Midostaurin

ADC本质上是一个靶向疗法，而靶向疗法治疗晚期肿瘤有天然缺陷，近些年在靶向药物围攻下多西他赛这样老药依然是打不死的小强。据统计2006-2020上市的53款靶向药物在FDA批准的92个适应症中只有22个显示了OS优势（24%），其余或者没有OS数据、或者OS数据为阴性（30%）（下图）。别忘了靶向药物也不一定选择性都足够好，比如这组药物中延长OS最显著的FLT3抑制剂（49个月） midostaurin是个十字孢碱简单衍生物，几乎肯定没有任何魔法可言、基本就是一个化疗药物。而直指肿瘤细胞心脏的Kras抑制剂却在NSCLC的对照试验中没有显示生存优势。 为什么会是这样呢？靶向疗法的天敌是异质性，而不幸的是晚期肿瘤如同热带雨林植被、最不缺的就是异质性。肿瘤有基因异质性和空间异质性，受影响的不仅是ADC这样的靶向疗法。如果肿瘤细胞空间上与药物无法接触、或者外排泵开足马力、或现在已知的十几个hallmark中的一个有超能力，无论靶向疗效还是化疗药物都束手无策。但一个完全依靠某一特定靶点的靶向疗效受到限制显然更大，因为肿瘤极少离开某个靶点就过不下去的，所以任何一个肿瘤患者都不会每个肿瘤细胞都特异表达某个靶点、甚至每个病灶中都是靶点阳性和阴性细胞共存（下图）。 一个病灶有靶点阴性肿瘤细胞还好说，ADC可以借助旁观者效应杀伤这部分肿瘤。靶点阴性病灶就很难通过旁观者杀伤清除了，这要求你系统药物暴露要达到治疗水平、这失去了靶向递送意义，而同一患者的不同转移病灶靶点表达水平也很少是一致的。肿瘤患者极少死于原发肿瘤，转移才是肿瘤患者死亡的主要原因，所以一个ADC药物要想显著延长患者寿命应该对所有转移病灶都有一定清除能力，否则就变成了局部疗法。这要求每个病灶都应该有一定水平的靶点蛋白表达，但肿瘤并不总是这样。而且DAISY试验中肿瘤通知我们它们甚至不需要降低靶点表达就可以轻易产生耐药，病灶有一定靶点表达只是提供了杀伤可能、而不是保证。 幸好制药工业多年探索找到一些并不完全依靠靶点特异性的优质药物。Enhertu在HER2低表达转移乳腺癌的疗效令人震惊，但是曲妥珠在HER2阴性早期乳腺癌的维持疗法中也曾显示一定收益。PARP抑制剂虽然理论上需要BRCA变异才有效，但在临床试验中在BRCA野生患者也有不错应答率、可能与其它DNA修复障碍有关。依喜替康挣扎多年无法解决治疗窗口问题，但独特药代和药动性质正好适合作为ADC毒素。这些临床意外发现有继续优化空间，是良好的起点。 转移肿瘤的治疗难度极大，据估计1991-2011年这20年肿瘤死亡率的下降只有4-8%是因为治疗干预，更主要是因为早期诊断和生活方式改变如大规模戒烟。肿瘤药物改善患者生存主要是作为手术后的维持疗法效果较好，所以更高效的早期诊断非常重要。但早期肿瘤治疗对药物安全性要求更高，ADC的毒性是一个需要自己解决的问题。ADC虽然疗效通常优于化疗，但毒性一点不比化疗低、甚至更严重，这将限制ADC在维持疗法的应用。更优质的毒素是一个重要研究方向，因为ADC毒素是其毒性的主要来源，但抗体毒性也不容忽视、比如曲妥珠心脏毒性也限制其使用。 组合疗法是应对异质性的一个实用策略，但这要求两个疗法各司其职，而不是都去杀同一类肿瘤细胞、都对另一类视而不见或无能为力。另外组合疗法功能上更趋近选择性较差的化疗，所以毒性负担也会更重，这也要求我们更精心优化ADC安全性。ADC被称作魔法子弹，听起来挺高大上。枪法准肯定杀伤力大，但是却没有人告诉你虽然你瞄的准但只能看见一个靶子（双抗ADC可以瞄准两个靶标，但这个策略有它自己的问题、这个以后再讲）。如果敌人海陆军立体侵略，而你只会击落战斗机、对步兵与军舰视而不见，你枪法再准也难逃被消灭厄运。当然这不是ADC特有的难题，所有依靠肿瘤或肿瘤微环境特异性提高选择性的策略都面临同样困境。

Data from the first two cohorts demonstrated that combination of iadademstat plus gilteritinib was safe and showed strong antileukemic activityA third cohort is ongoing following FDA’s OPTIMUS guidance MADRID and CAMBRIDGE, Mass., June 14, 2024 (GLOBE NEWSWIRE) -- Oryzon Genomics, S.A. (ISIN Code: ES0167733015, ORY), a clinical-stage biopharmaceutical company leveraging epigenetics to develop therapies in diseases with strong unmet medical need, today presents preliminary data from its ongoing Phase Ib FRIDA study investigating iadademstat in combination with gilteritinib in relapsed/refractory acute myeloid leukemia (AML) patients harboring a FMS-like tyrosine kinase mutation (FLT3 mut+) at the European Hematology Association (EHA) 2024 congress, being held in Madrid (Spain) on June 13–16. Dr. Amir Fathi, from the Massachusetts General Hospital and Principal Investigator of the study, will present a poster communication entitled “Preliminary results of the FRIDA study: iadademstat and gilteritinib in FLT3-mutated R/R AML”. Dr. Carlos Buesa, Oryzon’s CEO, stated, “We are very excited with these preliminary results, which showed in a mostly refractory patient population a higher-than-expected antileukemic activity in the first two cohorts. We, and others, have previously described the strong synergism of the combination of iadademstat with gilteritinib, and these clinical data confirm this synergism. The observed LSD1 full occupancy data in the first two cohorts outlines that we need to reduce the dose to optimize the marrow recovery and achieve a higher degree of complete responses. With the capability to quantify the levels of LSD1 occupancy, we are in an optimal situation to follow the FDA’s OPTIMUS guidance. The safety profile is so far adequate as expected and recruitment continues.” Summary of the main results reported at EHA-2024 The combination of iadademstat and gilteritinib appears safe and well-tolerated, with no dose limiting toxicities (DLTs) reported in the 28-day DLT evaluation period in the first two cohorts: initial cohort (n=6, iadademstat 100 μg) and DL-1 cohort (n=7, iadademstat 75 μg). There were no unexpected Treatment Emergent Adverse Events (TEAEs).Encouraging antileukemic activity observed, with 9 out of 13 patients (69%) achieving bone marrow (BM) blast clearance in the first cycle. Five out of 13 patients (38%) achieved complete remission (CR), complete remission with partial hematological recovery (CRh) or complete remission with incomplete blood count recovery (CRi). Of note, 11 out of 13 patients were refractory to prior standard regimens including venetoclax, 7+3 and midostaurin. Two patients have undergone hematopoietic stem cell transplantation.Platelet count recovery has been slow in most patients, limiting so far a rapid transition from morphologic leukemia-free state (MLFS) to CR/CRh. Since LSD1 plays a key role in hematopoiesis and both iadademstat doses evaluated in the first two cohorts (starting dose and DL-1) showed full LSD1 target engagement (≈90%), lower doses are being investigated with the aim of maintaining efficacy and improving platelet recovery, in accordance with the FDA’s Optimus Project requiring to identify the minimum safe and biologically active dose.FRIDA is currently accruing patients to the third cohort, DL-2 (iadademstat 75 μg, 3 weeks treatment per cycle). Two patients have been enrolled, with no reported DLTs to date.Pharmacokinetic (PK) data support there is no drug-drug interaction between iadademstat and gilteritinib. FRIDA (NCT05546580) is an escalation/expansion, open-label, single arm, multicenter Phase Ib trial to establish the safety, tolerability, and the recommended Phase II dose (RP2D) of the combination of iadademstat with gilteritinib. The study has been designed according to the FDA’s Project Optimus and consists of 2 parts: a dose finding part to evaluate the safety, tolerability, pharmacokinetic, pharmacodynamic and emerging activity of the combination, and to determine the pharmacologically-active dose (i.e., the minimum safe and biologically active dose) of iadademstat in combination with gilteritinib, and an expansion part at the specific dose(s) selected to evaluate the activity of iadademstat in combination with gilteritinib in patients with FLT3-mutated R/R AML. The trial is conducted in the US and plans to accrue up to approximately 45 patients. Oryzon is further expanding the clinical development of iadademstat in AML through an Investigator-initiated study (IIS) led by Oregon Health & Science University (OHSU). This trial is a Phase Ib dose-finding study to evaluate iadademstat in combination with the SoC, venetoclax and azacitidine, in first line AML patients and is expected to begin enrolling patients in the coming weeks. In addition, in neuroendocrine tumors, in the context of the CRADA agreement between Oryzon and the NIH, the NCI is sponsoring a randomized Phase I/II trial in 1L extensive disease small cell lung cancer combining iadademstat with immune checkpoint inhibitors. The IND for this trial was recently approved by the FDA. A copy of the EHA-2024 poster is available here. About Oryzon Founded in 2000 in Barcelona, Spain, Oryzon (ISIN Code: ES0167733015) is a clinical stage biopharmaceutical company and the European leader in epigenetics, with a strong focus on personalized medicine in CNS disorders and oncology. Oryzon’s team is composed of highly qualified professionals from the pharma industry located in Barcelona, Boston, and San Diego. Oryzon has an advanced clinical portfolio with two LSD1 inhibitors, vafidemstat in CNS and iadademstat in oncology, in several Phase II clinical trials. The company has other pipeline assets directed against other epigenetic targets like HDAC-6, where ORY-4001 has been nominated as clinical candidate for the treatment of certain neurological disorders such as CMT and ALS. In addition, Oryzon has a strong platform for biomarker identification and target validation for a variety of malignant and neurological diseases. For more information, visit www.oryzon.com About Iadademstat Iadademstat (ORY-1001) is a small oral molecule, which acts as a highly selective inhibitor of the epigenetic enzyme LSD1 and has a powerful differentiating effect in hematologic cancers (see Maes et al., Cancer Cell 2018 Mar 12; 33 (3): 495-511.e12.doi: 10.1016 / j.ccell.2018.02.002.). A FiM Phase I/IIa clinical trial with iadademstat in R/R AML patients demonstrated the safety and good tolerability of the drug and preliminary signs of antileukemic activity, including a CRi (see Salamero et al, J Clin Oncol, 2020, 38(36): 4260-4273. doi: 10.1200/JCO.19.03250). Iadademstat has shown encouraging safety and efficacy data in combination with azacitidine in a Phase IIa trial in elder 1L AML patients (ALICE trial) (see Salamero et al., ASH 2022 oral presentation). Iadademstat is currently being evaluated in combination with gilteritinib in the ongoing Phase Ib FRIDA trial in patients with relapsed/refractory AML with FLT3 mutations. Beyond hematological cancers, the inhibition of LSD1 has been proposed as a valid therapeutic approach in some solid tumors such as small cell lung cancer (SCLC), neuroendocrine tumors (NET), medulloblastoma and others. In a Phase IIa trial in combination with platinum/etoposide in second line ED-SCLC patients (CLEPSIDRA trial), preliminary activity and safety results have been reported (see Navarro et al., ESMO 2018 poster). Iadademstat is being evaluated in a collaborative Phase II basket study with the Fox Chase Cancer Center (FCCC) in combination with paclitaxel in R/R neuroendocrine carcinomas, and the company is preparing a new trial in combination with immune checkpoint inhibitors (ICI) in SCLC. Oryzon has entered into a Cooperative Research and Development Agreement (CRADA) with the U.S. National Cancer Institute (NCI) to collaborate on potential further clinical development of iadademstat in different types of solid and hematological cancers; a first trial in combination with ICI in SCLC has recently received FDA IND approval. In total iadademstat has been dosed so far to more than 130 cancer patients in four clinical trials. Iadademstat has orphan drug designation for SCLC in the US and for AML in the US and EU. FORWARD-LOOKING STATEMENTS This communication contains, or may contain, forward-looking information and statements about Oryzon, including financial projections and estimates and their underlying assumptions, statements regarding plans, objectives, and expectations with respect to future operations, capital expenditures, synergies, products and services, and statements regarding future performance. Forward-looking statements are statements that are not historical facts and are generally identified by the words “expects,” “anticipates,” “believes,” “intends,” “estimates” and similar expressions. Although Oryzon believes that the expectations reflected in such forward-looking statements are reasonable, investors and holders of Oryzon shares are cautioned that forward-looking information and statements are subject to various risks and uncertainties, many of which are difficult to predict and generally beyond the control of Oryzon that could cause actual results and developments to differ materially from those expressed in, or implied or projected by, the forward-looking information and statements. These risks and uncertainties include those discussed or identified in the documents sent by Oryzon to the Spanish Comisión Nacional del Mercado de Valores (CNMV), which are accessible to the public. Forward-looking statements are not guarantees of future performance and have not been reviewed by the auditors of Oryzon. You are cautioned not to place undue reliance on the forward-looking statements, which speak only as of the date they were made. All subsequent oral or written forward-looking statements attributable to Oryzon or any of its members, directors, officers, employees, or any persons acting on its behalf are expressly qualified in their entirety by the cautionary statement above. All forward-looking statements included herein are based on information available to Oryzon on the date hereof. Except as required by applicable law, Oryzon does not undertake any obligation to publicly update or revise any forward‐looking statements, whether as a result of new information, future events, or otherwise. This press release is not an offer of securities for sale in the United States or any other jurisdiction. Oryzon’s securities may not be offered or sold in the United States absent registration or an exemption from registration. Any public offering of Oryzon’s securities to be made in the United States will be made by means of a prospectus that may be obtained from Oryzon or the selling security holder, as applicable, that will contain detailed information about Oryzon and management, as well as financial statements. IR, USIR & Media, EuropeSpainOryzonAshley R. RobinsonSandya von der WeidPatricia Cobo/Mario CorderaEmili TorrellLifeSci Advisors, LLCLifeSci Advisors, LLCAtreviaChief Business Officer+1 617 430 7577+41 78 680 05 38+34 91 564 07 25+34 673 33 97 65+34 93 515 1313arr@lifesciadvisors.comsvonderweid@lifesciadvisors.compcobo@atrevia.commcordera@atrevia.cometorrell@oryzon.com