Cytarabine

本文梳理了近一个月（2024年10月16日～2024年11月15日）在研药物的临床试验取得不佳（研发成功率降低）进展的情况，同时，对部分药物的研究情况进行简述和分析，供研发人员参考。 据统计，在检索时间范围内，共有10个药物的临床试验数据进展不佳（表1），其中有5个处于暂停阶段，分别有2个处于Ⅱ、Ⅲ期阶段。适应症涉及库欣氏综合征、急性髓性白血病、艾滋病、抑郁症、近视黄斑变性、鼻息肉病、非结核分枝杆菌等。以下对部分药物的研究进展不佳原因进行简要介绍。 表1：近一个月（2024年10月16日～2024年11月15日）临床试验数据不佳的药物 Uproleselan 近期，根据GlycoMimetics公布的关于美国国家癌症研究所（NCI）和肿瘤临床试验联盟正在进行的适应性Ⅱ/Ⅲ期试验（NCT03701308）的Ⅱ期分析，在新诊断的适合接受强化化疗的60岁或60岁以上AML成人患者中，与单独化疗相比，Uproleselan和阿糖胞苷+柔红霉素（7+3）化疗联合治疗未能引起无事件生存期（EFS）的统计学显著改善。 Ⅱ期临床分析结果显示，Uproleselan组合未达到试验的主要终点EFS。NCI和肿瘤临床试验联盟的研究者正在努力进一步评价试验结果，这将包括亚组分析数据的评估，以确定是否有任何疗效信号需要进一步研究。此外，来自Ⅱ/Ⅲ期试验的主要数据将在未来的医学会议上分享。 2024年5月初，GlycoMimetics宣布，在一项全球性Ⅲ期试验（NCT03616470）纳入的R/R AML患者（n=388）意向治疗人群中，Uproleselan联合化疗与单独化疗相比，未能在总生存期（OS）方面取得统计学意义上的显著改善。初步结果显示，联合用药的中位OS为13个月，而单独化疗的中位OS为12.3个月。在安全性方面，不良反应与试验中使用的化疗药物的已知毒性特征一致。该研究已被终止。 这项随机、双盲、安慰剂对照的Ⅲ期研究评估了R/R AML患者接受Uproleselan与MEC（米托蒽醌、依托泊苷和阿糖胞苷）或FAI（氟达拉滨、阿糖胞苷和去甲氧柔红霉素）联合治疗的情况。患者纳入标准为年龄18～75岁，并且考虑接受强化诱导化疗。除了R/R疾病之外，患者之前不能接受超过1次的干细胞移植或接受试验方案中用于诱导的化疗方案。 Uproleselan是一种在研的、第一类E-选择素拮抗剂，已获得FDA的突破性疗法和快速通道认定，可用于治疗R/R AML成人患者。E-选择素是一种白细胞粘附分子，在血管和骨髓的内皮细胞上连续表达。有证据表明，在AML中，骨髓微环境（BME）保护性龛中的内皮细胞与白血病干细胞和原始细胞之间的E-选择素-配体相互作用会促进白血病细胞的存活，并使其免受AML疗法的影响。Uproleselan旨在破坏E选择素的结合，防止白血病髓系细胞利用骨髓微环境的保护龛。 ALTO-100 2024年10月22日，Alto Neuroscience发布其在研疗法ALTO-100治疗重度抑郁症（Major depressive disorder）Ⅱb期研究未达到其主要终点。该临床试验结果的公布使得2月份刚刚登陆资本市场的Alto股价在周二晚间的盘后交易中下跌了76%，市值也仅剩1.2亿美金。 ALTO-100是由Alto Neuroscience利用其生物标志物平台所开发的一款口服药物，其靶标为脑源性神经营养因子（BDNF），可恢复患者的神经可塑性，使大脑能够灵活适应新信息。Alto Neuroscience的核心管线ALTO-100最初来自于Palisade Bio的管线NSI-189，2021年时转让给了Alto Neuroscience（交易总额490万美元，预付款50万美元）。Alto Neuroscience在2024年2月初以其独特的精准精神病学平台成功上市，筹集了1.286亿美元。然而，仅仅9个月后，其利用人工智能生物标志物平台所开发的ALTO-100的Ⅱb期试验中未能达到预期效果。 该Ⅱb期试验是一项双盲实验，在美国进行，共有301名成年人参与，在治疗期间，参与者基于生物标志物被分成治疗组和安慰剂组，将从第1天到第42天每天给药两次ALTO-100片剂，同时安慰剂组给予两次安慰剂。为了评估ALTO-100与安慰剂对中度至重度抑郁症的疗效，通过蒙哥马利-奥斯伯格抑郁量表（MADRS）总分衡量第1天到第42天的变化。主要终点是比较6周治疗期结束时ALTO-100组与安慰剂组的MADRS评分。Alto称ALTO-100的安全性和耐受性符合预期，但ALTO-100给药组的患者在抑郁症状方面没有表现出统计学上的显著改善，该治疗也没有达到其他预先指定的关键次要终点。 SPR720 2024年10月29日，Spero Therapeutics宣布，由于其候选抗生素SPR720（Fobrepodacin，一种正在研究的非结核分枝杆菌肺病小分子治疗药物，图1）的Ⅱa期研究的中期分析未达到主要终点。公司暂停该项目，内部重组裁员约39%。 图1：SPR720的化学结构式 Spero Therapeutics公司的SPR720在Ⅱa期试验中表现不佳。中期分析显示了这款口服抗生素候选药物的双重打击：既未能胜过安慰剂，又显示出肝脏毒性的迹象。中期分析显示与安慰剂的对比——对其疗效投下了重大怀疑——以及引起对SPR720安全性担忧的不良事件。在每天口服1000mg SPR720的人中，Spero看到了潜在的剂量限制性安全问题。安全问题包括三例可逆的3级肝毒性。由于疗效不佳和令人担忧的安全性，Spero决定暂停其当前的开发项目。 2016年Spero从Vertex公司以50万美元预付款获得了SPR720，认为它有潜力成为非结核性分枝杆菌肺病的口服治疗药物。 【参考资料】 1. Informa数据库, 检索日期: 2024年11月19日. 2. 药渡数据库, 检索日期: 2024年11月30日. 3. 药明康德、医药魔方、学术经纬、医药观澜、医麦客等网络公开资源. 本文其它内容请见《全球药物创新快讯》2024年第10期（总第146期）。

TOKYO & BASKING RIDGE, N.J.--( BUSINESS WIRE )--The first patient has been dosed in the QuANTUM-Wild phase 3 trial evaluating Daiichi Sankyo’s (TSE: 4568) VANFLYTA ® (quizartinib) in combination with standard intensive induction and consolidation chemotherapy followed by single-agent maintenance in adults with newly diagnosed FLT3 -ITD negative acute myeloid leukemia (AML). AML is an aggressive blood cancer with a five-year overall survival rate of approximately 32%. 1, 2 Targeted therapy with FLT3 inhibitors has improved survival for some patients with FLT3 gene mutations, which most commonly occur as FLT3 -ITD. 3 However, about 90% of patients with AML overexpress FLT3 regardless of mutational status. 1, 4, 5 No FLT3 inhibitors are currently approved for patients without FLT3 mutations. “Preliminary data have shown promising results for VANFLYTA in patients with FLT3 -ITD negative acute myeloid leukemia, which includes patients without FLT3 mutations and patients with TKD mutations,” said Mark Rutstein, MD, Global Head, Oncology Clinical Development, Daiichi Sankyo. “We have initiated the QuANTUM-Wild trial to further confirm the potential role of VANFLYTA combined with standard chemotherapy and as subsequent maintenance monotherapy in this broader population of patients with AML who are in need of new treatment options to potentially reduce the risk of relapse and improve overall survival.” The QuANTUM-Wild trial was initiated based on results of the QUIWI phase 2 trial evaluating VANFLYTA in combination with standard intensive chemotherapy and as subsequent maintenance monotherapy in adult patients with newly diagnosed FLT3 -ITD negative AML. The final results of QUIWI were presented at the 2024 American Society of Hematology Annual Meeting. 6 About the QuANTUM-Wild Trial QuANTUM-Wild is a randomized, double-blind, placebo-controlled global phase 3 trial evaluating the efficacy and safety of VANFLYTA in combination with standard intensive induction and consolidation therapy, including allogenic hematopoietic stem cell transplant (HSCT), followed by maintenance monotherapy, in adult patients aged 18 to 70 with newly diagnosed FLT3 -ITD negative AML. Patients will be randomized 2:2:1 into three treatment arms. In Arms A and B, patients will receive VANFLYTA or placebo, respectively, in combination with cytarabine and anthracycline induction and cytarabine consolidation chemotherapy, followed by up to three years of single-agent maintenance therapy. The primary endpoint for Arms A and B is overall survival. Secondary endpoints include event-free survival, duration of complete response, relapse-free survival, complete remission rate (CR), CR with minimal or measurable residual disease negativity, pharmacokinetic assessments and safety measures including treatment emergent adverse events. For purposes of exploratory analyses in the maintenance setting, patients in a third study arm (Arm C), will receive VANFLYTA in combination with intensive induction and consolidation chemotherapy followed by placebo maintenance monotherapy. QuANTUM-Wild is expected to enroll approximately 700 patients across Asia, Australia, Europe, North America and South America. For more information, please visit ClinicalTrials.gov . About Acute Myeloid Leukemia One of the most common forms of leukemia in adults, AML is an aggressive blood cancer with a five-year overall survival rate of approximately 32%. 1, 2, 3 Approximately 144,000 new cases of AML were diagnosed globally with more than 130,000 deaths reported in 2021. 7 Targeted therapy with FLT3 inhibitors has improved survival for some patients with FLT3 gene mutations, which most commonly occur as FLT3 -ITD. 3 However, about 90% of all patients with AML overexpress FLT3 regardless of activating mutations. 1, 4, 5 No FLT3 inhibitors are currently approved for patients without FLT3 mutations. FLT3 is a receptor tyrosine kinase protein that plays an important role in blood cell development but, when constitutively activated, FLT3 can contribute to AML development and growth. 8 About VANFLYTA VANFLYTA is an oral, highly potent and selective type II FLT3 inhibitor approved in more than 30 countries in combination with standard cytarabine and anthracycline induction and standard cytarabine consolidation chemotherapy, and as maintenance monotherapy following consolidation, for the treatment of adult patients with newly diagnosed AML that is FLT3 -ITD positive based on the results from the QuANTUM-First trial. In the U.S., VANFLYTA is not indicated as maintenance monotherapy following allogeneic HSCT; improvement in overall survival with VANFLYTA in this setting has not been demonstrated. VANFLYTA also is approved in Japan for the treatment of patients with relapsed/refractory AML that is FLT3 -ITD mutation positive, as detected by an approved test, based on results from the QuANTUM-R trial. About the VANFLYTA Clinical Development Program The VANFLYTA clinical development program includes the QuANTUM-Wild phase 3 trial in adult patients with newly diagnosed FLT3 -ITD negative AML, a phase 1/2 trial in pediatric and young adult patients with relapsed/refractory FLT3 -ITD positive AML in Europe, Asia and North America and several phase 1/2 combination studies as part of a strategic collaboration with The University of Texas MD Anderson Cancer Center. VANFLYTA U.S. Important Safety Information WARNING: QT PROLONGATION, TORSADES DE POINTES, and CARDIAC ARREST VANFLYTA ® (quizartinib) prolongs the QT interval in a dose- and concentration-related manner. Prior to VANFLYTA administration and periodically, monitor for hypokalemia or hypomagnesemia, and correct deficiencies. Perform electrocardiograms (ECGs) to monitor the QTc at baseline, weekly during induction and consolidation therapy, weekly for at least the first month of maintenance, and periodically thereafter. Torsades de pointes and cardiac arrest have occurred in patients receiving VANFLYTA. Do not administer VANFLYTA to patients with severe hypokalemia, severe hypomagnesemia, or long QT syndrome. Do not initiate treatment with VANFLYTA or escalate the VANFLYTA dose if the QT interval corrected by Fridericia’s formula (QTcF) is greater than 450 ms. Monitor ECGs more frequently if concomitant use of drugs known to prolong the QT interval is required. Reduce the VANFLYTA dose when used concomitantly with strong CYP3A inhibitors, as they may increase quizartinib exposure. Because of the risk of QT prolongation, VANFLYTA is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the VANFLYTA REMS. Indication VANFLYTA is indicated in combination with standard cytarabine and anthracycline induction and cytarabine consolidation, and as maintenance monotherapy following consolidation chemotherapy, for the treatment of adult patients with newly diagnosed acute myeloid leukemia (AML) that is FLT3 internal tandem duplication (ITD)–positive as detected by an FDA-approved test. Limitations of Use VANFLYTA is not indicated as maintenance monotherapy following allogeneic hematopoietic stem cell transplantation (HSCT); improvement in overall survival with VANFLYTA in this setting has not been demonstrated. Contraindications VANFLYTA is contraindicated in patients with severe hypokalemia, severe hypomagnesemia, long QT syndrome, or in patients with a history of ventricular arrhythmias or torsades de pointes. Warnings and Precautions QT Prolongation, Torsades de Pointes, and Cardiac Arrest (See BOXED WARNING) VANFLYTA prolongs the QT interval in a dose- and concentration-dependent manner. The mechanism of QTc interval prolongation is via inhibition of the slow delayed rectifier potassium current, I Ks , as compared to all other medications that prolong the QTc interval, which is via the rapid delayed rectifier potassium current, I Kr . Therefore, the level of QTc prolongation with VANFLYTA that predicts the risk of cardiac arrhythmias is unclear. Inhibition of I Ks and I Kr may leave patients with limited reserve, leading to a higher risk of QT prolongation and serious cardiac arrhythmias, including fatal outcomes. Torsades de pointes, ventricular fibrillation, cardiac arrest, and sudden death have occurred in patients treated with VANFLYTA. Of the 1,081 patients with AML treated with VANFLYTA in clinical trials, torsades de pointes occurred in approximately 0.2% of patients, cardiac arrest occurred in 0.6% of patients, including 0.4% with a fatal outcome, and 0.1% of patients experienced ventricular fibrillation. These severe cardiac arrhythmias occurred predominantly during the induction phase. Of the 265 patients with newly diagnosed FLT3-ITD–positive AML treated with VANFLYTA in combination with chemotherapy in the clinical trial, 2.3% were found to have a QTcF greater than 500 ms and 10% of patients had an increase from baseline QTcF greater than 60 ms. The clinical trial excluded patients with a QTcF ≥450 ms or other factors that increased the risk of QT prolongation or arrhythmic events (eg, NYHA Class III or IV congestive heart failure, hypokalemia, family history of long QT interval syndrome). Therefore, avoid use in patients who are at significant risk of developing torsades de pointes, including uncontrolled or significant cardiac disease, recent myocardial infarction, heart failure, unstable angina, bradyarrhythmias, tachyarrhythmias, uncontrolled hypertension, high-degree atrioventricular block, severe aortic stenosis, or uncontrolled hypothyroidism. Do not initiate treatment with VANFLYTA if the QTcF interval is greater than 450 ms. Do not use VANFLYTA in patients with severe hypokalemia, severe hypomagnesemia, long QT syndrome, or in patients with a history of ventricular arrhythmias or torsades de pointes. Perform an ECG and correct electrolyte abnormalities prior to initiation of treatment with VANFLYTA. During induction and consolidation, perform an ECG prior to initiation and then once weekly during VANFLYTA treatment or more frequently as clinically indicated. During maintenance, perform ECGs prior to initiation, once weekly for at least the first month following dose initiation and escalation, and as clinically indicated thereafter. Do not escalate the dose if QTcF is greater than 450 ms. Perform ECG monitoring of the QT interval more frequently in patients who are at significant risk of developing QT interval prolongation and torsades de pointes, or following dose escalation. Monitor and correct hypokalemia and hypomagnesemia prior to and during treatment with VANFLYTA. Maintain electrolytes in the normal range. Monitor electrolytes and ECGs more frequently in patients who experience diarrhea or vomiting. Monitor patients more frequently with ECGs if coadministration of VANFLYTA with drugs known to prolong the QT interval is required. Reduce the VANFLYTA dose when used concomitantly with strong CYP3A inhibitors, as they may increase quizartinib exposure. Reduce VANFLYTA if QTc increases to greater than 480 ms and less than 500 ms. Interrupt and reduce VANFLYTA if QTc increases to greater than 500 ms. Permanently discontinue VANFLYTA in patients who develop recurrent QTc greater than 500 ms or QTc interval prolongation with signs or symptoms of life-threatening arrhythmia. VANFLYTA is available only through a restricted program under a REMS. VANFLYTA REMS VANFLYTA is available only through a restricted distribution program under a REMS called the VANFLYTA REMS because of the serious risk of QT prolongation, torsades de pointes, and cardiac arrest. Notable requirements of the VANFLYTA REMS include the following: Prescribers must be certified in the VANFLYTA REMS by enrolling and completing training. Prescribers must counsel patients receiving VANFLYTA about the risk of QT prolongation, torsades de pointes, and cardiac arrest, and provide patients with a Patient Wallet Card. Pharmacies that dispense VANFLYTA must be certified with the VANFLYTA REMS and must verify prescribers are certified through the VANFLYTA REMS. Further information about the VANFLYTA REMS is available at www.VANFLYTAREMS.com or by telephone at 1-855-212-6670. Embryo-Fetal Toxicity Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with VANFLYTA and for 7 months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with VANFLYTA and for 4 months after the last dose. Adverse Reactions The safety of VANFLYTA (35.4 mg orally once daily with chemotherapy, 26.5 mg to 53 mg orally once daily as maintenance) in adult patients with newly diagnosed FLT3-ITD positive AML is based on QuANTUM-First. Serious adverse reactions in ≥5% of patients who received VANFLYTA plus chemotherapy were: febrile neutropenia (11%). Fatal adverse reactions occurred in 10% of patients who received VANFLYTA plus chemotherapy, including sepsis (5%), fungal infections (0.8%), brain edema (0.8%), and one case each of febrile neutropenia, pneumonia, cerebral infarction, acute respiratory distress syndrome, pulmonary embolism, ventricular dysfunction, and cardiac arrest. Permanent discontinuation due to an adverse reaction in patients in the VANFLYTA plus chemotherapy arm occurred in 20% of patients. The most frequent (≥2%) adverse reaction which resulted in permanent discontinuation in the VANFLYTA arm was sepsis (5%). Dosage interruptions of VANFLYTA due to an adverse reaction occurred in 34% of patients. Adverse reactions which required dosage interruption in ≥2% of patients in the VANFLYTA arm included neutropenia (11%), thrombocytopenia (5%), and myelosuppression (3%). Dose reductions of VANFLYTA due to an adverse reaction occurred in 19% of patients. Adverse reactions which required dosage reductions in ≥2% of patients in the VANFLYTA arm were neutropenia (9%), thrombocytopenia (5%), and electrocardiogram QT prolonged (4%). The most common adverse reactions (≥10% with a difference between arms of ≥2% compared to placebo), including laboratory abnormalities, were decreased lymphocytes, decreased potassium, decreased albumin, decreased phosphorus, increased alkaline phosphatase, decreased magnesium, febrile neutropenia, diarrhea, mucositis, nausea, decreased calcium, abdominal pain, sepsis, neutropenia, headache, increased creatine phosphokinase, vomiting, upper respiratory tract infections, hypertransaminasemia, thrombocytopenia, decreased appetite, fungal infections, epistaxis, increased potassium, herpesvirus infections, insomnia, QT prolongation, increased magnesium, increased sodium, dyspepsia, anemia, and eye irritation. Drug Interactions Strong CYP3A Inhibitors VANFLYTA is a CYP3A substrate. Concomitant use of VANFLYTA with a strong CYP3A inhibitor increases quizartinib systemic exposure, which may increase the risk of VANFLYTA adverse reactions. Reduce the dosage of VANFLYTA. Strong or Moderate CYP3A Inducers Concomitant use of VANFLYTA with strong or moderate CYP3A inducers decreases quizartinib systemic exposure, which may reduce VANFLYTA efficacy. Avoid concomitant use of VANFLYTA with strong or moderate CYP3A inducers. QT Interval–Prolonging Drugs VANFLYTA prolongs the QT/QTc interval. Coadministration of VANFLYTA with other drugs that prolong the QT interval may further increase the incidence of QT prolongation. Monitor patients more frequently with ECG if coadministration of VANFLYTA with drugs known to prolong the QT interval is required. Use in Specific Populations Pregnancy VANFLYTA can cause embryo-fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to the fetus. Lactation Advise women not to breastfeed during treatment with VANFLYTA and for one month after the last dose. Females and Males of Reproductive Potential Pregnancy Testing Verify pregnancy status in females of reproductive potential within 7 days before starting treatment with VANFLYTA. Contraception Females Advise female patients of reproductive potential to use effective contraception during treatment with VANFLYTA and for 7 months after the last dose. Males Advise male patients with female partners of reproductive potential to use effective contraception during treatment with VANFLYTA and for 4 months after the last dose. Infertility Females Based on findings from animal studies, VANFLYTA may impair female fertility. These effects on fertility were reversible. Males Based on findings from animal studies, VANFLYTA may impair male fertility. These effects on fertility were reversible. Pediatric Use Safety and effectiveness of VANFLYTA have not been established in pediatric patients. Geriatric Use No overall differences in safety or efficacy were observed between patients 65 years of age and older and younger adult patients. Renal Impairment No dosage adjustment is recommended in patients with mild to moderate renal impairment (CLcr 30 to 89 mL/min). VANFLYTA has not been studied in patients with severe renal impairment (CLcr <30 mL/min). Hepatic Impairment No dosage adjustment is recommended in patients with mild hepatic impairment or moderate hepatic impairment. VANFLYTA 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 the FDA at 1-800-FDA-1088 or fda.gov/medwatch . Please see Full Prescribing Information , including Boxed WARNINGS, 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 Kennedy VE, et al. Front Oncol . 2020;10:612880. 2 National Cancer Institute SEER Program. Cancer Stat Facts: Leukemia - Acute Myeloid Leukemia . 3 Loschi M, et al. Int J Mol Sci . 2021;22(11):5873. 4 Li Y, et al. Blood . 2004;104(4):1137-44. 5 Gilliand G and Griffin J. Blood. 1 September 2002;100:5 6 Montesinos P, et al. Abstract #1512 . ASH 2024 Annual Meeting. 7 Zhou Y, et al . Biomark Res . 2024;12(1):101. 8 Daver N, et al. 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