DNMT3A

关注并星标CPHI制药在线FLT3是急性髓系白血病（AML）中经常出现的突变基因。当AML患者的FLT3基因发生突变时，他们的疾病预后往往较差，且更容易复发。因此，及时识别FLT3基因的突变情况，并选择恰当的治疗策略，对AML患者的治疗效果具有重要意义。       Fms样酪氨酸激酶3（FLT3）在细胞信号传递路径中起着关键作用，作为一种受体酪氨酸激酶。实际上，AML中出现的最常见的基因突变，其中一个就是在FLT3。这一基因的突变在成人AML患者中约占了30%的比例。其突变形式主要有两种，即FLT3的内部串联重复序列（FLT3-ITD）和酪氨酸激酶结构域（FLT3-TKD）突变。在这些突变中，FLT3-ITD是最常见的，其在AML中的检出率达到了25% [1]。       FLT3突变急性髓系白血病（AML）患者的临床特点通常为年纪偏大、白细胞与血小板计数偏高，以及骨髓原始细胞比例偏高。尽管这些患者的缓解率较低，且治疗后容易复发，但常规化疗的复发率也相对较高，且往往伴随着其他基因突变。特别值得关注的是，一些最常见的共存基因突变包括NPM1、DNMT3A、WT1、TET2、RAS、RUNX1以及PTPN11。对于FLT3-TKD突变，其预后仍然存在争议；相比之下，FLT3-ITD突变具有较强的异质性，预后受其等位基因比率（AR）、插入位点、ITD长度、核型以及其他伴随基因突变如NPM1、DNMT3A、WT1、RUNX1的影响而有所不同。值得关注的是，与NPM1突变同时出现的FLT3-ITD AML的预后相对较好，然而，当与IDH1/2、TET2、DNMT3A、WT1突变同时出现，或者同时合并NPM1和DNMT3A突变时，FLT3-ITD AML的预后则较差。随着对FLT3突变AML发病机制的深入了解、新的检测技术的出现以及FLT3抑制剂的广泛应用，其预后已得到显著改善。因此，根据欧洲白血病网（ELN 2022）的最新指南，所有FLT3-ITD AML现已被归类为中危。       FLT3抑制剂属于酪氨酸激酶抑制剂，通过竞争激酶活性区域的ATP结合位点抑制FLT3蛋白发生磷酸化，进而抑制相关下游生长信号通路（PI3K/Akt、Ras/MAPK和STAT5等）发挥治疗作用。根据FLT3抑制剂与FLT3结合的程度，可将FLT3抑制剂分为第一代和第二代抑制剂和新型FLT3抑制剂。       一代FLT3抑制剂       索拉非尼       索拉非尼是一种能够同时抑制RAF、VEGFR、KIT和FLT3等多个靶点的小分子药物。南方医科大学血液病研究院的刘启发教授领导的研究团队进行了一项临床研究[7]，他们评估了将索拉非尼与维奈克拉、阿扎胞苷和高三尖杉酯碱（简称VAH方案）联合使用，在患有FLT3-ITD阳性的复发/难治性急性髓系白血病（AML）患者中的治疗效果和患者的耐受程度。研究数据表明，患者接受这一治疗方案后的总缓解率高达82.4%。中位随访期为17.7个月，研究尚未观察到中位复合完全缓解（CRc）的持续时间。这些患者的总生存期（OS）平均为18.1个月，无事件生存期（EFS）平均为11.4个月。在接受治疗的患者中，出现3-4级不良事件（AE）的情况包括中性粒细胞减少症、血小板减少导致的贫血、发热性 中性粒细胞减少症、肺炎和脓毒症等。其中，有2名患者因治疗相关原因不幸去世。       米哚妥林欧洲药品管理局（EMA）和美国食品药品监督管理局（FDA）共同批准了米哚妥林与标准化疗相结合，作为针对FLT3突变成年急性髓系白血病（AML）患者的首选治疗策略。除此之外，对于经历过异基因造血干细胞移植（allo-HSCT）的患者，米哚妥林在维持治疗方面也表现出显著效果，它不仅能够优化患者的预后，而且其安全性也得到了充分验证[8]。这些进展为患有急性髓系白血病（AML）的患者提供了新的治疗选择和更好的康复机会。       二代FLT3抑制剂       吉瑞替尼（Gilteritinib）       2018年11月28日，美国食品药品监督管理局（FDA）正式批准吉瑞替尼作为治疗FLT3突变型复发或难治性急性髓系白血病（AML）成人患者的药物。随后，在2021年，吉瑞替尼获得中国批准并上市，用以治疗患有复发或难治性FLT3突变型AML的患者[9]。       由中国医学科学院血液病医院王健祥教授率领的团队，联合多个国家包括中国、俄罗斯、新加坡、泰国和马来西亚等，开展了一项名为COMMODORE的III期开放、多中心临床试验，对比了吉瑞替尼与挽救性化疗（SC）在治疗FLT3突变复发难治AML患者上的疗效[10]。研究显示，吉瑞替尼组（包含116名患者）的完全缓解（CR）率达到了16.4%，这一数据超过了挽救性化疗（SC）组（包含118名患者，CR率为10.2%）。此外，吉瑞替尼组患者的1年中位总生存期（mOS）也显著长于挽救性化疗（SC）组，分别为9个月和4.7个月（P=0.001 26）。这一研究成果再次确立了吉瑞替尼在针对FLT3突变复发难治AML治疗上的显著优势。       奎扎替尼（Quizartinib）       2023年7月20日，美国食品药品监督管理局（FDA）正式批准了奎扎替尼联合标准阿糖胞苷、蒽环类药物的诱导治疗与阿糖胞苷巩固治疗，以及在巩固化疗后单独使用奎扎替尼作为维持治疗，这一治疗方案针对的是新诊断的FLT3-ITD阳性急性髓系白血病（AML）成年患者。这项医疗进展意味着对白血病治疗的一个重要突破，可以为这些患者提供更好的治疗效果和生存率。       QuANTUM-First（NCT02668653）试验是一项双盲随机、安慰剂对照的研究，共纳入了539名新诊断的FLT3-ITD阳性急性髓系白血病患者。通过对奎扎替尼组与安慰剂组之间的对比分析，结果显示，奎扎替尼组在总生存期（OS）上具有显著的统计学意义改善[风险比（HR）0.78，95%置信区间（CI）0.62-0.98，两组比较p=0.0324]。这一数据进一步证明了奎扎替尼在治疗FLT3-ITD阳性急性髓系白血病患者中的疗效和安全性，为这一病症的治疗提供了新的选择。       Crenolanib       Richard M. Stone教授的研究团队，隶属于美国丹娜法伯癌症研究所，进行了一项关键性的II期研究[7]，旨在评估在新发现的FLT3突变急性髓系白血病（AML）病患中结合使用Crenolanib的治疗成效。       该研究涉及了44名患者（男性占22名），他们的中位数年龄是57岁（年龄范围：19-75岁）。结果显示，总体复合完全缓解（CRc）率高达73%（32/44）。特别是在经过两个周期的治疗后，总CRc率跃升至86%（38/44）。年轻患者的总体缓解率表现尤为突出，达到了90%，且其MRD阴性率高达89%。相较之下，尽管年长患者的总体缓解率为80%，但他们的MRD阴性率相对较低，为45%。此外，值得注意的是，超过70%的年轻患者在接受治疗后的三年时间里仍然存活。       这项研究的结果为FLT3突变急性髓系白血病的治疗提供了新的方向，尤其是对于那些年轻的患者，Crenolanib联合治疗方案展现出了显著的效果。       新型FLT3抑制剂       Tuspetinib       Tuspetinib，这是一种新兴的可口服FLT3抑制剂，凭借其强大的能力，被公认为一种高效的髓系激酶抑制药物。它的作用机制在于能够抑制导致AML细胞增殖异常的多种激酶，这当中就包括了SYK、FLT3、JAK1/2、RSK1/2、突变型KIT和TAK1-TAB1激酶等。       一项涉及I/II期的研究[13]对Tuspetinib单独使用（TUS）和与维奈克拉联合使用（VEN/TUS）治疗复发性或难治性AML（R/R AML）的安全性和疗效进行了评估，并确定了II期推荐剂量（RP2D）。该研究的结果表明，Tuspetinib单药治疗的安全性较高，总体完全缓解/完全缓解伴部分血液学恢复（CR/CRh）的比率为36%。对于FLT3突变型AML患者，这一比率高达50%，而对于FLT3野生型AML患者，这一比率则为25%。这些结果为Tuspetinib在AML治疗中的潜在应用提供了重要的临床依据。       EmavusertibEmavusertib作为一种创新型的FLT3抑制剂，其独特之处在于可以口服使用，为治疗提供了便利。它能够精确地针对IRAK4和FLT3进行作用，表现出令人满意且可管理的安全性。目前，TakeAim Leukemia试验正在深入研究Emavusertib在治疗复发/难治性急性髓性白血病（R/R AML）和高危骨髓增生异常综合征（HR-MDS）方面的安全性、临床疗效以及潜在的生物标志物，为未来的治疗策略提供更为坚实的科学依据。       EP0042       EP0042是一款口服型的药物，它能够有效抑制FLT3和Aurora激酶。研究表明，Aurora激酶在急性髓系白血病（AML）的发病过程中扮演着关键角色，并与FLT3抑制剂耐药性的产生密切相关。因此，EP0042通过同时针对FLT3和Aurora激酶，有望克服对选择性FLT3抑制所产生的获得性耐药性。为了探索EP0042的最 佳给药方案，一项I/IIa期研究采用了标准的3+3剂量递增设计，并纳入了复发/难治性AML或骨髓增生异常综合征（MDS）的患者进行临床试验[15]。       总结       FLT3抑制剂的研发成功，为那些罹患FLT3突变急性髓性白血病（AML）的患者提供了全新治疗策略。在临床应用中，目前已有一线和二线的FLT3抑制剂可供选用。不仅如此，新型的FLT3抑制剂，如Tuspetinib、Emavusertib和EP0042，也正在接受临床试验的检验，其初步成果显示出了良好的治疗潜力。随着对FLT3突变机制的深入研究以及药物研发的持续进步，我们有理由期待更多高效、精准的靶向治疗药物的出现。这些药物的问世，将为AML患者带来更加显著的治疗效果，帮助他们更好地战胜疾病。       参考文献：       [1] 邱林，马军. 急性髓系白血病靶向治疗研究进展[J]. 白血病·淋巴瘤， 2022,31(4):197-203. DOI：10.3760/cma.j.cn115356-20220210-00033 .       [2] Yu S, Zhang Y, Yu G, Wang Y, Shao R, Du X, et al. Sorafenib plus triplet therapy with venetoclax, azacitidine and homoharringtonine for refractory/ relapsed acute myeloid leukemia with FLT3ITD: A multicenter phase 2 study. J Intern Med.2023;00:1-13.       [3] 袁伟，张世忠，主鸿鹄. FLT3抑制剂治疗急性髓系白血病患者研究进展[J].浙江大学学报:医学版, 2022, 51(4):507-514.       [4]https://www.fda.gov/drugs/fda-approves-gilteritinib-relapsed-or-refractory-acute-myeloid-leukemia-aml-flt3-mutation       [5] Wang JX ， Jiang B ， Li J ，et al. Gilteritinib versus salvage chemotherapy for relapsed/refractory FLT3-mutated acute myeloid leukemia：a phase 3，randomized，multicenter，open-label trial in Asia[J]. Blood， 2021，138Suppl 1：695. doi: 10.1182/blood-2021-145436 .[6] https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-quizartinib-newly-diagnosed-acute-myeloid-leukemia[7] Eunice S. Wang, et al. 2022ASCO.Abstract#7007.[8] Naval Daver, et al. Tuspetinib Myeloid Kinase Inhibitor Safety and Efficacy As Monotherapy and Combined with Venetoclax in Phase 1/2 Trial of Patients with Relapsed or Refractory (R/R) Acute Myeloid Leukemia (AML). 2023 ASH. Abstract #162.[9] Eric S Winer, et al. Preliminary Safety and Efficacy of Emavusertib (CA-4948) in Acute Myeloid Leukemia Patients with FLT3 Mutation. 2023 ASH. Abstract #2924.[10] David Taussig, et al. EP0042, a Dual FLT3 and Aurora Kinase Inhibitor: Results from an Ongoing Phase I/IIa Dose-Finding/Dose Optimization Study in Patients with Relapsed/Refractory Acute Myeloid Leukemia. 2023 ASH. Abstract #4285.       [6] Zhao J , Agarwal S , Ahmad H ,et al.A review of FLT3 inhibitors in acute myeloid leukemia[J].Blood reviews, 2021:100905.       [7] 张钰, 邵若洋, 刘启发. FLT3突变急性髓系白血病的全程管理[J].临床血液学杂志,2023,36(5):303-308       [8] DöhnerH, WeiAH, Appelbaum FR, et al. Diagnosis ·and management of AML in adults: 2022 recommendations from an international expert panel on behalf of the ELN [J].Blood,2022,140(12):1345-1377.       [9] WANG Z, CAI J, CHENG J, et al. FLT3 inhibitors in acute myeloid leukemia: challenges and recent developments in overcoming resistance[J]. J Med Chem, 2021, 64(6): 2878-2900.       [10] 袁伟，张世忠，主鸿鹄. FLT3抑制剂治疗急性髓系白血病患者研究进展[J].浙江大学学报:医学版, 2022, 51(4):507-514.       [11] TALLMAN M S, WANG E S, ALTMAN J K, et al. Acute myeloid leukemia, version 3.2019, NCCN clinical practice guidelines in oncology[J]. J Natl Compr Canc Netw, 2019, 17(6): 721-749.       [12] LEVIS M. Midostaurin approved for FLT3-mutated AML[J]. Blood, 2017, 129(26): 3403-3406.       [13] SERVE H, KRUG U, WAGNER R, et al. Sorafenib in combination with intensive chemotherapy in elderly patients with acute myeloid leukemia: results from a randomized, placebo-controlled trial[J]. J Clin Oncol, 2013, 31(25): 3110-3118.       [14] YILMAZ M, KANTARJIAN H M, MUFTUOGLU M, et al. Quizartinib with decitabine +/- venetoclax is highly active in patients (pts) with FLT3-ITD mutated (mut) acute myeloid leukemia (AML): clinical report and signaling cytof profiling from a phase Ⅰb/Ⅱ trial[J]. Blood, 2020, 136(Supplement 1): 19-20.       [15] PERL A E, MARTINELLI G, CORTES J E, et al. Gilteritinib or chemotherapy for relapsed or refractory FLT3-mutated AML[J]. N Engl J Med, 2019, 381(18): 1728-1740.       [16] WANG R, LI Y, GONG P, et al. Arsenic/trioxide and sorafenib induce synthetic lethality of FLT3-ITD acute myeloid leukemia cells[J]. Mol Cancer Ther, 2018,17(9): 1871-1880.       [17] YILMAZ M, KANTARJIAN H, SHORT N J, et al. Hypomethylating agent and venetoclax with FLT3 inhibitor "triplet" therapy in older/unfit patients with FLT3 mutated AML[J]. Blood Cancer J, 2022, 12(5): 77.【智药研习社近期课程预告】来源：CPHI制药在线声明：本文仅代表作者观点，并不代表制药在线立场。本网站内容仅出于传递更多信息之目的。如需转载，请务必注明文章来源和作者。投稿邮箱：Kelly.Xiao@imsinoexpo.com▼更多制药资讯，请关注CPHI制药在线▼点击阅读原文，进入智药研习社~

*仅供医学专业人士阅读参考为了活命或转移，癌细胞已经成了模仿或伪装大师。它不仅能模仿正常细胞表达免疫检查点，抑制各类免疫细胞的攻击；还能伪装成比正常细胞更健康的细胞，加速周围正常细胞的汰掉；甚至还可以伪装成免疫细胞，四处转移，畅通无阻。“师夷长技以制夷”。既然癌细胞都懂这个道理，那么免疫细胞是不是也可以“偷师”癌细胞的技能，然后战胜癌症呢？前不久，由美国西北大学Jaehyuk Choi和加州大学旧金山分校Kole T. Roybal领衔的研究团队，在顶级期刊《自然》上发表一项重磅研究成果[1]，让免疫细胞成功“偷师”并制服癌细胞。他们大规模研究了T细胞淋巴瘤的潜在驱动基因变异，发现其中的一对基因的融合变异，竟然可以将T细胞抗实体肿瘤的能力提升百倍，而且没有任何毒性迹象。简单来说，他们发现了T细胞淋巴瘤的超能力，在将它移植给正常T细胞之后，正常T细胞就拥有了超级抗癌能力。真是天道好轮回啊！论文首页截图T细胞免疫疗法，虽然彻底改变了血液肿瘤治疗范式，但在占成人癌症90%的实体瘤中表现差强人意，直到上个月FDA才批准了第一款治疗实体瘤的T细胞疗法lifileucel[2]。与血液肿瘤相比，实体瘤之所以难以突破，主要是因为受到多种因素的限制，例如T细胞在体内持久性差、实体瘤的肿瘤微环境存在强烈的免疫抑制，以及T细胞耗竭等等问题。简单来说，要想让T细胞搞定实体瘤，就得进一步提升T细胞的实力。Choi和Roybal团队注意到，在预临床研究中提升T细胞抗癌效果的方法（PDCD1、TET2或DNMT3A失活），其实就是T细胞淋巴瘤中发现的突变。那既然如此，是不是可以从T细胞淋巴瘤找到解决上述问题的基因突变呢？为了回答这个问题，Choi和Roybal团队选取了T细胞淋巴瘤的71个潜在驱动基因变异，包括分布在40个不同基因中的61个点突变，以及10个基因融合变异。然后在特殊的报告细胞系中研究不同的基因变异对T细胞功能的影响。研究过程经过层层筛选，最终CARD11和PIK3R3的融合胜出。与其他的变异相比，CARD11-PIK3R3融合能显著增强NF-κB和AP-1信号，以及IL-2的生成，而不增加NFAT或PD1。之前已经有研究表明，NF-κB和AP-1信号的增强而不是NFAT信号的增强有助于对抗T细胞功能障碍；能产生高水平IL-2的CD8阳性T细胞亚群能更好地维持记忆表型和效应功能。显然，在CD4阳性皮肤T细胞淋巴瘤患者身上发现的CARD11-PIK3R3融合值得进行进一步研究。CARD11-PIK3R3融合表现最佳随后，Choi和Roybal团队在两种不同的CAR T细胞中检验了CARD11-PIK3R3融合对CAR T细胞抗癌活性的影响。他们发现，补充IL-2与否会影响普通CAR T细胞的抗癌效果，而不影响CARD11-PIK3R3融合的CAR T细胞抗癌效果（无论是否使用IL-2，都会清除几乎所有癌细胞）。要知道，上个月获批的全球首个实体瘤T细胞疗法就需要同时使用IL-2[2]。无论是否使用IL-2，CARD11-PIK3R3融合的CAR T细胞都会清除几乎所有癌细胞在7×106个CAR T细胞的较高剂量下，Choi和Roybal团队发现，对照组的普通CAR T细胞只能控制住43%的肿瘤，而CARD11-PIK3R3融合的CAR T细胞的肿瘤控制率为100%。值得注意的是，不含CD19-CAR的CARD11-PIK3R3融合T细胞没有抗肿瘤作用，这表明CARD11-PIK3R3融合增强的抗肿瘤活性需要抗原刺激。这也意味着，CARD11-PIK3R3融合CAR T细胞没有自主增殖的风险。此外，即使在高剂量处理下，CARD11-PIK3R3融合T细胞也表现出了良好的安全性。即使在回输后的第418天，也没有致淋巴瘤的迹象。CARD11-PIK3R3融合的CAR T细胞展现出强大的抗肿瘤活性虽然以上的研究都是在血液肿瘤小鼠模型中开展的，但是后续在间皮瘤、黑色素瘤和胃癌小鼠模型中，均发现CARD11-PIK3R3融合可以增强T细胞（CAR T细胞或TCR T细胞）的抗肿瘤效果。在黑色素瘤的研究中，Choi和Roybal团队吃惊地发现，即使CARD11-PIK3R3融合CAR T细胞的数量仅有普通CAR T细胞的百分之一，它也能控制住肿瘤，而普通CAR T却做不到。这意味着，CARD11-PIK3R3融合CAR T细胞的抗肿瘤活性提升了100倍以上。CARD11-PIK3R3融合CAR T细胞的抗肿瘤活性提升了100倍以上尤其值得一提的是，Choi和Roybal团队还发现，CARD11-PIK3R3融合CAR T细胞治疗甚至不需要清髓就能发挥良好的抗实体瘤效果。要知道，清髓已被证明能显著改善CAR T细胞的移植和疗效，以及具有诱变性、并增加继发性恶性肿瘤的风险；而CARD11-PIK3R3融合CAR T细胞却不需要这一步。这一方面说明，它的疗效确实更强了，另一方面可以避免不良事件的发生。总的来说，Choi和Roybal团队这招“师夷长技以制夷”，让T细胞成功获得了百倍功力，让其具备了强大的抗实体瘤能力，还进一步降低了CAR T细胞治疗的风险。据了解，Choi和Roybal团队已经组建了一家新公司Moonlight Bio，正在将这项新发现转化为抗癌新疗法。参考文献：[1].Garcia J, Daniels J, Lee Y, et al. Naturally occurring T cell mutations enhance engineered T cell therapies. Nature. 2024;626(7999):626-634. doi:10.1038/s41586-024-07018-7[2].https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-lifileucel-unresectable-or-metastatic-melanoma本文作者丨BioTalker

Total operating revenues for the full year 2023 were $16.3M, compared to $15.8M for the same period in 2022. As of March 7, 2024, Ryvu's cash position was $57.2M, excluding the first tranche of €8M in venture debt from the EIB, expected imminently. Together with other already secured funding sources, this cash position provides a runway through Q1 2026. Ryvu will present preclinical data from its synthetic lethality pipeline, RVU120, and MEN1703 (SEL24) at the upcoming 2024 American Association for Cancer Research (AACR) Annual Meeting (April 5-10, San Diego, California). After announcing the hematology-focused RVU120 development plan in Q4 2023, Ryvu launched two Phase II studies in early 2024. An additional two Phase II clinical trials for RVU120 are expected to be launched in mid-2024. By the end of the year, the company plans to enroll over 100 patients across all RVU120 Phase II studies and aims to present initial Phase II data. KRAKOW, Poland, March 13, 2024 /PRNewswire/ -- Ryvu Therapeutics (WSE: RVU), a clinical-stage drug discovery and development company focusing on novel small-molecule therapies that address emerging targets in oncology, summarizes its 2023 fiscal year and provides a corporate update. Pawel Przewiezlikowski, co-founder, largest shareholder, and Chief Executive Officer of Ryvu Therapeutics, said: - In 2023, we made significant progress in all key business areas and look forward to multiple catalysts in 2024. We have already started two Phase II studies of RVU120, and around mid-year, we plan to launch two more Phase II studies in hematology. By the end of the year, we plan to enroll more than 100 patients across these clinical trials. We also plan to launch a new Phase II study of MEN1703 (SEL24) in DLBCL, which is being developed under a license agreement with the Menarini Group. Study start-up activities for new trials of both RVU120 and MEN1703 are proceeding quickly. Krzysztof Brzozka, Ph.D., Executive Vice President, and Chief Scientific Officer, said: - We are pleased with the significant progress made in our early-phase projects. Among the most advanced projects from our synthetic lethality platform – PRMT5 and WRN – we plan to identify a clinical candidate in 2024. We are also seeing progress in the programs being developed by our partners – particularly BioNTech and Exelixis. We were excited to achieve the second milestone in the Exelixis collaboration, and we look forward to presenting data on our synthetic lethality assets and novel platform at AACR. 2023 SUMMARY AND RECENT CORPORATE EVENTS RVU120 clinical development plan In 2023 Ryvu prepared for the launch of two Phase II RVU120 trials, which then initiated in early 2024: 1) RVU120 as monotherapy in genetically defined cohorts of patients with relapsed/refractory acute myeloid leukemia (r/r AML) and high-risk myelodysplastic syndromes (HR-MDS, RIVER-52 study), and 2) RVU120 in combination with venetoclax for patients with relapsed/ refractory AML (RIVER-81 study). Ryvu will financially support the REMARK study's Phase II clinical trial of RVU120 in patients with low-risk myelodysplastic syndromes (LR-MDS). REMARK will be conducted as an investigator-initiated study through the EMSCO network, with Prof. Uwe Platzbecker, a globally renowned expert in the field of LR-MDS, as the Coordinating Principal Investigator. Start-up activities have already been launched, and patient enrollment will start in mid-2024. Study start-up is also underway for POTAMI-61, a Phase II study evaluating the efficacy of RVU120 in patients with myelofibrosis (MF). Initiation of patient recruitment is scheduled for mid-2024. Translational research on RVU120 in solid tumors will continue, including combination studies, as well as academic collaborations in the areas of medulloblastoma (MB) and sarcoma-related research. The company plans to enroll more than 100 patients across all RVU120 Phase II trials this year and aims to present initial Phase II data by the end of 2024. RVU120's updated clinical development plan includes studies (RIVER-52, RIVER-81, and POTAMI-61) that could lead to three drug approvals between 2026 and 2027. Key data presented during 2023 conferences In 2023, Ryvu Therapeutics presented data from the RVU120 program at several international conferences, including EHA 2023, ESMO 2023, and ASH 2023: RVU120 monotherapy demonstrated clinical activity in a Phase Ib study in which 50% of evaluable patients with r/r AML or HR-MDS achieved clinical benefit, including a complete response, morphologically leukemia-free status, clinically significant reduction of blasts including reductions that allowed bridging to a bone marrow transplantation, two-year disease stabilization, hematologic improvements, as well as reduction in bone marrow fibrosis. In particular, early signs of efficacy were observed in patients with an NPM1 mutation, DNMT3a mutation, and HR-MDS. The recommended Phase II dose (RP2D) of 250 mg was found to be safe and well-tolerated, achieving RVU120 concentrations in the pharmacologically active range, with a level of target inhibition between 50% and 70%. This level of target inhibition is expected to result in therapeutic efficacy in selected patients or in combinations with synergistic therapies. RVU120 is emerging as a potential candidate in the first-line treatment of AML, supported by its activity against leukemic stem cells. RVU120 acts synergistically with venetoclax in both sensitive and venetoclax-resistant models. At the ENA conference in October 2023, Ryvu presented preclinical data for PRMT5 and the synthetic lethality platform, and Ryvu's partner – Menarini Group, presented preclinical data for MEN1703 in advanced diffuse large B-cell lymphoma (DLBCL). Ryvu has developed potentially best-in-class MTA-cooperative PRMT5 inhibitors with outstanding drug-like physicochemical properties and the ability to block methyltransferase activity of PRMT5 with nanomolar concentrations and bioavailable upon oral administration. The novel, optimized inhibitors exhibit a significantly improved pharmacokinetic profile. In addition, the compounds show antitumor efficacy and target engagement in vivo, providing a solid foundation for further development towards clinical trials. MEN1703 (SEL24) has shown promising antitumor activity in translational studies in various types of DLBCL. These data justify the development of MEN1703 in Phase II clinical trials in this indication. Expansion of MEN1703 (SEL24) development by Ryvu's partner – Menarini Group, to include a new Phase II clinical trial in DLBCL. In September 2023, Ryvu announced the Menarini Group's decision to expand the development of MEN1703 (SEL24) by initiating a new Phase II clinical trial in patients with DLBCL. A Phase II study in DLBCL is scheduled to begin in mid-2024. The goal is to evaluate the activity of MEN1703 (SEL24) as monotherapy and in combination with standard therapy in patients with DLBCL. The study will be initiated based on the potent activity of MEN1703 (SEL24) observed in preclinical lymphoma models. Clinical trials have confirmed the acceptable safety profile and early signs of activity of MEN1703 (SEL24) as a monotherapy. Based on the available data, further program development will continue in patients with DLBCL and potentially in additional indications. Recent financial events On February 3, 2024, Ryvu received notice that the second financial milestone was achieved under the collaboration agreement with Exelixis, resulting in a $2M payment to Ryvu. Ryvu and Exelixis are working under a research collaboration and license agreement to develop antibody-drug conjugates (ADCs) with Ryvu's portfolio of STING agonists. On March 5, 2024, Ryvu received notice from the European Investment Bank (EIB) that it had met the conditions for disbursement of the first venture debt tranche of €8M. These funds are not yet included in the cash balance reported in this press release, but Ryvu expects to receive the funds on March 13, 2024. As part of the agreement announced in August 2022, Ryvu still has access to an additional €14M in venture debt from the EIB. UPCOMING EVENTS Ryvu will attend the AACR Annual Meeting (San Diego, USA) from April 5-10, 2024, to present preclinical data from its synthetic lethality pipeline, RVU120, and MEN1703 (SEL24). 2023 Fiscal Year Financial Update [1] Cash Position – On December 31, 2023, Ryvu Therapeutics held $63.7M in cash, cash equivalents, and bonds, compared to $23.2M at the end of 2022. On March 7, 2024, Ryvu Therapeutics held $57.2M in cash, cash equivalents, and bonds, which excludes €8M in venture debt from the EIB to be received imminently. Operating Revenues – In 2023, Ryvu recognized total operating revenues (including grants) of $16.3M, compared to 2022, when the total operating revenue amounted to $15.8M. Operating costs, excluding the non-cash cost of valuation of the Incentive Program ($2.0M) and valuation of NodThera shares ($0.9M) in the full year 2023, amounted to $37.6M, representing an increase compared to $26.4M in the previous year. Net Loss Attributable to Common Shareholders – In 2023, the net loss attributable to common shareholders, excluding the non-cash cost of valuation of the Incentive Program, amounted to $20.0M, compared to $13.8M in the previous year. About Ryvu Therapeutics Ryvu Therapeutics is a clinical-stage drug discovery and development company focused on novel small-molecule therapies that address emerging targets in oncology. Internally discovered pipeline candidates use diverse therapeutic mechanisms driven by emerging knowledge of cancer biology, including small molecules directed at kinase, synthetic lethality, and immuno-oncology targets. Ryvu's most advanced programs include RVU120, a selective CDK8/CDK19 kinase inhibitor with the potential to treat hematological malignancies and solid tumors, currently in Phase II development (i) as a monotherapy for the treatment of patients with relapsed/refractory acute myeloid leukemia (r/r AML) and high-risk myelodysplastic syndromes (HR-MDS) as well as (ii) in combination with venetoclax for the treatment of patients with r/r AML. Another clinical program, SEL24 (MEN1703), is a dual PIM/FLT3 kinase inhibitor licensed to the Menarini Group. Ryvu Therapeutics has signed multiple partnering and licensing deals with global companies, including BioNTech and Exelixis. The Company was founded in 2007 and is headquartered in Kraków, Poland. Ryvu is listed on the Warsaw Stock Exchange and is a component of the mWIG40 index. For more information, please see . [1] USD figures are provided at a conversion rate of: for the period from 01/01/2023 – 31/12/2023: PLN 4.1823; for the period from 01/01/2022 – 31/12/2022: PLN 4.4679; as of 7/03/2024: PLN 3.9485 as of 31/12/2023: PLN 3.9350 as of 31/12/2022: PLN 4.4018 SOURCE Ryvu Therapeutics