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点击蓝字 关注我们 编者按 小细胞肺癌（SCLC）是一种极具侵袭性的神经内分泌恶性肿瘤，以增殖迅速、早期转移和预后极差为特征。尽管一线治疗初始缓解率较高，但缓解持续时间有限，疾病复发后治疗选择匮乏，患者长期生存未见显著改善。过去十年间，随着对SCLC生物学特征特别是细胞表面蛋白组的深入认识，免疫治疗、T细胞衔接器、抗体药物偶联物、放射性偶联物及细胞疗法等新型治疗策略不断涌现，正在重塑SCLC的治疗格局。 近日，《柳叶刀》（The Lancet）与《柳叶刀呼吸医学》（The Lancet Respiratory Medicine）联合发表“肺癌治疗”系列综述，本篇聚焦小细胞肺癌治疗格局的演变，系统总结当前标准治疗、近期进展与新兴策略。 SCLC为什么难治：从流行病学到分子特征 小细胞肺癌（SCLC）约占肺癌的10%–15%，女性患者比例持续上升，目前约占全部SCLC病例50%。SCLC与烟草暴露高度相关，当前吸烟者较从不吸烟者的比值比达20–50，重度吸烟者（>30支/日）超过100。欧美患者人群中从不吸烟者仅占2%–5%，但中国研究报告23%的SCLC患者为从不吸烟者，提示病因可能存在种族或地理差异。此外，慢性阻塞性肺疾病是SCLC的独立危险因素，风险约增加2倍。 SCLC的5年总生存（OS）率长期低下，IV期患者从1975–1979年的3%–6%仅升至2010–2019年的6%–8%。近年来，随着新型治疗策略的不断涌现，患者生存已显著改善：局限期SCLC（LS-SCLC）放化疗后辅助度伐利尤单抗的3年OS率达57%，广泛期SCLC（ES-SCLC）化疗联合免疫治疗的3年OS率为16%–18%。 在分子层面，TP53与RB1双等位基因失活是SCLC最显著的基因组改变，分别发生于75%–90%和95%–100%的患者中。基于转录因子表达，SCLC可分为SCLC-A（ASCL1）、SCLC-N（NEUROD1）、SCLC-P（POU2F3）和SCLC-Y（YAP1）四种亚型，各亚型在神经内分泌特征、基因组改变及治疗脆弱性方面存在显著差异。值得注意的是，这些亚型并非固定不变，治疗压力下可相互转化，即谱系可塑性，是耐药的重要来源。 局限期SCLC同步放化疗序贯免疫巩固的确立 同步放化疗后免疫巩固已成为标准 同步放化疗长期以来是LS-SCLC的重要治疗模式，但治疗后仍有部分患者发生局部复发或远处转移，长期生存仍有改善空间。ADRIATIC试验旨在评估度伐利尤单抗用于局限期SCLC放化疗后巩固治疗的疗效，结果显示度伐利尤单抗组中位OS显著延长（56个月 vs 33个月），中位无进展生存期（PFS）亦显著改善（17个月 vs 9个月），首次证实，对于同步放化疗后未发生疾病进展的患者，免疫巩固能够改善PFS和OS，为这一治疗策略提供了明确的生存获益证据。 然而，免疫治疗与放疗的时序安排至关重要。NRG Oncology/Alliance LU005试验评估了阿替利珠单抗与放化疗同步给药的疗效，结果显示PFS无改善，OS甚至数值更差。这一结果提示，免疫治疗与胸部放疗同步可能削弱抗肿瘤免疫，因此免疫治疗应在放化疗完成后序贯给予，而非同步使用。 早期患者的手术临床价值 对于罕见的I–IIA期患者（肿瘤≤5 cm、局限于肺实质、淋巴结病理阴性），手术切除序贯辅助化疗是首选方案。早期支持手术优于放化疗的前瞻性数据来自1970–1990年代，但受限于当时的分期方法和治疗技术，证据强度有限。近期一项基于倾向评分匹配的回顾性分析纳入2000余例早期SCLC患者，结果显示手术组死亡风险较放化疗组降低38%（HR 0.62，95% CI 0.53–0.74），进一步支持手术作为早期患者的优选方案。若术后病理发现纵隔淋巴结受累，应考虑纵隔术后放疗。 对于肿瘤较大或淋巴结阳性的患者，则不推荐手术，而应选择放化疗诱导后免疫巩固。化疗方案为四个周期顺铂联合依托泊苷，无法耐受顺铂者可选用卡铂。胸部放疗应早期介入，从化疗第1或第2周期开始有生存获益。每日两次45 Gy（30次分割）为最佳方案，60–70 Gy每日一次为可接受替代。 预防性颅脑照射：从标准治疗到争议不断 值得一提的是，预防性颅脑照射（PCI）的地位日益受到争议。1990–2000年代的临床试验显示PCI可降低脑转移发生并改善OS，但这些试验未要求基线MRI，可能纳入了已存在但未被检出的脑转移患者，从而高估了PCI的预防效果。此外，PCI与显著的神经认知毒性相关。在高分辨率MRI时代，III期随机试验显示，对于基线MRI确认无脑转移的患者，PCI较MRI监测并无生存获益。因此，当前指南对LS-SCLC且对初始治疗有应答的患者，推荐PCI或MRI监测二者择一，未明确孰优孰劣。MAVERICK和PRIMALung研究结果可能为这一争议提供答案。 广泛期SCLC免疫联合化疗与维持治疗优化 免疫联合化疗确立一线标准 ES-SCLC以铂类联合依托泊苷化疗为基础，通常给药4–6个周期。尽管缓解率高达60%–80%，但缓解难以持久，几乎所有单纯化疗患者在一年内进展。在此背景下，IMpower133和CASPIAN两项里程碑试验分别评估了阿替利珠单抗和度伐利尤单抗联合化疗的疗效，两者均显示联合组中位OS较化疗组显著延长（12.3个月 vs 10.3个月；12.9个月 vs 10.5个月），2年OS率达22.9%。这两项研究共同确立了免疫联合化疗作为ES-SCLC一线标准治疗的地位。此后，PD-1抑制剂斯鲁利单抗和替雷利珠单抗亦在全球多国获批联合化疗一线治疗，生存结局与抗PD-L1疗法相当，进一步丰富了临床选择。 维持治疗策略的优化 IMforte研究旨在评估芦比替定联合阿替利珠单抗维持治疗ES-SCLC的疗效，结果显示联合组中位PFS为5.4个月 vs 2.1个月，中位OS为13.2个月 vs 10.6个月，提示在阿替利珠单抗基础上加用芦比替定可改善生存，但不良反应增加，尤其是血细胞减少。临床前证据提示高SLFN11表达、ISL1表达和低MYC水平可能预测芦比替定敏感性，凸显生物标志物驱动策略在识别最可能获益患者方面的重要性。 复发SCLC中T细胞衔接器重塑二线标准 复发SCLC的治疗长期面临困境，对于诱导治疗后6个月以上复发的患者，可考虑铂类联合依托泊苷再诱导，但缓解率和持续时间均较低。拓扑替康和伊立替康等DNA拓扑异构酶I抑制剂在多国获批用于复发SCLC，缓解率约25%。2020年，芦比替定基于II期研究35%的缓解率获FDA加速批准。然而，上述细胞毒性药物获益有限，中位PFS不足6个月，生存期最长约9个月，临床亟需更有效的治疗手段。 塔拉妥单抗作为首创的DLL3/CD3双特异性T细胞衔接器（TCE），可同时结合肿瘤细胞DLL3和T细胞CD3，介导T细胞活化及靶细胞裂解。II期研究显示其在复发转移性SCLC患者客观缓解率（ORR）为40%，中位缓解持续时间（DoR）近10个月。III期DeLLphi 304研究进一步评估了塔拉妥单抗对比化疗二线治疗SCLC的疗效，结果显示塔拉妥单抗组中位OS为13.6个月 vs 8.3个月，中位PFS为4.2个月 vs 3.7个月，为二线及后线治疗提供了新的希望。 在脑转移方面，早期研究显示经治脑转移颅内缓解率高达63%；在DeLLphi 304研究中，56%的可测量脑转移患者脑肿瘤缩小≥30%，提示塔拉妥单抗具有颅内抗肿瘤活性。安全性方面，塔拉妥单抗的不良反应特征与其他T细胞衔接器一致，主要为细胞因子释放综合征（56%）和免疫效应细胞相关神经毒性（6%），多为1-2级。 特殊人群；脑转移与转化型SCLC的管理 脑转移 脑转移是ES-SCLC常见的转移部位，约50%–60%的患者在病程中会出现脑转移。既往脑转移的治疗以全脑放疗（WBRT）为主，但近年来立体定向放射外科（SRS）的应用逐渐增多。FIRE-SCLC队列研究显示，一线WBRT较SRS可延长颅内控制时间，但未能改善总生存期（OS）。另一项单臂II期研究则显示，SRS治疗1-10个脑转移灶的1年神经死亡发生率为11%，低于WBRT的历史水平（17.5%），提示SRS可作为部分患者的替代治疗选择。 相比之下，全身治疗对颅内病灶的疗效尚不明确，原因在于关键临床试验多排除了未治疗或有症状的脑转移患者。铂类联合依托泊苷虽可产生颅内缓解，但持续时间通常较短；抗PD-L1治疗未能明确改善中枢神经系统（CNS）预后。塔拉妥单抗则显示出令人鼓舞的颅内抗肿瘤活性，其针对CNS疗效的前瞻性研究正在进行中。 转化型SCLC 转化型SCLC是驱动基因阳性NSCLC对酪氨酸激酶抑制剂（TKI）耐药的机制。一项研究在EGFR、TP53和RB1三突变肺癌患者中初始即给予铂类、依托泊苷和奥希替尼联合治疗，但未能预防转化，该高危亚组11例患者中仍有5例（45%）发生转化。 转化型SCLC治疗困难，中位OS为9–11个月；目前尚无前瞻性试验指导该人群的治疗，最佳管理策略尚不明确。当前推荐铂类联合依托泊苷，但免疫治疗的价值存在争议。TKI可考虑继续使用，但应避免与免疫治疗联用，以免增加肺炎风险。塔拉妥单抗在EGFR突变转化型SCLC中的缓解率仅为7%，其前瞻性研究正在进行中。 新兴治疗策略：从表面蛋白组靶向到亚型精准治疗 表面蛋白组：SCLC的“可靶向弱点” SCLC细胞表面蛋白景观提供了多个独特或高度富集的肿瘤特异性靶点，最具前景的包括DLL3、B7-H3和SEZ6。这些分子在肿瘤细胞表面表达，正常细胞表达极低，是理想的药物靶点。 抗体-药物偶联物（ADC）：ADC是目前SCLC靶向治疗领域的研究热点之一。目前尚无ADC获批用于SCLC，但多项创新药物临床研究正在积极开展，靶点涵盖DLL3、B7-H3、TROP-2和SEZ6。I/II期临床试验显示，复发/转移性SCLC的缓解率为40%-70%。双特异性ADC，如靶向EGFR/HER3的Izalontamab Brengitecan（Iza-Bren），缓解率可达75%，且未观察到间质性肺病（ILD）。ADC疗效取决于靶点选择、内化动力学以及抗体、连接子和载荷的工程化设计。目前多数SCLC ADC采用拓扑异构酶I抑制剂作为载荷，但载荷相关耐药可能导致后续使用相同载荷ADC时发生交叉耐药，因此载荷多样化具有重要意义。 放射性核素偶联物：放射性核素偶联物通过靶向分子将放射性核素递送至肿瘤，实现局部辐射。靶向DLL3抗体与89Zr偶联后，PET成像可清晰显示肿瘤特异性摄取。177Lu或225Ac标记的DLL3抗体在临床前模型中可诱导完全缓解并延长生存。177Lu-DOTATATE（Lutathera）已获批用于胃肠胰神经内分泌肿瘤，目前正在SCLC中开展探索。GD2靶向预靶向放射免疫治疗采用自组装/解聚双特异性抗体策略，在临床前模型中显示出剂量依赖性抗肿瘤活性，相关I期试验正在进行。 CAR-T细胞治疗：DLL3靶向CAR-T的I期研究中，17例SCLC患者中3例获得缓解，13例达到疾病控制。CAR-NK细胞不受HLA配型限制，具有通用型治疗潜力，目前尚处于早期临床前研究阶段。 亚型特异性脆弱性与生物标志物指导的治疗 基于转录因子表达谱，SCLC可分为SCLC-A、SCLC-N、SCLC-P、SCLC-Y及炎症型SCLC-I，各亚型具有不同的治疗脆弱性。 DLL3在神经内分泌高表达亚型（包括SCLC-A和SCLC-N）中富集，BCL2作为ASCL1下游靶点在SCLC-A中富集；但BCL2抑制剂因单药疗效有限及与BCL-XL交叉反应导致血小板减少，临床推进受限。 SCLC-N高表达BET蛋白，BET抑制剂在临床前显示前景，但尚未在SCLC中开展临床评价；高NEUROD1/MYC模型对Aurora激酶抑制剂敏感，alisertib相关II期试验正在进行。 SCLC-P在临床前对PARP抑制剂、抗叶酸/核苷类似物及mSWI/SNF ATPase降解剂敏感，但PARP抑制剂联合化疗的临床研究未显示OS获益，提示临床前脆弱性向临床转化仍存障碍。 SLFN11是DNA损伤反应和复制调节因子，为化疗敏感性的决定因素；SWOG S1929研究显示，在SLFN11阳性ES-SCLC中，阿替利珠单抗联合他拉唑帕利虽改善PFS，但获益有限且未转化为OS改善。PRISM研究是首个基于亚型个体化治疗策略探索研究，将SCLC-A或SCLC-N且SLFN11阳性患者随机分配至度伐利尤单抗±saruparib，SCLC-I患者分配至度伐利尤单抗±monalizumab，代表SCLC生物标志物选择研究的重要概念验证。 增强抗肿瘤免疫：从单一检查点阻断到多路径干预 鉴于抗PD-L1治疗仅在少数患者中产生持久缓解，研究者致力于将获益扩展至更广泛人群。然而，PD-L1表达和肿瘤突变负荷均未显示与SCLC免疫治疗获益相关。IMpower133转录组分析提示，高神经内分泌、低巨噬细胞浸润和高T细胞密度的肿瘤患者从化疗免疫治疗中获益更多。CheckMate-032分析则发现，抗原呈递机制相关基因高表达与免疫治疗反应最相关。临床前研究表明，许多SCLC通过EZH2和LSD1介导的表观遗传沉默抑制MHC-I表达，而Valemetostat（EZH1/2抑制剂）和iadademstat（LSD1抑制剂）可恢复MHC-I表达，目前正在维持期I期研究中与阿替利珠单抗联合探索。 T细胞衔接器（TCE）：通过同时结合肿瘤表面蛋白和T细胞CD3，绕过MHC-I需求，直接介导T细胞杀伤。除塔拉妥单抗外，多种DLL3靶向TCE正在开发中，包括具有更长半衰期的IgG样结构（obrixtamig）、三特异性分子（gocatamig）及靶向两个DLL3表位的分子（alveltamig）。靶向B7-H3的T细胞衔接器亦处于早期开发阶段。 双重阻断PD-L1和VEGF是另一策略。VEGF阻断可改善肿瘤血管结构，增强免疫细胞浸润。安罗替尼（口服VEGF抑制剂）在中国获批用于复发SCLC。依沃西单抗（VEGF/PD-1双抗）联合铂类和依托泊苷一线治疗广泛期SCLC的I期研究显示确认缓解率80%。Pumitamig（PD-L1/VEGF双抗）联合卡铂和依托泊苷的II期研究显示缓解率76%。两者均在III期研究中评估。 复制应激反应抑制剂：利用SCLC的合成致死弱点 SCLC的特征是RB1和TP53基因的普遍失活突变，这些突变破坏了G1/S检查点，导致E2F异常激活，使肿瘤细胞依赖ATR-CHK1-WEE1轴。抑制ATR、CHK1或WEE1可导致早熟有丝分裂、复制应激和细胞死亡，构成合成致死策略。目前，WEE1、ATR和CHK1抑制剂正在临床开发中，与化疗和免疫治疗的联合正在研究中。 总结与展望 SCLC的治疗格局已从单纯化疗发展为免疫治疗锚定一线、TCE与ADC在后线多点突破的多元体系。LS-SCLC确立了同步放化疗序贯度伐利尤单抗巩固的标准地位，ES-SCLC以免疫联合化疗为一线基石，芦比替定联合阿替利珠单抗维持治疗进一步拓展了生存获益。复发SCLC中，塔拉妥单抗作为首个在III期研究中显著延长OS的TCE，重新定义了二线治疗标准。靶向表面蛋白组的ADC、放射性偶联物和CAR-T细胞等新兴策略展现出令人鼓舞的初步疗效。然而，缺乏明确的驱动基因靶点，肿瘤异质性强，耐药机制复杂多样等核心问题仍亟待解决，导致能够获得长期生存的患者比例依然很低。 未来探索方向包括如下：第一，基于分子分型的精准治疗，利用SCLC-A、SCLC-N、SCLC-P、SCLC-I等亚型的特异性脆弱性，通过生物标志物指导的治疗选择实现个体化治疗。第二，耐药机制的深入解析与联合策略优化，针对免疫治疗耐药、化疗耐药及ADC载荷交叉耐药等问题，探索合理的联合方案与序贯策略。第三，新型治疗技术的临床转化，包括三特异性TCE、双靶点ADC、新型放射性偶联物及CAR-NK细胞治疗等。第四，治疗可及性与全程管理，优化塔拉妥单抗等新型药物的给药方式，降低治疗负担，推动从规范治疗向全程获益的转变。随着这些探索的持续推进，SCLC的治疗格局将不断迈向精准化、个体化的新时代。 参考文献：Ross J S, Hockemeyer K G, Redin E, et al. The Changing Therapeutic Landscape of Small-Cell Lung Cancer[J]. Lancet (London, England), 2026, 408(10559): 1041-1057. （来源：《肿瘤瞭望》编辑部） 声 明 凡署名原创的文章版权属《肿瘤瞭望》所有，欢迎分享、转载。本文仅供医疗卫生专业人士了解最新医药资讯参考使用，不代表本平台观点。该等信息不能以任何方式取代专业的医疗指导，也不应被视为诊疗建议，如果该信息被用于资讯以外的目的，本站及作者不承担相关责任。

PMS is a severely disabling genetic disorder related to autism U.S. prevalence is estimated at approximately 1 in 7,300 people HOPE-2 is partially funded through Oryzon’s VANDAM project under Med4Cure, an Important Project of Common European Interest (IPCEI) on Health The study is being advanced in collaboration with the Spanish Phelan–McDermid Syndrome Association MADRID and CAMBRIDGE, Mass., Sept. 28, 2026 (GLOBE NEWSWIRE) -- Oryzon Genomics, S.A. (ISIN Code: ES0167733015, ORY), a clinical-stage biopharmaceutical company and a global leader in epigenetics, today announced that the European Medicines Agency (EMA) has authorized its Clinical Trial Application (CTA) to initiate a Phase II study to evaluate vafidemstat for the treatment of Phelan-McDermid Syndrome (PMS). The study, named HOPE-2, is a single-center, single-arm, open-label Phase IIa study that will enroll 12 adult patients with Phelan-McDermid Syndrome, a genetic disease associated with autism spectrum disorder (ASD). The primary objective of the study is to evaluate the safety and tolerability of vafidemstat. Secondary objectives include assessing the effect of vafidemstat on anger and aggression, measured by the Aberrant Behavior Checklist (ABC) Irritability Subscale and the Clinical Global Impression of Severity - Anger and Aggression (CGI-S A/A), as well as the efficacy of vafidemstat in the treatment of overall disease in adults with PMS, measured by the Repetitive Behavior Scale-Revised (RBS-R), the Phelan-McDermid Syndrome Assessment of Severity (PMSA-S), and the ABC Subscales: Stereotypic Behaviour, Hyperactivity/Non-compliance, Inappropriate Speech, and Social Withdrawal. Vafidemstat will be administered for 12 weeks. After the first 12 weeks of treatment, the Investigator will assess whether the participant may continue treatment through week 24 based on clinical benefit. PMS is a highly disabling neurodevelopmental disorder caused by deletions or pathogenic mutations in the SHANK3 gene. It is characterized by varying degrees of developmental delay, intellectual disability, delayed or absent speech, and autism spectrum disorder or symptoms of autism. Despite the high prevalence and substantial burden of aggression in PMS, there are no approved pharmacologic treatments for PMS or specifically targeting aggression in PMS. As a result, aggression is often managed off-label with medications that have limited efficacy and significant safety concerns. “The initiation of the HOPE-2 study bolsters our strategy to expand the applicability of vafidemstat in CNS indications,” said Rolando Gutierrez-Esteinou, MD, Oryzon’s Chief Medical Officer for CNS. “Vafidemstat is the only LSD1 inhibitor in clinical development for Central Nervous System disorders, with a potent and unique mechanism of action that modulates transcriptional programs involved in neural plasticity, neuroinflammation and neuronal excitability. LSD1 inhibition has been shown to trigger a ‘reset’ of neuronal transcription and reverse social behavior and aggression phenotypes in ASD genetic models, including SHANK3-deficient mice. These preclinical findings and the clinical results observed in the REIMAGINE Phase IIa trial in ASD patients lead us to believe vafidemstat has unique potential to provide a promising treatment option for Phelan-McDermid Syndrome.” Oryzon will collaborate with the Spanish Phelan-McDermid Syndrome Association to support the identification of potential participants for the HOPE-2 study. “The approval of the HOPE-2 study is very important news for our families. Knowing that a potential treatment is being investigated to help manage agitation or aggressive behavior gives us great hope. We would like to thank the Oryzon team for involving us in this process from the outset. For us, it is essential to feel that we are part of these advances and to be able to contribute, drawing on our experience, to help research continue moving forward. We hope this study will bring us closer to new options that can improve the quality of life of our children,” said Norma Alhambra, President of the Spanish Phelan-McDermid Syndrome Association. The HOPE-2 study will be conducted in Spain, as part of Oryzon’s VANDAM project. VANDAM, which is part of the Med4Cure Important Project of Common European Interest (IPCEI) on Health, has received funding from the Spanish Ministry of Science, Innovation and Universities and the Centre for the Development of Industrial Technology and Innovation (CDTI), under the Recovery, Transformation and Resilience Plan, funded by the European Union – NextGenerationEU. About Oryzon Founded in 2000 and headquartered in Barcelona, Spain, Oryzon (ISIN: ES0167733015) is a clinical-stage biopharmaceutical company and a European leader in epigenetics, with a strong focus on personalized medicine for central nervous system (CNS) disorders and oncology. Oryzon’s team comprises highly experienced pharmaceutical professionals based in Barcelona, Boston, and New Jersey. The Company has an advanced clinical portfolio built around two LSD1 inhibitors: iadademstat, its oncology/hematology program, which is being evaluated in several ongoing Phase I and II studies and has demonstrated strong preliminary clinical activity in acute myeloid leukemia, including a 100% overall response rate (ORR) in first-line AML; and vafidemstat, its lead CNS program, which is Phase III–ready in borderline personality disorder (BPD). In addition, Oryzon is advancing a broader epigenetics pipeline targeting other mechanisms, including HDAC6, for which the Company has nominated ORY-4001 as a clinical candidate for potential development in Charcot–Marie–Tooth disease (CMT), amyotrophic lateral sclerosis (ALS), and other neurological disorders. The Company also operates a robust platform for biomarker identification and target validation across malignant and neurological diseases. For more information, visit . About Vafidemstat Vafidemstat (ORY-2001) is an oral, CNS-optimized LSD1 inhibitor with potential to address neuropsychiatric disorders through epigenetic modulation. In preclinical studies, vafidemstat has demonstrated effects on cognition, neuroinflammation, aggression, and social behavior, as well as neuroprotective and anti-inflammatory activity across multiple CNS disease models. Oryzon has completed several Phase II clinical trials with vafidemstat, including the REIMAGINE and REIMAGINE-AD trials in aggression in patients with different psychiatric disorders and in aggressive/agitated patients with moderate or severe AD, respectively, with positive clinical results reported in both trials. Following completion of the global randomized double-blind Phase IIb PORTICO trial in borderline personality disorder (BPD), vafidemstat is advancing as a Phase III-ready asset for aggression in BPD (PhIII in preparation). Vafidemstat is also being evaluated in the ongoing double-blind, randomized, placebo-controlled Phase IIb EVOLUTION trial in negative symptoms of schizophrenia. In addition, Oryzon is deploying a CNS precision medicine approach with vafidemstat in genetically defined patient subpopulations of certain CNS disorders, as well as in neurodevelopmental syndromes, including the HOPE-2 clinical trial in Phelan-McDermid Syndrome. 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All subsequent oral or written forward-looking statements attributable to Oryzon or any of its members, directors, officers, employees, or any person 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 document does not constitute an offer or invitation to purchase or subscribe shares in accordance with the provisions of Regulation (EU) 2017/1129 of the European Parliament and of the Council of 14 June 2017, and/or the restated text of the Securities Market Law, approved by Law 6/2023 of 17 March, and its implementing regulations. Nothing in this document constitutes investment advice. In addition, this document does not constitute an offer of purchase, sale or exchange, nor a request for an offer of purchase, sale or exchange of securities, nor a request for any vote or approval in any jurisdiction. The shares of Oryzon Genomics, S.A. may not be offered or sold in the United States of America except pursuant to an effective registration statement under the Securities Act of 1933 or pursuant to a valid exemption from registration. Spain Oryzon IR & Media, Europe & US Patricia Cobo/Mario Cordera Emili Torrell Sandya von der Weid Atrevia Chief BD Officer LifeSci Advisors, LLC +34 91 564 07 25 +34 673 33 97 65 +34 93 515 1313 +41 78 680 05 38 pcobo@atrevia.com mcordera@atrevia.com etorrell@oryzon.com svonderweid@lifesciadvisors.com