Bosutinib Monohydrate

Terns Pharmaceuticals (Nasdaq: TERN), headquartered in Foster City, California, announced that the US FDA granted Breakthrough Therapy Designation (BTD) to TERN-701, an oral allosteric BCR::ABL1 inhibitor, for adult patients with Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) in chronic phase without the T315I mutation who have received two or more prior tyrosine kinase inhibitors (TKIs). BTD provides intensive FDA guidance, rolling review of application sections, and senior agency involvement throughout development — benefits the company expects to apply toward advancing TERN-701 into a pivotal trial. No prior expedited designations for TERN-701 appear in the public record. The designation was supported by data from the ongoing Phase I/II CARDINAL trial (NCT06163430). At a December 2025 presentation at the 67th American Society of Hematology Annual Meeting, Terns reported results from 38 efficacy-evaluable patients at a September 13, 2025 data cutoff. Among patients without MMR at baseline, TERN-701 produced a major molecular response (MMR) rate of 64% by week 24, rising to 75% at doses of 320 mg once daily or higher. The cumulative MMR rate — combining patients who achieved or maintained MMR — was 74% (28 of 38 patients). A deep molecular response (DMR, defined as BCR::ABL1^IS ≤0.01%) was observed in 36% of efficacy-evaluable patients. No dose-limiting toxicities, treatment discontinuations due to adverse events, or dose reductions were recorded across any dose level up to 500 mg once daily. No clinically meaningful blood pressure changes were observed. The patient population in CARDINAL is heavily pretreated, with a median of four prior therapies, and includes patients who had previously received an allosteric TKI. In the subgroup defined by lack of efficacy to the last TKI, the MMR achievement rate was 63% (12 of 19 patients). In five patients with the T315I mutation — a population excluded from the BTD indication but enrolled in the broader trial — the MMR rate was 80%, though this subgroup is small and the finding should be interpreted with caution. CML is driven by the BCR::ABL1 fusion oncoprotein, and TKIs targeting its ATP-binding site have transformed the disease from a condition with limited treatment options into one where many patients achieve durable molecular remissions. However, a subset of patients develop resistance or intolerance after multiple lines of therapy, leaving a population where further treatment options narrow considerably. The competitive context for TERN-701 is shaped primarily by asciminib (Scemblix, Novartis), the first approved allosteric BCR::ABL1 inhibitor, which binds the myristoyl pocket rather than the ATP site. Asciminib received US FDA approval in 2021 for CML resistant to or intolerant of at least two prior TKIs and, separately, for T315I-mutant disease. Its Phase III ASCEMBL trial demonstrated a 25.5% MMR rate at 24 weeks versus 13.2% for bosutinib in the third-line setting. The CARDINAL data for TERN-701, while from a Phase I/II study without a comparator arm, show a 64% MMR-achievement rate in a similarly defined population, though cross-trial comparisons carry substantial methodological limitations. TERN-701 differs from asciminib in its binding characteristics within the allosteric pocket. Terns has described TERN-701 as retaining activity in patients who previously received asciminib, which, if confirmed in larger cohorts, would be a meaningful differentiator given that asciminib use is expanding in earlier lines of therapy. The CARDINAL data include patients with prior allosteric TKI exposure, and responses were observed in that subgroup, though precise rates for that specific cohort were not separately disclosed in the December 2025 presentation materials reviewed here. The broader later-line CML landscape includes ponatinib (Iclusig, Takeda), a third-generation ATP-site inhibitor with activity against T315I, and the combination of asciminib with ATP-site TKIs, which is under investigation. The cardiovascular risk associated with ponatinib has historically constrained its use, and the clean vascular safety profile reported for TERN-701 to date — absent blood pressure changes and without dose-related toxicity signals — may prove relevant to positioning, pending longer follow-up. Terns also disclosed in April 2026 that Merck has agreed to acquire the company, a transaction that, if completed, would transfer TERN-701’s development to a larger organization with resources to execute a registrational program. The BTD, combined with the pending acquisition, sets a context in which the path to a pivotal trial design and FDA interactions would benefit from the designation’s collaborative framework. CARDINAL continues to enroll, with dose expansion initiated in April 2025 and an additional mutation cohort added in January 2026. Exact response rates by individual dose cohort and longer-term durability data have not yet been disclosed publicly, and the absence of a control arm means that the observed MMR rates cannot yet be interpreted as definitive evidence of comparative benefit over available therapies. Your email address will not be published. Required fields are marked * Comment * Name * Email * Website

慢性移植物抗宿主病（cGVHD）是同种异体造血干细胞移植（allo-HSCT）后最常见且复杂的远期并发症，严重影响患者长期生活质量和总体预后。其临床表现为高度异质性的系统性免疫失调和纤维化，可累及皮肤、口腔、眼、肺、肝、肌肉筋膜和关节等多个器官系统。根据2014年美国国立卫生研究院共识标准，cGVHD的诊断性特征包括皮肤异色病、扁平苔藓样改变、硬化特征、干燥综合征等。 cGVHD概述 cGVHD通常在allo-HSCT后100天以上发生，其根本原因是供者来源的免疫细胞将宿主的组织抗原识别为“非己”，从而发起免疫攻击。器官受累广泛，例如皮肤受累可能导致瘙痒、硬化改变甚至溃疡；口腔cGVHD常表现为疼痛、干燥和敏感三联征；肺部受累可能引发闭塞性细支气管炎综合征（BOS），导致呼吸困难。cGVHD的总体发病率较高，2年累积发病率估计约为39%。其发生风险与移植类型、移植物抗宿主病预防策略、供受者年龄等因素密切相关。例如，患者和供者年龄增长是cGVHD发生和严重程度增加的确切风险因素；在移植物抗宿主病预防方案中加入兔抗胸腺细胞球蛋白（rATG）可显著降低cGVHD发生率。 cGVHD的免疫学机制 cGVHD的发病机制核心是多器官炎症和纤维化。NIH提出了cGVHD的三阶段模型：早期急性炎症期、慢性炎症和免疫失调期，以及最终的组织纤维化期。这一过程涉及宿主抗原与供者免疫应答之间复杂的相互作用。 初始阶段，供者T细胞识别宿主抗原提呈细胞提呈的主要组织相容性复合体（MHC）抗原或次要组织相容性抗原（mHA），导致T细胞（如Th17、Tfh）活化，同时抑制了调节性T细胞（Treg）的数量和功能。活化的T细胞通过释放穿孔素、颗粒酶以及Fas/FasL介导的凋亡信号直接破坏宿主细胞。Th17细胞释放IL-2、IL-17A、IFN-γ、GM-CSF和TNF-α等促炎细胞因子，加剧炎症反应。 B细胞也通过多种机制参与cGVHD发病：产生针对宿主抗原的自身抗体和同种抗体；向供者T细胞提呈抗原，促进其克隆扩增和存活；与滤泡辅助性T细胞在生发中心相互作用，导致B细胞异常活化和分化为浆母细胞；分泌细胞因子调节包括Treg在内的T细胞群；以及调节性B细胞（产生IL-10的B细胞）功能和数量的缺失。在慢性炎症环境中，转化生长因子-β（TGF-β）成为驱动纤维化的核心因子。TGF-β通过激活经典的Smad2/3信号通路上调COL1A1和FN1，诱导成纤维细胞活化和胶原合成。此外，TGF-β还激活非经典的ROCK2通路，进而通过肌球蛋白II和LIMK-cofilin重塑应力纤维，增强α-SMA表达，促使成纤维细胞向肌成纤维细胞转分化。同时，ROCK2直接磷酸化Foxp3，诱导其蛋白酶体降解，从而降低Treg比例，维持Th17/Tfh优势，这为慢性炎症和后续纤维化提供了持续动力。 cGVHD的一线治疗 cGVHD治疗的基本思路是抑制T细胞和B细胞活化、减少促炎细胞因子分泌、抑制自身抗体产生以及缓和器官纤维化进展。全身性糖皮质激素单药或联合钙调磷酸酶抑制剂是目前国际共识推荐的首选初始治疗方案。通常推荐泼尼松剂量为1 mg/kg/天。研究表明，该初始方案能在治疗4-6周内快速抑制淋巴细胞增殖并缓解受累器官的高级别炎症，6个月总体缓解率在48.6%–62.5%之间。然而，无需额外免疫抑制的12个月持续缓解率仅为15%–33%，提示长期控制不佳。多项评估在糖皮质激素一线治疗中加用其他免疫抑制或免疫调节剂的随机临床试验，均未能显著改善结局。 现实世界队列研究进一步表明，约半数患者对一线糖皮质激素治疗反应不足，最终根据临床特征被归类为激素依赖或激素难治性cGVHD。此外，长期暴露于超过生理剂量的糖皮质激素会导致一系列不良反应。因此，对于标准一线治疗4周后器官功能无改善，或第8周时泼尼松无法减量至1.0 mg/kg/天以下的患者，应考虑及时升级至cGVHD的二线系统治疗。 cGVHD的二线治疗 目前，全球尚未建立统一的cGVHD二线治疗方案标准。临床决策的选择需要仔细评估受累器官、疾病严重程度和患者个体特征。目前，已有三种口服药物获批用于糖皮质激素难治/耐药人群的二线治疗：伊布替尼、芦可替尼和贝组司他。阿沙妥单抗也属此类。二线治疗的研究主要分为三个方向：第一类是包括甲氨蝶呤、霉酚酸酯在内的传统免疫抑制剂；第二类是针对BTK、JAK或ROCK2等关键通路的分子靶向药物；第三类是包括生物制剂和细胞免疫疗法在内的新兴策略。跨方向验证和联合探索有望为不同cGVHD亚型提供更精准的治疗选择。 传统免疫抑制剂 •甲氨蝶呤：通过竞争性抑制二氢叶酸还原酶，干扰DNA和RNA合成，从而抑制快速增殖的T细胞和B细胞。在治疗背景下，常作为cGVHD的二线或激素减量药物使用。 •霉酚酸酯：在体内水解为活性代谢产物霉酚酸，通过选择性抑制次黄嘌呤单核苷酸脱氢酶-II消耗鸟嘌呤核苷酸池，阻滞供者效应T细胞和自身反应性B细胞在G1期，阻断其克隆扩增。然而，其临床疗效不一。一项前瞻性随机对照试验表明，在cGVHD初始系统治疗中加用霉酚酸酯并未改善结局。但在二线或挽救治疗中，霉酚酸酯显示出潜力。需注意的是，霉酚酸酯为基础的免疫抑制方案会增加感染并发症风险，且可能减弱移植物抗白血病效应。 •西罗莫司：通过抑制mTOR通路减少T细胞和B细胞活化，同时对IL-2依赖的Treg扩增影响甚微，甚至可能上调Foxp3表达，增加Treg比例，促进免疫耐受恢复。研究显示，西罗莫司联合钙调磷酸酶抑制剂治疗激素依赖/难治性cGVHD患者，6个月总体缓解率达55.6%。但需注意其相关不良反应，如高脂血症、血小板减少和中性粒细胞减少等代谢异常和骨髓抑制。西罗莫司与钙调磷酸酶抑制剂联用会大幅增加血栓性微血管病风险。 •硫唑嘌呤：通过干扰嘌呤的从头合成途径，抑制活化T/B淋巴细胞的增殖和功能。在cGVHD初始治疗中，常与泼尼松联用，该方案已被证明可降低类固醇失败率和复发率。但需警惕，其使用与移植后继发恶性肿瘤风险显著增加相关。 •沙利度胺：具有免疫调节和抗血管生成特性。II期临床试验表明，100–160 mg/天的沙利度胺单药治疗对约50%的难治性cGVHD患者有效。但加用泼尼松或环孢素A并未增强疗效，反而显著增加了不良反应。 小分子靶向疗法 •布鲁顿酪氨酸激酶抑制剂：伊布替尼是首个获批用于治疗cGVHD的口服、不可逆的BTK/IL-2诱导的T细胞激酶双重抑制剂。它通过阻断B细胞受体和T细胞共刺激信号下游的磷酸化级联反应，抑制B细胞增殖和自身抗体产生，下调Th17极化，从而减少IL-6、IL-17、TNF-α等促炎因子，同时降低TGF-β和PDGF等纤维化介质水平，逆转皮肤和肺的胶原沉积。关键性Ib/II期试验显示，在42名接受伊布替尼治疗的激素难治/依赖的广泛性cGVHD患者中，67%获得缓解。 •JAK抑制剂：芦可替尼可逆地结合JAK1/2激酶结构域，阻断IL-6、IFN-γ等促炎细胞因子的下游STAT1/STAT3磷酸化，从而抑制供者CD4+/CD8+ T细胞的增殖和效应分化，抑制Th1/Th17极化，减少IL-17、TNF-α等促炎因子分泌。它还能促进Treg扩增和功能稳定，减少CXCR3介导的T细胞向靶器官迁移，减轻皮肤、口腔黏膜、肺等组织的纤维化炎症。REACH3研究的3年随访数据显示，与最佳可用疗法相比，芦可替尼将中位无失败生存期从5.7个月显著延长至38.4个月。此外，选择性JAK1/2抑制剂巴瑞替尼也在研究中显示出潜力。 •ROCK2抑制剂：贝组司他是一种ROCK2抑制剂，通过免疫调节和抗纤维化双重机制发挥作用。它能选择性阻断ROCK2-STAT3信号，下调IL-17、IL-21等促炎因子，同时增强STAT5磷酸化，促进Foxp3+ Treg扩增，恢复Th17/Treg平衡。抑制RhoA-ROCK2-MRTF轴可阻止成纤维细胞向α-SMA+肌成纤维细胞转分化，减少TGF-β和PDGF释放，从而逆转皮肤、肺等靶器官的胶原沉积和纤维化。ROCKstar研究显示，贝组司他治疗对至少两种先前疗法失败的cGVHD患者，总体缓解率达到75%。 •酪氨酸激酶抑制剂：伊马替尼通过抗纤维化和免疫调节双重作用治疗cGVHD。它通过抑制PDGFR-α/β和TGF-β通路直接逆转器官纤维化，并通过调节TCR信号选择性抑制异常免疫应答。一项多中心II期试验显示，口服伊马替尼治疗激素难治/依赖的cGVHD患者，总体缓解率达58.3%。第二代TKI药物尼洛替尼也被研究用于cGVHD治疗，但其临床应用因不良反应谱而受到显著限制。博舒替尼等也在临床前研究中显示出潜力。 •BCL-2抑制剂：BCL-2抑制剂靶向抗凋亡蛋白，新兴证据表明其在预防和治疗cGVHD中具有潜在应用。在预防方面，临床前研究表明，选择性BCL-2抑制剂维奈克拉通过清除宿主自然杀伤细胞促进供者嵌合。在治疗方面，cGVHD患者皮肤病变和外周血中BCL-2表达显著上调，其表达水平与移植相关死亡率和激素难治性cGVHD密切相关。通过诱导T细胞凋亡，维奈克拉可能成为治疗激素难治性cGVHD的新型靶向药物，但目前临床证据有限。 •BCL-6抑制剂：B细胞淋巴瘤6是控制生发中心反应的关键转录因子，在驱动抗体介导的cGVHD中起核心作用。在预防方面，临床前研究表明，供者T细胞或B细胞中BCL-6缺陷可阻止生发中心形成，从而消除cGVHD的发展。在治疗干预方面，小分子BCL-6抑制剂79-6在已建立的cGVHD动物模型中显示出显著的治疗潜力。