Bayer HealthCare AG

MCL1 基因在癌症中经常发生扩增，这赋予了肿瘤对当前标准治疗的耐药。因此，MCL1 是一个有吸引力的抗癌靶点。这里，分享由 Trueline Therapeutics 、拜尔医药、麻省理工学院和哈佛大学布罗德研究所等合作开发的一款 MCL1 抑制剂，其设计及临床前研究发表于近期的 Nature Cancer。BRD-810 是一款高效的选择性 MCL1 抑制剂，其关键设计原理是快速全身清除，以尽可能减少与 MCL1 抑制相关的毒性。BRD-810 在体外 4 小时内快速诱导细胞杀伤，但在 4 小时窗口内，即使在超药理学浓度下，对人诱导多能干细胞来源的心肌细胞中的细胞活力或肌钙蛋白 I 释放没有影响。尽管 BRD-810 在血浆中的停留时间很短，但 BRD-810 在血液和实体瘤模型中仍具有体内药效。总的来说，临床前数据支持这样的假设：用 BRD-810 短期抑制 MCL1 可以诱导肿瘤细胞凋亡，同时保持可接受的安全性。因此，BRD-810 将进行人体临床试验。 1.  背景介绍 对程序性细胞死亡的抵抗（细胞凋亡）是癌症的一个标志。每个正常细胞都有能力感知外在和内在的应激信号，并维持促凋亡和抗凋亡因子的适当平衡，最终决定细胞的生或死。在恶性细胞中，Bcl-2 蛋白家族发挥着核心作用，而 MCL1 作为该蛋白家族的关键抗凋亡因子之一，已被确定可促进异常细胞存活。 与其他抗凋亡 Bcl-2 家族成员一样，MCL1 通过与促凋亡效应蛋白（包括 BAK、BAX 或 BOK）以及 BH3 激活蛋白（如 BIM、PUMA 或 NOXA）紧密结合来防止癌细胞死亡。未结合的促凋亡效应蛋白通过在线粒体外膜上形成孔来启动细胞死亡信号级联，导致线粒体外膜电位破坏，并将 Ca2+和细胞色素c释放到胞质。这会引发不可逆的 Caspase 激活和蛋白酶水解级联，最终导致细胞死亡。除了其抗凋亡作用外，MCL1 的 N 端截短亚型还位于线粒体内膜，促进三磷酸腺苷 (ATP) 的产生，保护线粒体能量转导并确保线粒体稳态。 MCL1 的功能和表达在转录、转录后、翻译和翻译后水平上受到严格调控，使其成为半衰期较短的蛋白质，因此需要不断补充。同时，MCL1 是所有癌症中过度表达程度最高的病理蛋白之一，包括肝癌、乳腺癌、非小细胞肺癌 (NSCLC)、尿路上皮癌、胰腺癌以及胰腺癌中的实体瘤恶性肿瘤；以及血液肿瘤，包括急性髓系或慢性淋巴细胞白血病、和非霍奇金淋巴瘤。MCL1 的过度表达通常与不良预后有关，以及对放射治疗和化疗的耐药。有趣的是，MCL1 也被证明还可以介导对靶向治疗的耐药，包括常用的 BRAF 抑制剂、受体酪氨酸激酶抑制剂 和多激酶抑制剂。 由于这些特性，MCL1 成为癌症治疗的一个非常有吸引力的靶点。MCL1 的抑制已被证明可以恢复对各种药物的敏感性。最近开发了多种 MCL1 的抑制剂，目前正在早期临床试验中进行研究。 不同结构类别的代表性Mcl-1抑制剂的结构，药效和共结晶。 在过去的5−10年中，在（专利）文献中披露了各种有效的、选择性的Mcl-1抑制剂，一些化合物达到临床开发，尽临床结果喜忧参半和存在毒性。抑制Mcl-1功能需要阻断蛋白−蛋白相互作用，大多数开发的抑制剂都是相当大的分子，许多特性如Log P、PSA和MW位于“non-Lipinski”超过五规则（bRo5）区域。上图 显示了这些复杂分子的化学空间，显示了过去十年中报道的具有代表性的抑制剂选择。 由于MCL1抑制剂导致肌钙蛋白水平升高，存在潜在心脏毒性的担忧，一些项目的临床开发已经放缓或停止。组织特异性 MCL1 敲除模型导致线粒体呼吸功能障碍和心肌收缩力丧失，从而证明了 MCL1 与心肌疾病之间的联系。最近还报道了 MCL1 在调节心肌细胞脂肪酸氧化方面的新作用。以及对人诱导的多能干细胞 (hiPS 细胞) 衍生的心肌细胞的体外研究表明，长期暴露于各种 MCL1 抑制剂会破坏线粒体形态，并最终损害心肌细胞功能。综上所述，长期暴露 MCL1 抑制剂可能会导致靶向心脏毒性，因此需要一种有效的 MCL1 抑制剂，其暴露量足以诱导肿瘤细胞凋亡，但半衰期足够短，以缩短心脏毒性时间。例如，艾伯维的选择性 MCL-1 抑制剂 ABBV-467在肿瘤模型中有效，但与患者心肌肌钙蛋白(troponin I) 增加有关。 大环 MCL-1 抑制剂 ABBV-467 基于结构的设计总结: 1.  BRD-810 结合 MCL1 的 BH3 口袋 BRD-810 在药物化学研发项目中被鉴定出来，该研究的目标是平衡大环类 MCL1 抑制剂的细胞效力和体内清除率。图1a 总结了此次优化工作中的三种关键化合物。在HTRF 测定中，该化合物可与人 MCL1 蛋白可逆结合，并阻断 MCL1 与仅 BH3 蛋白 Noxa 衍生的肽之间的相互作用，IC50= 1.7 nM（化合物1）。此外，与其他抗凋亡蛋白（例如 Bcl- XL和 Bcl-2）相比，该化合物类别对 MCL1 表现出选择性，因为没有一个关键化合物影响其他 Bcl-2 家族成员与其各自的 BH3 蛋白的相互作用。与广泛的酶、受体和离子通道组相比，亦没有表现出明显的脱靶结合（PanLabs SafetyScreen panel）。从 化合物1 开始进行先导化合物优化，通过向吲哚和萘部分引入卤素取代基，使 MCL1 蛋白结合亲和力提高了 20 倍（化合物2，解离常数Kd = 1.2 nM）。通过引入与大环氧原子相邻的吗啉代乙基侧链的化合物的细胞效力显著增强，被命名为 BRD-810 （未结合的 IC50 (IC50u) = 0.3 nM） 。 图 1：BRD-810 是抗凋亡蛋白 MCL1 的有效且选择性抑制剂 该药物化学项目受益于先前描述的晶体学平台，通过生成经实验证实的 >50 独特化合物的结合姿势，以指导迭代设计和测试。晶体结构表明，BRD-810 占据了 MCL1 的 BH3 结合口袋（图1b），具有明确的电子密度和缺乏与对称相关蛋白质分子的相互作用。萘环深深嵌入主要由 M250 的运动产生的诱导结合袋中，氟原子位于该袋的底部。BRD-810 羧酸酯通过双齿氢键与 R263 结合，并通过水介导的氢键桥与 T266 结合。BRD-810 的附加吗啉基团针对螺旋 3 进行包装，主要涉及 G230、M231 和 K234。 除了与化合物2相比细胞效力高出十倍之外，BRD-810 在对大鼠静脉内给药后被更快地清除，BRD-810 的平均停留时间 (MRT) 为 0.3 小时，而化合物2的平均停留时间 (MRT) 为 0.6 小时。总的来说，这些发现表明 BRD-810 可以有效且选择性地阻止促凋亡蛋白与 MCL1 结合，然后再从系统中快速清除。 2. BRD-810 触发癌细胞凋亡  为了研究 BRD-810 抑制细胞中 MCL1 和促凋亡蛋白复合物结合的潜力，作者开发了一种定量 ELISA 测定法。该测定测量了 BRD-810 剂量增加和不同暴露时间点下天然 MCL1 蛋白与 BAK 或 BIM 蛋白的相互作用。BRD-810 的短期处理（最早 15 分钟）以剂量依赖性方式阻断 MCL1 与 BAK 的相互作用（图1c），并且 BRD-810 破坏 MCL1-BAK 复合物所需的 IC50计算出细胞平均为 1.2 nM。相比之下，BRD-810 对 MCL1-BIM 复合物的破坏明显具有剂量和时间依赖性（图1d ），并且需要更长的暴露时间才能完全破坏复合物，这反映出 BIM 在 MCL1 蛋白上的靶标停留时间较长。当细胞暴露于浓度不断增加的 BRD-810 时，免疫共沉淀分析显示出类似的复杂破坏动力学。 接下来，研究了 MCL1 和促凋亡蛋白复合物破坏的下游细胞效应。用增加浓度的 BRD-810 处理乳腺癌细胞系 HMC1-8 会激活 caspase 3 并诱导细胞死亡。这些效应呈剂量依赖性，并且发生在相当浓度的 BRD-810 下（EC50 = 66 nM) 激活 Caspase， 并抑制细胞生长(IC50 = 63 nM)(图1e,f）。BAX和BAK的敲除可保护细胞免受 BRD-810 介导的细胞凋亡和细胞杀伤的诱导。这表明BRD-810诱导的细胞死亡确实是通过激活细胞内在凋亡途径的靶向机制发生的（图1e，f）。 为了证明 BRD-810 在完整细胞中的 MCL1 特异性，测量了已知与 MCL1 或 Bcl-XL相关的DLBCL 肿瘤细胞系中的 caspase 激活和生长抑制。用增加剂量的 BRD-810 处理 SU-DHL-5 和 SU-DHL-10 细胞（MCL1 依赖性细胞系）可产生强效（半胱天冬酶 EC50激活和 IC50细胞生长抑制 < 10 nM）和快速（在〜4小时内）诱导细胞凋亡，而在Bcl-XL依赖性细胞系（例如SU-DHL-4细胞）中，仅在浓度高>600倍时观察到细胞凋亡。总之，这些研究结果表明 BRD-810 是一种选择性 MCL1 抑制剂。 3. BRD-810 敏感性候选生物标志物 为了全面评估 BRD-810 的抗增殖活性，使用了一种称为 PRISM 的快速、高通量多重筛选。PRISM 方法能够对代表 32 种不同癌症谱系的 700 多种细胞系进行筛选。在多种实体和血液癌症模型中观察到BRD-810以亚微摩尔浓度的抗增殖活性，包括乳腺癌、肺癌、黑色素瘤、肉瘤、淋巴瘤和白血病（图 2a）。编码 Bcl-X 的BCL2L1 水平较低和高水平的BAK表达与 BRD-810 诱导的功效相关性最强，其中BCL2L1与BAK mRNA 水平的比率在所有细胞系中提供了最佳的相关性（图2b）。 图 2：BRD-810 在体外对多种癌症类型具有抗癌功效。 将 BRD-810 与其他已进入临床试验的 MCL1 抑制剂进行了比较。在 MCL1 和其他 Bcl-2 家族抑制剂类别中，克服与血浆蛋白的非特异性结合是一个主要的设计挑战，并且在结构不同的 BH3 模拟物之间观察到了广泛的蛋白质结合。在 PRISM 筛选中对一系列血液学和实体瘤癌症类型鉴定为 BRD-810 敏感的细胞系，并用 MCL1 抑制剂 BRD-810、AZD5991、AMG176 或 S64315 处理，以评估它们在抗增殖 IC 50值。PRISM 筛选出的所有细胞系确实对 MCL1 抑制剂敏感，并且 BRD-810 是测试的细胞系中最有效的 MCL1 抑制剂。 4. BRD-810 的细胞杀伤动力学 接下来，研究了 BRD-810 诱导的细胞杀伤的时间和剂量依赖性。这一点很重要，因为理想的 MCL1 抑制剂将提供足够的暴露来诱导 MCL1 依赖性肿瘤细胞死亡，但不会超出此范围，以便最大限度地减少靶向毒性。用不同浓度的 BRD-810 处理 MCL1 依赖性细胞系 5 分钟（表示为 0 小时）、1 小时、3 小时、6 小时或 24 小时，然后彻底清洗以去除细胞中的化合物。在24小时时间点测定抗增殖IC50值 (图3a)。在暴露持续时间为 1 小时或更短的情况下，大多数细胞系的 IC50u 远高于 10 nM，表明短期暴露需要大量 BRD-810 才能诱导有效的抗增殖作用。然而，暴露 3 小时后，癌细胞死亡严重，所有 MCL1 依赖性细胞系的 IC50u 值均低于 10 nM。重要的是，暴露时间超过 6 小时和长达 24 小时不会带来额外的好处。该结果表明约 4 小时的暴露足以杀死 MCL1 介导的肿瘤细胞，进一步暴露可能主要导致毒性而不是功效。 图 3：BRD-810 诱导的杀伤动力学表明，短期 1 小时覆盖足以诱导体内抗肿瘤功效。 5. BRD-810 的体内药效 根据体外鉴定的快速细胞杀伤动力学，作者假设高清除率 MCL1 抑制剂能够启动细胞凋亡并发挥体内功效。BRD-810 的药代动力学特征揭示了其快速清除，在小鼠中的半衰期为 0.6 小时（图3b），这转化为人类半衰期为 1.1 小时。为了表征 BRD-810 在体内的药效学作用，移植了 MOLP-8 多发性骨髓瘤细胞的小鼠注射了单剂量 6、12.5、25 或 50 mg·kg -1的 BRD-810，然后进行肿瘤活检在1、3、6、24、48和72小时，以允许测量裂解的caspase3水平作为细胞凋亡的指标（图3c）。BRD-810 静脉注射后 1 小时至 6 小时，所有剂量的裂解 caspase 3 水平均可检测到，这表明细胞凋亡的快速诱导，即使在化合物被肝胆转运系统从血浆中清除后，细胞凋亡仍持续存在。最大caspase诱导发生在 BRD-810 注射后约 3 小时，并且该时间依赖性在所有测试剂量中均相似。然而，caspase3的激活程度以剂量依赖性方式增加至25 mg·kg -1 ，并且在25至50 mg·kg -1之间相似，表明实现了最大的功能效果。 接下来评估了 BRD-810 在相同 MOLP-8 肿瘤模型中的抗肿瘤功效（图3d）。每周一次的 BRD-810 给药导致肿瘤生长的剂量依赖性抑制，同样在 25 mg kg -1时达到最大效果。与大多数 MCL1 抑制剂一样，BRD-810 不抑制小鼠 Mcl1；因此，无法在小鼠中评估 BRD-810 的靶向毒性。然而，作为脱靶毒性的一种衡量标准，我们观察到每周一次给药后对体重没有影响（图3e）。 为了了解 BRD-810 在不同癌症中更广泛的单药潜力，研究了 BRD-810 在两种血液学模型和两种实体瘤异种移植模型中的功效。在快速生长的多发性骨髓瘤异种移植模型AMO-1中，低至12.5 mg·kg -1的单剂量BRD-810在12天内诱导完全反应（图4a ）。在 SU-DHL-10 DLBCL 异种移植模型中，每周一次的 25 mg·kg -1剂量与每两周一次的 50 mg·kg -1剂量，发现较低频率、较高剂量的 BRD-810 导致肿瘤消退时间延长（图4b ）。 图 4：BRD-810 在血液学和实体瘤异种移植模型中的体内功效。 对于实体瘤异种移植模型，选择SNU398（肝脏）和A-427（NSCLC）肿瘤模型作为代表性实体瘤恶性肿瘤。用两次连续的30 mg·kg -1 注射（间隔2小时）处理异种移植小鼠，以在每个细胞模型中实现未结合IC 50的所需4小时覆盖。给药 2 天间隔 5 天的方式，BRD-810 在 SNU398 肝癌模型中显示出与标准护理（瑞格非尼）相当的疗效（图4c ）。对NSCLC模型A-427使用相同的治疗方案，发现BRD-810比标准化疗药物顺铂和依托泊苷的组合更大程度地引发强烈的肿瘤消退（图4d ）。 鉴于 MCL1 在促进对常规和靶向治疗产生耐药性方面的作用，还研究了 BRD-810 在难治性治疗中的抗肿瘤作用，无论是作为单一药物还是与标准护理相结合。在急性髓性白血病（AML）的THP-1模型中，Bcl-2抑制剂venetoclax和阿糖胞苷均未显示出明显的单药疗效（图4e ），与难治性AML患者的临床经验非常相似。相比之下，每周给药 50 mg·kg -1 BRD-810 在单一疗法中具有强大的抗肿瘤作用。当与阿糖胞苷联合使用时，BRD-810 的疗效得到改善，治疗后 2 周内没有观察到肿瘤生长。虽然其他人之前已经确定 Venetoclax 单一疗法会诱导 MCL1 表达并产生耐药性，但 BRD-810 和 Venetoclax 的组合具有协同作用，能够在所有动物中引起完全缓解，在治疗后的 4 周内没有肿瘤复发。在 MV-4-11 异种移植小鼠中也观察到类似的功效，其中 BRD-810 与氮胞苷或维奈托克的组合即使在治疗停止后也能显着改善总体生存率。 6. BRD-810 对心肌细胞的影响小 根据 MCL1 抑制剂的早期临床经验，记录 MCL1 抑制剂对正常心肌细胞的影响非常重要。研究指出了 MCL1 在心肌细胞功能中的重要作用，并且使用 BH3 模拟物的体外研究表明，长期暴露后，hiPS 细胞衍生的心肌细胞的存活率受损。因此，评估了 BRD-810 对 hiPS 细胞衍生的心肌细胞的影响，重点关注 BRD-810 在人体中的预期暴露时间。hiPS 细胞衍生的心肌细胞用 1 µM 阿霉素(对照)或两个剂量水平的 BRD-810 处理 72 小时。Caspase 激活被测量为细胞凋亡的指标，细胞活力的三个标记物（ATP 水平、乳酸脱氢酶（LDH）释放和细胞核计数）和心脏损伤的组织特异性标记（肌钙蛋白 I，troponin I）也被测量（图5a-e ）。 图 5：BRD-810 对 iPS 细胞来源的心肌细胞的影响。 相比之下，根据心脏毒性的五种测量方法中的任何一种，暴露于 0.1 µM 甚至 1 µM BRD-810 4 小时都不会导致心肌细胞毒性（图5a-e ）。这一结果表明，通过将暴露时间限制为发挥功效所需的最短时间，可以进一步扩大 BRD-810 等 MCL1 抑制剂的治疗窗口，并且具有快速清除曲线的化合物可能最好地实现这种瞬时抑制。 为了进一步探讨 BRD-810 的心脏安全性，在犬类体内进行了短期剂量研究。犬类动物 MCL1 与人类 MCL1 高度相似，犬被输注药物 4 小时，以产生足以在多种小鼠肿瘤模型中发挥体内功效的 BRD-810 血浆水平，剂量为 3、8 和 15 mg·kg -1 ，分别相当于体外细胞培养物浓度 0.5 、 1 和 2 µM。这种 4 小时的输注每周重复一次，总共 4 周，并在研究结束时测量肌钙蛋白 I 水平。在中剂量或高剂量的任何狗的血液中均未检测到肌钙蛋白 I。在低剂量组中，仅在犬类的三个重复测量之一中观察到肌钙蛋白I轻微升高。总体而言，短期暴露于 BRD-810 是抑制 MCL1 的可行治疗方法。 除了心肌肌钙蛋白测量之外，还进行了心电图检查，以证明重复给药 BRD-810 对关键心电图参数（PR、QRS、QT 和计算的 QTcV 间期）或心率没有影响（图6b-f ）。此外，在 4 周重复剂量研究结束时分析了尸检后所有犬类的心脏组织（图6a ）。与血液中肌钙蛋白 I 水平不存在增加相一致，心脏组织的组织病理学分析显示，BRD-810 治疗后没有心脏组织损伤的证据。总体而言，短期输注 BRD-810 不存在心脏毒性，表明其独特的药代动力学特征适合临床研究。 图 6：反复接受 BRD-810 治疗的犬类心脏组织的组织病理学分析和心电图分析。 7.  讨论 考虑到最近 MCL1 抑制剂早期临床开发过程中心脏安全信号的报道，以及 MCL1 在正常心肌细胞中的功能，关键问题是 MCL1 的抑制是否可以安全地用于癌症治疗。在这里，介绍 BRD-810，一种快速清除的 MCL1 抑制剂，在血液学和实体瘤癌症模型中具有强大的抗肿瘤功效。与其他临床阶段的 MCL1 抑制剂相比，BRD-810 与 MCL1 的 BH3 沟结合并阻断促凋亡蛋白的隔离，从而在 MCL1 依赖性细胞系中快速诱导 caspase 激活，具有更优异的效力。 重要的是，尽管在血浆中的停留时间很短，但 BRD-810 的单次注射足以超过血液癌和实体癌体内模型中的抗凋亡阈值，并早在最初的 24 小时内就导致了可测量的肿瘤体积减小。由于细胞凋亡是不可逆的，因此不需要长时间暴露于 MCL1 抑制剂即可有效减少肿瘤。短暂的 MCL1 抑制，可以最大限度地减少 MCL1 靶向疗法的潜在靶向毒性。4 小时的 MCL1 抑制足以将 MCL1 依赖性细胞推向不可逆的凋亡路径，而不会严重损害其他细胞（包括心肌细胞）的活力。因此，BRD-810 这样能迅速从体循环中清除的 MCL1 抑制剂将在人体中进行验证。 参考：https://www.nature.com/articles/s43018-024-00814-0#Sec25 声明：发表/转载本文仅仅是出于传播信息的需要，并不意味着代表本公众号观点或证实其内容的真实性。据此内容作出的任何判断，后果自负。若有侵权，告知必删！ 长按关注本公众号  粉丝群/投稿/授权/广告等 请联系公众号助手 觉得本文好看，请点这里↓

Conference Call and Webcast Today at 4:30 p.m. ET Development Program Highlights and Anticipated 2024 Milestones Ovaprene® hormone-free monthly intravaginal contraceptive candidate pivotal Phase 3 contraceptive efficacy study recruiting across the United StatesSildenafil Cream, 3.6% topical formulation of sildenafil being developed to treat female sexual arousal disorder continued operational progress toward a planned Phase 3 study; additional FDA feedback forthcoming; Phase 3 design, development, and collaboration strategy updates SAN DIEGO, Aug. 12, 2024 (GLOBE NEWSWIRE) -- Daré Bioscience, Inc. (NASDAQ: DARE), a leader in innovation for the health and wellbeing of women, today reported financial results for the quarter ended June 30, 2024 and provided a company update. “In addition to the continued commercialization by our collaborator Organon of XACIATO™ (clindamycin phosphate) vaginal gel 2%, the first FDA-approved product to emerge from our portfolio and a treatment for bacterial vaginosis in females aged 12 and older* that is available by prescription nationwide, we continue to advance our first-in-category Phase 3 development candidates. Enrollment in our Phase 3 study of Ovaprene, our potentially first-in-category hormone-free monthly intravaginal contraceptive candidate, is ongoing at sites across the U.S. and we continue to see a robust response to the central advertising campaign that went live in March. We are continuing our interactions with the FDA regarding the Phase 3 program for Sildenafil Cream 3.6% in female sexual arousal disorder. While we await additional FDA feedback, we have been performing operational activities to support the planned Phase 3 program. Despite its high prevalence, there are currently no FDA-approved treatments for female sexual arousal disorder,” said Sabrina Martucci Johnson, President and CEO of Daré Bioscience. “The progress across our portfolio, along with the $22 million we secured in the non-dilutive strategic royalty financing we announced in the second quarter, puts Daré on track for meaningful milestones in 2024. In addition, we are excited about the increased attention on the health and wellbeing of women, including by grant making agencies, and continue to execute on our mission to accelerate development of and bring to market innovative treatments that women want and need by advancing our late-stage candidates – all of which represent a first-in-category opportunity – as we seek to deliver value for all Daré stakeholders.” *Please see below for important safety and other information. Ovaprene® Phase 3 StudyOvaprene is a novel, investigational hormone-free monthly intravaginal contraceptive whose U.S. commercial rights are under a license agreement with Bayer HealthCare. Working with study collaborators at the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) of the National Institutes of Health (NIH) and commercial collaborator Bayer, Daré commenced patient enrollment in the Ovaprene® pivotal Phase 3 clinical study in December 2023. Non-hormonal contraception represents a significant commercial market opportunity, and there are currently no monthly, hormone-free contraceptives approved by the FDA. Ovaprene® has potential to be a disruptive product in the contraceptive category and an important option for women who cannot use hormone-based birth control products or prefer not to do so. Recruitment is currently underway at 20 sites across the United States, supported by a central advertising campaign for the study that launched in March 2024. Phase 3 study updates will be provided as relevant throughout 2024. Based on the current average enrollment rate across the 20 study sites, we anticipate that approximately half of our target number of participants to complete the study, or 125 women, will complete approximately 6 months of product use by the end of the second quarter of 2025. Sildenafil Cream, 3.6% Progress toward Phase 3 StudySildenafil Cream is a proprietary, investigational cream formulation of sildenafil, the active ingredient in Viagra®, for topical on-demand administration to treat female sexual arousal disorder. Daré completed all study analyses of data from the exploratory Phase 2b RESPOND clinical study and held an end-of-Phase 2 meeting with the FDA in December 2023. In prior quantitative studies, Sildenafil Cream increased genital tissue blood flow, and the Phase 2b at-home study was specifically designed to identify the patient population that experienced the most meaningful improvement from Sildenafil Cream and the questions to ask them that best reflect that improvement. The patient population and the endpoints proposed to the FDA for Phase 3 clinical development were those where Daré's exploratory post-hoc analyses of the Phase 2b study data showed that Sildenafil Cream demonstrated statistically significant and meaningful patient improvement. Daré continues to interact with the FDA on the development program for Sildenafil Cream as a treatment for female sexual arousal disorder, and is awaiting additional feedback from the FDA on the proposed endpoints, as well as additional information on data that may be needed in an NDA submission to appropriately qualify any ingredient (other than sildenafil) for the vaginal route of administration. Daré also requested clarification on the safety database (size and duration exposure) that the FDA will require for an NDA submission. Initiating a Phase 3 study is contingent on aligning with the FDA regarding the foregoing. Based on FDA feedback we have received, two successful Phase 3 clinical studies of Sildenafil Cream will be required to support an NDA for Sildenafil Cream for the treatment of FSAD, and we anticipate that each Phase 3 study will cost approximately $15.0 million. We will take into account our capital resources before initiating a Phase 3 study. Daré’s planned initial Phase 3 study of Sildenafil Cream, 3.6% would be the first ever Phase 3 pivotal study of a therapeutic candidate for the treatment of arousal disorder in women. Daré intends to provide updates on the Phase 3 program, as well as relevant updates on the initial Phase 3 study timing and Daré’s collaboration strategy as they become available. Financial Highlights for the Quarter ended June 30, 2024 Cash and cash equivalents: $16.4 million at June 30, 2024. In April 2024, Daré received $22 million in gross proceeds in a non-dilutive royalty monetization transaction with XOMA (US) LLC and a $1 million payment as the latest installment under an up to $49 million grant agreement with a foundation in support of nonclinical development of the investigational contraceptive, DARE-LARC1. To date, Daré has received approximately $29.3 million under the DARE-LARC1 grant agreement.General and administrative expenses: $2.4 million in 2Q-2024 as compared to $2.9 million in 2Q-2023, with the current quarter’s decrease primarily attributable to reduced headcount and reduced professional services expense.Research and development (R&D) expenses: $4.9 million in 2Q-2024 as compared to $6.0 million in 2Q-2023, a 19% decrease compared to Q2-2023, with the current quarter’s decrease primarily attributable to decreases in costs related to development activities for Sildenafil Cream as a result of the Phase 2b RESPOND clinical study completion in June 2023 and decreases in costs related to development activities for our other programs, offset by increases in costs related to our ongoing pivotal Phase 3 clinical trial of Ovaprene. Conference Call Daré will host a conference call and live webcast today, August 12, 2024, at 4:30 p.m. Eastern Time to review financial results for the quarter ended June 30, 2024 and to provide a company update. To access the conference call via phone, dial (646) 307-1952 (U.S.) or (888) 672-2415 (toll free). The conference ID number for the call is 6756565. The live webcast can be accessed under “Presentations, Events & Webcasts" in the Investors section of the company's website at http://ir.darebioscience.com. Please log in approximately 5-10 minutes prior to the call to register and to download and install any necessary software. The webcast will be archived under “Presentations, Events & Webcasts" in the Investors section of the company's website at http://ir.darebioscience.com and available for replay until August 26, 2024. About XACIATOTM (clindamycin phosphate) vaginal gel 2%XACIATO is indicated for the treatment of bacterial vaginosis in females 12 years and older. A single-dose user-filled disposable applicator delivers 5g of vaginal gel containing 100mg of clindamycin. Selected Safety Information XACIATO is contraindicated in individuals with a history of hypersensitivity to clindamycin or lincomycin. Clostridioides difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including clindamycin, and may range in severity from mild diarrhea to fatal colitis. Careful medical history is necessary since CDAD has been reported to occur over 2 months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibacterial use not directed against C. difficile may need to be discontinued. Polyurethane condoms are not recommended during treatment with XACIATO or for 7 days following treatment. During this time period, polyurethane condoms may not be reliable for preventing pregnancy or for protecting against transmission of HIV and other sexually transmitted diseases. Latex or polyisoprene condoms should be used. XACIATO may result in the overgrowth of Candida spp. in the vagina resulting in vulvovaginal candidiasis, which may require antifungal treatment. The most common adverse reactions reported in >2% of patients and at a higher rate in the XACIATO group than in the placebo group were vulvovaginal candidiasis and vulvovaginal discomfort. XACIATO has not been studied in pregnant women. However, based on the low systemic absorption of XACIATO following the intravaginal route of administration in nonpregnant women, maternal use is not likely to result in significant fetal exposure to the drug. There are no data on the effect of clindamycin on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for clindamycin and any potential adverse effects on the breastfed child from clindamycin or from the underlying maternal condition. Please see the Prescribing Information, Patient Information, and Instructions for Use. About Daré Bioscience Daré Bioscience is a biopharmaceutical company committed to advancing innovative products for women’s health. The company’s mission is to identify, develop and bring to market a diverse portfolio of differentiated therapies that prioritize women's health and well-being, expand treatment options, and improve outcomes, primarily in the areas of contraception, vaginal health, reproductive health, menopause, sexual health and fertility. The first FDA-approved product to emerge from Daré’s portfolio of women’s health product candidates is XACIATO™ (clindamycin phosphate) vaginal gel 2%, a lincosamide antibacterial indicated for the treatment of bacterial vaginosis in female patients 12 years of age and older, which is under a global license agreement with Organon. Organon commenced U.S. marketing of XACIATO in the fourth quarter of 2023. Daré’s portfolio also includes potential first-in-category candidates in clinical development: Ovaprene®, a novel, hormone-free monthly intravaginal contraceptive whose U.S. commercial rights are under a license agreement with Bayer; Sildenafil Cream, 3.6%, a novel cream formulation of sildenafil, the active ingredient in Viagra®, to treat female sexual arousal disorder (FSAD); and DARE-HRT1, a combination bio-identical estradiol and progesterone intravaginal ring for menopausal hormone therapy. To learn more about XACIATO, Daré’s full portfolio of women’s health product candidates, and Daré’s mission to deliver differentiated therapies for women, please visit www.darebioscience.com. Daré Bioscience leadership has been named on the Medicine Maker’s Power List and Endpoints News’ Women in Biopharma 2022. In 2023, Daré's CEO was honored as one of Fierce Pharma’s Most Influential People in Biopharma for Daré’s contributions to innovation and advocacy in the women’s health space. Daré Bioscience placed #1 in the Small Company category of the San Diego Business Journal’s 2023 Best Places to Work Awards. Daré may announce material information about its finances, product and product candidates, clinical trials and other matters using the Investors section of its website (http://ir.darebioscience.com), SEC filings, press releases, public conference calls and webcasts. Daré will use these channels to distribute material information about the company and may also use social media to communicate important information about the company, its finances, product and product candidates, clinical trials and other matters. The information Daré posts on its investor relations website or through social media channels may be deemed to be material information. Daré encourages investors, the media, and others interested in the company to review the information Daré posts in the Investors section of its website and to follow these X (formerly Twitter) accounts: @SabrinaDareCEO and @DareBioscience. Any updates to the list of social media channels the company may use to communicate information will be posted in the Investors section of Daré’s website. Forward-Looking Statements Daré cautions you that all statements, other than statements of historical facts, contained in this press release, are forward-looking statements. Forward-looking statements, in some cases, can be identified by terms such as “believe,” “may,” “will,” “estimate,” “continue,” “anticipate,” “design,” “intend,” “expect,” “could,” “plan,” “potential,” “predict,” “seek,” “should,” “would,” “contemplate,” “project,” “target,” “objective,” or the negative version of these words and similar expressions. In this press release, forward-looking statements include, but are not limited to, statements relating to plans and expectations with respect to Daré’s product candidates, including clinical development plans, trial design, timelines, costs and milestones, targeted indications, and anticipated regulatory approval pathways, the potential for FDA approval of Ovaprene based on a single pivotal clinical study, the expectation that a product candidate could be a first-in-category product, and the potential market size and opportunity for a product candidate, if approved. As used in this press release, the description of a product candidate as “first-in-category” is a forward-looking statement relating to the potential of the candidate to represent a new category of product if it were to receive marketing approval for the indication for which Daré is developing it. Forward-looking statements involve known and unknown risks, uncertainties and other factors that may cause Daré’s actual results, performance or achievements to be materially different from future results, performance or achievements expressed or implied by the forward-looking statements in this press release, including, without limitation, risks and uncertainties related to: Daré’s ability to raise additional capital when and as needed to advance its product candidates, execute its business strategy and continue as a going concern; Daré’s ability to develop, obtain FDA or foreign regulatory approval for, and commercialize its product candidates and to do so on communicated timelines; failure or delay in starting, conducting and completing clinical trials of a product candidate; Daré’s ability to design and conduct successful clinical trials, to enroll a sufficient number of patients, to meet established clinical endpoints, to avoid undesirable side effects and other safety concerns, and to demonstrate sufficient safety and efficacy of its product candidates; Daré’s dependence on third parties to conduct clinical trials and manufacture and supply clinical trial material and commercial product; the risk that positive findings in early clinical and/or nonclinical studies of a product candidate may not be predictive of success in subsequent clinical and/or nonclinical studies of that candidate; the risk that the FDA, other regulatory authorities, members of the scientific or medical communities or investors may not accept or agree with Daré’s interpretation of or conclusions regarding data from clinical studies of its product candidates; the risk that development of a product candidate requires more clinical or nonclinical studies than Daré anticipates; the loss of, or inability to attract, key personnel; the effects of macroeconomic conditions, geopolitical events, public health emergencies, and major disruptions in government operations on Daré’s operations, financial results and condition, and ability to achieve current plans and objectives; the risk that developments by competitors make Daré’s product or product candidates less competitive or obsolete; difficulties establishing and sustaining relationships with development and/or commercial collaborators; failure of Daré’s product or product candidates, if approved, to gain market acceptance or obtain adequate coverage or reimbursement from third-party payers; Daré’s ability to retain its licensed rights to develop and commercialize a product or product candidate; Daré’s ability to satisfy the monetary obligations and other requirements in connection with its exclusive, in-license agreements covering the critical patents and related intellectual property related to its product and product candidates; Daré’s ability to adequately protect or enforce its, or its licensor’s, intellectual property rights; the lack of patent protection for the active ingredients in certain of Daré’s product candidates which could expose its products to competition from other formulations using the same active ingredients; product liability claims; governmental investigations or actions relating to Daré’s product or product candidates or the business activities of Daré, its commercial collaborators or other third parties on which Daré relies; the impact of pharmaceutical industry regulation and health care legislation in the United States and internationally; global trends toward health care cost containment; cybersecurity incidents or similar events that compromise Daré’s technology systems or those of third parties on which it relies and/or significantly disrupt Daré’s business; and disputes or other developments concerning Daré’s intellectual property rights. Daré’s forward-looking statements are based upon its current expectations and involve assumptions that may never materialize or may prove to be incorrect. All forward-looking statements are expressly qualified in their entirety by these cautionary statements. For a detailed description of Daré’s risks and uncertainties, you are encouraged to review its documents filed with the SEC including Daré’s recent filings on Form 8-K, Form 10-K and Form 10-Q. You are cautioned not to place undue reliance on forward-looking statements, which speak only as of the date on which they were made. Daré undertakes no obligation to update such statements to reflect events that occur or circumstances that exist after the date on which they were made, except as required by law. Contacts: Media and Investors on behalf of Daré Bioscience, Inc:Camilla White / Simona KormanikovaDentons Global AdvisorsDareBioscience@dentonsglobaladvisors.com / 1.212.466.6450 Source: Daré Bioscience, Inc. Daré Bioscience, Inc. and Subsidiaries Condensed Consolidated Statements of Operations and Comprehensive Income (Loss) (Unaudited) Three months ended June 30, 2024 2023 Revenue Royalty revenue$22,438 $- Total revenue 22,438 Operating expenses General and administrative 2,448,130 2,920,672 Research and development 4,908,774 6,043,684 License fee expense 25,000 25,000 Total operating expenses 7,381,904 8,989,356 Loss from operations (7,359,466) (8,989,356) Other income (expense) Sale of royalty and milestone rights, net 20,379,376 - Other income (expense), net (109,254) 227,124 Net income (loss)$12,910,656 $(8,762,232) Foreign currency translation adjustments$14,563 $(31,151) Comprehensive income (loss)$12,925,219 $(8,793,383) Income (loss) per common share: Basic$1.53 $(1.22) Diluted$1.52 $(1.22) Weighted average number of shares outstanding: Basic 8,411,242 7,200,260 Diluted 8,476,231 7,200,260 Daré Bioscience, Inc. and Subsidiaries Condensed Consolidated Balance Sheets Data June 30, 2024 December 31, 2023 (unaudited) Cash and cash equivalents$16,414,992 $10,476,056 Working capital (deficit)$6,239,522 $(2,936,897) Total assets$23,606,239 $21,282,215 Total stockholders' equity (deficit)$2,671,506 $(5,047,640)

Newly outlined pathway provides a practical, expedient, repeatable immunobridging approach to potential emergency use authorization of serial, novel monoclonal antibodies (mAbs) to prevent and treat COVID-19 Pathway provides for the establishment of a master, registrational clinical trial protocol that is anticipated to streamline the evaluation of new mAbs in compact clinical programs Utilizing this framework, Invivyd plans to rapidly move towards a registrational clinical trial of VYD2311 that evaluates intravenous (IV) and potentially other routes of administration WALTHAM, Mass., May 31, 2024 (GLOBE NEWSWIRE) -- Invivyd, Inc. (Nasdaq: IVVD), a biopharmaceutical company devoted to delivering protection from serious viral infectious diseases, today announced general alignment with the U.S. Food and Drug Administration (FDA) on an expedient, repeatable immunobridging pathway to future potential emergency use authorizations (EUAs) for serial, novel monoclonal antibodies (mAbs) for the prevention and treatment of symptomatic COVID-19. Coupled with Invivyd’s proprietary mAb technology platform and engineering capabilities, this pathway provides the company with the opportunity to rapidly, efficiently, and durably deliver high value medicines that prevent and treat symptomatic COVID-19 in vulnerable populations. This pathway provides for the establishment of a master, registrational clinical trial protocol that could obviate the need to submit a new protocol for the evaluation of each new mAb, streamlining the process required to evaluate new mAbs in compact clinical programs envisioned to include hundreds of participants (e.g., 300-600) exposed to a new mAb, with the specific number of exposures to be determined in consultation with the FDA. This compact, repeatable immunobridging pathway is similar to the approach Invivyd used to obtain an EUA for PEMGARDA™ for pre-exposure prophylaxis (PrEP) but would leverage a more efficient route to obtaining the safety and pharmacokinetics (PK) data that could support future potential EUA requests. The direct clinical cost of generating the safety and PK data contemplated in this pathway is estimated at $25-40 million. “We are pleased to gain general alignment with the FDA on a repeatable, rapid pathway toward addressing the ongoing, critical unmet need for novel options for the prevention and treatment of symptomatic COVID-19. As the speed of SARS-CoV-2 viral evolution has become the defining feature that limits antibody development and commercialization, our work over the last two years has focused on driving novel development pathways to allow our technology to match or exceed the pace of viral evolution,” commented Marc Elia, Chairman of the Invivyd Board of Directors. “We look forward to discussing this approach with global regulators outside the U.S., as it represents a potentially transformational pathway to bring high value medicines to patients in need in a repeatable fashion, apace with rapid viral evolution.” “Our alignment on a defined pathway to potential future EUAs represents an important step forward for unlocking this unique class of medicines that can potentially both treat and prevent COVID-19,” said Mark Wingertzahn, SVP of Clinical Development and Medical Affairs. “The central challenge for advancing this COVID-19 mAb field has been the need for rapid discovery innovation combined with a rapid, clear, and reliable pathway for establishing the clinical evidence that can bring molecules to patients in need in an efficient manner. We are looking forward to innovating within this defined pathway as we seek to improve the patient and system-friendliness of our molecules by exploring, for example, intramuscular and other presentations that may have access advantages for both PrEP and treatment of COVID-19.” About PEMGARDA PEMGARDA™ (pemivibart) is a half-life extended investigational monoclonal antibody (mAb). PEMGARDA was engineered from adintrevimab, Invivyd’s investigational mAb that has a robust safety data package and provided evidence of clinical efficacy in a global Phase 2/3 clinical trial for the prevention and treatment of COVID-19. PEMGARDA has demonstrated in vitro neutralizing activity in pseudotyped virus-like particle and authentic virus neutralization assays against major SARS-CoV-2 variants, including JN.1. PEMGARDA targets the SARS-CoV-2 spike protein receptor binding domain (RBD), thereby inhibiting virus attachment to the human ACE2 receptor on host cells. PEMGARDA (pemivibart) injection (4500 mg), for intravenous use is an investigational mAb that has not been approved, but has been authorized for emergency use by the U.S. FDA under an EUA for the pre-exposure prophylaxis (prevention) of COVID-19 in adults and adolescents (12 years of age and older weighing at least 40 kg) who have moderate-to-severe immune compromise due to certain medical conditions or receipt of certain immunosuppressive medications or treatments and are unlikely to mount an adequate immune response to COVID-19 vaccination. Recipients should not be currently infected with or have had a known recent exposure to an individual infected with SARS-CoV-2. PEMGARDA is not authorized for use for treatment of COVID-19 or post-exposure prophylaxis of COVID-19. Anaphylaxis has been observed with PEMGARDA and the PEMGARDA Fact Sheet for Healthcare Providers includes a boxed warning for anaphylaxis. The most common adverse events (all grades, incidence ≥2%) observed in participants who have moderate-to-severe immune compromise treated with PEMGARDA included systemic and local infusion-related or hypersensitivity reactions, upper respiratory tract infection, viral infection, influenza-like illness, fatigue, headache, and nausea. For additional information, please see the PEMGARDA full product Fact Sheet for Healthcare Providers, including important safety information and boxed warning. To support the EUA for PEMGARDA, an immunobridging approach was used to determine if PEMGARDA may be effective for pre-exposure prophylaxis of COVID-19. Immunobridging is based on the serum virus neutralizing titer-efficacy relationships identified with other neutralizing human mAbs against SARS-CoV-2. This includes adintrevimab, the parent mAb of pemivibart, and other mAbs that were previously authorized for EUA. There are limitations of the data supporting the benefits of PEMGARDA. Evidence of clinical efficacy for other neutralizing human mAbs against SARS-CoV-2 was based on different populations and SARS-CoV-2 variants that are no longer circulating. Additionally, the variability associated with cell-based EC50 value determinations, along with limitations related to pharmacokinetic data and efficacy estimates for the mAbs in prior clinical trials, impact the ability to precisely estimate protective titer ranges. The emergency use of PEMGARDA is only authorized for the duration of the declaration that circumstances exist justifying the authorization of the emergency use of drugs and biological products during the COVID-19 pandemic under Section 564(b)(1) of the Federal Food, Drug, and Cosmetic Act, 21 U.S.C. § 360bbb-3(b)(1), unless the declaration is terminated or authorization revoked sooner. About Invivyd Invivyd, Inc. (Nasdaq: IVVD) is a biopharmaceutical company devoted to delivering protection from serious viral infectious diseases, beginning with SARS-CoV-2. The company’s proprietary INVYMAB™ platform approach combines state-of-the-art viral surveillance and predictive modeling with advanced antibody engineering. INVYMAB is designed to facilitate the rapid, serial generation of new monoclonal antibodies (mAbs) to keep pace with evolving viral threats. In March 2024, Invivyd received emergency use authorization (EUA) from the U.S. FDA for its first mAb in a planned series of innovative antibody candidates. Visit to learn more. Cautionary Note Regarding Forward Looking Statements This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Words such as “anticipates,” “believes,” “could,” “expects,” “intends,” “potential,” “projects,” and “future” or similar expressions (as well as other words or expressions referencing future events, conditions or circumstances) are intended to identify forward-looking statements. Forward-looking statements include statements concerning, among other things, the company’s general alignment with the U.S. FDA on a repeatable immunobridging pathway to future potential EUAs for serial, novel mAbs for the prevention and treatment of symptomatic COVID-19, including the company’s beliefs regarding the potential benefits, certain anticipated costs, and possible outcomes of utilizing such pathway; the potential of the company’s proprietary mAb technology platform and engineering capabilities; the company’s research and clinical development efforts, and the timing thereof, including the company’s expectations regarding establishment of a master, registrational clinical trial protocol that is anticipated to streamline the evaluation of new mAbs in compact clinical programs; the future of the COVID-19 landscape, the need for novel options for the prevention and treatment of symptomatic COVID-19, and progress towards unlocking a unique class of medicines that can potentially both treat and prevent COVID-19; potential discussions with global regulators; the company’s ability to bring high value medicines to patients in need and keep pace with viral evolution; the company’s EUA for PEMGARDA for PrEP of COVID-19 in certain immunocompromised people; the company’s devotion to delivering protection from serious viral infectious diseases, beginning with SARS-CoV-2; the design of the company’s INVYMAB platform approach to facilitate the rapid, serial generation of new mAbs to keep pace with evolving viral threats; the company’s expectation that PEMGARDA is the first mAb in a planned series of innovative antibody candidates; and other statements that are not historical fact. The company may not actually achieve the plans, intentions or expectations disclosed in the company’s forward-looking statements and you should not place undue reliance on the company’s forward-looking statements. These forward-looking statements involve risks and uncertainties that could cause the company’s actual results to differ materially from the results described in or implied by the forward-looking statements, including, without limitation: the company’s ability to effectively utilize an immunobridging pathway to potential EUA for serial, novel mAbs for the prevention and treatment of symptomatic COVID-19; whether the company is able to successfully submit any future EUA request to the FDA, and the timing, scope and outcome of any such EUA request; uncertainties related to the regulatory authorization or approval process, including the outcome of the company’s discussions with regulatory authorities concerning any clinical trial design; changes in the regulatory environment; the timing and progress of the company’s discovery, preclinical and clinical development activities; the company’s ability to streamline the evaluation of new mAbs in compact clinical programs through establishment of a master, registrational clinical trial protocol; unexpected safety or efficacy data observed during preclinical studies or clinical trials; the predictability of clinical success of the company’s product candidates based on neutralizing activity in preclinical studies; the risk that results of preclinical studies or clinical trials may not be predictive of future results, and interim data are subject to further analysis; the company’s reliance on third parties with respect to virus assay creation and product candidate testing and with respect to its clinical trials; how long the EUA granted by the FDA in March 2024 for PEMGARDA for PrEP of COVID-19 in certain immunocompromised people will remain in effect and whether such EUA is revoked or revised by the FDA; changes in expected or existing competition; the ability to maintain a continued acceptable safety, tolerability and efficacy pro PEMGARDA or any other product candidate following regulatory authorization or approval; whether PEMGARDA or any other product candidate is able to demonstrate and sustain neutralizing activity against major SARS-CoV-2 variants, particularly in the face of viral evolution; variability of results in models used to predict activity against SARS-CoV-2 variants; the complexities of manufacturing mAb therapies; the company’s dependence on third parties to manufacture, label, package, store and distribute clinical and commercial supplies of its product candidates; the company’s ability to leverage its INVYMAB platform approach to facilitate the rapid, serial generation of new mAbs to keep pace with evolving viral threats; any litigation and other proceedings or government investigations relating to the company; the company’s ability to continue as a going concern; and whether the company has adequate funding to meet future operating expenses and capital expenditure requirements. Other factors that may cause the company’s actual results to differ materially from those expressed or implied in the forward-looking statements in this press release are described under the heading “Risk Factors” in the company’s Annual Report on Form 10-K for the year ended December 31, 2023 filed with the Securities and Exchange Commission (SEC), and in the company’s other filings with the SEC, and in its future reports to be filed with the SEC and available at Forward-looking statements contained in this press release are made as of this date, and Invivyd undertakes no duty to update such information whether as a result of new information, future events or otherwise, except as required under applicable law. This press release contains hyperlinks to information that is not deemed to be incorporated by reference in this press release. Contacts: Media Relations (781) 208-1747 media@invivyd.com Investor Relations (781) 208-1747 investors@invivyd.com