 2024 I Today, Grünenthal announced that the first participants have been enrolled in a first-in-human Phase I clinical trial for a nociceptin (NOP) receptor agonist. The trial will include 90 healthy volunteers and aims to demonstrate a favourable safety and tolerability profile and to confirm the pharmacokinetic characteristics of the compound after single and multiple ascending doses. The results of the trial are expected in Q3 2025. “Grünenthal pioneered the research into NOP receptor agonists to deliver a unique and transformative first-in-class therapy option to millions of patients suffering from chronic pain,” says Gillian Burgess, Head of Research, Grünenthal. “With a unique mechanism of action for treating chronic pain, these molecules have the potential to deliver robust pain relief combined with an improved safety profile compared to the available standard of care.” Pre-clinical data show that NOP receptor agonists have the potential to act as potent analgesics without abuse liability. 1 Leveraging the clinical data Grünenthal obtained during the development of its NOP receptor programme, Grünenthal now brings forward a candidate that shows best-in-class potency and selectivity for the NOP receptor. These properties are predicted to provide robust pain relief in a broad range of chronic pain indications without the serious central nervous system related side effects associated with available opioids. Grünenthal’s R&D pipeline includes multiple programmes across different stages, targets, modalities, and mechanisms of action to deliver innovative treatment options for patients suffering from pain and related diseases. Recently, a Phase I clinical trial with a Glucocorticoid Receptor Modulator (GRM) has been completed. The compound is developed to provide patients with a therapy option for chronic inflammatory diseases. In addition, Grünenthal is running a Phase III clinical trial with Qutenza ® (capsaicin) 8% topical system in post-surgical neuropathic pain, aiming to expand its label in the United States. A global Phase III programme investigating the efficacy, safety and tolerability of Resiniferatoxin in patients with painful osteoarthritis of the knee is currently ongoing. About the NOP Receptor The nociceptin (NOP) receptor is a G protein-coupled receptor whose natural ligand is the 17 amino acid neuropeptide known as nociceptin (N/OFQ). 2 NOP Receptor agonists have been shown to act as potent analgesics without abuse liability in pre-clinical models. 1 Although the NOP Receptor shares some sequence identity (~60%) with the opioid receptors μ-OP (MOP), κ-OP (KOP), and δ-OP (DOP), they possess little or no affinity for opioid peptides or morphine-like compounds. Likewise, opioid receptors possess little affinity towards NOP’s endogenous ligand nociceptin. 3 About Grünenthal Grünenthal is a global leader in pain management and related diseases. As a science-based, fully integrated pharmaceutical company, we have a long track record of bringing innovative treatments and state-of-the-art technologies to patients worldwide. Our purpose is to change lives for the better – and innovation is our passion. We are focusing all our activities and efforts on working towards our vision of a World Free of Pain. Grünenthal is headquartered in Aachen, Germany, and has affiliates in 27 countries across Europe, Latin America, and the U.S. Our products are available in approx. 100 countries. In 2023, Grünenthal employed around 4,400 people and achieved revenues of €1.8 billion. More information: https://www.grunenthal.com Follow us on: LinkedIn: Grunenthal Group Instagram: grunenthal 1 Lin AP, Ko MC. The therapeutic potential of nociceptin/orphanin FQ receptor agonists as analgesics without abuse liability. ACS Chem Neurosci. 2013 Feb 20;4(2):214-24. doi: 10.1021/cn300124f. Epub 2012 Nov 6. PMID: 23421672; PMCID: PMC3582300. 2 Henderson G, McKnight AT (August 1997). “The orphan opioid receptor and its endogenous ligand– nociceptin/orphanin FQ”. Trends in Pharmacological Sciences. 18 (8): 293–300. doi:10.1016/S0165- 6147(97)90645-3. PMID 9277133. 3 Butour JL, Moisand C, Mazarguil H, Mollereau C, Meunier JC (February 1997). “Recognition and activation of the opioid receptor-like ORL 1 receptor by nociceptin, nociceptin analogs and opioids”. European Journal of Pharmacology. 321 (1): 97–103. doi:10.1016/S0014-2999(96)00919-3. PMID 9083791. SOURCE: Grünenthal Group

MONMOUTH JUNCTION, N.J.--( BUSINESS WIRE )--Tris Pharma, Inc. (Tris), a commercial-stage biopharmaceutical company focused on attention deficit hyperactivity disorder (ADHD), pain, addiction and neurological disorders, 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. Cebranopadol is the company’s first-in-class dual nociceptin/orphanin FQ peptide (NOP) receptor and µ-opioid peptide (MOP) receptor (dual-NMR) agonist designed to treat multiple types of pain. The findings will be shared in a poster presentation on September 4, 2024, at the 2024 PAINWeek conference in Las Vegas. “We’re pleased to share these important clinical findings at PAINWeek, which highlight the respiratory safety data of cebranopadol,” said James Hackworth, Ph.D., president, brand division at Tris Pharma. “We’ve seen the detrimental impact that opioids can have on patients who suffer from pain, and we’ve worked closely with regulatory agencies to conduct multiple studies that explore specific properties of cebranopadol’s efficacy and safety profile. Based on results from these studies, we have now advanced cebranopadol into two pivotal Phase 3 studies and look forward to sharing data from these studies once they are available.” Findings shared in the PAINWeek 2024 presentation titled “The Effects of Cebranopadol on Ventilatory Drive, Central Nervous System, and Pain,” demonstrate that NOP receptor activation with cebranopadol effectively attenuates respiratory depression and that its dual-NMR agonism produces potent, long-lasting analgesia. Key study results include: 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. Despite having a longer duration of effect, cebranopadol produces fewer respiratory adverse events over 24 hours, including apnea, respiratory depression and oxygen saturation decrease, compared to oxycodone. Respiratory depression, which is mediated by activation of the MOP receptor, is a life-threatening complication that can occur following opioid administration. In the double-blind, placebo-controlled study that will be presented at PAINWeek, investigators randomized 30 healthy volunteers over a four-week treatment period to receive cebranopadol or oxycodone at supratherapeutic doses (i.e., doses that are greater than the therapeutic concentration) or placebo. The trial specifically evaluated both cebranopadol’s and oxycodone’s impact on respiratory depression using a ventilatory response to hypercapnia model, the ability to produce analgesia and the potential presence of a respiratory depression ceiling effect for cebranopadol at higher doses. “Respiratory depression is one of the most life-threatening and dangerous side effects of opioid use and can lead to slow, shallow and irregular breathing or even death,” said lead study author Simone Jansen, M.D., Leiden University Medical Center, Leiden, The Netherlands. “These cebranopadol data are encouraging, because they support its overall safety profile, suggesting that cebranopadol’s novel mechanism of action uniquely delays the onset of respiratory effects and produces less respiratory depression compared to oxycodone. This delayed onset has multiple advantages, including extending the timeframe for any medical interventions, if needed, and thereby could potentially help physicians feel more confident in prescribing the medication if it is approved.” About Cebranopadol (TRN-228) Cebranopadol is an investigational, first-in-class dual nociceptin/orphanin FQ peptide (NOP) receptor and µ-opioid peptide (MOP) receptor (dual-NMR) agonist for the treatment of moderate-to-severe pain, as well as opioid use disorder (OUD). Cebranopadol offers a unique mechanism of action that takes advantage of the inherent properties of the NOP receptor, which has demonstrated both the potential to lessen the risk of misuse or addiction while still providing effective pain relief, and the potential to block drugs of abuse from producing drug-seeking behaviors. Studied in over 30 clinical trials in over two thousand 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 and only pain-relief therapy with the demonstrated ability to provide efficacy equivalent to opioids with significantly less potential for misuse or risk of physical dependence, addiction or overdose. 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 and neurological disorders, including addiction and diseases 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 .

MONMOUTH JUNCTION, N.J.--( BUSINESS WIRE )--Tris Pharma, Inc. (Tris), a commercial-stage biopharmaceutical company focused on attention deficit hyperactivity disorder (ADHD), pain, addiction and neurological disorders, 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. Cebranopadol is a first-in-class investigational new therapy, with a novel mechanism of action that targets both the nociceptin/orphanin FQ peptide (NOP) receptor and µ-opioid peptide (MOP) receptor, called dual-NMR agonist for the treatment of multiple types of pain. “There is a monumental need to improve upon available treatments for the millions of individuals who suffer from pain each day and are unable to live a normal life,” said Ketan Mehta, founder and chief executive officer at Tris Pharma. “The initiation of our pivotal Phase 3 clinical trials for cebranopadol, a potentially transformational new pain therapy, is a significant step toward providing patients with a solution that is both highly effective and has a strong safety profile. We look forward to sharing the results from each study when they are available.” The ALLEVIATE-1 and ALLEVIATE-2 clinical trials are registrational Phase 3 studies evaluating the efficacy of cebranopadol in patients undergoing abdominoplasty and bunionectomy, respectively. 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. “Currently, physicians are constrained to prescribing pain medicines that either don’t effectively alleviate pain or do treat pain but often come with risk of significant side effects, misuse, addiction and overdose,” said Jeffrey Gudin, MD, professor of anesthesiology, perioperative medicine and pain management at the University of Miami Miller School of Medicine. “I’ve witnessed firsthand the transformative potential of this novel pain management therapy, and the initiation of these Phase 3 trials is an important step toward helping both physicians and their patients feel more confident in safely managing pain.” If approved, cebranopadol will be the world’s first dual-NMR agonist. The investigational therapy is designed to leverage the body’s pain modulation processes, synergizing the analgesic and safety characteristics of the NOP receptor with the analgesic advantages of the MOP receptor to potentially deliver pain relief equivalent to opioids with minimized risk of significant side effects, dependence and potential addiction. Cebranopadol’s profile has been well-characterized in more than 30 efficacy and safety clinical trials involving over 2,000 patients to date. Data from these studies suggest that cebranopadol is effective at reducing acute and chronic pain, including neuropathic pain, while reducing many of the harmful side effects seen in opioids and may have significantly lower risk of addiction and overdose. About ALLEVIATE-1 The ALLEVIATE-1 clinical trial (NCT06545097) is a Phase 3 multicenter, randomized, double-blind, placebo-controlled study. Investigators at up to six clinical trial sites in the United States plan to enroll up to 300 patients. The primary objective of ALLEVIATE-1 is to evaluate the analgesic efficacy of cebranopadol compared with placebo for the management of moderate-to-severe pain following full abdominoplasty as measured by pain intensity (11-point numeric rating scale) assessments. Secondary objectives include assessing the analgesic efficacy of cebranopadol through use of rescue medication, early discontinuations and subject overall assessment of study medication. About ALLEVIATE-2 The ALLEVIATE-2 clinical trial (NCT06423703) is a Phase 3 multicenter, randomized, double-blind, placebo- and active-controlled study. Investigators at up to eight clinical trial sites in the United States plan to enroll up to 240 patients. The primary objective of ALLEVIATE-2 is to evaluate the analgesic efficacy of cebranopadol compared with placebo for the management of moderate-to-severe pain following bunionectomy as measured by pain intensity (11-point numeric rating scale) assessments. Secondary objectives include assessing the analgesic efficacy of cebranopadol using rescue medication and evaluating the relative safety and tolerability of cebranopadol compared with oxycodone. About Cebranopadol (TRN-228) Cebranopadol is a first-in-class investigational therapy that targets both the nociceptin/orphanin FQ peptide (NOP) and µ-opioid peptide (MOP) receptors, called a dual-NMR agonist for the treatment of moderate-to-severe pain, as well as opioid use disorder (OUD). Cebranopadol offers a unique mechanism of action that takes advantage of the inherent properties of the NOP receptor, which has demonstrated both the potential to lessen the risk of misuse or addiction while still providing effective pain relief, and the potential to block drugs of abuse from producing drug-seeking behaviors. Studied in over 30 clinical trials in over two thousand 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 significantly favorable safety profile. The FDA granted Fast Track Designation to cebranopadol for chronic low back pain, and if approved, it could become the first and only pain-relief therapy with the demonstrated ability to provide efficacy equivalent to opioids with significantly less potential for misuse or risk of physical dependence, addiction or overdose. 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 and addiction and diseases of the central nervous system. Tris is an established commercial organization with a robust portfolio of best-in-class ADHD products with a promising pipeline of differentiated near-term drug candidates. More information is available at www.trispharma.com and on LinkedIn @ TrisPharma .