Varoglutamstat

根据不完全统计，今年3月和4月共有13项临床研究宣告失败。比如，艾伯维与MacroGenics合作开发的ADAM9 ADC IMGC936止步I期研究；Amylyx的渐冻症新药Relyvrio因III期研究失败面临退市，还引发了公司生存危机，裁员70%；K药联合奥拉帕利一线治疗转移性非鳞状非小细胞肺癌的III期KEYLYNK-006研究错过双重主要终点……为大家筛选其中10项失败临床研究，以供参考。3月和4月失败临床研究1.varoglutamstat治疗阿尔兹海默病IIb期研究3月4日，Vivoryon Therapeutics公布了口服谷氨酰胺酰环化酶（QPCT）抑制剂varoglutamstat（PQ912）治疗早期阿尔茨海默病（AD）IIb期VIVIAD研究的初步结果。Varoglutamstat是一种针对有毒的pE3-Aβ（也就是礼来donanemab靶向的pGlu3-Aβ）开发的差异化口服小分子药物，其设计目的是在以淀粉样蛋白（Aβ）抗体为重点的治疗方法之前针对AD病理进行治疗。Varoglutamstat可阻断谷氨酰胺酰环化酶（QPCT）及其同工酶 QPCTL。QPCT催化pE3-Aβ的形成，pE3-Aβ是一种神经毒性特别强的Aβ变体，只存在于注意力缺失症患者体内，健康人的大脑中不存在这种变体，或与斑块沉积有关。此外，varoglutamstat还能影响突触损伤。通过另一种作用机制，即通过 QPCTL抑制CCL2的完全成熟，varoglutamstat可以调节促炎信号传导和tau病理学，从而同时解决AD的多种特征。然而，结果显示，VIVIAD研究未达到其主要终点，也未显示出认知能力随时间推移而发生变化的显著统计学差异。此外，该研究未达到测量认知能力、日常生活活动工具问卷和脑电图 全局θ功率的关键次要终点。Varoglutamstat的耐受性总体良好，严重和重度治疗紧急不良事件 （TEAE）发生率与安慰剂相似，不良事件导致的停药率较低，在临床环境中未发现有症状的 ARIAs（淀粉样蛋白相关成像异常）。此消息一出，Vivoryon公司股票当天暴跌90%。值得注意的是，先声药业于2021年6月与Vivoryon达成超5亿美元的合作，获得了包括varoglutamstat在内的2款阿尔茨海默病治疗药物在大中华区开发的权益。2.ADAM9靶向ADC I期研究3月7日，MacroGenics在2023年财报中透露将终止IMGC936的开发，原因是没有达到预期内的安全性和有效性目标。IMGC936是MacroGenics开发的第1款ADAM9靶向ADC，由高亲和力的人源化单克隆抗体、美登木素生物碱微管抑制剂载荷和稳定的三肽接头组成，DAR为2。在与艾伯维的共同合作下，ImmunoGen领导了临床开发，并完成了最初的I期剂量递增和剂量扩展研究。不过，MacroGenics和艾伯维都不打算进一步开发IMGC936，因为该分子没有达到预先建立的临床安全性和有效性基准。ADAM9（一种解整合素和金属蛋白酶结构域9）是ADAM多功能1型跨膜蛋白家族的成员，在肿瘤发生和癌症进展中发挥作用，并在多种癌症中过表达。MacroGenics认为，ADAM9仍然是一个有前途的替代细胞毒性有效载荷的靶点，并开发了第2款ADAM9 ADC药物MGC028，其有效载荷为拓扑异构酶I抑制剂SYNtecan E，DAR约为4。3.渐冻症药物III期研究3月8日，Amylyx Pharmaceuticals宣布Relyvrio（AMX0035）用于治疗肌萎缩侧索硬化（ALS）成人患者的III期PHOENIX研究未达到主要终点。4月，Amylyx还宣布将把该药物撤出美国和加拿大市场，并裁员约70%，以将其现金跑道延长至2026年。ALS，俗称渐冻症，是一种进行性神经退行性疾病，临床主要表现为进行性发展的骨骼肌萎缩、无力、肌束颤动，患者生存时间平均为3~5年，最常见的死因是呼吸衰竭。SOD1-ALS是ALS的一种罕见遗传性形式，仅占全球约16.8万ALS病例的2%，大多患者疾病进展迅速，发病后生存期不超过3年。PHOENIX研究共招募了664例ALS患者，结果并未达到主要终点，第48周时，与安慰剂组比，AMX0035治疗组肌萎缩侧索硬化功能评定量表（ALSFRS-R）评分较基线变化不具有显著统计学差异（p=0.667）。此外，该研究也未达到患者报告的生活质量结果评估、总生存期以及慢肺活量（SVC）衡量的呼吸功能等次要终点。受此消息影响，Amylyx股价当天暴跌83.5%。不过，AMX0035在III期研究中遭遇失败似乎意料之中，此前II期研究数据就曾面临过专家的质疑，上市之路颇为坎坷。AMX0035是一种由苯丁酸钠和牛磺酸二醇组成的专有口服固定剂量复方制剂。二者联合使用，靶向肌萎缩侧索硬化症和其他神经退行性疾病中的内质网和线粒体依赖性神经元退行性通路，减少神经元死亡和功能障碍。2022年9月，AMX0035获FDA批准上市，是首款在随机、安慰剂对照临床试验中显著延缓ALS疾病进展并能延长生存期的治疗药物，也是116年以来FDA批准的第3款ALS治疗药物。财报显示，2023年该产品销售额达3.8亿美元。2022年3月，FDA召开的外周和中枢神经系统药物咨询委员会（PCNSDAC）曾以6:4的投票，表达了对AMX0035现有数据说服力的怀疑——包括试验规模小、缺失数据、用于分析主要终点的统计方法的适当性以及随机化方案等问题。这些最终指向了一个结论——II期结果虽然具有统计学意义，但仍不足以确定AMX0035可以改善疾病进展。在II期CENTAUR试验中，研究人员在137名ALS患者中测试了AMX0035与安慰剂为期六个月的治疗效果，研究的主要终点是ALS功能评定量表总分的下降率。结果显示，接受AMX0035治疗的患者平均得分高出2.32分，下降速度减缓25.3%，具有统计学意义。长期随访研究表示，3年左右时AMX0035仍可表现一定生存益处。与安慰剂相比，AMX0035可将死亡风险降低约44%。但在6个月的随机期间，Amylyx没有发现统计学上显著的生存差异。2022年6月，FDA通知Amylyx，将AMX0035的PDUFA日期延长至2022年9月29日，以便有更多时间审查AMX0035临床研究数据的额外分析。2022年9月8日，PCNSDAC以7:2的投票结果赞成AMX0035的现有研究数据足以支持其用于治疗肌萎缩侧索硬化的上市申请。PCNSDAC的投票结果虽不具有约束力，但FDA批准AMX0035的上市申请应予以考虑了专家组的建议。随着III期验证性研究的失败，AMX0035的上市旅程终是被摁下了终止健。4.pimavanserin治疗精神分裂症阴性症状III期研究3月11日，Acadia Pharmaceuticals公布了pimavanserin治疗精神分裂症阴性症状的III期ADVANCE-2试验的最新结果。ADVANCE-2是一项为期26周的双盲、随机、安慰剂对照研究，454例患有主要阴性症状的精神分裂症成年患者分别接受了34mg的pimavanserin和安慰剂治疗，这些患者在接受抗精神病治疗后阳性症状得到了控制。在研究的主要终点，即阴性症状评估-16（NSA-16）总分从基线到第26周的变化上，pimavanserin与安慰剂相比没有显示出统计学上的显著改善（-11.8 vs. -11.1；P=0.4825）。Pimavanserin的安全性和耐受性与之前的临床试验一致，不良事件发生率为 30.4%，而安慰剂组为40.3%。Pimavanserin是一种选择性5-羟色胺（5-HT）反向激动剂和拮抗剂，优先靶向5-HT2A受体，于2016年4月获批，商品名为Nuplazid，是首款治疗与帕金森病精神病（PDP）相关的幻觉和妄想的药物。2023年，Nuplazid全球销售收入达5.49亿美元。在适应症拓展上，pimavanserin的开发之路走得并不顺利。此前，pimavanserin用于治疗与阿尔茨海默症精神病相关幻觉和妄想的补充新药上市申请（sNDA）已遭FDA两次拒绝。5. K药联合奥拉帕利一线治疗非鳞NSCLC III期研究3月21日，默沙东宣布其PD-1疗法Keytruda联合维持性PARP抑制剂Lynparza（奥拉帕利）一线治疗某些转移性非鳞状非小细胞肺癌（NSCLC）患者的III期KEYLYNK-006试验未达到总生存期（OS）和无进展生存期（PFS）的双重主要终点。在KEYLYNK-006试验中，与Keytruda联合化疗（培美曲塞+卡铂或顺铂）之后进行Keytruda+维持性化疗（培美曲塞）相比，Keytruda联合化疗随后进行Keytruda+维持性Lynparza不符合研究预先规定的OS或PFS统计标准。该试验中Keytruda和Lynparza的安全性与先前报道的单独治疗研究中观察到的结果一致。对这项研究数据的全面评估正在进行中。默沙东表示将与研究人员合作，与科学界分享研究结果。这已经不是Keytruda+奥拉帕利联合疗法失败的首个III期研究了。去年12月7日，默沙东宣布终止Keytruda与Lynparza（奥拉帕利）联合治疗转移性鳞状非小细胞肺癌（NSCLC）患者的III期KEYLYNK-008试验，原因是研究没有显示出OS的改善。6. S1P受体调节剂治疗克罗恩病III期研究3月28日，BMS宣布ozanimod用于中重度活动性克罗恩病的III期YELLOWSTONE项目中第一个为期12周的诱导研究未达主要终点。Ozanimod是一款1-磷酸鞘氨醇（S1P）受体调节剂，能够抑制一个特定亚组的活化淋巴细胞从淋巴结迁移到中枢神经系统，从而缓解免疫系统对神经髓鞘的攻击。目前，该产品已在美获批治疗多发性硬化症、溃疡性结肠炎。本次公布的III期YELLOWSTONE研究项目包含两项为期12周的诱导研究、一项为期52周的维持研究和264周的开放标签扩展研究，旨在评估ozanimod较安慰剂的安全性和有效性。其中，诱导研究主要终点为患者临床缓解情况，即克罗恩病活动指数（CDAI）评分低于150的患者比例。不过，这项诱导研究（n=600）结果显示，第12周时未达到临床缓解主要终点。7. 个性化癌症疫苗II期研究4月1日，Gritstone bio宣布其个性化癌症疫苗GRANITE在一线转移性微卫星稳定结直肠癌（MSS-CRC）中正在进行的II/III期研究的II期部分的数据。总体来说，该癌症疫苗未能触发循环肿瘤DNA（ctDNA）的变化，导致II期试验未达主要终点。具体来说，公告显示：GRANITE组观察到无进展生存（PFS）获益的早期趋势，所有患者的风险比为0.82，高危患者的风险比为0.52，中位PFS分别为12个月(GRANITE组) 和7个月(对照组)；长期循环肿瘤DNA（ctDNA）反应与PFS趋势一致，GRANITE组患者优于对照组患者；但由于诱导化疗后意想不到的持续ctDNA下降，短期分子反应无法提供信息；GRANITE组总体耐受性良好，不良事件可控；没有患者因不良事件而停药。研究人员随机选择了104例转移性MSS-CRC患者，让他们从两种一线疗法中选择一种。所有患者均接受诱导和维持化疗。在维持阶段，约一半的受试者还接受了Gritstone的个性化新抗原癌症疫苗、BMS的Yervoy、罗氏的Tecentriq。该试验主要终点是观察ctDNA的变化，而不是大家广泛接受和应用的PFS，Gritstone首席执行官Andrew Allen博士为此解释道，“假性进展的证据（evidence of pseudo progression）使我们对PFS‘有点怀疑’，所以将ctDNA设置为主要终点。”虽然这项研究没有达到主要终点，但Andrew Allen博士认为PFS数据结果“非常令人鼓舞”，在6个月和9个月后，疫苗组的PFS率高于对照组，他表示，“我们只是搞错了分子反应的定义，化疗后两组患者的ctDNA水平下降的时间比我们预期的要长，这在两组患者中产生了相似的短期分子反应率，使得我们对ctDNA变化的方案测量无法提供信息。”Gritstone成立于2015年，2018年9月IPO，是一家临床阶段的生物技术公司，通过创新载体和有效载荷来训练免疫系统的多个分支来攻击关键的疾病靶点。公司的管线专注于癌症疫苗和传染病疫苗。临床数据公布的同一天（4月1日），Gritstone宣布了公开募股计划，拟以1.65美元/股的价格出售3250万美元。但投资者似乎并不买账，次日（4月2日）股价下跌48.94%，仅1.2美元/股。Gritstone 2023年底的资金为7920万美元，该公司表示，这笔资金将用于2024年第3季度的运营。现在Gritstone的现金快用完了，此次募股也是无奈之举。Gritstone表示，预计将在2024年第3季度公布GRANITE的成熟的PFS数据，2025年上半年公布总体生存数据。8. MNK1/2抑制剂联合K药一线治疗NSCLC II期研究4月4日，eFFECTOR Therapeutics公布了tomivosertib的一项随机、安慰剂对照II期KICKSTART研究的主要分析结果。Tomivosertib是MNK1和MNK2的强效、高选择性小分子抑制剂，通过抑制肿瘤驱动的T细胞衰竭来激活对癌症的免疫反应，可抑制MNK依赖性的多种免疫抑制蛋白的过度产生，包括PD-1和LAG3。KICKSTART研究旨在评估tomivosertib与K药联用一线治疗PD-L1≥50%的非小细胞肺癌（NSCLC）患者的有效性与安全性。基于36个事件，采用分层考克斯比例危险模型计算的无进展生存期（PFS，该研究的主要终点）危险比为0.62（95%Cl：0.3-1.3），tomivosertib更优。基于分层对数秩检验，PFS双侧P值为0.21，未达到p≤0.2的预设阈值。Tomivosertib组的中位生存期为13.0周，安慰剂组的中位生存期为11.7周。总生存期结果仍不成熟，但没有观察到有利于tomivosertib的趋势。在tomivosertib组中，发生3级或3级以上治疗突发不良事件的比例为67%，而安慰剂组为37%。eFFECTOR总裁兼首席执行官Steve Worland博士表示：“虽然有证据表明tomivosertib具有一定的活性，但根据目前掌握的全部数据，我们认为继续开发tomivosertib治疗一线NSCLC的前景并不明显。”9. dalzanemdor治疗帕金森病II期研究4月17日，Sage Therapeutics公布了PRECEDENT研究的初步结果，该双盲、安慰剂对照II期研究旨在评估潜在同类首创NMDA受体正变构调节剂dalzanemdor在帕金森病（PD）轻度认知障碍（MCI）患者中的有效性与安全性。PRECEDENT研究未达到其主要终点，即在第42天时，接受每日一次dalzanemdor治疗的患者相较于接受安慰剂治疗的患者在WAIS-IV测试得分方面未显示显著统计学差异。Dalzanemdor的耐受性总体良好，没有发现新的安全性信号。根据数据，Sage不计划在PD中进一步开发dalzanemdo。“我们对II期PRECEDENT研究的结果感到失望，因为轻度认知障碍给PD患者及其家庭带来了沉重负担。”Sage公司首席执行官 Barry Greene 表示：“虽然认知障碍在神经退行性疾病中很常见，但PD的基本病理生理学和症状学是与众不同的，这些结果并不一定能预测dalzanemdor在其他神经退行性疾病中的治疗效果。我们期待着今年晚些时候亨廷顿氏病和阿尔茨海默病II期研究的初步数据。”10. CLK/DYRK激酶抑制剂治疗膝骨关节炎III期研究4月18日，Biosplice Therapeutics 宣布最近完成了CLK/DYRK激酶抑制剂lorecivivint治疗膝骨关节炎的两项III期试验，即OA-07长期结构、疼痛和功能研究以及OA-21短期疼痛研究。最初于2023年11月报告的OA-07研究的初步结果表明，患者关节结构实现了具有统计学意义和临床意义的改善。对OA-07结果的最终分析证实了这一结构上的获益，并进一步表明患者的疼痛也实现了统计学意义上的显著减轻（以第6个月和第12个月的WOMAC疼痛度量），功能也有了显著改善（以第12个月的WOMAC功能度量）。然而，关于较短期的OA-21研究，初步分析表明，该研究没有达到第12周疼痛减轻的主要终点。与已发表的关节内OA试验和Biosplice之前的试验相比，公司在这项试验中观察到了异常高的安慰剂反应。Biosplice目前正在分析这些初步的OA-21试验结果。Lorecivivint是一种Biosplice正在开发的拟应用于改善骨关节炎的药物，并有可能成为近年来首个获批用于骨关节功能改善的新机制创新药。2021年9月，海思科与Biosplice就lorecivivint达成了合作，交易条款总价值最高可达1.4亿美元，包括首付款和注册里程碑共2000万美金，以及一定的销售里程碑加上未来销售的特许权使用费。海思科获得独家负责lorecivivint在中国的开发、注册和商业化。Copyright © 2024 PHARMCUBE. All Rights Reserved.欢迎转发分享及合理引用，引用时请在显要位置标明文章来源；如需转载，请给微信公众号后台留言或发送消息，并注明公众号名称及ID。免责申明：本微信文章中的信息仅供一般参考之用，不可直接作为决策内容，医药魔方不对任何主体因使用本文内容而导致的任何损失承担责任。

Vivoryon Therapeutics N.V. Reports Full Year 2023 Financial Results and Provides Varoglutamstat and Strategic Updates In-depth analysis of VIVIAD Phase 2b results is ongoing, including pre-specified and exploratory endpoints; findings to date are consistent with previously announced topline data observing no statistically significant or clinically meaningful effect of varoglutamstat on cognition and function in early AD up to 600mg twice a day (BID) doseStatistically significant improvement in kidney function observed with varoglutamstat 600mg BID in VIVIAD over two years based on pre-specified analysis of the estimated glomerular filtration rateCompany plans to explore potential of varoglutamstat in kidney disease in a shift of strategic focus towards inflammatory and fibrotic disorders VIVA-MIND Phase 2 study to be discontinued early, in H2 2024, which will enable accelerated data analysis and inform varoglutamstat development strategyCompany is taking steps to reduce cash utilization and will prioritize resources on exploring varoglutamstat in kidney disease, VIVIAD and VIVA-MIND data analysis, select pipeline programs, and continuing business developmentBased on current financial and business plans, including the discontinuation of VIVA-MIND, Company’s cash runway is now expected to extend into Q2 2025 without additional financingManagement to host conference call today at 3:00pm CEST (9:00am EDT) Halle (Saale) / Munich, Germany, April 24, 2024 – Vivoryon Therapeutics N.V. (Euronext Amsterdam: VVY; NL00150002Q7) (Vivoryon), a clinical stage company focused on the discovery and development of small molecule medicines to modulate the activity and stability of pathologically altered proteins, today announced financial results for the twelve-month period ended December 31, 2023, and provided varoglutamstat and strategic updates including its pipeline development priorities and financial guidance. "2023 was a year of clinical progress as we prepared for the readout from our VIVIAD Phase 2b study and advanced our U.S. study, VIVA-MIND, in early Alzheimer’s disease. We were very disappointed to report negative results from VIVIAD in March of this year, given the significant unmet need for new disease-modifying therapies. Our ongoing analysis of the topline data confirms that there was no consistent effect of varoglutamstat on cognition and function at the 600mg dose and we are continuing our in-depth analysis to uncover key learnings and inform our long-term strategy in AD. Varoglutamstat’s safety profile continues to look encouraging and we are excited to report today that we have observed a statistically significant improvement in kidney function based on pre-specified analysis of the estimated glomerular filtration rate measured in VIVIAD. This is in line with our prior hypothesis and results of pharmacological research on the role of the QPCT/L pathway beyond AD and is a very promising development. We are now prioritizing our resources and research and development activities to maximize value from varoglutamstat and our pipeline, with a focus on exploring its potential role in inflammatory and fibrotic diseases, including kidney disease, and determining additionally whether a path forward is viable in AD,” said Frank Weber, M.D., CEO of Vivoryon. He continued, “Based on the VIVIAD analysis, and an assessment of funding needs, we have taken the decision, jointly with our principal investigator, to discontinue the VIVA-MIND study in early AD in the second half of 2024. This will enable us to accelerate analysis of patients treated in the study and explore varoglutamstat’s effect on certain endpoints including EEG theta power and kidney function and look for any trends in cognition. We hope the data from VIVA-MIND will increase our understanding of the role of QPCT/L inhibition in AD and evolve the science behind this devastating disease." In light of recent developments, the Company is today announcing prioritization of its resources into research and development activities it believes have the greatest potential to provide a meaningful impact for patients and for value creation. Key priorities reflect the strategic shift towards a focus on inflammatory and fibrotic diseases and include: Exploring varoglutamstat’s potential in inflammatory and fibrotic disorders, including of the kidney,Concluding VIVIAD Phase 2b clinical study program for varoglutamstat in Europe, including an in-depth analysis of the results presented on March 4, 2024, and further ongoing biomarker analysis,Discontinuing VIVA-MIND clinical Phase 2 study with varoglutamstat in the U.S. in the second half of 2024, earlier than planned, enabling accelerated analysis of the results which will contribute to the overall dataset informing varoglutamstat’s development strategy moving forward,Assessing the potential of varoglutamstat in doses higher than 600mg BID orally in early Alzheimer’s disease,Continuing to actively pursue potential business development and financing opportunities. 2023 and Post-Period Updates Varoglutamstat Clinical Program: VIVIAD study in early ADVIVIAD (NCT04498650) is a state-of-the-art Phase 2b study conducted in Europe and designed to evaluate the safety, tolerability, and efficacy of varoglutamstat in 259 subjects with mild cognitive impairment (MCI) and mild Alzheimer’s disease (AD). In March 2024, Vivoryon announced topline data for VIVIAD. The study, which evaluated varoglutamstat up to 600mg BID, did not meet its primary endpoint of a statistically significant difference in cognitive improvement over time, assessed by the combined Z-score of the three elements of the Cogstate 3-item scale, as well as key secondary endpoints measuring cognition and function including the Cogstate Brief Battery (CBB); complete Cogstate neuropsychological test battery (NTB); the Amsterdam Instrumental Activities of Daily Living Questionnaire (A-IADL-Q) and electroencephalogram (EEG) global theta power.Safety results from the study showed that varoglutamstat was generally well tolerated and showed rates similar to placebo of serious and severe treatment emergent adverse events (TEAEs), low discontinuation rates due to adverse events and no evidence of symptomatic ARIAs (amyloid-related imaging abnormalities) in the clinical setting.Vivoryon is conducting an in-depth analysis of the VIVIAD data. While these analyses remain ongoing, findings to date confirm the topline results. Additionally, no statistically significant or clinically meaningful effect of varoglutamstat up to 600mg BID was observed on pre-specified subgroups. The only significant difference observed in favor of varoglutamstat was a lower change from baseline in the WAIS IV coding test and the letter fluency test, both measuring cognitive dysfunction, at week 48. Pharmacokinetic and QPCT/L enzyme inhibition data in VIVIAD were consistent with previous results. VIVIAD study – results from kidney function exploratory analyses The VIVIAD protocol prospectively specified measurement of certain kidney function biomarkers. This was in line with the Company’s previously announced growth strategy to explore varoglutamstat’s potential effects on kidney function.Varoglutamstat 600mg BID increased the estimated glomerular filtration rate (eGFR) over the treatment period up to 96 weeks, indicating a potential benefit of varoglutamstat on kidney function. Analysis is ongoing including a closer analysis of VIVIAD results in patients with different eGFR levels at baseline.Given these statistically significant and clinically meaningful data, Vivoryon is evaluating a development path including business development and financing opportunities to further explore the potential of varoglutamstat and QPCT/L inhibitors in kidney disease. VIVA-MIND study in early ADVIVA-MIND (NCT03919162) is a Phase 2 study conducted in the U.S. evaluating the safety, tolerability, and efficacy of varoglutamstat in patients with early AD. Vivoryon announced today that, based on the ongoing review of VIVIAD data published March 4, 2024, and an assessment of funding needs, the Company has decided jointly with its principal investigator, to voluntarily discontinue the Phase 2 VIVA-MIND study in early AD in the U.S. in the second half of 2024. This will enable accelerated analysis of the results and will contribute to the overall dataset informing varoglutamstat’s development strategy moving forward. Initial data from the study is anticipated by the end of 2024.In October 2023, Vivoryon announced the study’s independent data and safety monitoring board (DSMB) recommended to continue VIVA-MIND with a 600mg BID dose throughout Phase 2a and 2b, which is an accelerated up-titration protocol compared to the VIVIAD Phase 2b study. This decision followed safety reviews and analyses of treatment-emergent adverse events of special interest (AESI) occurring in skin and subcutaneous tissue disorders and hepatobiliary disorders, target occupancy and pharmacokinetic (PK) data. VIVALONG study VIVALONG is an open-label extension (OLE) study offering a long-term treatment option to patients after completing VIVIAD or VIVA-MIND protocols. In line with the Company’s cost reduction measures and given the developments of VIVIAD and VIVA-MIND, Vivoryon has decided to stop VIVALONG OLE study preparation activities. Early-Stage Pipeline Vivoryon is revisiting the early-stage opportunities in its R&D activities in line with its strategic shift. Future pre-clinical activities will involve exploring QPCT/L inhibitors for use in inflammatory and fibrotic disorders as well as in other indications such as oncology and CNS.Opportunities with meprin inhibitors will continue to be explored, in particular for fibrotic disorders.The Company’s antibody program, PBD-C06, will remain active as a candidate for further potential partnering opportunities.The Company will continue to explore identification of second generation QPCT/L inhibitors with good blood brain barrier penetration. Corporate Development Updates In March 2024, Kugan Sathiyanandarajah and Professor Dr. Morten Asser Karsdal stepped down from Vivoryon’s Board of Directors. They had been previously appointed as Non-Executive Directors in June 2023.In March 2024, Anne Doering, CFA, assumed the role of Chief Financial Officer (CFO) of Vivoryon, following her previous position as Chief Strategy & Investor Relations Officer.In October 2023, Vivoryon hosted a virtual R&D Event with Key Opinion Leaders (KOLs), focusing on varoglutamstat.In September 2023, Vivoryon held an Extraordinary General Meeting (EGM) related to the appointment of Frank Weber, MD, as CEO and Executive member of the Board of Directors. He followed Dr. Ulrich Dauer, former CEO of Vivoryon, after Dr. Dauer’s announcement in June 2023 to not renew his contract with the Company.In August 2023, Vivoryon and Scenic Biotech B.V. (“Scenic”) reached an agreement regarding the settlement of their patent dispute in connection with certain of Vivoryon´s patents related to varoglutamstat (PQ912) and certain other QPCT inhibitors. As part of the settlement, Scenic’s affiliate, Scenic Immunology B.V., and Vivoryon have entered into a patent license agreement, under which Scenic Immunology B.V. granted to Vivoryon certain rights to certain patents controlled by Scenic Immunology B.V. in the field of oncology.In May 2023, Vivoryon successfully raised EUR 25 million through an accelerated bookbuild offering. The private placement totaled 1,785,715 ordinary shares, at an issue price of EUR 14.00 per share. Financial Results for the Full Year 2023 Revenues for the year ended December 31, 2023, reflected a EUR 3.6 million reversal in license revenue, compared to no revenue in the year ended December 31, 2022. The reversal is related to license revenues recognized in 2021 from a strategic regional licensing partnership with Simcere Pharmaceutical Group Ltd. (“Simcere”) to treat Alzheimer's disease (AD) in Greater China, which includes a variable compensation for the first milestone. This variable milestone payment of EUR 3.6 million is based on the initiation of the first human clinical trial of varoglutamstat in mainland China. After the end of the reporting period the anticipated first milestone revenues were re-assessed. Due to the VIVIAD Phase 2b study not meeting its primary and key secondary endpoints, it is expected that the first human clinical trial in mainland China will not start before further clarity from an in-depth analysis of the VIVIAD results as well as from additional analysis of the full data and its implications. Therefore, revenues for the variable compensation (first development milestone) are no longer highly probable. As a consequence, the milestone-receivable of EUR 3.6 million was impaired and the respected revenues were reversed, as of December 31, 2023. Research and development expenses decreased by EUR 2.6 million to EUR 17.6 million in the year ended December 31, 2023, compared to EUR 20.2 million in the year ended December 31, 2022. The decrease is primarily attributable to EUR 2.7 million lower third-party expenses, mainly due to EUR 3.6 million lower manufacturing costs, partially offset by EUR 1.7 million higher clinical costs, mainly due to the progress of the Phase 2b VIVIAD clinical study. General and administrative expenses were EUR 8.6 million in the year ended December 31, 2023, compared to EUR 8.9 million in the year ended December 31, 2022. The decrease of EUR 0.3 million is largely attributable to the release of EUR 2.6 million of previously capitalized capital raising costs in 2022, partially offset by EUR 2.2 million higher expenses for personnel, legal and consulting, as well as costs for Non-Executive Directors. The reasons for the cost increases in personnel and for the Non-Executive Directors of the Board were predominantly caused by accelerated share-option expenses (EUR 0.3 million) and severance payments (EUR 0.6 million) as a result of the 2023 Board changes. Net loss in the year ended December 31, 2023, was EUR 28.3 million, compared to EUR 28.2 million in the year ended December 31, 2022. The Company held EUR 18.6 million in cash and cash equivalents as of December 31, 2023, plus term deposits of EUR 10.0 million disclosed under current financial assets, compared to cash and cash equivalents of EUR 26.6 million as of December 31, 2022. Cash flows used in operating activities were EUR 21.5 million in the year ended December 31, 2023, compared to EUR 21.8 million in the year ended December 31, 2022. Cash flows used in investing activities were EUR 10.5 million in the year ended December 31, 2023, compared to EUR 13 thousand in the year ended December 31, 2022. This difference reflects the net purchase of term deposits in the amount of EUR 10.0 million during 2023. Cash flows provided from financing activities were EUR 24.2 million in the year ended December 31, 2023, compared to EUR 33.4 million in the year ended December 31, 2022. Outlook & Financial Guidance The Company expects, on the basis of its most recent financial and business plan, that its existing cash and cash equivalents will be sufficient to fund its operating plans, excluding any additional financings, into the second quarter of 2025. This cash runway guidance reflects an overall reduction in cash utilization including the ramp down of spending on VIVIAD as it approaches its conclusion, the discontinuation of VIVA-MIND, the discontinuation of VIVALONG preparation activities given the developments of VIVIAD and VIVA-MIND, as well as the streamlining of manufacturing costs and programs for API development. These activities also represent a change in focus of research and development resources towards inflammatory and fibrotic disorders, such as of the kidney, from an emphasis on Alzheimer’s disease. The viability of the Company beyond the second quarter of 2025 is dependent on its ability to raise additional funds to finance its operations which also depends on the success of its research and development activities such as those focusing on exploring opportunities in kidney disease. The financial statements have been prepared on the basis that the Company will continue as a going concern. The Company expects to have continuing operating losses for the foreseeable future and the need to raise additional capital to finance its future operations, and, as of April 24, 2024, the Company has concluded that the ability to continue as a going concern in the financial year 2025 depends on the ability to generate additional funding. Please refer to the Company’s Annual Report 2023 for further information. Conference Call and Webcast Vivoryon will host a conference call and webcast today, April 24, 2024, at 3:00 pm CEST (9:00 am EDT). A Q&A session will follow the presentation of the full year results. A live webcast and slides will be made available at: www.vivoryon.com/investors-news/news-and-events/presentations-webcasts/ To join the conference call via phone, participants may pre-register and will receive dedicated dial-in details to easily and quickly access the call via the following website: https://register.vevent.com/register/BI3fef74de02dc40daa7cbe0aac7731e74 It is suggested participants dial into the conference call 15 minutes prior to the scheduled start time to avoid any delays in attendance. Approximately one day after the call, a slide-synchronized audio replay of the conference will be available on: www.vivoryon.com/investors-news/news-and-events/presentations-webcasts/ ### Vivoryon Therapeutics N.V. Financial StatementsStatement of Operations and Comprehensive Loss for the Years Ended December 31, 2023 and 2022 in kEUR, except for share data20232022Revenue(3,620)—Cost of Sales525—Gross profit (3,095) —Research and development expenses(17,637)(20,224)General and administrative expenses(8,600)(8,908)Other operating income49519Other operating expense——Operating loss(28,837)(29,113)Finance income7261,710Finance expense(465)(952)Finance result261758Result before income taxes(28,576)(28,355)Income taxes234199Net loss for the period(28,342)(28,156)Items not to be reclassified subsequently to profit or loss Remeasurement of the net defined benefit pension liability(76)392Total other comprehensive (loss) / income(76)392Comprehensive loss(28,418)(27,764)Loss per share in EUR (basic and diluted)(1.12)(1.28) The accompanying notes are an integral part of these financial statements. Vivoryon Therapeutics N.V.Statements of Financial Position as December 31, 2023 and 2022 in kEUR20232022ASSETS Non-current assets Property, plant and equipment4049Intangible assets941494Right-of-use assets36127Financial assets—14Total non-current assets1,017684Current assets Financial assets10,1653,716Other current assets and prepayments1,085423Cash and cash equivalents18,56226,555Total current assets29,81230,694TOTAL ASSETS30,82931,378 Equity Share capital26,06724,105Share premium135,671113,382Other capital reserves13,5999,656Accumulated other comprehensive loss(256)(180)Accumulated deficit(148,799)(120,457)Total equity26,28226,506Non-current liabilities Pension liability1,3531,323Provisions long-term1212Lease liabilities—38Deferred tax liabilities—234Total non-current liabilities1,3651,607Current liabilities Trade payables2,8942,543Lease liabilities3894Other liabilities250628Total current liabilities3,1823,265Total Liabilities4,5474,872TOTAL EQUITY AND LIABILITIES30,82931,378 The accompanying notes are an integral part of these financial statements. Vivoryon Therapeutics N.V.Statements of Changes in Shareholders’ Equity for the Years Ended December 31, 2023 and 2022 in kEURShare capitalShare premiumOther capital reservesAccumulated other comprehensive lossAccumulated deficitTotal equityJanuary 1, 202220,05083,2116,168(572)(92,300)16,557Net loss for the period————(28,156)(28,156)Remeasurement of the net defined benefit pension liability———392—392Comprehensive (loss) / income———392(28,156)(27,764)Proceeds from the issuance of common shares4,05531,945———36,000Transaction costs of equity transactions—(1,774)———(1,774)Share-based payments——3,488——3,488December 31, 202224,105113,3829,656(180)(120,457)26,506Net loss for the period————(28,342)(28,342)Remeasurement of the net defined benefit pension liability———(76)—(76)Comprehensive (loss) / income———(76)(28,342)(28,418)Proceeds from the issuance of common shares1,78623,214———25,000Transaction costs of equity transactions—(2,095)———(2,095)Share-based payments——3,943——3,943Proceeds from exercise of share options1761,170———1,346December 31, 202326,067135,67113,599(256)(148,799)26,282 The accompanying notes are an integral part of these financial statements. Vivoryon Therapeutics N.V. Statements of Cash Flows for the Years ended December 31, 2023 and 2022 in kEUR20232022Operating activities Net loss for the period(28,342)(28,156)Adjustments for: Finance result(261)(758)Depreciation and amortization167161Share based payments3,9433,488Capitalized capital raising costs that were expensed—2,633Deferred income tax(234)(199)Reversal of Revenue and Accounts Receivable3,095—Changing in Financial assets—3,090Other current assets and prepayments(662)294Pension liabilities(94)(122)Provisions—(35)Trade payables538(1,724)Other liabilities(17)(471)Interest received3289Interest paid(2)(4)Cash flows used in operating activities(21,541)(21,794)Investing activities Purchase of plant and equipment(14)(11)Purchase of intangible assets(500)(2)Purchase of financial assets(19,000)—Proceeds from sale of financial assets9,000—Cash flows used in investing activities(10,514)(13)Financing activities Proceeds from the issuance of common shares25,00036,000Transaction costs of equity transactions(2,095)(1,774)Capital raising costs—(753)Payment of lease liabilities(94)(92)Proceeds from exercise of share options1,346—Cash flows provided by / (used in) financing activities24,15733,381Net decrease in cash and cash equivalents(7,898)11,574Cash and cash equivalents at the beginning of period26,55514,661Effect of exchange rate fluctuation on cash held(95)320Cash and cash equivalents at the end of period18,56226,555 The accompanying notes are an integral part of these financial statements.Annual Financial Report 2023 The financial statements of Vivoryon have been prepared in accordance with International Financial Reporting Standards (IFRS) of the International Accounting Standards Board, as adopted by the European Union (EU-IFRS) and with Section 2:362(9) of the Netherlands Civil Code. The auditor KPMG has issued an unqualified auditor's report for both statements. The reports are available on the Company’s website www.vivoryon.com. About Vivoryon Therapeutics N.V.Vivoryon is a clinical stage biotechnology company focused on developing innovative small molecule-based medicines. Driven by its passion for ground-breaking science and innovation, the Company strives to change the lives of patients in need suffering from severe diseases. The Company leverages its in-depth expertise in understanding post-translational modifications to develop medicines that modulate the activity and stability of proteins which are altered in disease settings. The Company has established a pipeline of orally available small molecule inhibitors for various indications including Alzheimer’s disease, inflammatory and fibrotic disorders, including of the kidney, and cancer. www.vivoryon.com. Vivoryon Forward Looking StatementsThis press release includes forward-looking statements, including, without limitation, those regarding the business strategy, management plans and objectives for future operations of Vivoryon Therapeutics N.V. (the “Company”), estimates and projections with respect to the market for the Company’s products and forecasts and statements as to when the Company’s products may be available. Words such as “anticipate,” “believe,” “estimate,” “expect,” “forecast,” “intend,” “may,” “plan,” “project,” “predict,” “should” and “will” and similar expressions as they relate to the Company are intended to identify such forward-looking statements. These forward-looking statements are not guarantees of future performance; rather they are based on the Management’s current expectations and assumptions about future events and trends, the economy and other future conditions. The forward-looking statements involve a number of known and unknown risks and uncertainties. These risks and uncertainties and other factors could materially adversely affect the outcome and financial effects of the plans and events described herein. The Company’s results of operations, cash needs, financial condition, liquidity, prospects, future transactions, strategies or events may differ materially from those expressed or implied in such forward-looking statements and from expectations. As a result, no undue reliance should be placed on such forward-looking statements. This press release does not contain risk factors. Certain risk factors that may affect the Company’s future financial results are discussed in the published annual financial statements of the Company. This press release, including any forward-looking statements, speaks only as of the date of this press release. The Company does not assume any obligation to update any information or forward-looking statements contained herein, save for any information required to be disclosed by law. For more information, please contact: Investor ContactStern IRPenelope BelnapTel: +1 212-362-1200Email: penelope.belnap@sternir.com Media ContactTrophic CommunicationsValeria FisherTel: +49 175 8041816Email: vivoryon@trophic.eu Attachment VVY YE23 Earnings Release