Duvelisib hydrate

Interim data from the first phase 3 study of a PI3K inhibitor to treat relapsed or refractory nodal T-follicular helper cell lymphoma (nTFHL) anticipated in early-2027 SUMMERLIN, Nev., June 09, 2025 (GLOBE NEWSWIRE) -- Secura Bio, Inc. ( www.securabio.com ), an integrated pharmaceutical company maximizing commercial outcomes for oncology medicines, today announced that the first patient has been dosed in its Phase 3 TERZO study of COPIKTRA (duvelisib) in adults with relapsed or refractory (R/R) nodal T-follicular helper cell lymphoma (nTFHL), a disease where there are currently no well-established standards of care for patients with relapsed or refractory disease. “Patients with relapsed or refractory nodal T-follicular helper cell lymphoma need meaningful treatment options, with the potential to extend and improve the quality of their lives,” said Dr. Graham Collins, UK Site Investigator for the Terzo Study. “I am grateful to Secura Bio for continuing to evaluate COPIKTRA for diseases where the standard treatment protocol has been challenged by recurring relapses and mutations.” The Phase 3 TERZO study is a multicenter, open-label, randomized controlled study of duvelisib versus investigator’s choice of gemcitabine or bendamustine in patients with R/R nTFHL. Patients in the European Union (CT: 2024-516605-23-00) and the United Kingdom (NCT06522737) will be randomized on a 1:1 basis and receive treatment until progressive disease (PD) or unacceptable toxicity. The primary endpoint of the study is progression-free survival. Secondary endpoints include overall survival, objective response rate, complete response rate, duration of response, number of participants with adverse events, and quality of life. The company expects to enroll approximately 124 patients with interim data from the study anticipated in early-2027. “We are very pleased to have dosed our first patient in this Phase 3 study of COPIKTRA based on the results from our Phase 2 study in T-cell lymphomas – in particular the results from angioimmunoblastic T-cell lymphoma (AITL), a subtype of peripheral T-cell lymphoma (PTCL) that is strongly associated with the T follicular helper (TFH) cell phenotype,” said Chip Romp, President and CEO of Secura Bio. “We look forward to developing COPIKTRA beyond its initial indication in R/R chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and continuing to build Secura Bio into a world-class biopharmaceutical company with a diverse portfolio of oncology assets.” About nodal T-Follicular Helper Cell Lymphoma Nodal T-follicular helper cell lymphomas (nTFHL) comprise a group of aggressive non-Hodgkin lymphomas that share common genetic, clinical, and cell of origin features. This group of lymphomas originates from a type of white blood cell called a T-follicular helper cell. nTFHLs generally occur in people aged 60 and older and are slightly more common in males. nTFHLs most commonly present with widespread, enlarged, typically painless lymph nodes in the neck, armpit, and/or groin. There are currently no well-established standards of care for patients with relapsed or refractory disease. About COPIKTRA (duvelisib) COPIKTRA is an oral inhibitor of phosphoinositide 3-kinase (PI3K) and the first US approved dual inhibitor of PI3K-delta and PI3K-gamma pathways, two enzymes known to help support the growth and survival of malignant cells. PI3K signaling may lead to the proliferation of malignant cells and is thought to play a role in the formation and maintenance of a supportive tumor microenvironment. COPIKTRA is indicated in the United States for the treatment of adult patients with relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) after at least two prior therapies. COPIKTRA is also being developed for the treatment of peripheral T-cell lymphoma (PTCL), for which it has received Fast Track status in the United States and is being investigated in combination with other agents through investigator-sponsored studies. Treatment of T-cell lymphomas is a disease category for which COPIKTRA is not currently indicated. For more information on COPIKTRA, please visit www.COPIKTRA.com . Information about duvelisib clinical trials can be found on www.clinicaltrials.gov . IMPORTANT SAFETY INFORMATION ABOUT COPIKTRA WARNING: FATAL AND SERIOUS TOXICITIES: INFECTIONS, DIARRHEA OR COLITIS, CUTANEOUS REACTIONS, and PNEUMONITIS See full prescribing information for complete boxed warning Fatal and/or serious infections occurred in 31% (4% fatal) of COPIKTRA-treated patients. Monitor for signs and symptoms of infection. Withhold COPIKTRA if infection is suspected. Fatal and/or serious diarrhea or colitis occurred in 18% (<1% fatal) of COPIKTRA-treated patients. Monitor for the development of severe diarrhea or colitis. Withhold COPIKTRA. Fatal and/or serious cutaneous reactions occurred in 5% (<1% fatal) of COPIKTRA-treated patients. Withhold COPIKTRA. Fatal and/or serious pneumonitis occurred in 5% (<1% fatal) of COPIKTRA-treated patients. Monitor for pulmonary symptoms and interstitial infiltrates. Withhold COPIKTRA. INDICATIONS AND USAGE COPIKTRA is a kinase inhibitor indicated for the treatment of adult patients with: Relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) after at least two prior therapies. WARNINGS AND PRECAUTIONS Hepatotoxicity: Monitor hepatic function. Neutropenia: Monitor blood counts. Embryo-Fetal toxicity: COPIKTRA can cause fetal harm. Advise patients of potential risk to a fetus and to use effective contraception. ADVERSE REACTIONS The most common adverse reactions (≥20%) are diarrhea or colitis, neutropenia, rash, fatigue, pyrexia, cough, nausea, upper respiratory infection, pneumonia, musculoskeletal pain, and anemia. DRUG INTERACTIONS CYP3A inducers: Avoid co-administration with strong or moderate CYP3A inducers. CYP3A inhibitors: Monitor for COPIKTRA toxicities when co-administered with strong or moderate CYP3A inhibitors. Reduce COPIKTRA dose to 15 mg twice daily when co-administered with strong CYP3A4 inhibitors. CYP3A substrates: Monitor for signs of toxicities when co-administering COPIKTRA with sensitive CYP3A substrates. USE IN SPECIFIC POPULATIONS Lactation: Advise women not to breastfeed. Please click here to see full Prescribing Information, including Boxed WARNING, for COPIKTRA (duvelisib). About Secura Bio, Inc. Secura Bio is an integrated, commercial-stage pharmaceutical company dedicated to the worldwide development and commercialization of impactful oncology therapies for physicians and their patients. For more information on Secura Bio, please visit https://www.securabio.com/. Investor & Media Contact Will Brown Chief Financial Officer Phone: 619-986-1364 ir@securabio.com Legal Disclaimer: EIN Presswire provides this news content "as is" without warranty of any kind. We do not accept any responsibility or liability for the accuracy, content, images, videos, licenses, completeness, legality, or reliability of the information contained in this article. 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DOI: 10.1021/acs.jmedchem.5c00408侃侃而言  学以致用PROTAC 技术是一种新兴的药物研发策略，与传统抑制剂相比，它能降解目标蛋白，并且具有降低毒性、克服药物抗性等优势。PI3Kδ 是 PI3K/AKT/mTOR 信号通路的关键成员，在白细胞中发挥重要作用，特别是 B 细胞的发育和成熟过程中。而 PI3Kδ 异常表达与则与血液恶性肿瘤、淋巴瘤、自身免疫性疾病密切相关。现有 PI3Kδ 抑制剂存在毒性等局限性问题，开发新的治疗策略成当务之急，比如说 PROTACs 疗法。近日（May 31），西安交通大学医学部药学院在 J. Med. Chem. 上披露了一种基于赖氨酸靶向共价策略的、新型的、高效的 PI3Kδ PROTAC 类降解剂。01PI3Kδ的重要性与现有疗法的局限性 1.1   PI3Kδ的重要性磷脂酰肌醇 3- 激酶（PI3K）是 PI3K/AKT/mTOR 信号通路的关键元素，在细胞生长、增殖和存活中起着重要作用。PI3Kδ 主要表达于白细胞中，参与 B 细胞受体（BCR）信号传导，与 B 细胞的发育和成熟密切相关，其异常表达与血液恶性肿瘤、淋巴瘤和自身免疫性疾病等有很强的关联，因此 PI3Kδ 抑制剂被认为是有前景的治疗血液癌症的药物。 1.2   现有疗法的局限性尽管已有一些 PI3Kδ 抑制剂如 idelalisib、duvelisib 和 umbralisib 等显示出显著的临床疗效，但由于不可避免的毒性问题，它们都受到严格监测，因此开发新的 PI3Kδ 靶向治疗方法成为当前关注的焦点。 1.3   PROTAC 疗法PROTAC 技术可以降解目标蛋白，与传统小分子抑制剂相比，具有独特的作用机制，能够降低毒性并克服药物抗性，近年来在多种蛋白质靶点中得到广泛研究。然而，靶向 PI3Ks 的 PROTACs 研究较少，且已报道的 PROTACs 针对 PI3K 的降解活性和亚型选择性有限，如下图，几乎没有针对 PI3Kδ 亚型的活性报道。因此，研究团队设定了探索 PI3Kδ 靶向降解剂的新方案。02PI3Kδ 靶向降解剂探索 2.1   PI3Kδ 降解剂设计思路研究人员计划开发基于 PROTAC 的 PI3Kδ 降解剂，鉴于 PROTAC 的结构组成特征，共设计了两套方案进行优化：（1）方案1：基于已报道的 PI3Kδ 可逆抑制剂，设计 A 系列分子，如下图，并针对连接子和 E3 连接酶配体进行优化、筛选。（2）方案2：结合结构对接研究，基于PI3Kδ 共价抑制剂，设计 B 系列分子，如下图，并针对连接子、和 E3 连接酶配体进行优化、筛选。 2.2   基于可逆抑制剂的PROTAC探索如下图中，化合物 5 是一个已知的 PI3Kδ 可逆抑制剂，从结构对接模拟可以看出配体与靶标结合口袋的关键相互作用，其中四氢吡喃酰基扩展向溶剂区，因此吡咯烷可作为 PROTAC 连接子的输出位点。为此，研究人员利用不同的连接子和 CRBN、VHL 配体设计了 9 个不同的 PROTACs 分子，如下表。然而，这些化合物对细胞增殖和 PI3Kδ 激酶活性的抑制效果不佳。从结构对接的结果来看，如下图，A 系列分子的 E3 配体无法从 PI3Kδ 的结合口袋中伸出，因此无法有效招募 E3 连接酶。 2.3   基于共价抑制剂的PROTAC探索随后，研究人员转向探索共价抑制剂系列探索，如下图，化合物 6 是已知的 PI3Kδ 共价抑制剂，靶向 K779 残基，IC50 =0.27 nM。如下表，通过调整 PI3Kδ 配体、E3 配体以及不同长度的连接链，对 PROTAC 分子进行筛选和结构-活性关系研究，最终确定了 B 系列中的一些化合物（如 B9、B10、B14 等）表现出较强的 PI3Kδ 降解和抗增殖活性，对 SU-DHL-6 细胞的抗增殖能力优于 idelalisib。 2.4   多维度表征与机制验证随后研究人员针对化合物 B9、B10、B14 进行进一步的评估。如下图，在 SU-DHL-6 细胞中，它们都以浓度依赖方式有效地诱导靶标降解，并且在p-AKT 的水平相应降低。三个化合物 对 p110δ 的DC50 值分别为 1.26、5.35、3.98 nM。此外，三个化合物 B9、B10 和 B14 被证实能提高 SU-DHL-6 细胞中 LC3II/LC3I 的比例，推测这会促进细胞内环境中的自噬作用。三个化合物降解 p110δ 的时间过程如下图所示，均表现出时间依赖性降解。总体上，处理期内 B9 和 B14 的 p110δ降解率均高于 B10，因此这两个化合物被选择进一步通过冲洗实验进行评估，如下图。B9、B14 均具有较长的降解效果，相比之下 B14 降解维持时间更长。另一方面，组成 B14 的 VHL-2 比组成 B9 的VHL-1 具有更高的E3连接酶亲和力，导致 p110δ 的泛素化和随后的降解更容易。针对 B14，研究人员构建了两个衍生物 B14-N（非共价）、B14-S（对映异构体，缺少E3连接酶亲和力），以此来对比研究共价和 VHL 有效相互作用对降解效果的影响，如下图。两个衍生物的的细胞抗增殖能力、靶标降解能力显著降低。这些结果表明 B14 对 p110δ 的共价结合和与 VHL 的有效相互作用是降解效果的关键和决定因素。选择性研究：通过对SU-DHL-6 细胞全蛋白质组评估，B14 对 PI3Kδ 的选择性比其他亚型高 70 倍以上，如下图。B14 是一种 PI3Kδ 高选择性降解剂。接下来，研究人员评估了 B14 对 SU-DHL-6 细胞周期进程和凋亡的影响，B9 作为仅次效力化合物，也一同进行检测。B14 能诱导 SU-DHL-6 细胞发生细胞周期阻滞，并促使细胞凋亡，在 0.1 μM 浓度下诱导的细胞凋亡比例显著高于同浓度的 idelalisib。体内抗肿瘤效果：在 SU-DHL-6 异种移植模型中，B14 显示出显著的抗肿瘤效果，以 2 和 10 mg/kg 剂量给药时，肿瘤生长抑制率（TGI）分别为 59.1%和 73.3%，且未引起明显的体重变化和器官损伤，表明其具有良好的体内耐受性。作用机制研究：研究发现 B14 通过与 p110δ 的 Lys779 共价结合，招募 E3 泛素连接酶，形成“E3-PROTAC-PI3Kδ”三元复合物，进而导致 PI3Kδ 的泛素化和降解，且降解过程涉及泛素-蛋白酶体途径。03总结与展望这篇研究首先提出了 PI3Kδ 在疾病治疗中的重要性与现有的局限性，为了解决 PI3Kδ抑制的现有问题，其研究研究思路如下：（1）首先基于 PI3Kδ 可逆抑制剂进行设计 PROTACs 分子，然而对细胞增殖和 PI3Kδ 激酶活性的抑制效果不佳；（2）继而转向基于 PI3Kδ 共价抑制剂设计新型 PROTACs 分子，通过调整优化，筛选出具有更好靶标降解和抗增殖活性的化合物；（3）通过体内/外多维度验证与机制解析，获得了赖氨酸靶向共价 PTOTACs。有效性：成功开发出一系列基于 PROTAC 的 PI3Kδ 降解剂，其中 B14 是首个具有显著降解效果和体内、体外强效抗肿瘤活性的 PI3Kδ 靶向 PROTAC。创新性：采用赖氨酸靶向共价策略为设计 PI3Kδ 靶向 PROTAC 提供了有效的方法，并为开发更有效的 PI3Kδ 靶向 PROTACs 奠定了基础。选择性：B14 对 PI3Kδ 具有选择性降解和抑制活性，对其他 PI3K 亚型（p110α、p110β、p110γ）的降解和抑制效果较弱，显示出较好的选择性这篇研究从可逆策略失败到共价策略成功，通过 SAR优化、活性筛选、机制验证、系统性证明共价 PROTACs 在 PI3Kδ 靶向中的优势，形成了完美的逻辑闭环，也为同类靶点的药物开发提供了指南！很赞。声明：发表/转载本文仅仅是出于传播信息的需要，并不意味着代表本公众号观点或证实其内容的真实性。据此内容作出的任何判断，后果自负。若有侵权，告知必删！长按关注本公众号   粉丝群/投稿/授权/广告等请联系公众号助手 觉得本文好看，请点这里↓