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– Positive results confirm findings from prior studies evaluating the abuse potential of cebranopadol, further highlighting its potential as a safe and potent alternative to traditional opioids – – Registrational phase 3 clinical trials of cebranopadol in moderate to severe acute pain are on track to initiate in Q4 2023 – MONMOUTH JUNCTION, N.J.--(BUSINESS WIRE)-- Tris Pharma, Inc. (Tris), a commercial-stage biopharmaceutical company focused on ADHD, pain and neurological disorders, today announced new data from a human abuse potential (HAP) study of cebranopadol (TRN-228) which suggest the investigational compound has significantly lower abuse potential compared to both schedule II and schedule IV opioids. The findings will be shared on Thursday, September 7, in a poster presentation at the 2023 PAINWeek conference in Las Vegas. Cebranopadol is the first and only dual nociceptin/orphanin FQ peptide (NOP) receptor and µ-opioid peptide (MOP) receptor agonist (dual-NMR) analgesic in clinical development for the treatment of moderate to severe pain​, as well as opioid use disorder (OUD). Clinical studies to date suggest that the first-in-class dual-NMR analgesic has the potential to become the first pain-relief therapy to provide efficacy equivalent to traditional opioids with significantly less potential for abuse or risk of physical dependence, addiction or overdose. “Given that the opioid epidemic continues to have a devastating impact on a global scale and millions of people live each day with pain that is not well managed, the importance of developing novel safe and effective pain management therapies cannot be overstated,” said Ketan Mehta, founder and chief executive officer at Tris Pharma. “The data shared today validate our clinical efforts to advance cebranopadol and reinforce the potential of this investigational therapy to contribute to a future where pain can be managed without further exacerbating the impact of drug addiction.” HAP studies are required prior to U.S. Food and Drug Administration (FDA) approval in therapeutic classes with abuse potential. The cebranopadol oral HAP study was a randomized, double-blind, five-way crossover study of 45 participants, designed to evaluate the abuse potential of cebranopadol in adult nondependent recreational opioid users versus placebo; oxycodone, a schedule II narcotic; and tramadol, a schedule IV narcotic. Eligible participants underwent a naloxone challenge to confirm non-dependence to opioids and a qualification phase to assess that they could tolerate oxycodone and tramadol and discriminate their effects from placebo. Study participants randomly received a single dose of placebo, cebranopadol 600 μg, cebranopadol 1000 μg, tramadol IR 600 mg or oxycodone IR 40 mg. The primary endpoint was maximum drug liking “at this moment,” measured using a bipolar 100-point visual analog scale (VAS). Key secondary endpoints included “overall drug liking” and “take drug again” scores measured by the VAS. Overall, study findings suggest that cebranopadol has significantly lower abuse potential compared to schedule II and schedule IV opioids, with less likability, longer time to peak effect, fewer perceived good effects and more perceived bad effects than both oxycodone and tramadol. Specifically, maximum drug liking “at this moment” for both cebranopadol 600 μg and 1000 μg was significantly less than tramadol 600 mg (17.34 and 7.77 on the VAS, respectively; 95% confidence interval [CI]) and oxycodone 40 mg (24.43 and 14.86 on the VAS, respectively; 95% CI). Additionally, all key secondary endpoints were consistent with cebranopadol being less preferred, including that perceived “good drug effects” associated with both the 600 μg (24.7) and 1000 μg (43.8) doses of cebranopadol were lower than both oxycodone (69.6) and tramadol (54.3), while the perceived “bad drug effects” associated with cebranopadol 600 μg (12.8) and 1000 μg (23.7) were higher than both oxycodone (7.8) and tramadol (21.2). The difference between the good effects and bad effects of drugs have been linked to their abuse potential. Also, these data were consistent with the holistic measures “overall drug liking,” where subjects rated both doses of cebranopadol lower than either of the active comparators, and “take drug again,” where subjects indicated a reduced interest in taking cebranopadol again when compared to both oxycodone and tramadol. Based on previous studies suggesting cebranopadol provides relief for acute, chronic nociceptive and neuropathic pain that is on par with or superior to traditional opioids, these findings suggest the compound may serve as a much-needed alternative treatment option. “These data provide further evidence that, as the first dual-NMR analgesic, cebranopadol has the potential to deliver effective pain management without the level of addictive potential seen with schedule II and schedule IV drugs,” said Marc Lesnick, Ph.D., chief development officer at Tris Pharma. “We hope that these findings are encouraging for patients and clinicians who are awaiting new options and we look forward to initiating our phase 3 clinical trials.” About Cebranopadol (TRN-228) Cebranopadol is the first and only full, dual nociceptin/orphanin FQ peptide (NOP) receptor and µ-opioid peptide (MOP) receptor agonist (dual-NMR) analgesic in clinical development for the treatment of moderate to severe pain, as well as opioid use disorder (OUD). Cebranopadol offers a compelling and truly 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 abuse while still providing effective pain relief, and to block drugs of abuse from producing drug-seeking behaviors. In 2017, the FDA granted Fast Track Designation to cebranopadol for chronic low back pain. Cebranopadol’s pro been well-characterized in pain management, and if approved, it could become the first and only pain-relief therapy with the demonstrated ability to provide efficacy equivalent to traditional opioids with significantly less potential for abuse 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 and on LinkedIn @TrisPharma.

Funding will support preclinical through Phase 2 studies, with preclinical research expected to initiate in Q4 2023 MONMOUTH JUNCTION, N.J.--(BUSINESS WIRE)-- Tris Pharma, Inc. (Tris), a commercial-stage biopharmaceutical company focused on ADHD, pain and neurological disorders, today announced that the company has been awarded a grant expected to provide up to $16.6M over five years from the National Institute on Drug Abuse (NIDA), part of the National Institutes of Health (NIH). Through the Helping to End Addiction Long-term® Initiative (NIH HEAL Initiative®), NIH has awarded grants to fund the optimization of new therapies to prevent and treat opioid use disorder (OUD). Under their NIDA grant, Tris will collaborate with experts at multiple global institutions, including Marc Greenwald, Ph.D., of Wayne State University, and Professor Roberto Ciccocioppo of Unicam: Università degli Studi di Camerino, to complete preclinical through Phase 2 studies evaluating cebranopadol for the treatment of OUD. Cebranopadol is an investigational, dual nociception/orphanin FQ peptide (NOP) receptor and µ-opioid peptide (MOP) receptor agonist. “Opioid overdose, misuse and dependence have had a devastating impact on individuals, families and communities, currently affecting an estimated three million Americans and accounting for $35 billion in U.S. healthcare costs every year,” said Ketan Mehta, founder and chief executive officer at Tris Pharma. “We are honored that NIDA has chosen to support the further development of cebranopadol as a potential new treatment to help address this complex, growing and costly global problem.” Current treatments for OUD have well-known limitations, including high risks for overdose, withdrawal symptoms and physical dependence. Activation of the NOP receptor has been shown in preclinical studies to block addictive drugs from producing drug-seeking behaviors. Further, cebranopadol has demonstrated reduced cocaine and heroin self-administration and drug-seeking behaviors, reinforcing its potential as an effective treatment for OUD. Cebranopadol is the first and only full, dual NOP/MOP receptor agonist in clinical development. Tris is clinically evaluating the compound’s potential to provide safe and effective pain management without contributing to the global public health emergency of opioid addiction. Unlike FDA-approved opioids, the dual action of cebranopadol’s NOP/MOP receptor agonism modulates its addictive potential, as evidenced in multiple studies to date. In 2017, the FDA granted Fast Track Designation to cebranopadol for chronic low back pain. Under the five-year NIDA grant, Tris Pharma will conduct preclinical studies to assess cebranopadol’s ability to deter the self-administration of Schedule II opioids, as well as to assess the respiratory function during co-administration of cebranopadol and Schedule II opioids in preclinical models. Additionally, the company will conduct clinical studies to assess the addictive potential of cebranopadol, as well as the dosage of cebranopadol needed to block withdrawal and subjective effects of opioid dependence. “This NIDA award will help accelerate exploration of cebranopadol as a potential tool to address the opioid crisis, moving Tris closer to our goal of offering a novel and effective solution that could help change the trajectory of the countless lives afflicted by this disease,” said Joseph Grieco, M.S., Ph.D., vice president of clinical development. “We understand the urgency for new OUD treatment options, and I am optimistic about the potential of our upcoming NIDA-supported trials. We look forward to sharing updates on our progress.” Research reported in this publication was supported by the National Institute on Drug Abuse of the National Institutes of Health under Award Number UG3DA059285. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. About Cebranopadol (TRN-228) Cebranopadol is the first and only full, dual nociceptin/orphanin FQ peptide (NOP) receptor and µ-opioid peptide (MOP) receptor agonist in clinical development for the treatment of moderate to severe pain, as well as opioid use disorder (OUD). Cebranopadol offers a compelling and truly 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 abuse while still providing effective pain relief, and to block drugs of abuse from producing drug-seeking behaviors. In 2017, the FDA granted Fast Track Designation to cebranopadol for chronic low back pain. Cebranopadol’s pro been well-characterized in pain management, and if approved, it could become the first and only pain-relief therapy with the demonstrated ability to provide efficacy equivalent to traditional opioids with significantly less potential for abuse 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 and on LinkedIn @TrisPharma. View source version on businesswire.com: Contacts Company Contact Cheryl Patnick Tris Pharma, Inc. cpatnick@trispharma.com Source: Tris Pharma, Inc. View this news release online at:

在继续努力改进阿片类止痛药的过程中，来自中国科学院和美国北卡罗来纳大学的研究人员在一项新的研究中利用低温电镜技术解决了整个阿片类受体（opioid receptor）家族与其天然的肽结合的详细结构。 在继续努力改进阿片类止痛药的过程中，来自中国科学院和美国北卡罗来纳大学的研究人员在一项新的研究中利用低温电镜技术解决了整个阿片类受体（opioid receptor）家族与其天然的肽结合的详细结构。他们随后进行了结构指导下的生化研究，以更好地了解肽-阿片类受体的选择性和信号传导药物的作用机制。他们提供了一个全面的结构框架，应当有助于药物开发者合理地设计出更安全的药物来缓解剧痛。相关研究结果于2023年1月12日在线发表在Cell期刊上，论文标题为“Structures of the entire human opioid receptor family”。论文通讯作者为中国科学院受体研究重点实验室的Eric Xu博士、Youwen Zhuang博士和北卡罗来纳大学教堂山分校的Bryan L. Roth博士。 阿片类药物（opioid drug）通过模拟我们神经症状中自然产生的止痛功能来缓解疼痛。它们是我们拥有的最好、最强的止痛剂。不幸的是，它们也有副作用，其中的一些副作用较为严重，如麻木、成瘾和呼吸抑制，在过量服用时可导致死亡。 科学家们多年来一直试图以多种方式克服副作用问题，所有这些方式都涉及四种阿片类受体---μOR、δOR、κOR和NOPR---中的一种或多种，但都无济于事。科学家们继续探索的一种方式是构建肽或由肽启发的小分子药物。 肽是短的氨基酸链；可以把它们看作是短的蛋白。某些天然存在的或内源性的肽与细胞表面上的阿片类受体结合，产生镇痛效果，也被称为止痛。可把镇痛剂想象成麻醉剂，只是镇痛剂不会“关闭”神经以麻痹身体或改变意识。因此，一种想法是构建一种具有强烈镇痛效果的肽类药物，而不麻痹神经或改变意识，也不引起消化、呼吸或成瘾问题。 Roth说，“该领域存在的一个问题是我们一直缺乏对阿片类肽及其受体之间相互作用的分子理解。我们需要这种理解，以便尝试合理地设计有效和安全的肽或由肽启发的药物。” 利用低温电镜，以及在细胞中进行的一系列生物力学实验，Xu实验室和Roth实验室系统地解决了与所有四种阿片类受体结合的内源性肽的详细结构。这些结构揭示了特定的天然的阿片类肽如何选择性地识别和激活阿片类受体的细节和见解。他们还在一些实验中使用了外源性肽，或类似药物的化合物，以了解它们如何激活阿片类受体。 激动剂结合的阿片类受体与它们的G蛋白效应物（称为它们的活性状态）的低温电镜结构代表了这些阿片类受体在细胞中进行信号传导时的样子，给出了肽-阿片类受体相互作用的详细结构图。这些由Roth实验室利用Xu实验室解析出的结构来指导设计阿片类受体突变体，然后在细胞的生化试验中测试这些阿片类受体突变体，以确定它们如何改变受体信号传导。了解这些相互作用可以用来设计对阿片类受体亚型具有选择性的药物，以及产生某些可能比传统阿片类药物更有益的信号传导结果。 论文共同第一作者、Roth实验室博士生Jeff DiBerto说，“这项合作揭示了所有四种阿片类受体的保守性激活和识别机制，以及可用于构建阿片类受体亚型选择性药物的肽识别差异。我们提供了更多需要的信息，以继续推动该领域的发展，并解答我们之前一直无法解答的基础科学问题。” 图片来自Cell, 2023, doi:10.1016/j.cell.2022.12.026。 之前的研究已显示了阿片类受体在非活性或类似活性状态下的结构，活性状态下的结构只存在于µ型阿片类受体（μOR）亚型，这是芬太尼和吗啡等药物的主要作用靶标。在这项新的研究中，这些作者展示了激动剂结合的阿片类受体与它们的G蛋白效应物结合在一起形成的复合物，这通过低温电镜技术得以实现，而在当前使用的药物之前在开发时时，这种技术还不存在。 奥施康定（oxycontin）、羟考酮（oxycodone）和吗啡等药物在细胞内和整个神经症状中引起多种效应，包括缓解疼痛。但它们在消化系统和呼吸系统中也有影响，并与细胞相互作用，导致成瘾。与此同时，芬太尼是另一种强大的止痛剂，但它与阿片类受体结合的方式会导致严重的副作用，包括呼吸系统的关闭。 Xu和Roth领导的这项研究背后的主旨是在不触发导致严重副作用和过量服用的细胞机制的情况下，深入了解止痛效果的机制原因。 Roth说，“我们正试图建立更好的阿片类药物。如果没有这些基本的分子见解，我们永远无法达到这个目标，而在这项新的研究中，我们可以看到为什么疼痛得到缓解，为什么会出现副作用。”（生物谷 Bioon.com） 参考资料： 1. Yue Wang et al. Structures of the entire human opioid receptor family. Cell, 2023, doi:10.1016/j.cell.2022.12.026. 2. Scientists take another step toward creating better pain medicationshttps://phys.org/news/2023-01-scientists-pain-medications.html