Soquelitinib

▎药明康德内容团队编辑 本期看点 1. 小分子白细胞介素-2诱导的T细胞激酶（ITK）抑制剂soquelitinib用于治疗T细胞淋巴瘤的早期临床试验结果积极，18个月的无进展生存率优于标准治疗药物。 2. PLN-101095联用PD-1抑制剂治疗免疫检查点抑制剂（ICI）难治性晚期或转移性实体瘤患者，在一项1期临床试验中使50%的患者达到确认的部分缓解（PR）。 3. SMSbiotech公司旨在逆转慢性阻塞性肺疾病（COPD）患者肺损伤或恢复肺功能的干细胞疗法获批在澳大利亚启动1期临床试验。 药明康德内容团队整理 Soquelitinib：公布1/1b期临床试验数据 Corvus Pharmaceuticals公司公布了其小分子白细胞介素-2诱导的T细胞激酶（ITK）抑制剂soquelitinib用于治疗T细胞淋巴瘤的1/1b期临床试验数据。ITK是一种主要表达于T细胞中的酶，在T细胞和自然杀伤（NK）细胞的免疫功能中起重要作用。通过抑制ITK，soquelitinib有望抑制自身免疫和炎症反应。 此次公布的结果显示，在23名疗效可评估的患者中，有9例（39%）患者达到客观缓解，包括6例完全缓解（CR）和3例PR。9例达到客观缓解患者的中位缓解持续时间（DOR）为17.2个月，估计的中位无进展生存期（PFS）为6.2个月。18个月的无进展生存率为30%，优于标准治疗药物，后者在同一时间段内的无进展生存率＜20%。安全性方面，soquelitinib的耐受性良好，没有报告新的安全性信号、药物中断或剂量减少。 PLN-101095：公布1期临床试验的中期数据 Pliant Therapeutics公司公布了其正在进行的1期临床试验的前三个队列的数据，该试验评估了PLN-101095联用PD-1抑制剂pembrolizumab治疗ICI难治性晚期或转移性实体瘤患者的效果。PLN-101095是Pliant Therapeutics公司开发的口服靶向整合素αvβ8和αvβ1的双重选择性小分子抑制剂，用于治疗对免疫检查点抑制剂耐药的实体肿瘤。TGF-β信号传导的增加被认为是肿瘤细胞对免疫检查点抑制剂耐药的潜在原因。PLN-101095靶向肿瘤微环境中表达的整合素αvβ8和αvβ1，能够调节TGF-β的活性，旨在恢复肿瘤对PD-1/PD-L1抑制剂的敏感性。 此次公布的结果显示，在所有测试剂量中，PLN-101095通常耐受性良好。在接受PLN-101095治疗的6名患者中，观察到3名（50%）患者达到了确认的PR，包括1名非小细胞肺癌患者（第18周时肿瘤缩小74%）、1名胆管癌患者（第42周时肿瘤缩小48%）和1名黑色素瘤患者（第27周时肿瘤缩小42%）。 Small Mobile Stem cell：获批在澳大利亚启动1期临床试验 SMSbiotech公司宣布，其创新的干细胞疗法Small Mobile Stem cell获批在澳大利亚启动1期临床试验，用于评估其治疗COPD的安全性和耐受性。这也是该疗法首次在人体中进行试验。COPD是一种逐步损害呼吸功能的进行性肺病，现有疗法的目的主要集中在缓解症状上，而不是逆转损伤或恢复肺功能。SMSbiotech公司的干细胞技术旨在通过再生受损的肺泡组织，有望修复组织损伤并恢复肺功能。 BB-301：公布1b/2a期临床试验中前3例患者的数据 Benitec Biopharma公司公布了其开发用于治疗眼咽肌营养不良（OPMD）的沉默和取代基因疗法BB-301在1b/2a期临床试验中的前3例患者的积极数据。该疗法利用一种新型的、经过改良的AAV9载体，表达一种独特的、单一的双功能构建体，从而能够促进密码子优化的PABPN1基因和两个针对PABPN1突变体siRNA的共同表达。这两个siRNA被塑造成微RNA骨架，以抑制有缺陷的PABPN1突变体的表达，同时允许表达经过密码子优化的PABPN1基因，用PABPN1蛋白的功能性版本取代突变体。 此次公布的结果显示，所有3名受试者的总吞咽困难症状负担均显著减轻。1号患者和2号患者在接受BB-301治疗后12个月均实现了持久且具有临床意义的吞咽功能改善，其中2号患者在症状负担显著减轻后达到了临床上正常的吞咽状态。3号患者接受BB-301治疗后3个月观察到显著的吞咽功能改善，随后也达到了临床上正常的吞咽状态。安全性方面，未报告严重不良事件。 TTI-101：公布1期临床试验数据 Tvardi Therapeutics宣布，其口服小分子STAT3抑制剂TTI-101在晚期实体瘤患者中的首个人体1期研究结果已发表在Clinical Cancer Research上。STAT3是一种关键的调节蛋白，长期以来一直被认为是肿瘤学的主要靶标。临床前实验中，TTI-101展现优异的药代动力学特征、减弱pY705-STAT3磷酸化的效果，并在头颈癌、肺癌、乳腺癌和肝癌的动物模型中表现出抗癌活性。 此次公布的结果显示，TTI-101的耐受性良好，未观察到剂量限制性毒性或致命的治疗相关不良事件（TRAE）。在41例疗效可评估的患者中，有5例（12%）达到了确认的PR，17例（41%）达到了疾病稳定（SD）。17例肝细胞癌患者中有3例（18%）达到了确认的PR。另外2例获得确认的PR的患者分别患有卵巢癌和胃癌。 LX-101：公布1a期临床试验数据 Lirum Therapeutics公司宣布，其创新药物LX-101治疗甲状腺眼病（TED）的首批数据获选在北美神经眼科学会（NANOS）年会上展示。LX-101是一种针对胰岛素样生长因子-1受体（IGF-1R）的靶向治疗，能够将甲氨蝶呤（一种广泛用于自身免疫疾病的药物，在TED中有使用历史）精确递送到导致疾病的关键效应细胞（如IGF-1R+活化的T细胞和眼眶成纤维细胞），有望提供一种新颖且差异化的方法来治疗TED。 此次公布的结果表明，LX-101能够有效靶向驱动TED发病机制的潜在过程，包括减少或控制TED患者中异常活跃的眶成纤维细胞的功能和增殖、减少关键炎症因子的产生、减少细胞外基质促纤维化成分的产生，以及调节TED患者中异常活跃T细胞的功能和行为。 PBGENE-HBV：IND申请获得FDA许可 Precision BioSciences公司宣布，美国FDA已批准PBGENE-HBV的IND申请。PBGENE-HBV旨在通过消除乙型肝炎病毒（HBV）的共价闭合环状DNA（cccDNA），同时灭活整合在肝细胞中的HBV DNA，以达到功能性治愈慢性乙型肝炎的目的。根据新闻稿，PBGENE-HBV是首个在美国获批进入临床阶段的在研体内基因编辑疗法。 ▲欲了解更多前沿技术在生物医药产业中的应用，请长按扫描上方二维码，即可访问“药明直播间”，观看相关话题的直播讨论与精彩回放 参考资料（可上下滑动查看） [1] Precision BioSciences Announces Clearance of Investigational New Drug Application by the U.S. FDA for First-in-Class PBGENE-HBV Designed to Eliminate Root Cause of Chronic Hepatitis B. 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Trial for this rare genetic disease to be conducted by NIH/NIAID in partnership with Corvus ITK inhibition intended to address dysregulation of T cells that causes ALPS and has been shown to be effective at treating the disease in preclinical models March 12, 2025 -- Corvus Pharmaceuticals, Inc. (NASDAQ: CRVS), a clinical-stage biopharmaceutical company, today announced that the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH), has initiated a Phase 2 clinical trial of soquelitinib for the treatment of patients with autoimmune lymphoproliferative syndrome (ALPS), a rare genetic disease. The lead investigator of the trial is V. Koneti Rao, MD, FRCPA, Senior Research Physician, Primary Immune Deficiency Clinic (ALPS Clinic) at NIH Clinical Center. Dr. Rao previously presented preclinical data supporting the potential of soquelitinib in patients with ALPS. Other trial sites include Children’s Hospital of Philadelphia and Texas Children’s Cancer and Hematology Center. “Developing safe and effective targeted treatments to address ALPS and related disorders is a priority at the NIAID since this condition was first discovered in NIAID in the early 1990s,” said Dr. Rao. “ALPS typically begins to manifest by age two and most patients live into adulthood with burdensome symptoms often related to refractory autoimmune cytopenias (low blood counts). This requires ongoing surveillance and the risk for potentially fatal conditions such as infection, hemorrhage and malignant lymphoma. We look forward to investigating the potential of ITK inhibition with soquelitinib to improve immune system balance and reduce the buildup of dysfunctional T cells in lymph nodes and spleens and autoantibodies that drive the disease.” ALPS is most often caused by a mutation in the gene for the Fas protein, which spans the cell membrane and helps facilitate apoptosis, or programmed cell death. When this protein is missing or defective, T cells can build up and disrupt the immune system, leading to potentially debilitating symptoms and an increased risk for developing serious health conditions, including autoimmune diseases and lymphoma. There currently is no cure for ALPS and the disorder is managed by a variety of empirical methods aimed at addressing pathological changes caused by the disease, such low blood-cell counts (cytopenias), excessive lymphocyte production (lymphoproliferation), enlarged spleen or lymph nodes, and lymphoma. Treatments may include corticosteroids such as prednisone and other immunosuppressive medications to modulate the immune system, or cancer therapies to address lymphoma. “We are excited to expand the potential of ITK inhibition to address people with ALPS, which is a serious genetic disease that begins in childhood and gets worse due to progression during young adulthood and lacks good treatment options,” said Richard A. Miller, M.D., co-founder, president and chief executive officer of Corvus. “There is compelling preclinical evidence that soquelitinib may address the immune dysregulation in T cells that is a hallmark of the disease. It also bridges the biology of T cell lymphomas and autoimmunity, highlighting the role that ITK inhibition may play in restoring immune balance in lymphoma and immune disease. This adds to our conviction for the potential of soquelitinib as we continue to enroll patients in our registrational Phase 3 trial in PTCL and Phase 1 trial in atopic dermatitis.” The Phase 2 clinical trial (NCT06730126) is designed to enroll up to 30 patients aged 16 or older with confirmed ALPS-FAS based on genetic testing. Two dosing cohorts will be studied. The patients will receive soquelitinib doses of 200 mg or 400 mg twice per day for a period of up to 360 days. The primary endpoint of the trial is efficacy determined by reductions in splenomegaly and lymph node volumes as measured by computed tomography (CT) or positron emission tomography/computed tomography (PET/CT). Improvements in cytopenias will be assessed by complete blood count (CBC). Cytopenias are caused by autoantibodies as well as splenic sequestration that may lead to destruction of red blood cells, platelets and/or neutrophils leading to anemia, thrombocytopenia or neutropenia. Improvements in cytopenias can improve quality of life and overall health, and they also serve as a valuable biomarker associated with ALPS disease activity. Secondary endpoints include safety and tolerability. This is the third indication under clinical development for soquelitinib, which is also in a registrational Phase 3 trial for peripheral T cell lymphoma (PTCL) and a Phase 1 trial for atopic dermatitis (AD). Corvus also plans to initiate a Phase 1 clinical trial of soquelitinib in patients with solid tumors in the second quarter 2025. ALPS is a rare genetic disease inherited as a germline autosomal dominant pattern or due to somatic mosaicism affecting children that manifests with lymphadenopathy, splenomegaly, cytopenias (low blood counts) and autoimmunity. The disease is caused by a mutation in the Fas gene, which provides instructions for making a signaling protein involved in the induction of apoptosis to get rid of redundant lymphocytes. The mutation results in immune dysregulation due to accumulation abnormally high levels of “double negative” T cells (CD4 and CD8 double negative), which infiltrate the blood, spleen and lymphoid tissues. Fas signaling is regulated by ITK and T cell receptor signaling and patients with ALPS have an imbalance in this regulation resulting in a failure of T cells to undergo apoptosis and an accumulation of abnormal T cells. Soquelitinib (formerly CPI-818) is an investigational small molecule drug given orally designed to selectively inhibit ITK (interleukin-2-inducible T cell kinase), an enzyme that is expressed predominantly in T cells and plays a role in T cell and natural killer (NK) cell immune function. Soquelitinib has been shown to affect T cell differentiation and induce the generation of Th1 helper cells while blocking the development of both Th2 and Th17 cells and production of their secreted cytokines. Th1 T cells are required for immunity to tumors, viral infections and other infectious diseases. Th2 and Th17 helper T cells are involved in the pathogenesis of many autoimmune and allergic diseases. The Company believes the inhibition of specific molecular targets in T cells may be of therapeutic benefit for patients with cancers, including solid tumors, and in patients with autoimmune and allergic diseases. Recent studies have demonstrated that ITK controls a switch between the differentiation of Th17 proinflammatory cells and T regulatory suppressor cells. Inhibition of ITK leads to a shift toward T regulatory cell differentiation which has the potential to suppress autoimmune and inflammatory reactions. Based on interim results from a Phase 1/1b clinical trial in patients with refractory T cell lymphomas, which demonstrated tumor responses in very advanced, refractory, difficult to treat T cell malignancies, the Company has initiated a registrational Phase 3 clinical trial (NCT06561048) of soquelitinib in patients with relapsed PTCL. Soquelitinib is also being investigated in a randomized placebo-controlled phase 1 clinical trial in patients with atopic dermatitis. A recent publication describing the chemistry, enzymology and biology of soquelitinib appeared in npj Drug Discovery in December 2024 and is available online at the Nature website and on the Publications and Presentations page of the Corvus website. Corvus Pharmaceuticals is a clinical-stage biopharmaceutical company pioneering the development of ITK inhibition as a new approach to immunotherapy for a broad range of cancer and immune diseases. The Company’s lead product candidate is soquelitinib, an investigational, oral, small molecule drug that selectively inhibits ITK. Its other clinical-stage candidates are being developed for a variety of cancer indications. The content above comes from the network. if any infringement, please contact us to modify.