Tofacitinib Citrate

-01-引言系统性红斑狼疮（SLE）是一种慢性多系统的自身免疫性疾病，通常影响育龄妇女。SLE患病率为每10万人20至150例，主要取决于遗传因素。SLE的特征在于严重程度，持续时间和器官受累的高度异质性，这种临床异质性源于构成该疾病基础的多种相互关联的免疫和信号传导途径的失调。SLE的病程通常遵循高疾病活动性与疾病静止期交替的一般模式。这些疾病发作的持续时间，炎症强度和器官受累相对不可预测。在过去的十年中，随着两种单克隆抗体（belimumab和anifrolumab）和voclosporin治疗狼疮性肾炎的批准，SLE新疗法的开发取得了重大进展，包括针对特定免疫途径的方法，以及恢复免疫稳态的努力，例如消除致病性B细胞的CAR-T细胞疗法，低剂量IL-2或调节性T细胞疗法。而许多在研药物的II/III期阳性临床试验预示着更多新药有望获得批准。-02-一、SLE的疾病异质性SLE由于多器官受累，患者表现出多种症状和实验室异常。SLE可以影响粘膜皮肤系统，导致脱发，口腔溃疡和阳光敏感的面部皮疹，以及更深的炎症性皮疹，甚至引起永久性疤痕。当它影响肌肉骨骼系统时，SLE会导致关节和/或腱鞘发炎，导致慢性关节松弛。它还可以影响血液系统，引起血细胞减少症，浆膜炎症导致心包炎和/或胸膜炎。SLE特别针对肾脏，在几乎一半的患者中引起肾小球肾炎（狼疮性肾炎，LN），这是SLE最常见的严重器官表现。最后，SLE可影响神经系统，引起多种症状，最明显的是脑血管事件，癫痫发作和器质性脑综合征。机制上讲，SLE归因于适应性免疫应答的异常，最终导致自身抗体的产生，调节性（Treg）T细胞功能的降低，自我定向的细胞毒性T细胞应答的增加以及炎性细胞的扩增和浸润。引发的病理学因素包括IL-2水平的降低、先天免疫细胞如单核细胞，中性粒细胞以及血小板的激活。这些免疫介质并非独立的工作，而是相互交织形成复杂的致病网络。在细胞水平上同样存在复杂的致病网络，包括激酶和磷酸酶的激活，转录因子的失调，异常的糖酵解，谷氨酰胺分解和氧化磷酸化，以及氧化应激和线粒体异常。遗传因素与普通人群相比，SLE患者的亲属患SLE的风险增加（二级亲属为3.6倍，一级亲属为10.3倍）。现在已知有许多非常罕见的单基因突变可以单独引起SLE，每种突变都通过独特的途径。其中突出的是补体因子缺陷-例如补体C1q亚组分缺陷，导致凋亡细胞清除不良；或C4缺陷，导致自身反应性B细胞缺失缺陷；以及DNAse缺陷，导致循环DNA裂解不良。编码Toll样受体7（TLR 7）基因的功能获得突变也可能引起SLE。环境和表观遗传因素SLE也可以通过分子模拟和TLR的参与由环境因素触发。SLE疾病最常见的两种环境触发因素是紫外线和致病病原体。紫外线可以促使角质形成细胞死亡并释放自身抗原，从而激活自身反应性细胞。它可能进一步募集和激活嗜中性粒细胞以产生NETs，并进一步促进皮肤炎症。EBV病毒通过分子模拟或调节多个转录因子位点来促进细胞的自身免疫表型，从而引发SLE。研究还发现了SLE患者的微生物组改变。还有高度暴露于细颗粒物等空气污染物也与SLE发病有关，尤其是在高遗传风险的患者中。除了这些环境因素之外，一些药物如普鲁卡因胺（抗心律失常），肼苯哒嗪（血管扩张剂）或米诺环素（抗生素）等也可能具有表观遗传效应，有助于SLE的发展。性别相关因素SLE多发于女性，性激素，特别是雌激素是重要因素。此外，女性SLE的发病率也受到第二条X染色体的影响，该染色体编码免疫相关蛋白，如TLR-7和TLR-8，女性SLE患者的X染色体不完全失活与自身免疫的发展有关。-03- 二、SLE的传统治疗大多数SLE疾病发作最初是用不同剂量的皮质类固醇治疗的。然而，皮质类固醇并不是都有效，并且具有时间和剂量依赖性的副作用，这些副作用会增加SLE的发病率和死亡率，包括体重增加，糖尿病，心血管疾病，感染，骨质疏松症和白内障。因此，新药开发的主要策略之一是寻找可以减少甚至消除皮质类固醇使用的治疗方法。羟氯喹（HCQ）是一种干扰内体TLR信号传导的抗疟药，是SLE疾病缓解治疗的基石。HCQ可减少疾病活动，已被证明可降低SLE发病率和死亡率。HCQ通常耐受性良好，但长时间使用后可能导致视网膜毒性。另外，HCQ通常不足以作为单一疗法，需要额外的免疫抑制药物-通常是抗代谢药物，如甲氨蝶呤或硫唑嘌呤来控制疾病活动。有丝分裂抑制剂环磷酰胺是另一种公认的SLE药物。它可以减缓LN向终末期肾病的进展。然而，环磷酰胺被发现对膀胱和骨髓有毒副作用，并且导致SLE患者的严重感染和卵巢早衰。-04-三、针对免疫细胞的抗体治疗B细胞清除由于自身抗体和B细胞在SLE发病机制中的重要性，B细胞清除疗法备受瞩目。第一种用于SLE清除B细胞的生物制剂是利妥昔单抗，一种抗CD20嵌合单克隆抗体。利妥昔单抗在两项针对SLE随机临床试验（RCT）中进行了测试，然而却没显示出比安慰剂更好的效果。这可能是由于B细胞清除不完全，特别是在淋巴结等组织中。另外两个抗CD20抗体obinutuzumab和ocrelizumab也在SLE的临床研究中进行了测试。ocrelizumab的试验不太顺利，一个因为无效，一个因为感染风险太高而提前终止。但Obinutuzumab在狼疮肾炎的 III 期试验中取得了成功，和标准治疗联用，显著提高了肾脏完全缓解 CR 的比例（46.4%比33.1%，P=0.02)。这再次证明了 B 细胞靶向治疗的价值。此外，CD20 主要在未成熟和成熟 B细胞上表达，而在产生大量致病抗体的浆母细胞和浆细胞上表达量很低。所以，研究人员也在寻找其他靶点，比如 CD19，CD22，BAFF-R 和CXCR5 。这些靶点分别位于B 细胞发育的不同阶段，多个靶向药物正处于临床研究中。浆细胞清除浆细胞代表B细胞分化为抗体分泌细胞的最后阶段，这些浆细胞是长期自身免疫的主要驱动因素。浆细胞表达多种抗原：其中一些是浆细胞特异性的（例如CD138或BCMA），有一些（如CD19或CD38）也存在于其他免疫细胞。Daratumumab最初是为多发性骨髓瘤开发的CD38靶向抗体，其清除CD38+细胞，其在SLE和LN患者中显示出有希望的结果。其他多个靶向CD38的单克隆抗体也在SLE药物开发管线中，包括mezagitamab（NCT03724916）和felzartamab（NCT05140824）。靶向FcRnFc受体（FcRn）的新生儿同种型促进循环免疫球蛋白的再循环，从而大大延长其半衰期。Nipocalimab是一种靶向FcRn的去糖基化IgG1抗体，已被证明可以剂量依赖性地降低总抗体和自身反应性抗体。其目前在SLE患者中正进行II期试验（NCT04882878）。靶向pDCI型干扰素（IFN-I）在SLE中的作用已得到充分证明，浆细胞样树突状细胞（pDC）是其主要来源，这促进开发了针对pDC的治疗方法。Litifilimab是一种IgG1的单克隆抗体，可识别pDC特异性标记物血液树突状细胞抗原II（BDCA）。Litifilimab在两项II期试验中对皮肤狼疮患者和SLE患者显示出临床疗效，但对关节狼疮表现的疗效较差。Daxdilimab是靶向免疫球蛋白样转录物7（ILT7）的单克隆抗体，在II期非肾脏SLE试验（NCT04925934）中未达到其主要疗效终点，但目前正在进行另一项LN研究（NCT05540665）。针对共刺激受体的抗体抗原呈递后的T细胞活化需要共刺激，这是通过T细胞和抗原呈递细胞的细胞表面上的同源受体与细胞表面配体的结合来提供的。阻断CD40/CD40L轴是SLE开发中最有前景和最领先的，其他几种途径也正在开发中。Dapirolizumab最近已在SLE中进行了测试，尽管II期试验未达到其主要剂量反应疗效结果，但据报道III期研究呈阳性。相比之下，在LN患者中，BI655064的CD40阻断性抗体显示出令人失望的结果，已停止开发。另一种抗CD40单克隆抗体（iscalimab）目前正在SLE和LN患者的试验中进行测试（NCT03656562和NCT03610516）。Abatacept是CTLR-4的FC融合蛋白，可以阻断CD28与其配体CD80/86的结合，然而，Abatacept在SLE的II期试验中未能显示出临床疗效。此外，BTLA激动剂（LY3361237）目前处于SLE的II期，预计很快就会有结果（NCT05123586）。-05-四、抗细胞因子疗法BAFF和APRILBAFF（也称为B淋巴细胞刺激因子）是由骨髓细胞，树突状细胞或其他抗原呈递细胞以及多种其他细胞类型分泌的细胞因子，可促进B细胞，浆母细胞和浆细胞的存活。BAFF受体BAFF-R在这些产生自身抗体的B细胞中上调，因此，BAFF/BAFF-R轴是SLE发展和持续性自身免疫的中心驱动因素。Belimumab是一种中和循环BAFF的IgG1抗体，已在非肾性SLE的两项III期研究中进行了评估，自身抗体滴度以及粘膜皮肤，关节和血管疾病相关表现均得到改善。这些结果促使belimumab被批准，成为50多年来SLE的第一种批准药物。Telitacicept是一种TACI-FC融合蛋白，可识别并阻断BAFF和增殖诱导配体（APRIL）。Telitacicept在IIb期研究中显示出对非肾性SLE患者的疗效，目前正在III期研究（NCT05306574）中进行测试。1型IFN1型IFN升高存在于50-90%的SLE患者中，并对先天性和适应性免疫细胞产生多种去调节作用。然而，rontalizumab和sifalimumab在内的几种IFN-α靶向单克隆抗体未能在SLE中显示出疗效，这可能是由于无法抑制所有的IFN-α亚型。Anifrolumab是一种IgG1的单克隆抗体，靶向IFNAR受体，在SLE的两项III期试验（TULIP-1和TULIP-2）中进行了评估。虽然试验之间存在差异，但许多次要终点有利于anifrolumab组，这促使其被批准用于治疗SLE。anifrolumab在粘膜皮肤SLE表现的患者中显示出优异的疗效。然而，阻断1型IFN的代价是病毒感染或再激活的风险增加，例如水痘带状疱疹或流感。IL-23和IL-17IL-23参与幼稚CD4+T细胞极化为TH17致病表型，而TH17细胞通过产生IL-17参与SLE疾病进展和器官炎症。ustekinumab是一种通过中和IL-23p40亚基来抑制TH17极化的单克隆抗体，虽然ustekinumab的II期试验在SLE中显示出有希望的结果，但这些结果在随后的III期试验中没有重复。Guselkumab是另一种针对IL-23的单克隆抗体，目前正在LN患者中进行测试（NCT04376827）。抗IL-17A单克隆抗体secukinumab已在III期试验中进行了测试，该试验在无效分析后早期终止（NCT04181762）。其他细胞因子靶标评估针对SLE中其他细胞因子的单克隆抗体的试验，例如IL-6（PF-04236921），IL-6受体（vobarilizumab，NCT02437890）或IL-21（BOS161721，NCT03371251）尚未显示出临床上有意义的改善。类似地，用单克隆抗体BT063（NCT02554019）抑制IL-10（一种参与B细胞成熟并具有免疫调节特性的细胞因子）也未能证明其功效。-06-五、免疫细胞信号抑制剂许多公认的细胞因子及其同源受体使用共享的细胞内信号传导途径。这开辟了通过抑制所涉及的信号传导途径同时抑制几种细胞因子的可能性。JAK–STAT途径是细胞因子参与的主要细胞内信号传导途径之一，因此受到了广泛关注。JAK抑制剂JAK-STAT途径与SLE中的几种关键细胞因子有关，例如1型IFN和IL-10，以及IL-12和IL-23。JAK-STAT信号传导在调节T细胞中的干扰素途径和B细胞中自身抗体的产生中很重要，所有这些都与SLE易感性有关。Tofacitinib 是一种 pan JAK 抑制剂，早期研究显示它能抑制1型IFN信号，减少低密度粒细胞和中性粒细胞胞外陷阱（NETs）。Baricitinib主要抑制 JAK1 和 JAK2，II 期试验中显示出改善皮肤关节症状和降低抗 dsDNA 抗体的效果，但 III 期产生不一致的结果，一个成功 （BRAVE1），一个失败（BRAVE2）。还有 Filgotinib （JAK1抑制剂）和 Lanraplenib（SYK 抑制剂）的联合试验，以及 Upadacitinib （JAK1抑制剂）和 Elubrutinib （BTK 抑制剂）的联合试验，都在探索中。此外，FDA 对高剂量的 pan JAK 抑制剂比如 Tofacitinib 发出了安全警告，提示可能存在血栓、心血管事件甚至癌症风险。由于大约三分之一的SLE患者具有抗磷脂抗体（这会增加血栓栓塞和心血管事件的风险），因此开发此类治疗剂需要格外谨慎。TYK2抑制剂TYK2 是 JAK 家族的另一个成员，其选择性抑制也能影响多个促炎细胞因子的信号。Deucravacitinib 是一种新型的选择性 TYK2 抑制剂，II 期试验显示高于安慰剂的药效，但感染和皮肤问题比如皮疹、痤疮的发生率也更高。还有一项正在进行的II期研究正在测试另一种用于SLE的TYK2抑制剂GLPG3667（NCT05856448）。BTK抑制剂布鲁顿酪氨酸激酶（BTK） 是 B 细胞受体信号通路中的关键分子，抑制它能限制 B 细胞的活化。许多BTK 抑制剂，比如 Evobrutinib、Fenebrutinib、Branrutinib、Orelabrutinib、Elubrutinib，都在 SLE 中进行了 II 期试验。evobrutinib（NCT02975336）和fenebrutinib（NCT02908100）均未显示对SLE疾病严重程度的显著影响。Orelabrutinib在I/II期联合临床试验中进行了评估，结果显示蛋白尿，抗dsDNA和IgG水平降低，总B细胞计数与补体C4水平升高。IIb期临床试验（NCT05688696）目前正在进行中。mTOR抑制剂雷帕霉素（mTOR）途径哺乳动物靶标的过度活化导致Treg细胞的抑制，自身反应性T效应细胞的促进，自身反应性B细胞的存活并分化为抗体产生细胞，免疫细胞中的高代谢状态以及单核细胞过量产生干扰素，所有这些都导致自身免疫反应增加。mTOR抑制剂Sirolimus 在真实世界和Meta 分析中显示出一定的益处。此外，双重mTORC1/mTORC2抑制剂INK128 这种更强力的 mTOR 抑制剂在动物模型中也显示出效果。未来，mTOR 抑制剂可能与现有免疫抑制剂联合使用，以期达到更好的疗效。磷酸酶抑制剂钙调神经磷酸酶是一种钙-钙调蛋白依赖性磷酸酶，参与介导T细胞活化的细胞内信号传导途径。钙调神经磷酸酶抑制剂，如环孢菌素和他克莫司，已经在SLE中使用了几十年，因为它们不仅抑制T细胞活化，而且稳定足细胞的细胞骨架。长期研究证明了环孢菌素作为维持治疗的安全性和有效性，环孢菌素的另一个优点是可以在怀孕期间使用。然而，肾毒性仍然是一个问题，限制了它的使用。Voclosporin 是一种更新一代的Calcineurin 抑制剂，它的药代动力学和安全性有所改善。根据AURA-LV和AURORA-1试验的结果，Voclosporin已被批准用于LN，与安慰剂相比，高剂量组的完全肾反应率约为50%。-07-六、Treg细胞增强方法Treg细胞在发展和维持自身耐受中起关键作用，并且在包括SLE和类风湿性关节炎在内的自身免疫性疾病中在数量和功能上受损。因此，通过增强Treg细胞来恢复免疫平衡和自我耐受是缓解甚至治愈SLE的合理策略。IL-2通过促进Treg细胞的发育和功能在免疫耐受中发挥重要作用。在自身免疫条件下刺激Treg细胞的低剂量IL-2（IL-2LD）疗法已被广泛评论。大量的临床试验已经证实了IL-2LD在 SLE 中的有效性，它能改善疾病活动指数 SLEDAI、SRI 4，减少蛋白尿，减少激素用量，改善皮肤、关节、脱发等症状，还能降低致病性的T 细胞比如 Tfh、Th17和 B 细胞。总体而言，IL-2LD为恢复SLE 患者的免疫平衡提供了一个非常有希望的方向。除了 IL 2，直接输注扩增后的Treg 细胞也是一个方向，但如何保证这些细胞在体内稳定持久地工作，还是个技术难题。-08-七、靶向补体系统LN中通过经典途径和凝集素途径持续激活补体系统。所以，靶向补体系统也是一个治疗策略。Avacopan 是一种口服的 C5a 受体拮抗剂，C5a 是补体激活后产生的一种强效炎症介质，Avacopan 在 ANCA 相关血管炎中显示出非常好的效果，现在也在 SLE 中进行评估。Ravulizumab 是一种抗C5 的单抗，能阻止膜攻击复合物 MAC 的形成，Ravulizumab已经获批用于治疗阵发性睡眠性血红蛋白尿症、非典型溶血性尿毒综合征和重症肌无力，现在也在早期狼疮肾炎和IgA 肾病中进行试验。 替代补体途径因子D的口服抑制剂Vemircopan（ALXN2050）也正在LN和IgA肾病患者中进行评估（NCT05097989）。补体因子B抑制剂iptacopan的测试正在进行II期试验（NCT05268289）。-09-八、细胞疗法靶向B细胞的CAR-T细胞疗法CAR-T细胞疗法现在是SLE和其他自身免疫性疾病的主要研究重点。在一项单中心研究中，8名严重难治性SLE患者接受了靶向B细胞特异性抗原CD19的自体第二代CAR-T细胞治疗，其中五人经历了低度的细胞因子释放综合征。同时，观察到外周B细胞快速清除，自身抗体滴度和疾病活性迅速降低。令人兴奋的是，尽管B细胞在3-4内完全再生，但未发现临床复发迹象。此外，在难治性LN患者中使用双特异性CD19/BCMA CAR-T细胞的概念验证I期研究中显示出阳性结果。在这项研究中，所有自身抗体消失。基于Treg的细胞疗法恢复SLE中的Treg细胞调节功能和免疫稳态至关重要，这可以通过基于Treg细胞本身操作的疗法来实现。目前，受到关注的是自身抗原特异性CAR-Treg细胞的过继转移。在最近的一项动物研究中，原代人Treg细胞与CD19 CAR的mRNA共转染，在SLE的人源化小鼠模型中，所得的CAR Treg细胞抑制了B细胞并降低自身免疫标志物。间充质干细胞间充质干细胞是具有免疫调节特性的非造血多能成纤维细胞干细胞的子集。它们存在于所有器官中，可以从脐带血中收集。包括随机对照试验在内的多项研究报道，干细胞注射可改善严重SLE，但荟萃分析显示，12岁后临床获益不持久。-10-九、靶向其它机制血小板抑制血小板参与SLE免疫失调的许多方面，包括pDC产生IFN-1，中性粒细胞活化和Treg细胞功能障碍，所有这些都会导致器官损伤。血小板可以通过抑制其活化直接靶向，也可以通过靶向具有促炎特性的血小板分子如CD40L或P-选择素间接靶向。免疫代谢代谢途径是免疫细胞功能的重要决定因素，代谢调节可以纠正其异常功能并改善疾病活动。二甲双胍是一种用于治疗糖尿病的药物，在SLE患者中进行了试验，结果显示中度至重度眩晕减少，皮质类固醇使用减少。另一种抗糖尿病药物格列福嗪在免疫介导的肾小球肾炎中表现出抗蛋白尿和肾保护作用，它们可能改善SLE患者的肾脏和心血管结局。用于治疗糖尿病和肥胖症的胰高血糖素样肽1（GLP-1）类似物也可能对SLE和LN产生影响。抗氧化药物活性氧参与包括SLE在内的多种疾病的发病机制，抗氧化剂可用作辅助治疗。N-乙酰半胱氨酸是一种口服抗氧化剂，在双盲RCT213中显示出功效。正在进行更大规模的试验（NCT00775476）。-11-十、双特异性抗体最初开发用于癌症适应症的双特异性T细胞接合器，可以靶向B细胞和T细胞的bsAb是自身免疫性疾病中有前途的治疗手段Teclistamab是一种靶向BCMA和CD3的bsAb，已成功治疗难治性SLE患者以及其他全身性自身免疫性疾病。Mosunetuzumab，一种CD3XCD20的bsAb目前正在进行SLE测试（NCT05155345）。Blinatomumab，一种CD19×CD3的bsAb在严重系统性硬化症和类风湿性关节炎中显示出疗效，SLE的II期临床试验正在开始（NCT06570798）。CD22×CD20的bsAb也被认为可能用于SLE。Rozibafusp alfa（AMG 570）是一种靶向ICOS和BAFF的bsAb，两者都参与调节T细胞活化和B细胞存活。SLE的临床研究已经完成，但结果尚未报道（NCT04058028）。Obexelimab（XmAb5871）是一种靶向CD19和FcγRIIb的bsAb，未能达到其主要终点。PRV-3279是一种靶向FcγRIIb和CD79B的新型bsAb，是另一种正在探索其在SLE中治疗潜力的候选药物（NCT05087628）。这些研究表明，使用双特异性或三特异性抗体治疗SLE是有效靶向免疫途径并使用协同方法控制疾病的非常有前途的途径。-12-结语自从 Belimumab 批准以来，SLE 的治疗领域像是经历了一场革命，各种新思路、新药物层出不穷。但同时，多个失败的临床试验也在提示我们，SLE不是由单一原因造成的，而是多个相互关联的病理过程共同作用的结果。指望一种药能解决所有问题，几乎是不可能的。所以，未来我们需要更好的生物标志物，能引导我们对患者用药。此外，联合用药是趋势，把针对不同通路的药物组合起来覆盖更多患者。目前，人工智能和大数据分析有助于我们整合各种信息，为每个患者量身定制最佳方案。SLE 的治疗之路依然漫长，但方向已经越来越清晰。参考资料：1.Advances in the treatment of systemic lupus erythematosus. 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The positive FDA feedback allows for: A novel Phase 2 RHB-204[1] study, planned to be the first ever clinical study in a specifically defined Mycobacterium avium subspecies paratuberculosis infected (MAP-positive) Crohn's disease (CD) patient population Groundbreaking approach testing MAP as a root cause of CD, supporting RHB-204 as a potential paradigm-shifting therapy treating both the suspected cause of Crohn's disease and its symptoms RedHill has initiated two new collaborations with leading academic centers utilizing cutting-edge rapid and accurate MAP detection diagnostics – the lack of which has previously been a major barrier to advancing the Company's novel anti-MAP Crohn's disease program Innovative design enables a smaller sample size allowing for lower study costs and faster time to completion Funding for this ground-breaking program expected to be non-dilutive; Grant application submitted and discussions ongoing for additional non-dilutive financing Patent protected through 2041, orally-administered RHB-204, a next-generation optimized formulation of RedHill's RHB-104 designed to further enhance tolerability, safety and patient adherence, is supported by positive RHB-104[2] Phase 3 safety and efficacy results, which delivered a statistically significant 64% improvement in efficacy[3] Expected transferal of pediatric orphan drug designation to RHB-204 as well as potential for breakthrough therapy designation, fast track designation, additional regulatory exclusivity and priority review voucher The multibillion-dollar Crohn's disease market is expected to expand significantly, with sales in the key markets growing from $13.6 billion in 2024 to over $19 billion in 2033[4], presenting significant commercial potential for new, paradigm changing, FDA-approved therapies RALEIGH, N.C. and TEL AVIV, Israel, July 21, 2025 /PRNewswire/ -- RedHill Biopharma Ltd. (Nasdaq: RDHL) ("RedHill" or the "Company"), a specialty biopharmaceutical company, today announced that it received positive feedback from the U.S. Food and Drug Administration (FDA), following a scheduled Type C meeting, in which the FDA provided guidance on the pathway to approval for the Company's potentially groundbreaking RHB-204 Crohn's disease (CD) development program. The positive FDA feedback allows for the planned RHB-204 Phase 2 study to be the first ever clinical trial in Crohn's disease to test a specifically defined population of Mycobacterium avium subspecies paratuberculosis infected (MAP-positive) CD patients. Testing MAP as a root cause of Crohn's, this groundbreaking approach could potentially make RHB-204, if approved, a paradigm-shifting new therapy treating both the suspected cause of the disease and its symptoms. A major hurdle in previous clinical studies for new therapies directed at MAP has been the ability to rapidly and accurately detect MAP – one of the slowest growing bacteria on the planet. The Company is collaborating with two leading academic centers for the provision of cutting-edge MAP detection diagnostics, supporting the study's novel design and the potential future commercial application of RHB-204. The Phase 2 study is expected to have primary endpoints of mucosal remission (considered by FDA as a new gold standard in efficacy evaluation in Crohn's disease), correlated with MAP status and clinical remission, per FDA guidance. These endpoints are supported by the positive RHB-104 Phase 3 study safety and efficacy results. The endpoints and expected use of imaging and cutting-edge MAP detection methods to correlate mucosal healing with MAP infection eradication, enable a potentially smaller sample size allowing for substantially lower study costs and faster time to completion. Patent protected until 2041, RHB-204, is a novel next-generation optimized formulation of Phase 3-stage RHB-104, designed to support enhanced tolerability, safety and adherence, with a 40% pill burden reduction, and thus, potentially, better outcomes. The development of RHB-204 is supported by a strong foundation of clinical efficacy and safety data from the randomized, double-blind, placebo-controlled 331-patient Phase 3 study of RHB-104 in active CD, which successfully met its primary and secondary endpoints, showing RHB-104 plus standard of care (SoC) to be 64% more effective than SoC alone. The data from this study, published in the peer-reviewed journal, Antibiotics[5], also demonstrated the safety and efficacy of concomitant use of RHB-104 with anti-TNFs, immunomodulators and steroids, suggesting that RHB-204 could be a transformative safe and effective, stand-alone or combination, oral therapy. Up to 40% of CD patients fail to respond to anti-TNF treatment, and over time a similar number of responders lose response and have disease flare-ups[5]. Additionally, many existing treatment options are both expensive and intravenously administered, further increasing the cost burden. Moreover, several of these existing therapies have known safety issues, including Black Box Warnings. A safe and effective orally administered therapy would provide a welcome alternative approach. The CD market is expected to expand significantly over the 2024–2033 forecast period, with sales in the United States, Japan, and five major European markets, growing from $13.6 billion to $19.1 billion at a compound annual growth rate (CAGR) of 3.87%[4]. Funding for this ground-breaking program is expected to be non-dilutive. RedHill is actively pursuing partnering and collaborations for this program, including via an innovation development grant application already submitted and ongoing discussions with non-dilutive external funding sources. RHB-204 is expected to benefit from the transferal of pediatric orphan drug designation from RHB-104 and, where applicable, the Company intends to explore the potential for additional regulatory process designations, such as breakthrough therapy designation and fast track designations that may provide additional exclusivity or potential for priority review vouchers. About Crohn's Disease Crohn's disease (CD) is a form of Inflammatory Bowel Disease (IBD) causing inflammation of digestive tract tissue that can lead to abdominal pain, severe diarrhea, fatigue, weight loss and malnutrition. CD can be highly debilitating and remains a serious burden for both patients and healthcare systems: destroying quality of life and even leading to life-threatening complications. There is no known cure for Crohn's disease. According to the Cleveland Clinic, experts estimate that more than three-quarters of a million Americans and approximately 6-8 million people globally have Crohn's disease Commonly used FDA-approved therapies in the treatment of CD include: Abbvie's Humira® (adalimumab), Janssen's Remicade® (infliximab) and Stelara® (Ustekinumab), BMS's Zeposia® (ozanimod) and Pfizer's Xeljanz® (tofacitinib). About RHB-204 RHB-204 is a proprietary, fixed-dose oral capsule containing a combination of clarithromycin, rifabutin and clofazimine, at specific doses designed to safely and effectively treat Mycobacterium avium subspecies paratuberculosis-positive (MAP-positive)-related Crohn's disease. Patent protected until at least 2041, and with an expected pediatric orphan designation (subject to FDA approval to transfer from RHB-104), RHB-204 is a next-generation formulation of RHB-104 with an optimized formulation for the treatment of CD. It contains the same three antimicrobial agents with potent intracellular, anti-mycobacterial and anti-inflammatory properties, and with an optimized dosing profile, RHB-204 provides the potential for enhanced tolerability, safety and compliance with a 40% pill burden reduction. RHB-204 is supported by a strong foundation of clinical data from the positive safety and efficacy results achieved in the Phase 3 study of RHB-104 in CD, with its potential further demonstrated using mucosal healing imaging, considered to be the gold standard for efficacy evaluation in CD. Originally developed for the treatment of pulmonary NTM disease caused by MAC, RHB-204 was granted FDA Fast Track and Orphan Drug Designation, in addition to QIDP Designation under the Generating Antibiotic Incentives Now Act (GAIN Act), extending U.S. post-approval U.S. market exclusivity to a potential total of 12 years. RHB-204 has additionally been granted EU Orphan Designation, providing eligibility for 10 years EU post-approval market exclusivity. RedHill has protection for RHB-204, and its use in treating pulmonary MAC disease, until 2041. About RedHill Biopharma RedHill Biopharma Ltd. (Nasdaq: RDHL) is a specialty biopharmaceutical company primarily focused on U.S. development and commercialization of drugs for gastrointestinal diseases, infectious diseases and oncology. RedHill promotes the FDA-approved gastrointestinal drug Talicia, for the treatment of Helicobacter pylori (H. pylori) infection in adults[6], with submission planned for marketing authorization in other territories. RedHill's key clinical late-stage development programs include: (i) opaganib (ABC294640), a first-in-class, orally administered sphingosine kinase-2 (SPHK2) selective inhibitor with anticancer, anti-inflammatory and antiviral activity, targeting multiple indications with U.S. Government and academic collaborations for development for radiation and chemical exposure indications such as Gastrointestinal-Acute Radiation Syndrome (GI-ARS), a Phase 2 study in prostate cancer in combination with Bayer's darolutamide and a Phase 2/3 program for hospitalized COVID-19 patients; (ii) RHB-204, an all-in-one, fixed-dose, orally administered, combination antibiotic therapy with a planned Phase 2 study for Crohn's disease and Phase 3-stage for pulmonary nontuberculous mycobacterial (NTM) disease; (iii) RHB-104, with positive results from a first Phase 3 study for Crohn's disease; (iv) RHB-107 (upamostat), an oral broad-acting, host-directed, serine protease inhibitor with potential for pandemic preparedness, is in late-stage development as a treatment for non-hospitalized symptomatic COVID-19 and is also targeting multiple other cancer and inflammatory gastrointestinal diseases; and (v) RHB-102, with potential UK submission for chemotherapy and radiotherapy induced nausea and vomiting, positive results from a Phase 3 study for acute gastroenteritis and gastritis and positive results from a Phase 2 study for IBS-D. RHB-102 is partnered with Hyloris Pharma (EBR: HYL) for worldwide development and commercialization outside North America. More information about the Company is available at / X.com/RedHillBio. Forward Looking Statements This press release contains "forward-looking statements" within the meaning of the Private Securities Litigation Reform Act of 1995 and may discuss investment opportunities, stock analysis, financial performance, investor relations, and market trends. Such statements may be preceded by the words "intends," "may," "will," "plans," "expects," "anticipates," "projects," "predicts," "estimates," "aims," "believes," "hopes," "potential" or similar words. Forward-looking statements are based on certain assumptions and are subject to various known and unknown risks and uncertainties, many of which are beyond the Company's control and cannot be predicted or quantified, and consequently, actual results may differ materially from those expressed or implied by such forward-looking statements. Such risks and uncertainties include, without limitation: market and other conditions; the Company's ability to regain and maintain compliance with the Nasdaq Capital Market's listing requirements; the risk that the addition of new revenue generating products or out-licensing transactions will not occur; the risk of current uncertainty regarding U.S. government research and development funding and that the U.S. government is under no obligation to continue to support development of our products and can cease such support at any time; the risk that acceptance onto the RNCP Product Development Pipeline or other governmental and non-governmental development programs will not guarantee ongoing development or that any such development will not be completed or successful; the risk that the FDA does not agree with the Company's proposed development plans for its programs; the risk that the Company's development programs and studies may not be successful and, even if successful, such studies and results may not be sufficient for regulatory applications, including emergency use or marketing applications, and that additional studies may be required; the risk of market and other conditions and that the Company will not successfully commercialize its products; as well as risks and uncertainties associated with (i) the initiation, timing, progress and results of the Company's research, manufacturing, pre-clinical studies, clinical trials, and other therapeutic candidate development efforts, and the timing of the commercial launch of its commercial products and ones it may acquire or develop in the future; (ii) the Company's ability to advance its therapeutic candidates into clinical trials or to successfully complete its pre-clinical studies or clinical trials or the development of any necessary commercial companion diagnostics; (iii) the extent and number and type of additional studies that the Company may be required to conduct and the Company's receipt of regulatory approvals for its therapeutic candidates, and the timing of other regulatory filings, approvals and feedback; (iv) the manufacturing, clinical development, commercialization, and market acceptance of the Company's therapeutic candidates and Talicia®; (v) the Company's ability to successfully commercialize and promote Talicia®; (vi) the Company's ability to establish and maintain corporate collaborations; (vii) the Company's ability to acquire products approved for marketing in the U.S. that achieve commercial success and build its own marketing and commercialization capabilities; (viii) the interpretation of the properties and characteristics of the Company's therapeutic candidates and the results obtained with its therapeutic candidates in research, pre-clinical studies or clinical trials; (ix) the implementation of the Company's business model, strategic plans for its business and therapeutic candidates; (x) the scope of protection the Company is able to establish and maintain for intellectual property rights covering its therapeutic candidates and its ability to operate its business without infringing the intellectual property rights of others; (xi) parties from whom the Company licenses its intellectual property defaulting in their obligations to the Company; (xii) estimates of the Company's expenses, future revenues, capital requirements and needs for additional financing; (xiii) the effect of patients suffering adverse experiences using investigative drugs under the Company's Expanded Access Program; (xiv) competition from other companies and technologies within the Company's industry; and (xv) the hiring and employment commencement date of executive managers. More detailed information about the Company and the risk factors that may affect the realization of forward-looking statements is set forth in the Company's filings with the Securities and Exchange Commission (SEC), including the Company's Annual Report on Form 20-F filed with the SEC on April 10, 2025. All forward-looking statements included in this press release are made only as of the date of this press release. The Company assumes no obligation to update any written or oral forward-looking statement, whether as a result of new information, future events or otherwise unless required by law. 1. RHB-204 is an investigational new drug, not available for commercial distribution in the United States. 2. RHB-104 is an investigational new drug, not available for commercial distribution in the United States. 3. Graham DY, et al. Randomized, Double-Blind, Placebo-Controlled Study of Anti-Mycobacterial Therapy (RHB-104) in Active Crohn's Disease. Antibiotics (Basel). 2024 Jul 25;13(8):694. doi: 10.3390/antibiotics13080694. PMID: 39199994; PMCID: PMC11350828. 4. DataMonitor - Disease Analysis: Crohn's Disease, September 2024. 5. Singh S, George J, Boland BS, Vande Casteele N, Sandborn WJ. Primary Non-Response to Tumor Necrosis Factor Antagonists is Associated with Inferior Response to Second-line Biologics in Patients with Inflammatory Bowel Diseases: A Systematic Review and Meta-analysis. J Crohns Colitis. 2018 May 25;12(6):635-643. doi: 10.1093/ecco-jcc/jjy004. PMID: 29370397; PMCID: PMC7189966. 6. Talicia® (omeprazole magnesium, amoxicillin and rifabutin) is indicated for the treatment of H. pylori infection in adults. For full prescribing information see: . Category: R&D Company contact: Adi Frish Chief Corporate & Business Development Officer RedHill Biopharma +972-54-6543-112 [email protected] Logo: SOURCE RedHill Biopharma Ltd. 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