Granulocyte colony-stimulating factor(Shire Pharmaceuticals Services Ltd.)

▎药明康德内容团队报道 今日（9月20日），誉衡生物宣布靶向趋化因子受体4（CXCR4）的多肽类药物莫替福肽（APHEXDA®，motixafortide）近日获得中国澳门特别行政区药物监督管理局正式批准上市。该产品用于在多发性骨髓瘤（MM）患者中联合粒细胞集落刺激因子（G-CSF）动员造血干细胞，用于外周血的干细胞单采及随后的自体移植。莫替福肽已于2023年9月获美国FDA批准上市，为一款用于MM患者的创新干细胞动员剂。 在骨髓微环境中，CXCR4与基质细胞衍生因子1（SDF-1/CXCL12）在造血干细胞归巢和驻留、调节免疫细胞分布的过程中起重要作用，造血干细胞通过CXCR4与SDF-1/CXCL12相互作用被锚定在骨髓基质内。 莫替福肽是一款皮下注射的CXCR4拮抗剂，具有高亲合力的创新环肽结构，受体占有时间超过72小时，并有延长的体内活性。莫替福肽通过6个位点与干细胞表面CXCR4受体结合，精准阻断CXCR4与SDF-/CXCL12的相互作用，使得干细胞失锚定从骨髓中释放并迁移到外周血中，从而显著提高CD34+细胞采集量，缩短采集次数，增加移植成功率。同时调节免疫细胞的迁移与活化，影响机体的免疫反应。 根据誉衡生物新闻稿介绍，莫替福肽的批准是基于GENESIS全球多中心3期注册研究的结果，该研究旨在比较莫替福肽+G-CSF与安慰剂+G-CSF在自体干细胞移植（ASCT）前接受造血干细胞动员的MM患者中的安全性和有效性。这项随机、双盲、安慰剂对照研究均达到了所有主要和关键次要终点，安全性良好且耐受。研究结果已于《自然-医学》（Nature Medicine）杂志发表。 这项临床研究显示，在莫替福肽+G-CSF可高效动员干细胞。仅一次用药，88.8%的患者通过一次单采、92.5%的患者最多通过两次单采即可获得理想剂量6×106/公斤体重CD34+细胞；接受安慰剂+G-CSF的患者中比例分别为9.5%和26.2%。莫替福肽显著提高了造血干细胞的采集效率和质量，为移植成功奠定基础。此外，数据还表明，莫替福肽诱导了多种造血干细胞和祖细胞（HSPC）亚群的全动员，这些亚群能够进行广泛的多谱系造血重建。 另一项研究也显示莫替福肽无论是单独使用还与G-CSF联合使用，其疗效都明显优于小分子CXCR4阻断剂，可快速动员细胞（中性粒细胞、单核细胞和造血祖细胞）进入外周血，并且在注射后24小时内仍保持较高的动员水平。 基于莫替福肽的生物学机制以及广泛的临床前及临床探索，该药物还具有更广的应用潜力，例如在肿瘤免疫治疗和放化疗中展现出显著的增效减毒作用，也可以增强感染高风险和免疫力低下人群的免疫力。 基于莫替福肽的作用机制特点和已有的临床数据，誉衡生物计划在实体肿瘤及细胞治疗中开发其他潜在适应症，包括与全人源PD-1单抗赛帕利单抗联合用药治疗一线胰腺癌。此前一项莫替福肽与PD-1抑制剂及标准化疗联合用药治疗一线胰腺癌的二期临床研究（CheMo4METPANC）在2023年AACR会议上发布。研究显示探索性阶段入组的11例患者，总体应答率（ORR）为64%；无进展生存期中位数（mPFS）为9.6个月，疾病控制率（DCR）为82%。其它潜在适应症包括细胞治疗中的CD34+细胞动员、改善化疗药物的骨髓抑制、升白、免疫修复等。 参考资料： [1] 誉衡生物宣布莫替福肽（APHEXDA®，motixafortide）获中国澳门药物监督管理局批准上市.Retrieved Sep 20，2024, from https://mp.weixin.qq.com/s/FsUpkYKIti9ilEMY75XNMw 本文由药明康德内容团队根据公开资料整理编辑，欢迎个人转发至朋友圈。转发授权或其他合作需求，请联系wuxi_media@wuxiapptec.com。 免责声明：药明康德内容团队专注介绍全球生物医药健康研究进展。本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。

Plinabulin/Docetaxel Combination Demonstrated Favorable Benefit/Risk Ratio over Docetaxel Alone: Significant Improvement in Overall Survival, Progression Free Survival, and Objective Response, with additional Significant Reduction of Grade 4 Neutropenia (>80% relative reduction), and Improved Patients’ Quality of LifeFLORHAM PARK, N.J., Sept. 16, 2024 (GLOBE NEWSWIRE) -- BeyondSpring Inc. (NASDAQ: BYSI) (“BeyondSpring” or the “Company”), a clinical-stage global biopharmaceutical company developing innovative cancer therapies, presented final data on Dublin-3 study (2L/3L EGFR wild-type NSCLC) focusing on safety outcomes on September 14, 2024 at European Society for Medical Oncology (ESMO) Congress 2024 in Barcelona, Spain. Full data on Dublin-3 study was published on September 9, 2024 in the Lancet Respiratory Medicine (https://doi.org/10.1016/S2213-2600(24)00178-4). Docetaxel remains the standard of care for patients with 2L/3L NSCLC without targetable alterations despite severe neutropenia (>40%) that greatly impair patients’ quality of life. Six recent phase 3 studies in patients with EGFR wild-type NSCLC who were previously treated with immune checkpoint inhibitors failed to show overall survival (OS) benefit compared with docetaxel (SAPPHIRE, LEAP-008, CONTACT01, EVOKE-01, CARMEN-LC03, and CANOPY-2). Two phase 3 studies (LUNAR and TROPION-Lung01) showed positive but mixed outcomes compared with docetaxel. The DUBLIN-3 study was a multicenter, single-blinded, randomized controlled trial that enrolled patients from 58 medical centers across Australia, China, and the USA. 559 patients with epidermal growth factor receptor (EGFR) wild-type NSCLC were randomly assigned (1:1) to receive either docetaxel and plinabulin (n=278) or docetaxel and placebo (n=281). The plinabulin/docetaxel combination significantly improved overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) compared to docetaxel alone. (Click here for related press release.) This poster presentation focused on plinabulin and docetaxel combination safety vs. docetaxel alone, as shown below: The combination is well tolerated: Similar percentages of patients experienced ≥1TEAE (treatment emergent adverse events); 99.6% in the combination arm and 99.3% in the docetaxel arm. There was less grade 4 TEAE in the combination arm (19.0%) vs. 42.8% in the docetaxel arm.The combination had >80% relative reduction in Grade 4 neutropenia (p<0.001): The combination arm had a 5.3 % Grade 4 neutropenia in Cycle 1 Day 8 compared to 27.8% in docetaxel alone (81% reduction, p<0.0001). The combination arm had a 5.1 % Grade 4 neutropenia in all cycles Day 8 compared to 33.6% in docetaxel alone (85% reduction, p<0.0001). In addition, hospital admission due to febrile neutropenia was lower in the combination arm (7 [2.6%] patients) vs. docetaxel arm (14 [5.0%] patients).The combination had reduced use of granulocyte-colony stimulating factor (G-CSF) in all cycles: Post-hoc analysis showed reduced G-CSF use in the combination arm (152 [56%] patients) vs. docetaxel arm (182 [66%] patients) and at cycles 1 to 4.The combination had improved quality-of-life (QoL) based on Q-TWiST data: Exploratory analysis showed better QoL based on Q-TWiST in the combination arm, with a clinically meaningful relative gain to the docetaxel arm of 18.5%(p=0.0393).The combination had a significant reduction in cycle-adjusted serious adverse events (SAE): Patients randomized to the combination received more cycles of treatment. When cycles were adjusted for SAEs, plinabulin significantly decreased Grade 3/4 SAEs (p=0.0235) and Grade 4 SAEs (p<0.0001).The combination had manageable side effects: Plinabulin induced mostly asymptomatic transient hypertension, which mostly resolved within 4-6 hours after infusion without medication. In addition, plinabulin induced GI side effects, including nausea, vomiting, and diarrhea, which were effectively managed following a protocol adjustment to add the prophylactic use of antiemetics and increase time of infusion. “NSCLC patients without targetable alterations whose disease has progressed on previous platinum-based therapy have a poor prognosis. Docetaxel is the current standard of care with >40% severe neutropenia and poor quality of life. In second or third-line NSCLC patients with EGFR wild-type, the phase 3 data suggest that adding plinabulin to docetaxel has a favorable benefit/risk ratio compared to docetaxel alone in significantly improving anti-cancer efficacy, and significantly reducing severe neutropenia and improving quality of life. This combination could be considered as a new option for second or third-line NSCLC patients without driver mutation, which is a severe unmet medical need,” said Dr. Feinstein, one of the lead principal investigators of Dublin-3 study at Piedmont Cancer Center, Atlanta. ESMO Congress 2024 Presentation (1358P): Plinabulin/Docetaxel Versus Docetaxel in Survival Benefits of 2L/3L EGFR Wild-Type NSCLC after Platinum Regimens (DUBLIN-3): a Randomized Phase 3 Trial Presenter: Dr. Trevor M. FeinsteinPoster Session: NSCLC, metastatic Citation:Han B., et al. Plinabulin plus docetaxel versus docetaxel in patients with non-small-cell lung cancer after disease progression on platinum-based regimen (DUBLIN-3): a phase 3, international, multicentre, single-blind, parallel group, randomised controlled trial. Lancet Respir Med. 2024 Sep 09: S2213-2600(24)00178-4. About PlinabulinPlinabulin is a novel first-in-class dendritic cell (DC) maturation therapeutic with durable anti-cancer benefit observed across multiple clinical studies. As a reversible binder at a distinct tubulin pocket, plinabulin does not change tubulin dynamics or antagonize tubulin stabilizing agents, such as docetaxel, which contributes to its differentiated activity and tolerability compared to other tubulin binders. Importantly, clinical data suggests that plinabulin enhances the cancer immunity cycle when used sequentially with chemotherapy/radiation and a checkpoint inhibitor. In addition, plinabulin significantly reduces chemotherapy induced neutropenia and could thereby increase docetaxel tolerability. Over 700 patients have been treated with plinabulin with good tolerability. About Dublin-3 StudyDublin-3 NSCLC was a global phase 3 randomized, controlled clinical trial comparing the combination of plinabulin and docetaxel to an active control arm of docetaxel alone (1:1 randomization) in second- and third-line NSCLC patients who had failed platinum doublet therapies, and who were epidermal growth factor receptor (EGFR) wild-type. Docetaxel was given on Day 1 in both arms at 75 mg/m2 in each 21-day cycle. Plinabulin was given on Day 1, one hour after docetaxel, and on Day 8, both at 30 mg/m2 in each cycle. The primary endpoint for the study was OS, and secondary endpoints were PFS, ORR, Duration of Response (DoR), Grade 4 neutropenia and Quality of Life. About BeyondSpringBeyondSpring is a global clinical-stage biopharmaceutical company developing innovative therapies to improve clinical outcomes for patients with high unmet medical needs. The Company is advancing its first-in-class lead asset, plinabulin, a potent inducer of dendritic cell maturation, in late-stage clinical development as a direct anti-cancer agent in NSCLC and a variety of cancer indications. BeyondSpring’s pipeline also includes three preclinical immuno-oncology assets. Additionally, BeyondSpring is an equity owner of SEED Therapeutics, Inc which is a pioneer in Target Protein Degradation technology and its application in innovative drug development. Learn more by visiting https://beyondspringpharma.com. Investor Contact:IR@beyondspringpharma.com Media Contact:PR@beyondspringpharma.com