Pexidartinib Hydrochloride

今日，和誉医药宣布，评估匹米替尼治疗腱鞘巨细胞瘤（TGCT）的3期MANEUVER研究达到主要终点，即第 25 周时的客观缓解率 （ORR） 为54.0%，而安慰剂组为3.2%（p<0.0001）；此外，在所有关键次要终点（包括疼痛和僵硬）方面，也取得了有统计学意义和临床意义的显著改善。 关于最新研究数据 3期MANEUVER研究是一项由三部分组成的、随机、双盲、安慰剂对照临床研究，旨在评估匹米替尼对符合接受系统性治疗条件且既往未接受过抗CSF1/CSF1R 治疗的 TGCT 患者中的疗效和安全性。 该试验在中国、欧洲、美国和加拿大开展，是一项具有里程碑意义的全球性研究，也是首个在多个地区以均衡比例招募亚洲和西方腱鞘巨细胞瘤患者的全球性试验。 第1部分双盲研究阶段将患者以 2：1 的比例，随机接受 50 mg QD 的匹米替尼（n=63）或安慰剂 （n=31）治疗24 周。主要终点是在意向治疗人群中第 25 周时的客观缓解率 （ORR），由独立盲审委员会基于实体瘤反应评估标准 （RECIST）1.1 版进行评估；次要终点包括基于肿瘤体积的评分、主动关节活动度、数字评定量表（NRS）测定的僵硬程度、简要疼痛量表（BPI）测定的疼痛程度和 PROMIS 身体功能评估。完成第 1 部分双盲研究后，符合条件的受试者可以继续接受开放标签的第 2 部分，治疗最长 24 周。完成第 2 部分的患者可以进入开放标签延长期（第 3 部分）以进行延长治疗和安全随访。 截至2024年6月30日，此前报告的42名50 mg剂量组患者的数据如下： 最佳ORR为85.0%。中位治疗持续时间为20.67个月（0.5, 30.1），54.8%的患者持续治疗时间≥18个月，38.1%的患者持续治疗时间≥24个月。 中位缓解持续时间尚未达到（NR），69.0%的患者仍在接受治疗。 肿瘤持续缩小、疼痛程度和僵硬缓解程度以及关节活动能力逐步改善。 总体安全性状况与既往报道保持一致，未观察到胆汁淤积性肝毒性发生。  关于匹米替尼 匹米替尼（Pimicotinib，ABSK021）是一款CSF-1R小分子抑制剂，是中国公司开发的首个进入临床Ⅲ期临床试验的高选择性CSF-1R 抑制剂。该药物采用每日一次的口服给药方式，有助于提高患者的长期依从性。匹米替尼曾获NMPA授予突破性疗法认定及FDA授予的快速通道指定，用于治疗不适合手术的TGCT。 2023年12月，和誉医药与德国默克达成许可协议，授予其在中国大陆、香港、澳门和台湾地区的独家商业化许可，以及匹米替尼全球商业权利的独家选择权；合作首付款和里程碑付款高达6.055 亿美元，除此之外，德国默克还将向和誉医药支付两位数百分比的销售提成。 除TGCT，Pimicotinib未来有望被开发用于多个适应症领域，目前来看：1）针对慢性移植物抗宿主病(cGVHD)的临床II 期研究进行中；2）针对1L 胰腺癌的II 期临床研究方案规划中；3）针对肌萎缩侧索硬化（ALS）的临床试验计划中。 关于CSF-1R药物 CSF-1R是细胞因子CSF-1受体，同时是受体酪氨酸激酶中的重要一员，该靶点与炎症的发生、发展紧密相关。CSF-1R 调节人体多种巨噬细胞,包括：1）肿瘤相关巨噬细胞(TAM),在抗肿瘤免疫方面起关键作用；2）小胶质细胞调节神经元生成和神经元功能,与神经退行性疾病密切相关。 据不完全统计，目前针对CSF-1R开发的单靶点药物约五十余种，国内尚未有相关产品获批。 关于腱鞘巨细胞瘤 腱鞘巨细胞瘤（TGCT）是由关节滑液、囊或腱鞘滑膜引起的罕见良性增生性炎症性疾病，根据生长模式可分类为弥漫性腱鞘巨细胞瘤（D-TGCT）和局限性腱鞘巨细胞瘤（L-TGCT）。前者更具侵袭性，多发病于膝关节、踝关节和髋关节，后者更常见，多发病于膝关节、手和腕关节。 美国罕见疾病组织的报告指出，TGCT 发病率约43/100 万。根据流行病学数据，其发病率在1999-2012 年间总体呈增长趋势，2012 年发病率为49 人每百万人。 TGCT 每百万人发病患者数 TGCT 的治疗方法包括手术、放射疗法、冷冻疗法、全身疗法。治疗结果表明，手术可以切除TGCT，但可能引起多种并发症多，且可能伴有有复发风险。一项荷兰的统计报告指出，2009-2014年间，近65%L-TGCT 患者与49%D-TGCT 患者使用开放性手术进行治疗，随访后计算复发率分别为4%与14%。另外有超过20%的TGCT 患者使用关节镜手术进行治疗，随访后计算复发率分别为6%与40%。 TGCT 复发率情况 CSF-1 在所有TGCT 中高表达，为靶向CFS-1R 提供基础，使用CSF-1R 抑制剂，可以显著缩小肿瘤，改善症状，实现长期的疾病控制。 TGCT 的治疗范式 全球范围内，除Pimicotinib外，针对TGCT 的主要已获批及后期在研CSF1R 抑制剂还包括Pexidartinib 和Vimseltinib。相比之下，Pimicotinib具有潜在“同类最佳”的治疗潜力。 关于和誉医药 和誉医药成立于2016年，专注于开发小分子肿瘤靶向药物，以自主研发为主。自成立以来，公司凭借优秀的药物发现团队及技术平台，建立起强大的内部研发引擎，已搭建由10个临床阶段项目及6 个研发阶段的项目组成的接续性良好的研发管线。 2023年以来公司已完成两笔交易合作。除与默克的交易外，公司还于3月1日与艾力斯医药就新一代EGFR抑制剂ABK3376 在中国区域达成授权合作，该药可高效抑制三代EGFI-TKI 耐药后产生的C797S 突变，目前处于申报临床阶段；公司可从协议中获得最高不超过1.879亿美元的首付款、开发及销售里程碑付款以及相应比例净销售额的许可提成费。 参考资料 1、公司官网 2、中泰证券 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↓

BASKING RIDGE, N.J.--( BUSINESS WIRE )--Daiichi Sankyo (TSE: 4568) will highlight new clinical research and real-world data from seven abstracts for TURALIO ® (pexidartinib) at the Connective Tissue Oncology Society (#CTOS2024) 2024 Annual Meeting. TURALIO is the first and only oral systemic therapy approved in the U.S. for adult patients with tenosynovial giant cell tumor (TGCT) associated with severe morbidity or functional limitations and not amenable to improvement with surgery. TGCT is a rare and typically non-malignant tumor that affects small and large joints. 1,2,3 Data at CTOS will highlight ongoing TURALIO research, including two analyses from the ENLIVEN phase 3 trial. One analysis evaluates the efficacy of TURALIO according to surgical history and the feasibility of surgery following treatment with TURALIO. The other is an exploratory analysis examining the dose of TURALIO at the time of objective response and the first timepoint response of progressive disease in relation to adverse events. “ These latest data being presented at CTOS continue to support the role of TURALIO as a treatment option for certain patients with tenosynovial giant cell tumor,” said Dan Switzer, Head of U.S. Oncology Business, Daiichi Sankyo, Inc. “ As a leader in TGCT research and development, Daiichi Sankyo has made significant progress in transforming the treatment landscape for patients with this rare, debilitating tumor and we remain committed to educating the medical community on identifying appropriate patients who may be eligible for treatment with TURALIO.” Additional TURALIO data at CTOS include health-related quality of life (HRQOL) outcomes from a phase 4 trial evaluating the discontinuation and re-treatment in patients with TGCT previously treated with TURALIO and a trial-in-progress of a phase 4 trial evaluating the risk of idiosyncratic cholestatic hepatoxicity associated with TURALIO treatment. Other clinical research includes interim results from an investigator-initiated phase 1 trial evaluating the safety and tolerability of TURALIO in pediatric patients and young adults with TGCT, a case study reporting the use of TURALIO as an upfront treatment strategy for TCGT and results of a real-world assessment evaluating symptom change in patients with TGCT receiving TURALIO. An overview of TURALIO data to be presented at CTOS includes: Presentation Title Author Presentation (PST) Pexidartinib use in patients with tenosynovial giant cell tumor: an analysis of the phase 3 randomized ENLIVEN clinical trial according to surgical history J. Healey Oral Presentation Saturday, November 16 3:30 – 4:30 pm Tumor response and regrowth in relation to clinical events among pexidartinib-treated subjects in the phase 3 ENLIVEN trial J. Desai Poster Session Thursday, November 14 5:45 – 6:45 pm Health-related quality of life from a phase 4 study to evaluate discontinuation and rechallenge of pexidartinib in patients with tenosynovial giant cell tumor previously treated with pexidartinib J. Desai Poster Session Thursday, November 14 5:45 – 6:45 pm A long-term phase 4 study to evaluate the risk of hepatotoxicity associated with pexidartinib treatment A. Singh Poster Session Thursday, November 14 5:45 – 6:45 pm Tenosynovial giant cell tumor in children: interim results from a phase 1 study of TURALIO J. Lake Poster Session Thursday, November 14 5:45 – 6:45 pm Pexidartinib upfront in a case of tenosynovial giant cell tumor: proof of concept for a treatment paradigm shift E. Palmerini Poster Session Thursday, November 14 5:45 – 6:45 pm Real-world experience of patients newly initiated on pexidartinib for tenosynovial giant cell tumor D. Dai Poster Session Thursday, November 14 5:45 – 6:45 pm About TGCT (PVNS/GCT-TS) TGCT, also referred to as pigmented villonodular synovitis (PVNS) or giant cell tumor of the tendon sheath (GCT-TS), is a rare, typically non-malignant tumor that can be locally aggressive. TGCT affects the synovium-lined joints, bursae and tendon sheaths, resulting in reduced mobility in the affected joint or limb. 1,2,3 While the exact incidence of TGCT is not known, it is estimated that the worldwide incidence of TGCT is 43 patients per million person-years. 4,5,6 TGCT is subcategorized into two types: localized, which is more common and accounts for 80% to 90% of cases, and diffuse, which accounts for 10% to 20% of cases. 5,6 The current standard of care for TGCT is surgical resection. 1,7 However, in patients with recurrent, difficult-to-treat, or the diffuse form of TGCT, the tumor may wrap around bone, tendons, ligaments and other parts of the joint. In these cases, the tumor may be difficult to remove and/or may not be amenable to improvement with surgery. Multiple surgeries for more severe cases can lead to significant joint damage, debilitating functional impairments and reduced quality of life, and amputation may be considered. 7,8,9 Recurrence rates for localized TGCT are estimated to be up to 15% following complete resection. 3,6,10,11,12 Diffuse TGCT recurrence rates are estimated to be up to 55% following complete resection. 3,6,10,13 TGCT affects all age groups with the diffuse type on average occurring most often in people below the age of 40, and the localized type typically occurring in people between 30 and 50 years old. 1,4,5,6 About TURALIO TURALIO (pexidartinib) is an oral small molecule that targets colony stimulating factor 1 receptor (CSF1R), KIT proto-oncogene receptor tyrosine kinase (KIT), and FMS-like tyrosine kinase 3 (FLT3) harboring an internal tandem duplication (ITD) mutation. Overexpression of the CSF1R ligand promotes cell proliferation and accumulation in the synovium. TURALIO is approved in the U.S. for the treatment of adult patients with symptomatic TGCT associated with severe morbidity or functional limitations and not amenable to improvement with surgery based on the results of the ENLIVEN trial. Important Safety Information Indication TURALIO Ⓡ (pexidartinib) is indicated for the treatment of adult patients with symptomatic tenosynovial giant cell tumor (TGCT) associated with severe morbidity or functional limitations and not amenable to improvement with surgery. WARNING: HEPATOTOXICITY TURALIO can cause serious and potentially fatal liver injury. Monitor liver tests prior to initiation of TURALIO and at specified intervals during treatment. Withhold and dose reduce or permanently discontinue TURALIO based on severity of hepatotoxicity. TURALIO is available only through a restricted program called the TURALIO Risk Evaluation and Mitigation Strategy (REMS) Program. Contraindications None Warnings and Precautions Hepatotoxicity Hepatotoxicity with ductopenia and cholestasis occurred in patients treated with TURALIO. Across 768 patients who received TURALIO in clinical trials, there were two irreversible cases of cholestatic liver injury. One patient with advanced cancer and ongoing liver toxicity died and one patient required a liver transplant. The mechanism of cholestatic hepatotoxicity is unknown and its occurrence cannot be predicted. It is unknown whether liver injury occurs in the absence of increased transaminases. In ENLIVEN, 3 of 61 (5%) patients who received TURALIO developed signs of serious liver injury, defined as alanine aminotransferase (ALT) or alanine aminotransferase (AST) ≥3 × upper limit of normal (ULN) with total bilirubin ≥2 × ULN. In these patients, peak ALT ranged from 6 to 9 × ULN, peak total bilirubin ranged from 2.5 to 15 × ULN, and alkaline phosphatase (ALP) was ≥2 × ULN. ALT, AST and total bilirubin improved to <2 × ULN in these patients 1 to 7 months after discontinuing TURALIO. Avoid TURALIO in patients with preexisting increased serum transaminases, total bilirubin, or direct bilirubin (>ULN); or active liver or biliary tract disease, including increased ALP. Monitor liver tests, including AST, ALT, total bilirubin, direct bilirubin, ALP, and gamma-glutamyl transferase (GGT), prior to initiation of TURALIO, weekly for the first 8 weeks, every 2 weeks for the next month and every 3 months thereafter. Withhold and dose reduce, or permanently discontinue TURALIO based on the severity of the hepatotoxicity. Rechallenge with a reduced dose of TURALIO may result in a recurrence of increased serum transaminases, bilirubin, or ALP. Monitor liver tests weekly for the first month after rechallenge. TURALIO REMS Requirements include: 1) prescribers must be certified by enrolling and completing training, 2) patients must complete and sign an enrollment form for inclusion in a patient registry, and 3) pharmacies must be certified and must dispense only to patients who are authorized (enrolled in the REMS patient registry). Further information is available at www.TURALIOREMS.com or 1-833-887-2546. Embryo-fetal toxicity TURALIO may cause fetal harm when administered to a pregnant woman. Advise patients of reproductive potential of the potential risk to a fetus. Verify pregnancy status in females of reproductive potential prior to the initiation of TURALIO. Advise females of reproductive potential to use an effective nonhormonal method of contraception. TURALIO can render hormonal contraceptives ineffective during treatment with TURALIO and for 1 month after the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with TURALIO and for 1 week after the final dose. Potential Risks Associated with a High-Fat Meal Taking TURALIO with a high-fat meal increases pexidartinib concentrations, which may increase the incidence and severity of adverse reactions, including hepatotoxicity. Instruct patients to take TURALIO with a low-fat meal (approximately 11 to 14 grams of total fat) and to avoid taking TURALIO with a high-fat meal (approximately 55 to 65 grams of total fat). Adverse Reactions The most common adverse reactions (>20%) were increased lactate dehydrogenase (92%), increased AST (88%), hair color changes (67%), fatigue (64%), increased ALT (64%), decreased neutrophils (44%), increased cholesterol (44%), increased ALP (39%), decreased lymphocytes (38%), eye edema (30%), decreased hemoglobin (30%), rash (28%), dysgeusia (26%), and decreased phosphate (25%). Drug Interactions Hepatotoxic products: Avoid coadministration in patients with increased serum transaminases, total bilirubin, or direct bilirubin (>ULN) or active liver or biliary tract disease. Moderate or strong CYP3A inhibitors and UGT inhibitors: Concomitant use may increase pexidartinib concentrations. Reduce TURALIO dosage if concomitant use cannot be avoided. Strong CYP3A inducers: Avoid concomitant use due to decreased pexidartinib concentrations. Acid-reducing agents: Avoid concomitant use of proton pump inhibitors due to decreased pexidartinib concentrations. Use histamine-2 receptor antagonists or antacids if needed. CYP3A substrates: Avoid concomitant use where minimal concentration changes may lead to serious therapeutic failure (e.g., hormonal contraceptives) due to decreased concentrations of CYP3A substrates. Use in Specific Populations Lactation: Advise not to breastfeed and for at least 1 week after the final dose. Renal impairment: Reduce the dosage for patients with mild to severe renal impairment. Hepatic impairment: Reduce the dosage for patients with moderate hepatic impairment. TURALIO has not been studied in patients with severe hepatic impairment. To report SUSPECTED ADVERSE REACTIONS, contact Daiichi Sankyo, Inc, at 1-877-437-7763 or FDA at 1-800-FDA-1088 or fda.gov/medwatch . Please see accompanying full Prescribing Information , including Boxed WARNING , and Medication Guide . About Daiichi Sankyo Daiichi Sankyo is an innovative global healthcare company contributing to the sustainable development of society that discovers, develops and delivers new standards of care to enrich the quality of life around the world. With more than 120 years of experience, Daiichi Sankyo leverages its world-class science and technology to create new modalities and innovative medicines for people with cancer, cardiovascular and other diseases with high unmet medical need. For more information, please visit www.daiichisankyo.com . References: 1 de Saint Aubain, et al. WHO. 2013;100-103. 2 Rao AS, et al. J Bone Joint Surg AM . 1984;66(1):76-94. 3 Ravi V, et al. Curr Opin Oncol . 2011;23:361-366. 4 Myers BW, et al. Medicine (Baltimore). 1980;59(3):223-238. 5 Mastboom MJL, et al. Acta Orthopaedica . 2017;88(6):688-694. 6 Ehrenstein V, et al. J Rheumatol. 2017; 44(10):1476-1483. 7 Verspoor FGM, et al. Future Oncol. 2013;10:1515-1531. 8 Verspoor FGM, et al. Rheumatol. 2014;53(11):2063-2070. 9 Brahmi M, et al. Curr Treat Options Oncol. 2016;17(2):10. 10 Gouin F, Noailles T. Orthop Traumatol Surg Res. 2017;103(1S):S91-S97. 11 Palmerini E, Staals EL, Maki RG, et al. Eur J Cancer. 2015;51(2):210-217. 12 Dines JS, et al. Arthroscopy. 2007;23(9):930-937. 13 Xie GP, et al. PLOS One. 2015;10(3):e0121451.