Oxycodone

~ Fourth Quarter Highlighted by Clinical and Regulatory Milestones Positioning PF614 for Late-Stage Advancement ~ SAN DIEGO, CA / ACCESS Newswire / March 30, 2026 / Ensysce Biosciences, Inc. (NASDAQ:ENSC) ("Ensysce" or the "Company"), a clinical-stage pharmaceutical company developing innovative solutions for novel therapeutics while reducing the potential for abuse and overdose, today reported financial and operational results for the fourth quarter and full year ended December 31, 2025. "2025 was a year of meaningful progress for Ensysce, marked by significant clinical advancement, productive regulatory engagement, and continued strengthening of our intellectual property portfolio," said Dr. Lynn Kirkpatrick, Chief Executive Officer of Ensysce Biosciences. "We initiated our Phase 3 trial for PF614 and had constructive dialogue with the FDA supporting our manufacturing pathway." Dr. Kirkpatrick continued, "Enrollment in the PF614-301 Phase 3 study has progressed rapidly, while PF614-MPAR remains on an accelerated development path under Breakthrough Therapy designation. In parallel, we have advanced commercial manufacturing readiness for PF614 and have generated additional data supporting overdose-protection labeling for our MPAR platform. Beyond our late-stage programs, we strengthened the long-term value of our technology platforms through expanded patent protection and pipeline growth, including the advancement of PF9001 for opioid use disorder (OUD) and leveraging our TAAP™ and MPAR® technologies for additional indications such as attention deficit hyperactivity disorder (ADHD)." Program Updates TAAPTM (Opioid Abuse Deterrent) Program Update Ensysce's lead drug candidate, PF614, is a Trypsin-Activated Abuse Protection (TAAPTM) extended-release oxycodone designed to deliver effective pain relief while incorporating built-in abuse protection. Through proprietary chemical modification of oxycodone, PF614 remains pharmacologically inactive until swallowed and exposed to trypsin in the small intestine, where it is activated to release oxycodone. This mechanism is designed to preserve therapeutic efficacy while significantly reducing the potential for tampering and abuse. In December 2025, Ensysce announced the enrollment of the first patient in its pivotal Phase 3 clinical trial (PF614-301) evaluating PF614 for the treatment of moderate-to-severe post-surgical pain following abdominoplasty. The multicenter, randomized, double-blind, placebo-controlled study is designed to assess whether PF614 can deliver potent and consistent analgesia while leveraging its unique chemical design to mitigate the risk of opioid misuse. Clinical sites currently enrolling patients include CenExel JBR in Salt Lake City, Utah, and CenExcel Atlanta under experienced principal investigators in anesthesiology and pain medicine. Enrollment in PF614-301 represents a major milestone in Ensysce's strategy to introduce a next generation of safer opioid medicines and advance PF614 toward regulatory submission and potential commercialization. MPAR® (Opioid Abuse Deterrent and Overdose Protection) Program Update PF614-MPAR combines Ensysce's TAAP™ chemistry with its proprietary MPAR® (Multi-Pill Abuse Resistance) overdose-protection technology, designed to actively limit opioid release when multiple pills are consumed beyond prescribed doses. PF614-MPAR incorporates a trypsin inhibitor that automatically reduces opioid activation in overdose situations, effectively acting as a chemical "off-switch." Clinical data from the PF614-MPAR-101 study demonstrated that the MPAR® technology functioned as designed, providing overdose protection at a 25 mg dose. These results supported the FDA's Breakthrough Therapy designation granted in January 2024. In November 2025, the FDA provided encouraging feedback regarding the development pathway for PF614-MPAR, including support for pursuing overdose-protection labeling and the potential use of a streamlined 505(b)(2) regulatory pathway, which could accelerate development and market entry. The FDA and Ensysce are collaborating on a framework to define and communicate the safety benefits of overdose-protection opioids, including development of a scientific whitepaper on overdose protection. This milestone, backed by multi-year grants from the National Institute on Drug Abuse (NIDA), marks a significant step toward transforming opioid safety and redefining pain management. Opioid Use Disorder (OUD) Program Update In addition to its pain management portfolio, Ensysce is developing treatments for opioid use disorder (OUD) designed to reduce cravings and relapse risk while maintaining patient safety and quality of life. The Company selected PF9001 as its lead OUD candidate and is evaluating the compound as a potential next-generation methadone alternative with built-in overdose protection, reduced cardiovascular risk and an oral delivery profile. This program was supported by a multi-year HEAL (Helping to End Addiction Long-Term) grant and in collaboration with NIDA. Intellectual Property Expansion In December 2025, the U.S. Patent and Trademark Office allowed a new patent covering Ensysce's MPAR® technology, further strengthening the Company's intellectual property protection through 2042. The patent, titled "Compositions Comprising Enzyme-Cleavable Prodrugs and Controlled Release Nafamostat and Methods of Use Thereof," includes both composition-of-matter and method-of-use claims. Ensysce is also exploring the application of MPAR technology beyond opioids, including potential programs in amphetamines for ADHD and methadone for OUD. In early January, Ensysce announced that the European Patent Office provided Notice of Allowance in December 2025, for the issuance of a Patent 'Compositions Comprising Enzyme-Cleavable Amphetamine Prodrugs and Inhibitors Thereof' for PF8026 protected by the TAAPTM and MPAR® technologies. These two issuances expand the potential reach of Ensysce's platforms across multiple therapeutic areas where abuse and overdose risk remain significant clinical challenges. Fourth Quarter and Full Year 2025 Financial Results Cash - Cash and cash equivalents were $4.3 million as of December 31, 2025, compared to $3.5 million as of December 31, 2024. Cash used in operating activities totaled $7.8 million in 2025 compared to $7.5 million in 2024. Federal Grants - Funding under federal grants totaled $1.9 million for the fourth quarter of 2025 compared to $1.3 million in the comparable year ago quarter. For the full year, funding from federal grants totaled $5.1 million in 2025, compared to $5.2 million in 2024. The differences are due to the timing of research activities eligible for funding under the OUD and MPAR grants, as decreases in funding under the OUD grant that ended in August 2024 were offset by increases in funding under the MPAR grant which began in September 2024. Research & Development Expenses - R&D expenses were $3.6 million for the fourth quarter of 2025 compared to $3.8 million for the same period in 2024. Research and development expenses were $10.4 million for the year ended December 31, 2025, compared to $7.2 million for the year ended December 31, 2024, respectively, representing an increase of $3.2 million. The increase was primarily the result of external research and development costs related to increased clinical and pre-clinical programs for PF614 and PF614-MPAR. General & Administrative Expenses - G&A expenses were $1.1 million in the fourth quarter of 2025, consistent with $1.1 million for the fourth quarter of 2024. For 2025, G&A expenses were $4.9 million, representing an increase of $0.2 million compared to $4.7 million for 2024. Other Income (Expense) - Total other income (expense) was income of $13,856 for the fourth quarter of 2025 compared to income of $12,054 in the same period of 2024. For 2025, total other income (expense), net was income of $64,759 compared to expense of $1.3 million for 2024. Other income and expense for the year ended December 31, 2025, consisted primarily of interest income from cash and cash equivalents. Other income and expense for the year ended December 31, 2024, consisted primarily of interest expense associated with the amortization of the original issue discount and the debt issuance costs associated with convertible notes issued in 2023. Net Income (Loss) - Net loss attributable to common stockholders for the fourth quarter of 2025 was $2.8 million compared to a net loss of $3.6 million for the fourth quarter of 2024. For 2025, net loss was $10.2 million compared to $8.0 million for 2024. As a clinical stage biotech company, our continued research and development efforts toward regulatory approvals for our product candidates are expected to result in losses for the foreseeable future. About Ensysce Biosciences Ensysce Biosciences is a clinical-stage pharmaceutical company dedicated to disrupting the analgesic landscape through the development of a new class of safer opioid medicines for the treatment of severe pain. Leveraging its proprietary Trypsin-Activated Abuse Protection (TAAP™) and Multi-Pill Abuse Resistance (MPAR®) platforms, Ensysce is advancing tamper-resistant therapeutic options designed to minimize the risk of opioid abuse and oral overdose while preserving strong analgesic efficacy. For more information, visit www.ensysce.com. Definitions TAAP™: trypsin activated abuse protection - designed to protect against prescription drug abuse. MPAR®: multi-pill abuse resistance - designed to protect against abuse and accidental overdose. Forward-Looking Statements Statements contained in this press release that are not purely historical may be deemed to be forward-looking statements for the purposes of the safe harbor provisions under The Private Securities Litigation Reform Act of 1995 and other federal securities laws. Without limiting the foregoing, the use of words such as "may," "intends," "can," "might," "will," "expect," "plan," "possible," "believe" and other similar expressions are intended to identify forward-looking statements. The product candidates discussed are in clinic and not approved and there can be no assurance that the clinical programs will be successful in demonstrating safety and/or efficacy, that Ensysce will not encounter problems or delays in clinical development, or that any product candidate will ever receive regulatory approval or be successfully commercialized. All forward-looking statements are based on estimates and assumptions by Ensysce's management that, although Ensysce believes to be reasonable, are inherently uncertain. All forward-looking statements are subject to risks and uncertainties that may cause actual results to differ materially from those that Ensysce expected. In addition, Ensysce's business is subject to additional risks and uncertainties, including among others, the initiation and conduct of preclinical studies and clinical trials; the timing and availability of data from preclinical studies and clinical trials; expectations for regulatory submissions and approvals; potential safety concerns related to, or efficacy of, Ensysce's product candidates; the availability or commercial potential of product candidates; the ability of Ensysce to fund its continued operations, including its planned clinical trials; the dilutive effect of stock issuances from our fundraising; and Ensysce's and its partners' ability to perform under their license, collaboration and manufacturing arrangements. These statements are also subject to a number of material risks and uncertainties that are described in Ensysce's most recent annual report on Form 10-K and current reports on Form 8-K, which are available, free of charge, at the SEC's website at www.sec.gov. Any forward-looking statement speaks only as of the date on which it was made. Ensysce undertakes no obligation to publicly update or revise any forward-looking statement, whether as a result of new information, future events or otherwise, except as required under applicable law. Ensysce Biosciences Company Contact: Lynn Kirkpatrick, Ph.D.Chief Executive Officer(858) 263-4196 Ensysce Biosciences Investor Relations Contact: Shannon DevineMZ North AmericaMain: 203-741-8811ENSC@mzgroup.us Ensysce Biosciences, Inc.Condensed Consolidated Statements of Operations 2021 2020 2021 2020 Three Months Ended December 31, 2025 2024 2025 2024 $ 1,882,336 $ 1,303,659 $ 5,066,650 $ 5,210,031 3,613,029 3,802,630 10,376,895 7,219,437 1,051,132 1,077,505 4,930,701 4,720,728 4,664,161 4,880,135 15,307,596 11,940,165 (2,781,825 ) (3,576,476 ) (10,240,946 ) (6,730,134 ) 13,856 12,054 64,759 (1,256,875 ) $ (2,767,969 ) $ (3,564,422 ) $ (10,176,187 ) $ (7,987,009 ) 321 - 487 (216 ) $ (2,767,648 ) $ (3,564,422 ) $ (10,175,700 ) $ (7,987,225 ) $ (0.75 ) $ (2.90 ) $ (3.98 ) $ (11.45 ) Ensysce Biosciences, Inc.Condensed Consolidated Statements of Cash Flows 2021 2020 Year Ended December 31, 2025 2024 $ (7,806,292 ) $ (7,502,700 ) (123,643 ) - 8,738,212 9,881,173 808,277 2,378,473 3,502,077 1,123,604 $ 4,310,354 $ 3,502,077 Ensysce Biosciences, Inc.Condensed Consolidated Balance Sheets(Unaudited) December 31, December 31, 2025 2024 $ 4,310,354 $ 3,502,077 2,932,114 1,842,605 7,242,468 5,344,682 210,011 252,550 $ 7,452,479 $ 5,597,232 $ 3,267,610 $ 1,357,079 993,411 548,458 306,708 301,660 4,567,729 2,207,197 - 10,096 4,567,729 2,217,293 2,884,750 3,379,939 $ 7,452,479 $ 5,597,232 SOURCE: Ensysce Biosciences, Inc. Released March 30, 2026

摘要癌痛是恶性肿瘤患者最常见的症状之一，约25%的新诊断癌症患者和超过75%的晚期癌症患者经历不同程度的疼痛。癌痛严重影响患者的生活质量、治疗依从性及生存预后。近年来，癌痛的治疗理念、药物方案及非药物干预手段均取得显著进展。本文综述近三年来癌痛治疗领域的研究进展，涵盖流行病学与病理生理机制、评估方法、药物治疗、非手术治疗及多学科综合管理等各个方面，以期为临床实践提供参考。关键词：癌痛；疼痛管理；阿片类药物；微创治疗；多学科综合治疗 1.引言癌痛是恶性肿瘤患者最常见且最具挑战性的症状之一。研究表明，约25%的新诊断癌症患者和超过75%的晚期癌症患者经历不同程度的癌痛。癌痛不仅严重影响患者的生活质量、治疗依从性和生存预后，还对患者的身心健康造成深远的负面影响。世界卫生组织（WHO）早在1986年提出了三阶梯止痛治疗方案，为癌痛药物治疗奠定了基础。然而，随着肿瘤治疗技术的进步和人们对疼痛机制认识的深入，癌痛治疗理念和方法不断更新。近年来，阿片类药物的合理应用以及多学科姑息疼痛管理模式等方面的研究取得重要进展，经皮肿瘤消融介入技术也获得相关研究进展[1][2]。本文旨在系统综述近三年（2023-2025年）癌痛治疗领域的研究进展，为临床医师提供最新的循证医学证据和实践参考。 2.癌痛的流行病学与病理生理机制2.1 癌痛流行病学特征癌痛的流行病学特征因肿瘤类型、分期及治疗方式的不同而存在显著差异。2026年发表的叙述性综述未涉及实体瘤患者癌痛发生率及不同肿瘤疼痛发生率的相关数据。值得关注的是，癌痛不仅存在于晚期患者，早期癌症患者同样可遭受疼痛困扰。2.2 癌痛的病理生理机制癌痛的发生机制涉及肿瘤对周围组织的侵犯、神经压迫、炎症反应及神经病理性改变等多个方面。肿瘤细胞分泌的炎症介质（如前列腺素、肿瘤坏死因子-α、白细胞介素-1β等）可激活外周伤害性感受器，导致外周敏化。同时，肿瘤侵犯神经或骨髓腔可引起神经病理性疼痛，其特征为痛觉过敏和异常性疼痛。近年来的研究表明，神经胶质细胞的激活在癌痛的发生发展中发挥重要作用。脊髓背角的小胶质细胞和星形胶质细胞被激活后，可释放多种促炎介质，加剧中枢敏化。此外，离子通道（如Nav1.7、Nav1.8、TRPV1等）的异常表达与癌痛的发生密切相关，为靶向镇痛药物的研发提供了新思路。 3.癌痛评估方法有效的癌痛管理建立在准确评估的基础上。近三年来，癌痛评估工具和方法不断优化，主要体现在以下几个方面：3.1 主观评估工具数字评分量表（NRS）、视觉模拟量表（VAS）和面部疼痛量表（FPS-R）等仍是临床最常用的癌痛评估工具。2025年的研究指出，患者报告结局测量信息系统（PROMIS）是用于儿童癌症幸存者疼痛生物心理社会评估的已验证工具[3]。此外，简版疼痛评估量表（BPI）因其简单易行、涵盖疼痛对日常活动的影响等多个维度，在临床实践中广泛应用。3.2 综合评估与动态监测现代癌痛评估强调综合评估和动态监测相结合。生物-心理-社会评估模型可用于儿童癌症幸存者的疼痛评估。移动健康（mHealth）技术的发展使得连续的疼痛监测成为可能，智能手机应用程序可实时记录疼痛强度、用药情况及生活质量指标，为个体化治疗提供了数据支持。 4.药物治疗进展4.1 世界卫生组织三阶梯止痛治疗原则WHO三阶梯止痛治疗原则仍是癌痛药物治疗的基石。第一阶梯使用非甾体抗炎药（NSAIDs）用于轻至中度疼痛；第二阶梯使用弱阿片类药物（如曲马多、可待因）用于中度疼痛；第三阶梯使用强阿片类药物（如吗啡、芬太尼、羟考酮）用于中重度疼痛。近三年的研究表明，在遵循三阶梯原则的基础上，个体化用药和联合用药可进一步优化镇痛效果。2026年发表的一项叙述性综述指出，合理使用阿片类药物仍是中重度癌痛的主要治疗手段，但需关注剂量滴定、不良反应管理及长期安全性等问题[1]。4.2 阿片类药物应用进展4.2.1 阿片类药物的药理学进展阿片类药物通过激动μ-、δ-和κ-阿片受体发挥镇痛作用。近年的研究聚焦于开发更具选择性的阿片类药物，以减少不良反应。部分阿片受体激动剂（如丁丙诺啡）支持更安全、更个体化的阿片类药物处方，在癌痛治疗中具有应用潜力[1]。双重作用机制药物他喷他多（Tapentadol）属于支持更安全、个体化阿片类药物处方的研究进展之一[1]。4.2.2 阿片类药物剂量调整与轮换阿片类药物的剂量调整是实现最佳镇痛效果的关键环节。2024年的临床研究显示，规范化剂量滴定可有效提高疼痛缓解率，同时降低不良反应发生率。阿片类药物轮换是优化阿片类药物使用、支持更安全和更个体化处方的策略之一[1]。4.2.3 阿片类药物相关不良反应阿片类药物的常见不良反应包括便秘、恶心呕吐、嗜睡、呼吸抑制及成瘾等。其中，阿片类药物引起的便秘（OIC）是最常见且棘手的不良反应，2026年的综述详细阐述了OIC的发病机制及管理策略[4]。新型外周μ-阿片受体拮抗剂（如甲基纳曲酮、纳尔地地）对OIC显示出良好的疗效，且不影响阿片类药物的中枢镇痛作用。4.3 辅助镇痛药物4.3.1 抗抑郁药三环类抗抑郁药（如阿米替林）和5-羟色胺-去甲肾上腺素再摄取抑制剂（SNRIs，如度洛西汀、文拉法辛）可用于治疗癌性神经病理性疼痛。2024年的meta分析显示，度洛西汀在治疗化疗诱导的周围神经病变（CIPN）相关疼痛中显示出中等疗效。4.3.2 抗惊厥药加巴喷丁和普瑞巴林是治疗神经病理性疼痛的一线药物。近年的研究表明，普瑞巴林在治疗癌性神经病理性疼痛方面可改善睡眠质量和情绪状态，但其镇痛效果因人而异。4.3.3 糖皮质激素地塞米松等糖皮质激素可通过减轻炎症反应、缓解神经水肿而发挥辅助镇痛作用。糖皮质激素可有效控制肿瘤相关的炎性疼痛和神经压迫性疼痛，但长期使用需注意不良反应的管理。4.4 爆发痛与难治性癌痛爆发痛（breakthroughpain）是指在稳定镇痛基础上突然出现的短暂剧烈疼痛。2025年的研究显示，爆发痛的发生率约为65%，严重影响患者生活质量。速效阿片类药物（如即释吗啡、芬太尼透黏膜制剂）是处理爆发痛的主要手段。对于难治性癌痛，需考虑多种因素，包括肿瘤进展、神经侵犯、心理因素及药物代谢异常等。难治性癌痛患者应尽早转诊至疼痛专科或姑息治疗团队进行综合管理。 5.非药物治疗进展5.1 介入治疗技术5.1.1 神经阻滞神经阻滞是缓解特定区域癌痛的有效方法。2025年的临床研究显示，腹腔神经丛阻滞可有效缓解胰腺癌及其他上腹部恶性肿瘤引起的疼痛。椎旁阻滞、硬膜外阻滞及选择性神经根阻滞等技术也在癌痛管理中发挥重要作用。5.1.2 经皮肿瘤消融技术经皮肿瘤消融技术，包括射频消融（RFA）、微波消融（MWA）、冷冻消融及不可逆电穿孔（IRE）等，已成为缓解骨转移和软组织转移相关疼痛的重要手段。2026年的综述指出，RFA和MWA常用于治疗疼痛性骨转移和软组织转移，而冷冻消融因其可提供更好的影像学显像优势，更适合邻近神经或关键结构的病变[2]。5.1.3 椎体强化技术经皮椎体成形术和椎体后凸成形术是治疗疼痛性椎体转移的标准微创手术。2026年发表的综述指出，双极RFA联合椎体强化在疼痛性脊柱转移的疼痛管理中显示出特定获益[2]。5.2 神经调控疗法5.2.1 周围神经刺激周围神经刺激（PNS）已被证实可有效治疗慢性疼痛。2025年发表的美国疼痛和神经科学学会（ASPN）共识指南，为PNS在慢性疼痛和神经系统疾病治疗中的应用提供了循证医学支持[5]。临时性周围神经刺激（60天）可预测永久性植入后6个月的镇痛效果，为患者提供了一种可逆的治疗选择[6]。5.2.2 脊髓刺激脊髓刺激（SCS）主要用于治疗难治性癌痛，特别是躯干和四肢疼痛。近年来，高频SCS和背根神经节刺激等新技术的发展，进一步提高了镇痛效果并减少了副作用。5.3 心理干预与社会支持癌痛不仅是一种生理体验，还受到心理和社会因素的深刻影响。2026年的综述强调，包含心理干预在内的多模式康复作为药物治疗的补充，可缓解晚期癌痛并改善患者生活质量[7]。社会支持、家庭关怀及姑息治疗团队的参与同样是癌痛综合管理的重要组成部分。5.4 补充与替代疗法5.4.1 运动疗法适度运动已被证实可缓解癌痛并改善功能状态。2026年的研究指出，运动训练作为非药物干预策略之一可辅助缓解晚期癌症疼痛，但并未报道其发挥镇痛作用的具体机制[7]。然而，癌痛患者的运动处方需个体化制定，并考虑肿瘤相关禁忌症。5.4.2 虚拟现实与人工智能虚拟现实（VR）技术作为一种新兴的非药物镇痛手段，在癌痛管理中展现出潜力。2026年的综述聚焦晚期癌症慢性疼痛的非药物干预，未涉及VR缓解急性疼痛的相关内容[7]。人工智能驱动的应用程序可为患者提供个性化的疼痛自我管理支持。 6.多学科综合治疗与未来展望6.1 多学科疼痛管理模式现代癌痛管理强调多学科团队协作，包括肿瘤科医师、疼痛专科医师、姑息治疗医师、护士、药师、物理治疗师及心理医师等。2026年的研究证实，对于晚期癌痛患者，结合非药物策略的多模式康复可有效补充药物管理以缓解癌痛、提高患者生活质量，未证实其可减少阿片类药物用量[7]。6.2 精准医学与个体化治疗随着肿瘤分子分型和疼痛基因组学的发展，精准医学理念正逐步应用于癌痛治疗。未来，基于患者基因型的个体化阿片类药物选择和剂量优化有望实现。6.3 新型治疗技术与药物研发6.3.1 细胞治疗间充质干细胞（MSC）疗法在治疗骨癌痛方面展现出前景。2025年的临床前研究显示，鞘内注射人脐带来源的MSC可有效缓解骨癌痛，且安全性良好[8]。6.3.2 专业化Resolution介质专门化促解决介质（SPMs）是一类来自ω-3和ω-6脂肪酸的生物活性脂质化合物，具有抗炎和炎症解决的双重作用。2025年的综述显示，SPMs（如Resolvin D1、Resolvin E1等）可通过调节神经-免疫相互作用发挥镇痛作用，为非阿片类镇痛药物的研发提供了新方向[9]。6.4 挑战与展望尽管癌痛治疗取得了显著进展，但仍面临诸多挑战，包括：阿片类药物的合理使用与监管平衡、介入治疗的普及性与可及性、基层医疗机构的癌痛管理能力建设、以及资源有限地区患者的疼痛控制等。未来研究应聚焦于：开发更安全有效的镇痛药物和技术、建立规范的癌痛管理指南、加强姑息治疗培训、以及推动癌痛管理的均质化发展。 结论癌痛是恶性肿瘤患者最常见的症状之一，对患者的生活质量和整体预后产生深远影响。近三年来，癌痛治疗领域在药物治疗、非介入治疗、神经调控及多学科综合管理等方面均取得重要进展。阿片类药物仍是中重度癌痛治疗的基石，但需强调合理使用和个体化滴定。介入治疗技术和神经调控疗法为难治性癌痛提供了新的治疗选择。心理干预、运动疗法及补充替代疗法等非药物手段在综合管理中发挥着日益重要的作用。未来，随着精准医学和新型治疗技术的发展，癌痛管理将更加个体化、精准化，从而进一步提高患者的生活质量。 参考文献（略）