Enobosarm

聚焦 “ GPCR & 肥胖治疗” 肥胖，本质上是一种由遗传、环境、神经内分泌和行为因素共同驱动的慢性、复发性代谢疾病，不是单纯的生物方式问题，也不是单纯的意志力问题。这也是为什么单纯依靠生活方式干预通常难以长期维持。 近日（May 13），哥本哈根大学诺和诺德基金会基础代谢研究中心、礼来、德国 Helmholtz 糖尿病和肥胖研究中心等在 Nature Reviews Drug Discovery 上发文，系统性梳理了肥胖药物治疗的演进历程与当代格局。 【续上篇】👉   文献来源 01 肥胖药物治疗格局 续上篇…… GLP-1R/GIPR 双重靶向的替尔泊肽的成功，标志着肥胖药物治疗进入了多靶点受体作用的新纪元。 1.5、GLP-1R / GCGR 双重靶点共激动剂 胰高血糖素受体（GCGR） 的核心特点是： （1）显著提高能量消耗。 （2）同时可能升高血糖、增加心率、影响肌肉代谢。 因此，GCGR 是当前肥胖药物研发中最重要、也最“危险”的代谢靶点之一。长期以来，GCGR 因会升高血糖而被视为胰岛素的对立面；但它在肥胖治疗中，可通过独特的机制发挥减重作用。 GCGR 的核心机制：增加能量消耗 （1）GCGR  激动剂能够激活肝脏 GCGR，促进肝糖输出，增加糖原分解和生酮作用，升高血糖。 （2）GCGR 激动剂能够诱导肝脏进行无效底物循环，即，在没有 ATP 合成情况下消耗能量并产生热量，从而能增加能量消耗，增加基础代谢。 （3）GCGR 激动剂能够促进氨基酸摄取和分解代谢，降低循环氨基酸水平，但这也可能导致肌肉流失，因此需要注意平衡的安全问题。 （4）GCGR 激动剂可以促进肝脏脂肪酸氧化，减少肝脏内脂质堆积。 因此，单纯的 GCGR 激动会增加能量消耗，也会导致血糖升高、心率升高、并伴有潜在的肌肉流失，需要其他代谢靶点，如 GLP-1 来平衡，抵消各自不良反应。 GLP-1 能够压制 GCGR 的升糖副作用，同时保留 GCGR 的燃脂能力，于是，GLP1R-GCGR 双重激动剂来了！ 这类药物旨在结合 GLP-1R 的抑制食欲和 GCGR的增加能量消耗的优势。两者协同，能够实现“少吃、多消耗”，是现代肥胖治疗的最理想模式。 如何开发呢？平衡之道！ （1）改造胰高血糖素多肽序列 胰高血糖素本身是一种天然的强 GCGR 激动剂，并带有 GLP-1R若活性。 因此，首个完全合成的单分子 GLP1R-GCGR 协同激动剂来源于 2009 年通过对人源胰高血糖素多肽序列的反复修饰改造，以赋予其 GLP-1R 活性。 （2）优化内源性 GLP1R-GCGR激动剂 胃泌酸调节素（oxyntomodulin）是一种内源性的 GLP1R-GCGR 协同激动剂，虽在药理学上不平衡，但常作为化学优化改造的模板。 其本身存在的问题有：半衰期太短、活性不平衡，因此不适合药物化，需要进一步的优化改造。 本质上的开发策略是通过对天然模板进行氨基酸替代，做一个“混合肽”，使其兼具 GLP-1 和胰高血糖素的结构特征。 双重受体激动剂实现实体平衡最为重要，将决定成败！ （1）GCGR 太强，则会使血糖升高、心率增加、肌肉流失、并具有肝脏风险。 （2）GLP-1R太强，则双重激动剂就退化为普通 GLP-1R 药物，失去提高代谢、燃脂、在非酒精性脂肪性肝炎（MASH）治疗中的优势。 因此，开发的目标不是最大激动，而是最优比例平衡。 代表性药物如下 （1）Mazutide（玛仕度肽） 由礼来首研，礼来和信达生物联合推进的一种 GLP1R-GCGR双重激动剂，于2025年在中国上市，每周注射一次，用于成人肥胖或超重患者的长期体重控制。 这是一种胃泌酸调节素类似物，玛仕度肽通过激动GLP-1R促进胰岛素分泌、降低血糖和减轻体重，同时激动GCGR增加能量消耗、改善肝脏脂肪代谢。 临床研究表明其治疗24周可使体重降幅达21%，降低肝脏脂肪含量超80%，并显著改善腰围、血脂、血压、血尿酸及胰岛素敏感性等代谢指标。 （2）Survodutide 由Zealand 制药首研，并由勃林格殷格翰和Zealand联合开发的一种GLP1R-GCGR双重激动剂，每周一次注射。目前进入临床 III 期，用于肥胖和 MASH治疗。 这是一种 GLP-1R 偏向性共激动剂（8倍于GCGR），临床24周减重12.1%，但伴随有肠胃道不良反应，需要注意肝酶指标。 （3）Pemvidutide 由Spitfire制药首研，一种 GLP1R-GCGR共激动剂，每周注射一次，48周减重13.4%。目前进入临床II 期。这是一种平衡性共激动剂，肌肉流失风险较低。 这些GLP1R-GCGR双重共激动剂都主打：减重降脂、脂肪肝 MASH 适应症。 此外，也有不那么成功的案例： 比如 NN1177，以3：1比例有利于 GLP1R激活，在临床 I 期，12周减重高达 12.6%，但出现心率升高、不良肝脏生物标志物和血糖控制受损等安全信号，进而终止。 1.6、GLP-R / GIPR / GCGR 三重靶点激动剂 双重可以，那么三重也未尝不可一试！ 开发 GLP-1R/GIPR/GCGR 三重受体共激动剂，旨在通过单分子同时激活三个不同的受体，整合三种激素的生理效应，以期达到超越现有双靶点药物的减重效果，并改善代谢指标。 三大受体的协同机制：取长补短、协同增效，把“少吃、多消耗、更强代谢重塑”整合到一个分子里。 （1）GLP-1R 负责少吃：中枢控制食欲、延缓胃排空、促进胰岛素分泌；实现热量摄入减少、降糖。 （2）GIPR 负责增强协同：中枢增强饱腹感、改善胰岛素敏感性、减轻GLP-1R引起的恶心；实现减重和改善耐受性。 （3）GCGR 负责多消耗：增加能量消耗、促进肝脏脂肪酸氧化；实现减重幅度提升、改善 MASH。 GLP-1R系统 GIPR共同抑制食欲；GIPR还可以通过表达在血脑屏障等部位增强 GLP-1R 激动剂的中枢暴露；GCGR 增加能量消耗，对抗减重引起的代谢适应；GLP-1R 还可抵消 GCGR 激动可能引起的高血糖风险。 三重叠加，实现更强的减重、更干净的减脂、以及更好的代谢获益。 代表性药物：Retatrutide 由礼来开发，最具代表性的，也是该领域唯一已进入临床 III 期的分子。 该分子的设计是基于葡萄糖依赖性促胰岛素多肽（GIP）的多肽序列，通过加入 GLP-1R、GCGR 活性位点，不断地进行改造的。GIP 骨架更容易扩展、更稳定、更适合多受体兼容，是开发多受体共激动剂的主流模板。 通过不断地多肽序列位点突变、筛选、SAR 优化，本质上还是混合序列优化，实现最优三受体平衡优化。 Retatrutide 故意设计为 GIPR 偏向型三受体共激动剂，以增强耐受性、抗恶心、改善 CNS 协同；而 GCGR 故意相对较弱，这也是重点，以避免心率过高、高血糖、肌肉流失。 Retatrutide 同时引入 C20 脂肪酸二酸化改造，以实现长效化。半衰期约为 6 天，支持每周一次给药。 这是目前肥胖药物治疗最高的水准： （1）五糖尿病患者，40周实现22.1% 平均体重减轻； （2）2型糖尿病患者，40周治疗实现14.3%体重减轻； （3）对于特殊人群，不仅减重显著，还伴有其他获益，如改善膝骨关节炎疼痛和功能、改善 MASH。 然而，尽管疗效惊人，三重激动剂也面临独特的安全性挑战： （1）心血管风险，观察到剂量依赖性心率增加，随时间推移有所回落，但仍需长期监测。 （2）胃肠道耐受性，如恶心、呕吐、腹泻等仍是常见不良事件，发生率与现有 GLP-1 类似物相当。 （3）肌肉流失与氨基酸代谢，动物研究提示有剂量依赖性，仍需关注长期治疗影响。 此外，还有其他几种 GLP1R-GIPR-GCGR三受体激动剂在开发中。 Efocipegtrutide，由 Hanmi 制药开发，处于临床 II 期，主要用于 MASH 治疗。 UBT251，由诺和诺德开发，在中国人群的 II 期试验显示出 17.7%的减重效果。 GLP-1R/GIPR/GCGR 三重共激动剂代表了当前药理学设计的最高复杂度。它不仅仅是“加法”，而是通过平衡 GIPR 的代谢调节、GLP-1R 的食欲抑制和 GCGR 的能量消耗，试图打破单纯节食减肥带来的“代谢适应”瓶颈。 1.7、胰淀素（Amylin）受体激动剂 胰淀素（Amylin）是一种由胰岛β细胞分泌的肽类激素，其受体（AMYNR）实际上是降钙素受体（CalcR）与三种受体活性修饰蛋白（RAMP1-3）组成的异源二聚体，分为AMY1R、AMY2R、AMY3R三种亚型，其中 AMY3R 是介导减重的关键亚型。 AMYNR激动剂及其与GLP-1R激动剂的组合疗法，是继肠促胰素（Incretin）疗法后，肥胖药物治疗的新一代重要前沿。 胰淀素的作用机制：Amylin在餐后与胰岛素共同分泌，其核心作用机制分为一下两点。 （1）作用中枢神经系统，特别是下丘脑和脑干，产生饱腹感、抑制食欲，调节中脑边缘奖赏通路，降低对食物的渴求。 （2）作用外周系统，调控代谢，以延缓胃排空、延长饱腹感，抑制餐后胰高血糖素分泌、平稳餐后血糖、改善胰岛素敏感性，恢复瘦素敏感性。 即，Amylin被激活后，可抑制食欲、延缓胃排空、改善葡萄糖处理，以减脂肪为主，对肌肉影响温和。 Amylin 受体激动剂主要分为两类： （1）DACRA，即非选择性 Amylin 受体激动剂，同时激活 CalcR和 AMLNR。 代表性药物如，Pramlintide，通过对人源 Amylin 多肽序列引入大鼠脯氨酸序列，破坏人源 Amylin的二级结构，减少纤维形成，开发的第一代受体 Amylin 受体激动剂，2005年获批用于2型糖尿病，但需每日多次高剂量注射，不适用于长期体重管理。 Cagrilintide，诺和诺德开发，经过长效脂肪酸酰化改造，每周一次，26周体重下降 7.8%，主要用于与司美格鲁肽联用。 （2）SARA，即选择性 Amylin 受体激动剂，仅激活Amylin受体复合物，不激活活性降钙素受体，可能减少厌恶恶心副作用，其中主要激活 AMY3R。 代表性药物如 Elorallintide，礼来开发的高选择性 AMY3R 激动剂，48周减重可达 19.7%，耐受性由于非选择性 DACRA，且恶心等不适感更少，安全性更佳。 其他 DACRAs、SARAs药物如下表。 胰淀素受体激动剂从弹药减重幅度上看远不如 GLP-1R类激动剂，但是它们通过靶向不同的中枢神经通路，在现有的 GLP-1R 激动剂药物的基础上可进一步压低体重设定点，为追求更高减重目标提供了未来。 Amylin 与 GLP-1 机制互补：Amylin 主要作用于中枢“饱腹感”通路，GLP-1 作用于中枢“厌食”通路，两者部分重叠但不完全相同。这种多通路打击，是克服肥胖者瘦素抵抗、食欲反弹的关键。 在中枢层面，Amylin 和 GLP-1 均作用于脑干-下丘脑饱食通路，叠加抑制摄食。 在外周层面，GLP-1 抵消 Amylin 潜在的血糖波动；Amylin 强化 GLP-1 减重效力。 表现在身体成分上，对脂肪的作用占比更高，瘦体重流失更少。 因此，GLP-1/Amylin 双受体激动剂备受关注！ GLP-1 / Amylin 双受体激动剂的主要开发策略： （1）固定比例复方制剂策略 诺和诺德的 CagriSema，由Cagrilintide和Semaglutide组成。 在III期临床实现了 17.3% 的平均体重减轻，相比于单用司美格鲁肽，不仅增强了减重效果，还有助于改善血糖控制和脂肪肝。 （2）单分子双受体共激动剂策略 设计思路是将 GLP-1 和 Amylin 的活性融合到单分子中，实现统一的药代动力学，简化制剂和临床开发。代表性药物如下。 Zenagamtide，由诺和诺德开发的全球首个 GLP-1/Amylin 受体单分子双激动剂。在结构上，将Semaglutide 和 DACRA 结构融合在一起。包含每周一次的皮下注射以及每一一次口服片剂两种剂型。 皮下注射，36周减重 23.9%；每日口服，12周减重11.8%。减脂比例高，肌肉保留好，安全性与 GLP-1类相当。目前是减重效力第一梯队，接近三受体激动剂。且对血糖、脂肪肝、代谢综合征均有显著改善。耐受性由于多受体激动剂，无GCGR 带来的心率上升问题。 02 新一代口服减肥疗法 肥胖治疗正在迎来一场颠覆性的变革，研发的重心也在从单纯的“强效减重”转向“高质量减重、高依从性与整体代谢健康”。值此之际，口服药物凭借极高的便利性、可及性和成本优势，正在成为各大药企竞逐哦的下一个蓝海。 新一代口服肥胖治疗，呈现三大核心趋势。 2.1、口服肽类：打破生物利用度壁垒 传统多肽类药物极易在肠胃道被分解，因此长期依赖注射。 新一代口服多肽通过技术革新，正在实现与注射剂相当的疗效。 （1）口服 GLP-1R 激动剂 以口服司美格鲁肽为代表，利用吸收促进剂钠盐普罗札特（SNAC）的渗透促进技术，促进胃黏膜的跨细胞吸收，提高生物利用度（仅为0.5-1%）。 每日50mg口服，68周体重下降12.7%；每日25mg，64周体重下降11.4%。于2026年，25mg剂量已获得 FDA 批准用于体重管理。 口服 Ecnoglutide (VRB-101），通过偏向 cAMP 信号和渗透促进剂（T2026）技术，预计每周一次口服给药即可达到甚至超越现有注射剂的周暴露量，兼具强效减重潜力与极高的患者依从性。 （2）GLP-1R/Amylin 双激动剂 以口服 Zenagmitide 为代表，采用 SNAC 渗透促进技术，12周体重下降11.8%，已经入 III 期临床。 （3）GLP-1R/GIPR 双激动剂 以口服 VK2735 为代表，口服 13 周最高剂量体重下降 13%，在III 期临床阶段。 2.2、小分子小分子：摆脱多肽限制 小分子药物具有合成成本低、无需冷链、无饮食限制等优势。近年来得益于GLP-1R晶体结构的解析，成功开发出多个临床分子。 代表性药物：口服小分子 GLP-1R激动剂：Orforglipron 礼来开发的一种高亲和力部分激动剂，偏向 cAMP 信号，几乎不招募β-arrestin，减少脱敏。支持每日一次口服，无需空腹或限制饮水。 在III期试验中显示出约11.5%的减重效果，已于2026年获批上市。 高亲和力小分子 GLP-1R 激动剂的开发不仅验证了用非肽分子靶向该受体的可行性，也激发了设计低分子量、非肽的其他 B 类 GPCR 激动剂的兴趣。因此，临床前研究正在开发针对 GIPR、GCGR、CalcR和AMLNR的小分子肥胖疗法。 其他临床中的分子如下表： 2.3、追求“高质量减重”与全新靶点 下一代疗法不再仅仅盯着体重秤上的数字，而是更加关注减掉的到底是“脂肪”，还是“肌肉”，以及能否从根源上改善代谢。 （1）大麻素1受体（CB1R）拮抗剂的复苏 CB1R 拮抗剂在肥胖治疗领域确实经历了一段跌宕起伏的“前世今生”。早期全面溃败，如今借着新技术，王者归来。这一复苏主要得益于对药物机制和安全性的深刻反思与革新。 CB1受体在调节食欲、脂肪储存和能量代谢中起着核心作用。上世纪90年代，首个选择性CB1受体拮抗剂利莫那班（Rimonabant）问世，在临床试验中展现了出色的减重和改善代谢指标的效果，并于2006年在欧盟获批。 然而，它的辉煌极其短暂。由于CB1受体广泛分布于中枢神经系统，利莫那班在阻断食欲的同时，也引发了严重的神经精神副作用（如重度抑郁、焦虑甚至自杀倾向）。这导致其在2008年被强制撤市，整个CB1拮抗剂赛道也因此被长期冻结。 新一代 CB1R 拮抗剂在研发上进行了根本性挑战，主要集中在三个方向： 第一、外周限制性，这是主流策略。设计分子，限制其穿透血脑屏障，使其仅作用于肝脏、脂肪、胰腺等外周组织的 CB1R，从而保留代谢调节的同时，最大程度避免对大脑影响。 第二、中性拮抗剂。只阻断受体而不影响其他基础信号，以免重蹈利莫那班反向激动剂的作用，致使抑郁，以提升安全性。 第三、双重/多重靶点机制。将CB1R拮抗与其他代谢靶点，如iNOS抑制结合，通过协同作用，在降低剂量的同时增加疗效。 代表性药物，如 monllunabant，在IIa临床试验数据显示，16周体重减轻7.4%。然而，伴有轻度至中毒剂量依赖性神经精神副作用，如焦虑、易怒等。 （2）瘦体保留的药理学策略 肥胖治疗已进入“减肥增肌”的2.0时代！在高效减重的同时保留甚至增加肌肉，即高质量减重，已成为竞逐的核心焦点。 当前，针对肌肉的保护的药物开发策略主要集中三大方向。 第一、靶向肌肉萎缩素、活化素、ActRII通路，这是核心药物赛道。利用单克隆抗体或可溶性受体，阻断肌肉萎缩素、活化素A与其受体（ActRIIA/B）的结合，从而抑制肌肉分解并促进肌肉合成。 代表性药物，如礼来的 Bimagrumab，通过结合ActRIIA和ActRIIB受体，同时阻断肌肉萎缩素和活化素A。II期临床显示，单药治疗即可在减少脂肪的同时增加3.6%的瘦体重。礼来正推动其与替尔泊肽（Tirzepatide）联用，以实现“瘦身不瘦肌”。 第二、选择性雄激素受体调节剂（SARMs），旨在模拟雄激素的合成代谢作用，促进肌肉生长，但极力避免对前列腺等组织的副作用。 代表性药物如 Enobosarm，与司美格鲁肽联用，使患者肌肉流失减少71%。 第三、新型“保肌减肥”机制探索，如GRK 偏向性β2肾上腺素受体激动剂、口服四重激动剂NA-931等。 03 减重以外的受益 肥胖治疗已经不仅仅局限于减重与血糖控制，更为患者带来了广泛深远的健康获益，极大改善患者的生活质量与长期预后。 3.1、显著的心血管保护 这是目前证据最确凿、临床意义最重大的额外获益：降低重大心血管风险、全因死亡率下降、改善心力衰竭、降低心血管代谢风险。 3.2、骨关节炎与身体机能改善 减重药物对肥胖相关骨关节炎的治疗效果是近些年来的重大突破。 显著缓解关节疼痛、改善身体机能、提升日常活动能力。 3.3、广泛的代谢与器官保护 除了降糖，当前的肥胖药物还能对多个代谢指标和器官功能产生积极影响：改善脂肪肝（MASLD/MASH）、保护肾脏功能、改善阻塞性睡眠呼吸暂停（OSA)、全面优化代谢指标等。 3.4、神经保护与生活质量提高 降低神经退行性疾病风险、改善心理与认知状态。 现代肥胖药理治疗的核心目标，已经从单纯的“减轻体重”升维到了“全面改善健康”。通过降低心血管死亡风险、缓解关节疼痛、保护肝肾及改善代谢综合征，这些药物正在帮助患者获得更长、更健康的生命，而不仅仅是更轻的体重。 04 新兴治疗理念 未来的肥胖治疗将搞不一刀切模式，走向基于遗传背景、代谢特征、和临床表型的精准医疗。 （1）个体化联合疗法：定根据患者具体情况，定制联合用药方案。 （2）精准靶向递送：如通过多肽药物偶联（PDC）或肝靶向技术，将药物精准递送至特定组织，在增强疗效的同时最大程度减少全身副作用。 （3）基因与生物技术探索：从根源上调节与脂肪储存和食欲相关的基因通路，提供更具有决定性的解决方案。 05 挑战与未来 肥胖治疗取得革命性突破同时，也面临几大核心挑战： （1）生物学挑战：代谢适应与体重反弹的长期安全性担忧。 （2）减重质量问题：肌肉流失的隐忧。 （3）可负担性和公平获取。 肥胖治疗还面临着严峻的转化壁垒：有科学验证与生物标志物的转化瓶颈；也有医患认知鸿沟与系统性障碍；此外，也存在经济成本与标准化流失问题。 针对肥胖症治疗，单纯依靠抑制食欲来减少能力摄入，往往会触发机体防御机制，导致体重反弹。因此，靶向能量消耗成为了突破减重瓶颈、维持长期代谢健康的核心新兴理念。 参考文献： 1. Petersen, J., Finan, B., Johansen, V.B.I. et al. The evolving landscape of obesity pharmacotherapy. Nat Rev Drug Discov (2026).  DOI：10.1038/s41573-026-01427-1 2. Liskiewicz, D., Novikoff, A., Khalil, A. et al. GLP-1R–GIPR–PPARα/γ/δ quintuple agonism corrects obesity and diabetes in mice. Nature (2026).  DOI: 10.1038/s41586-026-10427-5（开源） 3. 摩熵医药检索 往期相关回顾推荐 扒一扒礼来口服小分子GLP-1 激动剂 Orforglipron 的制备和其它化学型激动剂 2025-04-20 礼来：小分子 GLP-1 激动剂 3 期临床显示同注射制剂一致性结果，有望迎来小分子 pk 多肽 2025-04-18 当代GPCRs药物发现 2024-07-31 GPCR配体发现：DEL联合化学相似性搜索，发现新型 GLP-1R 小分子激动剂 2026-01-26 欢迎关注 “早研早聊” 了解更多DEL、环肽 以及药物早期发现 咨询

--Phase 2b PLATEAU clinical study evaluating enobosarm + semaglutide is actively enrolling and on track for i nterim analysis first quarter calendar year 2027 — --Company to host conference call and webcast today at 8:00 a.m. ET— MIAMI, FL, May 13, 2026 (GLOBE NEWSWIRE) -- Veru Inc. (NASDAQ: VERU), a late clinical stage biopharmaceutical company focused on developing innovative medicines for the treatment of cardiometabolic and inflammatory diseases, today announced financial results for its fiscal 2026 second quarter ended March 31, 2026, and provided a corporate update. "We are extremely pleased with the progress of the enrollment of the Phase 2b PLATEAU clinical trial to evaluate the effect of enobosarm 3mg on total body weight, fat mass, lean mass, physical function, bone mineral density and safety in older patients who have obesity and receiving a semaglutide GLP-1 RA treatment for weight reduction. We are on track for presenting the results of the interim analysis which is expected in Q1 calendar year 2027,” said Mitchell Steiner, M.D., Chairman, President, and Chief Executive Officer of Veru Inc. Veru Obesity Program – Study of Enobosarm in combination with GLP-1 RA for higher quality weight reduction Phase 2b PLATEAU Clinical Study – Actively enrolling Phase 2b PLATEAU clinical trial is a double-blind, placebo-controlled study to evaluate the effect of enobosarm 3mg on total body weight, fat mass, lean mass, physical function, bone mineral density and safety in approximately 200 older patients (age ≥ 65 years) who have obesity (BMI ≥ 35) and are initiating semaglutide treatment for weight reduction. The Phase 2b PLATEAU study is designed to assess the ability of enobosarm treatment to break through the weight loss plateau observed in patients with obesity receiving GLP-1 RA treatment by preserving muscle mass and physical function to achieve clinically meaningful incremental weight reduction by 68 weeks. The primary efficacy endpoint of the study is the percent change from baseline in total body weight at 68 weeks. An interim analysis will be conducted at 36 weeks to assess the percent change from baseline in lean body mass and fat mass, as measured by DXA scan. The key secondary endpoints are total fat mass, total lean mass, physical function (stair climb test), mobility disability assessment, bone mineral density, and patient reported outcome questionnaires for physical function, HbA1c, and insulin resistance. Semaglutide was selected as the GLP-1 RA for the Phase 2b PLATEAU study to build on Veru’s previous clinical experience using enobosarm in combination with semaglutide in the positive Phase 2 QUALITY clinical study. Further, the clinical data from the Phase 2b PLATEAU clinical trial using injectable semaglutide may support the use of oral semaglutide in combination with oral enobosarm in future Phase 3 clinical studies. In contrast, there is no approved oral formulation for tirzepatide. The Principal Investigator for the Phase 2b PLATEAU clinical trial is Steven Heymsfield, MD, a Professor and the Director of the Body Composition-Metabolism Laboratory at the Pennington Biomedical Research Center in Baton Rouge, Louisiana. Dr. Heymsfield was also the Principal Investigator of Veru’s Phase 2 QUALITY clinical study. An interim analysis to assess change in lean body mass and fat mass as measured by DXA will be conducted at 36 weeks with data expected in the first quarter of calendar year 2027. Final topline clinical data is expected in the fourth quarter of calendar year 2027. Phase 2b QUALITY Clinical Study – Completed The Phase 2b QUALITY clinical study was a positive multicenter, double-blind, placebo-controlled, randomized, dose-finding clinical trial designed to evaluate the safety and efficacy of enobosarm 3 mg, enobosarm 6 mg, or placebo as a treatment to augment fat loss and to prevent muscle loss in 168 older patients (≥60 years of age) receiving semaglutide (Wegovy®) for weight reduction. After the efficacy dose-finding portion of the Phase 2b QUALITY clinical trial was completed at 16 weeks, participants continued into a Phase 2b maintenance extension study where all patients discontinued semaglutide treatment, but continued receiving placebo, enobosarm 3 mg, or enobosarm 6 mg as monotherapy in a double-blind fashion for 12 weeks. The Phase 2b QUALITY and Maintenance Extension clinical trial was a positive study that demonstrated that preserving lean mass and physical function with enobosarm plus semaglutide led to greater fat loss during the 16 week active weight loss period. While weight loss was similar across treatment groups in this short 16 week study, we anticipate that preservation of lean mass and function will lead to increased energy expenditure, and this effect coupled with the direct effects of enobosarm on the additional selective reduction in fat mass will result in incremental weight reduction in a longer 68 week clinical study in patients who have obesity. Second Quarter Financial Summary: Fiscal 2026 vs Fiscal 2025 Research and development expenses decreased to $3.1 million from $3.9 million General and administrative expenses decreased to $4.1 million from $5.2 million Operating loss from continuing operations decreased to $7.2 million from $8.1 million Net loss decreased to $2.7 million, or $0.12 per share, compared to $7.9 million, or $0.54 per share Year-to-Date Financial Summary: Fiscal 2026 vs Fiscal 2025 Research and development expenses decreased to $4.5 million from $9.6 million General and administrative expenses decreased to $8.2 million from $10.4 million Operating loss from continuing operations decreased to $12.6 million from $18.4 million Net loss decreased to $8.1 million, or $0.37 per share, compared to $16.8 million, or $1.15 per share Balance Sheet Information ​​​​​Cash, cash equivalents and restricted cash were $27.6 million as of March 31, 2026 versus $15.8 million as of September 30, 2025 Event Details The audio webcast will be accessible under the Home page and Investors page of the Company’s website at . To join the conference call via telephone, please dial 1-800-341-1602 (domestic) or 1-412-902-6706 (international) and ask to join the Veru Inc. call. An archived version of the audio webcast will be available for replay on the Company’s website for approximately three months. A telephonic replay will be available at approximately 12:00 p.m. ET by dialing 1-855-669-9658 (domestic) or 1-412-317-0088 (international), passcode 8826955, for one week. About Veru Inc. Veru is a late clinical stage biopharmaceutical company focused on developing innovative medicines for the treatment of cardiometabolic and inflammatory diseases. The Company’s drug development program includes two late-stage novel small molecules, enobosarm and sabizabulin. Enobosarm, an oral selective androgen receptor modulator (SARM), is being developed as a next generation drug that makes weight reduction by GLP-1 RA drugs more tissue selective for loss of fat and preservation of lean mass to improve body composition and physical function which is expected to result in clinically meaningful incremental weight reduction versus GLP-1 RA therapy alone. Sabizabulin, a microtubule disruptor, is being developed for the treatment of chronic inflammation related to atherosclerotic cardiovascular disease. Forward-Looking Statements This press release contains "forward-looking statements" as that term is defined in the Private Securities Litigation Reform Act of 1995, including, without limitation, express or implied statements related to the planned design, enrollment, timing, commencement, interim, topline and full data readout timing, scope and regulatory pathways for the continued development of enobosarm in patients with obesity, including the PLATEAU Phase 2b study; the planned design, number of sites, timing, endpoints, patient population and patient size of such trial and whether the PLATEAU trial will successfully meet any of its primary or secondary endpoints; whether the results of the Phase 2b QUALITY study and the extension maintenance study of enobosarm, including weight loss, preservation of lean mass and physical function and loss of fat mass, will be replicated to the same or any degree in the PLATEAU Phase 2b study or in any future Phase 3 studies; whether and when the PLATEAU Phase 2b study of enobosarm will produce an interim analysis and/or topline data; whether enobosarm in combination with a GLP-1 RA drug will provide a higher quality and/or greater quantity weight loss in patients and whether this combination therapy will be the next generation drug that makes weight reduction more tissue selective for loss of fat, preservation of lean mass and physical function, improved body composition and maintaining or increasing bone mineral density; whether patients treated with enobosarm in the PLATEAU Phase 2B study will preserve lean mass and physical function leading to an increased use of energy and whether such effects will result in incremental weight reduction; whether patients treated with enobosarm in the PLATEAU Phase 2B study will break through the weight loss plateau and achieve clinically meaningful incremental weight reduction by preserving muscle mass and physical function; and whether the oral form of semaglutide may be used in combination with enobosarm in future Phase 3 clinical studies and whether the injectable semaglutide used in the PLATEAU Phase 2B study data of enobosarm will support the use of oral semaglutide formulation in combination with oral enobosarm in future Phase 3 clinical studies; The words "anticipate," "believe," "could," "expect," "intend," "may," "opportunity," "plan," "predict," "potential," "estimate," "should," "will," "would" and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. Any forward-looking statements in this press release are based upon current plans and strategies of the Company and reflect the Company's current assessment of the risks and uncertainties related to its business and are made as of the date of this press release. The Company assumes no obligation to update any forward-looking statements contained in this press release because of new information or future events, developments, or circumstances. Such forward-looking statements are subject to known and unknown risks, uncertainties and assumptions, and if any such risks or uncertainties materialize or if any of the assumptions prove incorrect, our actual results could differ materially from those expressed or implied by such statements. Factors that may cause actual results to differ materially from those contemplated by such forward-looking statements include, but are not limited to: the development of the Company’s product portfolio and the results of clinical studies, including any interim or topline analysis, possibly being unsuccessful or insufficient to meet applicable regulatory standards or warrant continued development; although the Company has sought and received feedback from the FDA on the designs of its clinical trials and intends to continue to do so, the FDA may ultimately disagree that the Company’s clinical trials support approval; the Company’s ability to reach agreement with FDA on study design requirements for the Company’s planned clinical studies, including for the Phase 2b program for enobosarm as a weight loss or body composition drug and the number of future Phase 3 studies to be required and the cost thereof; potential delays in the timing of and results from clinical trials and studies, including as a result of an inability to enroll sufficient numbers of subjects in clinical studies or an inability to enroll subjects in accordance with planned schedules; the ability to fund planned clinical development as well as other operations of the Company; the Company plans to prioritize the use of its current internal cash to the development of enobosarm, with a primary near-term focus on funding its PLATEAU Phase 2b clinical trial, and as a result advancement of sabizabulin as a treatment for slowing progression of or promoting regression of atherosclerosis disease will depend upon the Company securing additional funding; whether the Company will be able to partner with another company in the development of enobosarm or sabizabulin; the timing of any submission to the FDA or any other regulatory authority and any determinations made by the FDA or any other regulatory authority; the potential for disruptions at the FDA or other government agencies to negatively affect our business, including as a result of a future shutdown of the U.S. government; any products of the Company, if approved, possibly not being commercially successful; the ability of the Company to obtain sufficient financing, including any partnership or collaboration agreements, on acceptable terms when needed to fund development and operations and to enable us to continue as a going concern; the effect of the SEC’s “baby shelf” rules on the Company’s ability to raise sufficient capital when needed; demand for, market acceptance of, and competition against any of the Company’s products or product candidates; new or existing competitors with greater resources and capabilities and new competitive product approvals and/or introductions; changes in regulatory practices or policies or government-driven healthcare reform efforts, including pricing pressures and insurance coverage and reimbursement changes; the Company’s ability to protect and enforce its intellectual property; costs and other effects of litigation, including regulatory challenges, product liability claims, intellectual property, securities litigation and litigation with the purchaser of the Company’s FC2 business; the Company’s ability to identify, successfully negotiate and complete suitable acquisitions or other strategic initiatives; the Company’s ability to successfully integrate acquired businesses, technologies or products; and other risks detailed from time to time in the Company’s press releases, shareholder communications and Securities and Exchange Commission filings, including the Company's Form 10-K for the year ended September 30, 2025, and subsequent quarterly reports on Form 10-Q. These documents are available on the “SEC Filings” section of our website at . Wegovy® is a registered trademark of Novo Nordisk A/S. FINANCIAL SCHEDULES FOLLOW Veru Inc. Condensed Consolidated Balance Sheets (unaudited) March 31, September 30, 2026 2025 Cash, cash equivalents, and restricted cash $ 27,596,820 $ 15,794,562 Investments in equity securities 3,167,733 2,525,305 Prepaid expenses and other current assets 2,590,923 595,251 Total current assets 33,355,476 18,915,118 Property and equipment, net 308,421 364,808 Operating lease right-of-use assets 2,479,348 2,746,014 Goodwill 6,878,932 6,878,932 Other assets 60,549 930,847 Total assets $ 43,082,726 $ 29,835,719 Accounts payable $ 2,071,710 $ 3,121,448 Accrued compensation 2,164,000 3,510,237 Accrued expenses and other current liabilities 382,876 394,529 Operating lease liability, short-term portion 770,257 758,946 Total current liabilities 5,388,843 7,785,160 Operating lease liability, long-term portion 2,063,089 2,358,018 Other liabilities 845,173 1,359,871 Total liabilities 8,297,105 11,503,049 Total stockholders' equity 34,785,621 18,332,670 Total liabilities and stockholders' equity $ 43,082,726 $ 29,835,719 Veru Inc. Condensed Consolidated Statements of Operations (unaudited) Three Months Ended Six Months Ended March 31, March 31, 2026 2025 2026 2025 Operating expenses: Research and development $ 3,145,783 $ 3,932,102 $ 4,489,965 $ 9,648,932 General and administrative 4,073,185 5,164,433 8,153,018 10,391,546 Total operating expenses 7,218,968 9,096,535 12,642,983 20,040,478 Gain on sale of ENTADFI® assets — 974,303 — 1,669,519 Operating loss (7,218,968 ) (8,122,232 ) (12,642,983 ) (18,370,959 ) Non-operating income: Gain on extinguishment of debt — — — 8,624,778 Other non-operating income, net 4,126,418 269,839 4,217,854 83,885 Total non-operating income 4,126,418 269,839 4,217,854 8,708,663 Net loss from continuing operations (3,092,550 ) (7,852,393 ) (8,425,129 ) (9,662,296 ) Net income (loss) from discontinued operations, net of taxes 351,418 (49,226 ) 351,418 (7,184,670 ) Net loss $ (2,741,132 ) $ (7,901,619 ) $ (8,073,711 ) $ (16,846,966 ) Net loss from continuing operations per basic and diluted common shares and pre-funded warrants outstanding $ (0.13 ) $ (0.54 ) $ (0.39 ) $ (0.66 ) Net income (loss) from discontinued operations per basic and diluted common shares and pre-funded warrants outstanding $ 0.02 $ (0.00 ) $ 0.02 $ (0.49 ) Net loss per basic and diluted common shares and pre-funded warrants outstanding $ (0.12 ) $ (0.54 ) $ (0.37 ) $ (1.15 ) Basic and diluted weighted average common shares outstanding 23,050,320 14,638,614 21,655,705 14,638,502 Veru Inc. Condensed Consolidated Statements of Cash Flows (unaudited) Six Months Ended March 31, 2026 2025 Net loss $ (8,073,711 ) $ (16,846,966 ) Adjustments to reconcile net loss to net cash used in operating activities (2,679,386 ) 2,525,640 Changes in operating assets and liabilities (4,331,318 ) (4,748,124 ) Net cash used in operating activities (15,084,415 ) (19,069,450 ) Net cash provided by investing activities 3,520,328 18,393,168 Net cash provided by (used in) financing activities 23,366,345 (4,221,611 ) Net increase (decrease) in cash, cash equivalents, and restricted cash 11,802,258 (4,897,893 ) Cash, cash equivalents and restricted cash at beginning of period 15,794,562 24,916,285 Cash, cash equivalents and restricted cash at end of period $ 27,596,820 $ 20,018,392 Investor and Media Contact: Samuel Fisch Executive Director, Investor Relations and Corporate Communications Email: veruinvestor@verupharma.com