Mitoxantrone Hydrochloride

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）。

Publication follows oral presentation at the American Society of Hematology (ASH) Annual Meeting Combination in r/r follicular lymphoma shows best ORR of 97% and CR rate of 77% with 12-month PFS of 95% Additional IIT data also presented at ASH on ZYNLONTA monotherapy in marginal zone lymphoma shows ORR of 91% and 70% CR LAUSANNE, Switzerland, Dec. 9, 2024 /PRNewswire/ -- ADC Therapeutics SA (NYSE: ADCT), a commercial-stage global leader and pioneer in the field of antibody drug conjugates (ADCs), today announced updated data from the investigator-initiated Phase 2 clinical trial evaluating ZYNLONTA® (loncastuximab tesirine-lpyl) in combination with rituximab to treat relapsed or refractory (r/r) follicular lymphoma (FL) were published in the December issue of The Lancet Haematology, following an oral presentation of the data at the recent 66th American Society of Hematology (ASH) Annual Meeting and Exposition. "We are excited by the publication of these results in The Lancet Haematology demonstrating ZYNLONTA's robust clinical activity in follicular lymphoma, particularly in patients classified as high-risk POD24 and those with high tumor burden where there remains significant unmet need," said Mohamed Zaki, MD, PhD, Chief Medical Officer of ADC Therapeutics. "In addition, encouraging data from another investigator-initiated trial of ZYNLONTA as a single agent to treat marginal zone lymphoma were also presented at ASH. Collectively, we believe these data underscore ZYNLONTA's promise for patients with indolent B-cell lymphomas and add to a growing body of evidence showing the potential of ZYNLONTA beyond diffuse large B-cell lymphoma." ZYNLONTA in combination with rituximab to treat r/r follicular lymphoma (FL) The investigator-initiated trial conducted at the Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine evaluated the combination in patients with r/r FL treated with ≥1 line of systemic therapy presenting high-disease burden as defined by GELF criteria or POD24 at enrollment. The primary endpoint of the study is complete response rate (CR) by week 12 PET/CT based on Lugano 2014 criteria. The trial enrolled 39 patients, all of which were evaluated for safety and 35 of which were evaluated for efficacy. Patients were a median age of 68 years (range 47 to 89) and the majority received one previous line of therapy (n=26; 67%). R-CHOP was the most common first-line therapy (n=22; 56%) followed by bendamustine with rituximab (n=10; 26%), single-agent rituximab (n=6; 15%) and fludarabine, mitoxantrone and dexamethasone (n=1; 3%). Highlights from the results published in The Lancet Haematology included: Best overall response rate (ORR) of 97.4% (n=38) and CR rate of 76.9% (n=30) After a median follow-up of 15.6 months, the median progression-free survival (PFS) was not reached, and the 12-month PFS was 94.6% The most common treatment-emergent adverse events (TEAEs) were hyperglycemia (n=17; 43.6%) followed by increased alkaline phosphatase (n=16; 41%) and neutropenia, fatigue and increased aspartate aminotransferase and alanine aminotransferase (n=15; 38.5%) The most common grade ≥3 TEAE were lymphopenia (n=8; 20.5%) followed by neutropenia (n=5; 12.9%) No Grade 5 TEAEs occurred. The publication titled, "Loncastuximab tesirine with rituximab in patients with relapsed or refractory follicular lymphoma: a single centre, single arm Phase 2 trial," is now available online and will be published in the December issue of The Lancet Haematology. The results were also presented during a session on indolent B-cell lymphomas at ASH by Juan Pablo Alderuccio, MD, lead investigator and Associate Professor of Medicine and Hematologist at Sylvester. More details on the trial can be found at (identifier: NCT04998669). ZYNLONTA as a single agent to treat r/r marginal zone lymphoma (MZL) Data from an open-label, multi-institutional investigator-initiated trial evaluating the safety and efficacy of ZYNLONTA in 23 adult r/r MZL patients, previously treated with ≥1 line of systemic therapy, were also shared as a poster presentation at ASH by lead investigator, Izidore Lossos, MD, Professor of Medicine and Chief of the Lymphoma Section of the Division of Hematology at the Sylvester Comprehensive Cancer Center, University of Miami. The median age in this study was 65 years (range 45-82). The median number of previous treatments was 2 (range 1 to 4). As of October 15, 2024, 23 patients were evaluable for response. Highlights from the results presented include: ORR of 91% (n=21); 70% CR (n=16). ZYNLONTA led to CR in 7 of 11 patients (64%) with POD24 assessed for response and one patient who progressed after CAR-T. All but 1 CR are currently maintained with the longest follow-up of 27 months from the start of treatment (median duration of CR is 11.5 months). All of the 23 enrolled patients experienced expected adverse events (AE), most commonly grade 1 or 2. Grade 3 and 4 AEs were observed in 15 and 1 (neutropenia) patients, respectively. Local edema was observed in 10 (43.4%) patients. Three patients needed dose reduction and one patient discontinued treatment after cycle 4 because of cholestatic hepatitis. The patient clinically fully recovered with normalization in liver function test abnormalities. More details on this ongoing Phase 2 clinical trial can be found at (identifier: NCT05296070). About ZYNLONTA® (loncastuximab tesirine-lpyl) ZYNLONTA® is a CD19-directed antibody drug conjugate (ADC). Once bound to a CD19-expressing cell, ZYNLONTA is internalized by the cell, where enzymes release a pyrrolobenzodiazepine (PBD) payload. The potent payload binds to DNA minor groove with little distortion, remaining less visible to DNA repair mechanisms. This ultimately results in cell cycle arrest and tumor cell death. The U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have approved ZYNLONTA (loncastuximab tesirine-lpyl) for the treatment of adult patients with relapsed or refractory (r/r) large B-cell lymphoma after two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified (NOS), DLBCL arising from low-grade lymphoma and also high-grade B-cell lymphoma. The trial included a broad spectrum of heavily pre-treated patients (median three prior lines of therapy) with difficult-to-treat disease, including patients who did not respond to first-line therapy, patients refractory to all prior lines of therapy, patients with double/triple hit genetics and patients who had stem cell transplant and CAR-T therapy prior to their treatment with ZYNLONTA. This indication is approved by the FDA under accelerated approval and in the European Union under conditional approval based on overall response rate and continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. Please see full prescribing information including important safety information about ZYNLONTA at . ZYNLONTA is also being evaluated as a therapeutic option in combination studies in other B-cell malignancies and earlier lines of therapy. About ADC Therapeutics ADC Therapeutics (NYSE: ADCT) is a commercial-stage global leader and pioneer in the field of antibody drug conjugates (ADCs). The Company is advancing its proprietary ADC technology to transform the treatment paradigm for patients with hematologic malignancies and solid tumors. ADC Therapeutics' CD19-directed ADC ZYNLONTA (loncastuximab tesirine-lpyl) received accelerated approval by the FDA and conditional approval from the European Commission for the treatment of relapsed or refractory diffuse large B-cell lymphoma after two or more lines of systemic therapy. ZYNLONTA is also in development in combination with other agents and in earlier lines of therapy. In addition to ZYNLONTA, ADC Therapeutics has multiple ADCs in ongoing clinical and preclinical development. ADC Therapeutics is based in Lausanne (Biopôle), Switzerland, and has operations in London and New Jersey. For more information, please visit the Company website at adctherapeutics.com and follow us on LinkedIn. ZYNLONTA® is a registered trademark of ADC Therapeutics SA. Forward-Looking Statements This press release contains forward-looking statements within the meaning of the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. In some cases you can identify forward-looking statements by terminology such as "may", "will", "should", "would", "expect", "intend", "plan", "anticipate", "believe", "estimate", "predict", "potential", "seem", "seek", "future", "continue", or "appear" or the negative of these terms or similar expressions, although not all forward-looking statements contain these identifying words. Forward-looking statements are subject to certain risks and uncertainties that can cause actual results to differ materially from those described. Factors that may cause such differences include, but are not limited to: whether the interim results for the investigator-initiated trials led by the University of Miami studying FL and MZL are predictive of future results and the timing and success of the same IIT trials, the potential regulatory and/or compendia strategy and the future opportunity for FL and MZL; the expected cash runway into mid-2026 the Company's ability to grow ZYNLONTA® revenue in the United States; the ability of our partners to commercialize ZYNLONTA® in foreign markets, the timing and amount of future revenue and payments to us from such partnerships and their ability to obtain regulatory approval for ZYNLONTA® in foreign jurisdictions; the timing and results of the Company's or its partners' research and development projects or clinical trials including LOTIS 5 and 7, ADCT 602 as well as early research in certain solid tumors with different targets, linkers and payloads; the timing and outcome of regulatory submissions for the Company's products or product candidates; actions by the FDA or foreign regulatory authorities; projected revenue and expenses; the Company's indebtedness, including Healthcare Royalty Management and Blue Owl and Oaktree facilities, and the restrictions imposed on the Company's activities by such indebtedness, the ability to comply with the terms of the various agreements and repay such indebtedness and the significant cash required to service such indebtedness; and the Company's ability to obtain financial and other resources for its research, development, clinical, and commercial activities. Additional information concerning these and other factors that may cause actual results to differ materially from those anticipated in the forward-looking statements is contained in the "Risk Factors" section of the Company's Annual Report on Form 10-K and in the Company's other periodic and current reports and filings with the U.S. Securities and Exchange Commission. These statements involve known and unknown risks, uncertainties and other factors that may cause actual results, performance, achievements or prospects to be materially different from any future results, performance, achievements or prospects expressed in or implied by such forward-looking statements. The Company cautions investors not to place undue reliance on the forward-looking statements contained in this document. CONTACTS: Investors Marcy Graham ADC Therapeutics [email protected] +1 650-667-6450 Media Nicole Riley ADC Therapeutics [email protected] +1 862-926-9040 SOURCE ADC Therapeutics SA WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED