Aimmune Therapeutics, Inc.

肉毒素作为一种神经毒素，被广泛应用于除皱、塑形等医美领域，以及神经、康复、泌尿等临床治疗领域，且适应症仍在不断探索扩大中。根据ISAPS发布的Global Survey 2023数据，2023年全球共进行肉毒素注射约888万例，占非手术医美的46.3%，位居医美非外科手术处理类榜首。 目前，全球上市的肉毒素产品主要为天然A型肉毒素，市场主要被BOTOX®、Dysport®、XEOMIN®、Letybo®、NABOTA®、衡力®等几大产品占据。随着重组蛋白技术的发展，经过肉毒素领域科学家和研发专家多年探索，重组A型肉毒素开发获得成功并已推进到临床。重组A型肉毒素凭借其高纯度、低生物风险、低免疫风险、高生产效率、低成本等优势，有望带领肉毒素行业进入新时代。 01 肉毒素市场较为集中，产品创新发展加速 目前全球肉毒素市场集中，呈现寡头状况 早在上个世纪，肉毒素已在斜视、眼睑痉挛、除皱等应用领域进行治疗探索。1989年，美国FDA批准了肉毒素用于治疗眼睑痉挛和斜视；2002年，美国FDA批准了全球首个A型肉毒素产品——BOTOX®，用于改善中至重度眉间纹。目前，全球范围内已有超10款天然肉毒素产品上市。 天然肉毒素由肉毒杆菌发酵产生，其品质高度依赖于肉毒杆菌菌株的特性，同时由于活的肉毒杆菌具有高生物风险，相关生产在大部分国家受到限制甚至禁止，且生产设施投资成本高昂，再加之天然肉毒素的生产工艺复杂、产量有限等局限性，行业发展较为缓慢。并且肉毒素产品不同于传统药物，可应用于临床治疗及医美领域，而在医美市场的销售表现则较依赖于消费者对产品及品牌的认知。因此，肉毒素赛道的生产准入和商业竞争的门槛高，导致市场较集中。目前，在全球范围内，肉毒素主要产地集中在美国、欧洲、中国、韩国等少数几个国家，市场份额被BOTOX®为主的5-6个品牌所占据。 天然肉毒素产品在医美市场销售可观。ISAPS调查数据显示，近5年来肉毒素治疗量稳居医美非外科手术处理类TOP 1，从2019年的627.1万例增长到2023年的887.8万例，五年内增长约40%，市场规模不断扩大。 根据公司年报信息，2023年，Allergen的BOTOX®产品在医美领域和临床治疗分别获得26.8亿美元、30.0亿美元的销售业绩；Ipsen的Dysport®销售额达到约7.1亿美元；Hugel的Letybo®销售额为1.2亿美元。BOTOX®凭借其先发上市的优势、产品品质的优良及品牌的高认知度，2023年以56.8亿美元的销售额远超其它肉毒素品牌，在全球独占鳌头。此外，韩国在肉毒素领域拥有的生产企业和品牌最多，主要都应用于医美领域，但多个韩国品牌的肉毒素菌株来源未得到相关机构认证，专利纠纷多次发生，甚至产品许可被吊销。总体韩国的肉毒素生产企业实力、能力、质量等良莠不齐，在全球肉毒素市场份额中比例仍然较低。 资料来源：公司年报，沙利文分析 进口产品占据中国肉毒素市场主要份额，本土研发创新引领产业格局变迁 在中国市场，根据国家药品监督管理局（NMPA）信息，截至2024年9月13日，已有6款A型天然肉毒素产品上市，分别是Allergen公司研发的BOTOX®（保妥适®）、中国兰州生物制品研究所的衡力®、Ipsen公司研发的Dysport®（吉适®）、Hugel公司研发的Letybo®（乐提葆®），以及2024年2月上市的来自德国Merz的XEOMIN®（西马）和9月新获批的复星医药引进的Revance的达希斐®（Daxxify®）。其中，BOTOX®凭借其在医美领域的先发上市、品牌影响力、营销能力等优势，常年占据中国A型肉毒素市场份额TOP 1。 资料来源：NMPA，沙利文分析 同时，多家企业的多款A型肉毒素产品处于临床III期及上市申请阶段，包括大熊制药、爱美客（引进韩国的Huons）、Inibio、誉颜制药；艾尔建和兰州生物的已上市肉毒素产品处于拓展适应症的临床III期阶段。其中，誉颜制药的YY001管线为全球首个创新性采用重组蛋白技术并进入临床的重组A型肉毒素。重组A型肉毒素具有生物风险低、高纯度、免疫风险低、生产效率高、产能可控等优势，可破解天然A型肉毒素存在的限制成为新一代肉毒产品，有望改变现有A型肉毒素赛道格局。 资料来源：NMPA，沙利文分析 肉毒素在创新技术迭代上仍有很大的拓展空间。传统的天然A型肉毒素由于分子结构确定，主要应用场景已基本开发。而重组A型肉毒素在重组蛋白技术上，可进一步与分子异构、融合蛋白等技术联合应用，对A型肉毒素的分子结构及作用靶点进行分析与调控，从而针对实际需求开发出起效更快、效期更长、注射更精准、使用更方便、弥散度可调控等的新型肉毒素。 02 肉毒素应用场景广，在医美和治疗领域均具有重要价值 A型肉毒素作用机制 A型肉毒素属于Zn2+依赖的蛋白水解酶家族，由一条100kD的重链与一条50kD的轻链组成。A型肉毒素的重链可特异性地与神经细胞包膜结合进入细胞，轻链可特异性地水解突触前膜上的SNAP-25蛋白，从而影响参与细胞内吞、胞吐功能的SNARE蛋白活性，阻碍乙酰胆碱等神经递质小泡与突触前膜融合，不能释放神经递质，引起肌肉松弛、抑制腺体分泌等化学性去神经作用。 A型肉毒素根据使用场景的差异，包括在医美机构使用，目的为改善面颈部皮肤状态、局部塑形或治疗脱发等的医美领域，以及在医院神经、康复等科室使用，通过调节神经、肌肉、腺体等功能而发挥治疗疾病作用的临床治疗领域。 A型肉毒素在医美领域深受消费者青睐 在医美领域，A型肉毒素是一种深受消费者欢迎的微创医美手段，可应用于面颈部除皱、轮廓塑形、面部提升、改善腺体分泌、治疗脱发、预防性治疗等场景。 面颈部除皱：A型肉毒素通过阻断神经肌肉间的冲动传递，放松过度收缩的小肌肉，可以改善面部动力性皱纹。A型肉毒素常用于眉间纹、额纹、鱼尾纹、皱鼻纹、口周纹、木偶纹、颈横纹等面颈部皱纹的改善治疗。 轮廓塑形：A型肉毒素阻止神经肌肉接头处乙酰胆碱的释放，导致神经无法支配肌肉运动，使肌肉因失去功能而萎缩减小，达到雕塑轮廓线条的目的。A型肉毒素可用于咬肌注射瘦脸，腓肠肌注射瘦腿，斜方肌注射改善肩颈部线条等。 面部提升：对面部降肌表浅肌纤维注射A型肉毒素，可削弱其肌肉拉力，使升肌作用占据优势，从而达到提升等目的。A型肉毒素提升外眼角和眉尾的下垂，颈阔肌注射可降低其对中下面部皮肤的牵拉，提升下面部，使下颌缘轮廓更清晰。 改善腺体分泌：皮脂腺表达α7烟碱型乙酰胆碱受体（α7nAchR），故A型肉毒素可通过阻断胆碱能信号传导和抑制神经调节作用来有效减少皮脂产生、缩小毛孔。肉毒素微滴注射主要部位为皮脂溢出区，相关研究多见于前额。 治疗脱发：雄激素性脱发与二氢睾酮（DHT）及微循环不足相关。肉毒素可松弛头皮肌肉，改善局部血液灌注及含氧量，进而清除局部积累的DHT并减少DHT产生，从而减轻雄激素对易感毛囊的作用，减少毛发脱落。 预防性治疗：SAMCEP学会共识指出，随着人们认识到肉毒素注射对面部皱纹的预防和治疗以及面部稳定（主要是眉尾和嘴角）均有显著作用，越来越多的人要求在更早的年龄注射肉毒素。Rivkin等人研究发现，长期、连续性使用肉毒素可使皮肤和表皮重塑，预防皱纹形成，并具有改善皮肤质量潜在收益。 医疗领域潜在适应症众多，肉毒素临床价值持续展现 肉毒素具有强效的神经阻滞作用，对于肌肉过度收缩相关的异常运动或姿势、疼痛、自主神经功能亢进等疾病，肉毒素可能是有效的对症疗法。 治疗运动障碍：肉毒素具有降低痉挛肌肉肌张力的作用，改善痉挛发作频率和强度，可用于治疗眼睑痉挛、偏侧面肌痉挛、颈部肌张力障碍、喉肌肌张力障碍、肢体肌张力障碍、震颤、抽动障碍、口下颌肌张力障碍等疾病。 改善痉挛状态：肉毒素可用于上运动神经元损害所致的上、下肢痉挛状态。如对脑卒中所致上肢痉挛状态，肉毒素可降低受累腕指屈肌的肌张力或痉挛状态程度，减轻残疾程度；对成人上运动神经元损伤继发的下肢痉挛，肉毒素可降低肌张力，减少多发性硬化所致的下肢痛性痉挛，改善被动功能。 调节自主神经功能障碍：双侧腮腺或下颌下腺注射肉毒素，可改善患者流涎频率，减少唾液分泌量及严重性。在腋部、掌跖部注射肉毒素可抑制由胆碱能神经支配的汗腺分析，从而治疗多汗症。此外，肉毒素可改善神经源性膀胱过度活动症，改善膀胱容量、顺应性和逼尿肌稳定性。 镇痛：肉毒素可用于慢性偏头痛（有或无药物过量使用性头痛）的预防性治疗，可减少头疼发作天数；在三叉神经痛、带状疱疹后神经痛、糖尿病性周围神经痛等神经病理性疼痛也有应用，注射后患者疼痛改善或完全缓解。 预防和治疗瘢痕：肉毒素已被用于预防和治疗病理性瘢痕，但具体机制尚不明确，可能与肉毒素降低成纤维细胞增殖、减少胶原纤维沉积、抑制炎症因子释放和减少血管新生等机制有关。预防性治疗建议在术后14天内进行肉毒素注射；肉毒素联合糖皮质激素皮损内注射治疗增生性瘢痕或瘢痕疙瘩可能由于单糖皮质激素治疗。 治疗慢性鼻炎：A型肉毒素可改善慢性鼻炎症状，尤其是对流涕症状安全有效、疗效持久。作用机制可能包括：抑制鼻部或蝶腭神经节突触前胆碱能神经末梢释放乙酰胆碱，诱导鼻黏膜腺细胞凋亡，抑制鼻黏膜中炎症介质释放，减少鼻黏膜中的嗜酸粒细胞浸润和毛细血管扩张。 03 天然肉毒素监管严格，肉毒素行业准入壁垒高 监管审批门槛 天然肉毒素由肉毒杆菌发酵产生，若在生产过程中发生肉毒杆菌的泄露及传播，将造成严重的生化风险和公共卫生事件。因此，各国政府机构对天然肉毒素的研发和生产严格监管，开发和制造天然肉毒素除满足GMP要求外，还需在BSL-3或更高级别的环境中进行，并受到CDC监管。因监管严格，导致天然肉毒素产品生产门槛极高，从研发到上市的周期较长，因此产品集中在少数品牌。同时，过去由于肉毒素企业的销售和盈利可观，加之用肉毒杆菌研发过程存在安全风险，业内创新研发的动力和能力不足，监管也一直停留在传统的认知，偏于保守。 但是随着肉毒素产品技术研发热度提升，尤其是重组蛋白技术在肉毒素研发上的突破，研究领域、工业领域和监管机构对肉毒素的认知越来越深刻，对风险评估越来越客观，把控也越来越专业，加之监管机构自身的规范管理，提升效率等举措，目前肉毒素的审批时间已与其它药品类似，如分析乐提葆®（100单位/瓶）在中国药监局的上市审批时间表，从申请提报到注册获批总体历时约16个月。 生产工序复杂 肉毒杆菌是一种严格厌氧菌，对培养基要求严格，生产过程需使用BSL-3或以上的特殊建筑和设备，并对纳米加工水平要求高；鉴定纯化毒素，验证安全性及有效性较为困难；肉毒素产品贮存和运输过程普遍也需保持全程冷链。 批次间稳定性 肉毒杆菌生产肉毒素时会产生其它蛋白物质，天然肉毒素效果受到菌株、提纯工艺等因素影响，产品批次间可能出现差异。在定量检测阶段，由于制剂中蛋白含量在纳克级别，普通仪器难以精确检测，通常使用动物实验进行定量。但实验动物存在个体间偏差较大的问题，如何保证动物试验检测系统的稳定性和准确性，是肉毒素产品研发中一个关键环节，存在较高的技术壁垒。研发能力和经验强的团队，从菌株到工艺最终到动物实验的定量检测可形成系统性优势，使得批间产品质量更稳定一致，并体现为患者治疗的反应率更高，反之就可能出现产品质量起伏不定，患者治疗反应率低。 超敏反应 肉毒素本身为异体蛋白，注射后可能诱发机体发生超敏反应。目前上市的天然肉毒素产品，除XEOMIN®外，其它A型肉毒素产品均含有一组由若干血细胞凝集素（HA）和非毒性非血细胞凝集素（NTNH）组成的结合蛋白（NAPs），加之赋形剂的存在，注射后可能引起皮肤发生迟发型超敏反应。 免疫耐受 A型肉毒素通常注射后3~14天起效，有效期通常为3~6个月，需多次重复注射。随着肉毒素注射次数增多，机体产生的中和抗体的滴度逐步提高，可能导致注射后继发性无应答，出现多次使用后疗效降低的情况。 04 重组肉毒素具有更高的纯度、安全性和更显著的反应率 A型肉毒素主要技术路线分析 根据生产技术的差异，A型肉毒素可以分为天然A型肉毒素和重组A型肉毒素两类。 天然A型肉毒素：使用肉毒杆菌发酵进行生产，提纯后获得天然A型肉毒素。 重组A型肉毒素：通过将A型肉毒素的基因序列表达在大肠杆菌等工程菌中，工程菌发酵产生肉毒素前体蛋白，激活后获得重组A型肉毒素。 资料来源：公开信息，沙利文分析 重组肉毒素潜力看好，海内外多家企业相继布局 海外布局重组肉毒素的企业代表为Ipsen。官网数据显示，Ipsen目前仅IPN10200一条重组肉毒素管线。IPN10200为E型重组肉毒素，以患者未满足的长效治疗需求为动力，用于治疗神经系统相关的肌肉僵硬、痉挛和疼痛；通过工程化设计，提高肉毒素对受体亲和力，增强内化作用；降低肉毒素扩散到周围组织的风险，提高使用者的耐受性。IPN10200已于2021年进入临床研究，截至2024年3月，该管线有两个适应症处于临床II期试验，分别为中度至重度上面部皱纹、成人上肢痉挛。 国内布局重组肉毒素技术的企业较少。根据国家药品监督管理局药品审评中心（CDE）数据，截至2024年9月13日，仅有3款重组A型肉毒素管线进入临床阶段，分别为誉颜制药的YY001管线、君合盟生物的JHM03管线和迪新宸科的DN001管线。三家企业的研发进度不一，且产品管线的技术工艺上也有所区别： 誉颜制药：CDE数据显示，誉颜制药的YY001于2022年3月获批开展临床I/II期试验，适应症为中至重度眉间纹，是全球范围内首个进入临床的重组A型肉毒素产品。I/II期临床试验已于2023年5月完成。同时，CDE数据显示该管线已于2023年12月启动III期临床。根据公司披露信息，YY001已于2024年9月12日召开了临床总结会，宣布完成III期临床，并启动BLA的申报。该管线采用大肠杆菌作为工程菌，模拟天然肉毒素产生过程，生产出的重组A型肉毒素YY001与天然A型肉毒素从分子结构、理化表征、生物活性等高度一致；且纯度高达99%以上，远超目前市场上占据绝大部分销售的天然A型肉毒素；临床试验显示使用效果更佳、安全性更优。此外，YY001还于2024年7月获CDE批准开展成人上肢肌肉痉挛临床试验，并于2024年9月14日宣布完成了第一例受试者入组，这是全球首次将重组A型肉毒素应用于医疗领域的重要里程碑。 君合盟：继誉颜制药之后，君合盟的重组肉毒素管线JHM03于2023年12月获CDE批准开展I/II期临床，适应症是中、重度眉间纹。根据公司披露信息，目前JHM03的II期临床试验即将结束。君合盟与誉颜制药均采用大肠杆菌发酵生产肉毒素，但据专业人士分析，其工艺技术和誉颜制药有所区别。该工艺与天然肉毒素产生过程有所不同，而是采取轻重链分别表达然后二硫键结合的工艺，可能导致分子结构变化，结构发生变化的分子也许不能完全等同于天然肉毒素，其在有效性、安全性和免疫原性等方面还有待大量长期的临床运用来验证。 迪新宸科：迪新宸科的重组A型肉毒素管线DN001于2024年8月获CDE批准开展I/II期临床，适应症也为中、重度眉间纹。对于该管线，公开信息尚无更多的披露。 根据公开信息，国内布局重组肉毒素赛道的企业还有若弋生物、耀海诺信等，其管线均处于临床前阶段： 若弋生物：通过自主建立了昆虫细胞-杆状病毒新型生产工艺平台，致力于开发自抑制型、减毒A型肉毒素，目前已完成上游、下游、制剂等工艺环节的开发，并进入商业批规模生产，预计2024年Q4申报IND。 耀海诺信：官网显示公司于2024年1月自研立项重组肉毒素开发，包括A型和E型两类重组肉毒素，且重组A型肉毒素已完成菌株筛选和成药性研究工作，其纯度超97%，活性在2*107 U/mg以上。 05 誉颜制药重组肉毒素临床表现优异，研发进度全球领先 誉颜制药在研管线YY001技术特点 誉颜制药运用基因重组和蛋白表达技术开发，使用工程化大肠杆菌进行A型重组肉毒素开发。YY001的产生过程与天然肉毒素产生过程一致，先使用工程化大肠杆菌发酵产生单链蛋白，再经蛋白酶切割后变为一条重链蛋白和一条轻链蛋白，重链和轻链蛋白通过一个二硫键连接构成150kDa单一活性双链蛋白，即重组肉毒素。YY001的分子结构与天然A型肉毒素相同。鉴于天然A型肉毒素已有超过三十年的使用经验，保证了具有同样分子结构的YY001的生物功能和药理药效作用。 誉颜制药创新设计了三重过滤技术，YY001产品纯度高、比活性高、反应率显著，150kDa神经毒素比例可高达99%以上，显著高于大多数天然肉毒素（通常占制剂的13%-15%）。YY001的高纯度可降低局部给药剂量，I/II/III期临床试验显示没有特异性抗体产生，安全性更好，免疫耐受性更低。 此外，公司建设了符合GMP规范的生产设施，设计YY001冻干制剂年基础产能为200万瓶，已于2023年第一季度开始投入使用；未来YY001上市后，誉颜制药YY001产能可根据市场需求灵活调整，产能储备可满足YY001商业化后5年内的20%以上市场总需求。 YY001应用场景广泛，临床数据优异 YY001具有多个潜在适应症类型，包括眉间纹、上肢肌肉痉挛、眼睑痉挛、咬肌肥大、以及潜在的疤痕、疼痛等。在2024年9月12日针对已完成的中、重度眉间纹适应症的III期临床总结会上，誉颜制药公布的临床数据显示，YY001在大规模人群的III期临床试验中，表现出与已完成的I/II期临床结果高度的一致性，其有效性、安全性、免疫原性等都全部达到既定的临床终点，较对照药的数据表现优异。此外，誉颜制药凭借其重组蛋白的技术平台，依靠肉毒素领域内全球性的专家人才和多年积累的丰富研发经验，可展开对A型肉毒素进一步优化升级，同时开发肉毒素的更多亚型；并通过分子异构、蛋白融合等技术，有望开发出更具临床价值、适应症更广的迭代创新产品。 获批在望，YY001先发优势显著 据悉，誉颜制药在成功完成YY001的III临床试验后，即将向NMPA提交上市申报，在全球范围内重组A型肉毒素的开发进展最快，先发优势明显。参比近几年中国获批上市的肉毒素产品注册申报时间，如吉适®注册申报时间约22个月，乐提葆®注册申报时间约16个月，达希斐®注册申报时间约17个月。考虑誉颜制药作为国内本土生产企业，相比国外生产企业在资料准备和沟通上的便捷性，预计YY001的上市申报有望更高效率实现，成为全球首款上市的重组A型肉毒素产品，从而在商业化销售上延续先发优势，将更有利于YY001上市后的市场表现。 携手华东医药，加快推进YY001市场渠道布局 2023年11月，华东医药与誉颜制药签署了产品独家经销协议，获得YY001在中国大陆、香港、澳门地区医美适应症领域的独家经销协议。 华东医药业务覆盖医药全产业链，其中医美业务板块聚焦全球医美高端市场，包括Sinclair、欣可丽美学等多家子公司，在全球多国设有研发中心及生产基地，建立了近300人的专业化市场推广团队，已搭建起全球化医美营销网络，产品销售已覆盖全球80多个国家和地区。其中，欣可丽美学为华东医药在国内的市场运营平台，在其推广下，再生型填充剂Ellansé®伊妍仕®自上市不到3年时间，已实现合作医院数量超600家，培训认证医生数超1,100人。YY001借助华东医药的医美市场营销平台，有望在上市后快速渗透全国医美机构，改写国内肉毒素竞争格局，并凭借其出色疗效成为全球化肉毒素品牌。 在重组肉毒素赛道，中国企业研发进度已走在世界前沿。未来，预计随着YY001作为全球首款重组肉毒素获批上市，中国将成为重组肉毒素制造和生产大国，引领全球肉毒素行业步入新时代。 关于沙利文生命科学事业部 沙利文生命科学事业部在生命科学领域拥有专业的分析能力和丰富的项目经验。依托沙利文全球智库资源和大中华区跨行业业务发展平台，沙利文生命科学事业部在生命科学产业投融资服务有着独特核心优势。沙利文生命科学事业部在中国拥有广泛的企业客户，并在过去20年里建立了庞大的客户网络，积累大量生命科学各细分领域的项目经验。 项目类型包括知识中心服务（深度内容宣传、品牌活动宣传）、国际化战略服务（出海策略、行业评估、全球品牌宣传、出海管线价值评估）、Pre-IPO服务（DCF估值、商业计划书服务）、IPO上市服务（行业顾问、临床稽查、募投撰写）、市场调研及战略咨询等，并与国内外知名的资讯平台及投融资机构合作，为企业提供生命科学专业细分领域行业一站式解决方案，受到投资者的广泛关注。 联系方式： 李谦（咨询总监）：18917935734（同微信） 徐潮（项目经理）：+86.21.3209.6800 ext. 8863 联系邮箱：hcknowledgecenter@frostchina.com 更多精彩！

The Food and Drug Administration is defending the record of Jeff Shuren, former director of the agencys medical device center, after The New York Times reported on how his role intersected with his wifes work as legal counsel for medtech companies.Shurens wife, Allison Shuren, is co-chair of the life sciences and healthcare regulatory practice at law firm Arnold & Porter, and represented medical device companies. Shuren led the FDAs Centers for Devices and Radiological health for 15 years and, in July, announced he would retire. Shuren will stay with the agency as it finds and transitions to a new leader.The CDRH authorizes new medical devices to enter the U.S. market and monitors product safety through postmarket surveillance and recalls.The FDA defended Shuren in an email to MedTech Dive amid the ethics controversy raised by the Times and a patient safety advocate.FDA has no indication that any FDA regulatory decisions were impacted by Dr. Shurens wifes employment nor that Dr. Shuren made any decisions in the interest of parties other than the public served by the FDA, agency spokesperson Shannon Hatch said in the statement.The Times article examined potential overlap between the work of Shuren and his wife in cases involving the discredited blood testing company Theranos, Allergens breast implant recall, which came after the devices were connected to a specific form of cancer, and a proposal to strengthen regulation of LASIK eye surgery.The FDA, which reviewed the information raised by the Times, found no evidence Shuren violated the criminal conflict of interest statute, according to Hatch.Still, it appears there were certain instances from about 10 years ago for which Dr. Shuren should have either recused himself or sought ethics authorization to participate to avoid any potential appearance of bias, said Hatch.As a result, Shuren has been advised to exercise greater caution in matters concerning recusal obligations and is being provided additional administrative support to ensure future compliance, Hatch wrote.A spokesperson for Arnold & Porter said the law firm has long had strict protocols in place to assure compliance with the FDAs requirements governing financial conflicts of interest and impartiality.We are confident that Allison Shuren has acted in compliance with all such requirements dictated by her husbands affiliation with the FDA, the spokesperson wrote in an email.Advamed, the medical device industrys largest lobbying group, did not return a request for comment from MedTech Dive.Shuren retiresThe Times article comes two months after Shuren announced his retirement as CDRH director in an email to staff. Michelle Tarver, the FDAs deputy director for transformation, was named acting director of the center.In a separate July email, FDA Commissioner Robert Califf told agency staff that Shuren would transfer to the commissioners office and assist in the leadership transition at CDRH while the FDA searches for a permanent successor. Shuren is expected to leave the agency later this year.The FDA is proud of Shurens commitment and integrity in serving the public over the course of his government career, said Hatch. Senior leadership is required to adhere to ethics requirements that include filing annual public financial disclosure reports. Guidance on recusal obligations and reminders of those obligations are provided during financial disclosure reviews, the spokesperson added.The agency stands by his science-based public health decisions and those made by others within the Center for Devices and Radiological Health, including those that were discussed in the recent New York Times article, Hatch said.Shurens ethics documents also were vetted by the FDAs Office of Ethics and Integrity and ethics attorneys in the Department of Health and Human Services Office of General Counsel over multiple administrations, added Hatch.Patient advocate groups and lawmakers have called for improvements to the FDAs medical device safety system to better protect people from faulty products. In recent years, the FDA has faced criticism amid several high-profile product safety events that have involved patient harm tied to breast implants, Bayers Essure birth control device, Medtronics heart pump, and Philips years-long recall of more than 15 million respiratory machines.The Government Accountability Office is reviewing the agencys device recall process after a request from Dick Durbin, D-Ill., and Richard Blumenthal, D-Conn. The Times article said reports of device-related injuries rose to 900,000 in 2023 from about 190,000 in 2012, citing an analysis of FDA data by the company Device Events.Robert Steinbrook, director of consumer rights group Public Citizens health research arm, called on the HHS Office of Inspector General to launch an investigation into allegations in the Times article that Shuren did not fully recuse himself from working on matters involving clients of his wifes firm.There are long-standing concerns that the FDAs regulation of medical devices has been too friendly to industry under Shurens leadership and has not prioritized patient safety and the effectiveness of novel medical devices, Steinbrook said in a statement, calling the report very troubling.An HHS-OIG spokesperson declined to comment on the matter when contacted by MedTech Dive. '

SER-155 Phase 1b placebo-controlled Cohort 2 clinical readout on track for September VOWST asset sale to provide $175M cash infusion, less approximately $20M in settlement of net obligations between the Parties, at close Transaction proceeds to fully retire debt and support advancement of wholly-owned cultivated live biotherapeutic pipeline to improve patient outcomes in medically vulnerable populations Based on existing cash, deal economics and operating plans, Seres expects to fund operations into Q4 2025 Conference call at 8:30 a.m. ET today CAMBRIDGE, Mass., Aug. 13, 2024 (GLOBE NEWSWIRE) -- Seres Therapeutics, Inc. (Nasdaq: MCRB), (“Seres” or “the Company”), a leading live biotherapeutics company, today reported second quarter 2024 financial results and provided business updates. “Our recently announced VOWST asset sale will, pending approval by stockholders and upon closing, significantly strengthen Seres’ balance sheet and advance our goal to improve patient outcomes in medically vulnerable patient populations through the use of our wholly-owned cultivated live biotherapeutics,” said Eric Shaff, President and Chief Executive Officer of Seres. “We intend to leverage our clinical, CMC, and regulatory successes by applying our therapeutic approach to new patient groups that face heightened risks of serious bacterial infections, which frequently lead to extensive and costly treatments and, unfortunately too often, death.” Mr. Shaff continued, “Our lead SER-155 program remains on track for a clinical data readout from the placebo-controlled study Cohort 2 in patients receiving allogeneic hematopoietic stem cell transplant (allo-HSCT) in September. This dataset has the potential to highlight the extensive clinical value and commercial opportunities of both our SER-155 program and our biotherapeutic approach more generally. Multiple patient groups are known to experience a disrupted gastrointestinal (GI) microbiome and a high risk of life-threatening enteric-derived bacterial infections as well as blood stream infections arising from translocated bacteria. Our development efforts are targeting multiple medically vulnerable patient groups, including potentially those with chronic liver disease, cancer neutropenia and solid organ transplants. In the longer term, we plan to develop our biotherapeutics to treat GI-related immune diseases such as inflammatory bowel disease.” Corporate Highlights In April, the Company announced the completed enrollment of Cohort 2 of the SER-155 Phase 1b study, which included 45 participants. Cohort 2 study data are anticipated in September and will include safety, drug pharmacology and efficacy-related measures, including the rates of bacterial infections and febrile neutropenia, through day 100 following allo-HSCT—a period in which patients frequently experience serious infections. SER-155 is designed to prevent GI-derived infections and resulting bloodstream infections, enhance epithelial barrier integrity and induce immune tolerance responses to reduce the incidence of graft-versus-host-disease (GvHD). The Company previously announced SER-155 Phase 1b Cohort 1 clinical data that showed SER-155 was well-tolerated, resulted in successful drug bacteria engraftment and a substantial reduction in pathogen domination in the GI microbiome compared to a reference cohort of patients. SER-155 received FDA Fast Track Designation. The Company’s cultivated biotherapeutics are manufactured from single strain bacteria isolates through fermentation methods that allow for efficient, scalable processes.On August 6, the Company announced that it signed an agreement with Société des Produits Nestlé S.A (“SPN”), a wholly-owned subsidiary of Nestlé S.A., for the sale of its VOWST business to SPN (the “Purchase Agreement”). Under the terms of the Purchase Agreement, upon the deal close, Seres will receive capital infusions, including an upfront payment, a prepaid milestone payment and an equity investment. In addition, Seres is due to receive installment payments in 2025, contingent upon the Company’s material compliance with transition obligations, as well as potential future milestone payments based on VOWST net sales targets. The completion of the transaction, which is subject to Seres’ stockholder approval and other customary conditions, is expected to occur within 90 days following the signing of the Purchase Agreement. Seres continues to support VOWST commercial supply, and production capacity remains strong. Following the expected close of the asset sale transaction, Seres will provide transition services through the first quarter of 2025 and manufacturing support through the end of 2025, subject to SPN’s limited ability to extend, and will continue to share 50/50 in the profits or losses of the business through the fourth quarter of 2025.Seres intends to evaluate SER-155 and other cultivated live biotherapeutic candidates in additional medically vulnerable patient populations, including chronic liver disease, cancer neutropenia, and solid organ transplants. Future development plans will be informed by pending SER-155 Cohort 2 results, and the Company plans to share more information regarding its SER-155 development plans later in 2024.Seres is also developing another proprietary live biotherapeutic composition, SER-147, designed to prevent GI-derived infections and resulting bloodstream infections and to improve clinical outcomes in patients with metabolic disease, including those with chronic liver disease and at high risk of bacterial infections. We anticipate IND readiness for SER-147 in the second half of 2025. VOWST Commercial Performance Seres collaborator SPN and certain of its affiliates (collectively, “Nestlé Health Science”) have continued to lead VOWST commercialization efforts. Since the VOWST product launch in June 2023, the breadth of utilization has steadily increased among healthcare providers. Second quarter 2024 net sales were approximately $14.4 million, reflecting an increase of approximately 43% compared to first quarter net sales of $10.1 million. Seres shares equally with Nestlé Health Science in the VOWST commercial profits or losses. Seres’ share of the VOWST net loss for the second quarter of 2024 was $6.6 million, which was included in the Company’s operating results within Collaboration (profit) loss sharing-related party. Financial Results Seres reported a net loss of $32.9 million for the second quarter of 2024, as compared to net income of $46.6 million for the same period in 2023. The difference is primarily the result of a $125 million milestone payment received from Nestlé in the second quarter of 2023, upon the FDA approval of VOWST, offset by operating expense reductions.Research and development (R&D) expenses for the second quarter of 2024 were $17.9 million, compared with $46.8 million for the same period in 2023. The decrease in R&D expenses was primarily driven by VOWST commercial manufacturing costs no longer being recognized in the Seres profit and loss (P&L) following the product approval in April 2023, but instead being capitalized and recognized on the Company’s balance sheet, as well as lower personnel and other costs as a result of the restructuring plan announced in November 2023.General and administrative (G&A) expenses for the second quarter of 2024 were $16.1 million, compared with $28.1 million for the same period in 2023. The decrease in G&A expenses was primarily driven by a reduction in professional fees and lower personnel costs as a result of the restructuring plan. Cash RunwaySeres plans to use the capital obtained from the VOWST asset sale transaction to fully retire its senior secured debt facility with Oaktree Capital Management. Additionally, the Bacthera manufacturing contract will be terminated upon close of the transaction, and Seres will have no further obligations to Bacthera. Various VOWST-related capabilities, including product manufacturing, will transition to Nestlé Health Science as part of the asset sale. As a result, Seres expects that more than a third of its employees will transfer to Nestlé Health Science following the close of the transaction. Moving forward, Seres will be a streamlined and more focused organization, and the Company’s cash burn rate is expected to be reduced. As of June 30, 2024, Seres had $71.2 million in cash and cash equivalents. Based on existing cash and operating plans, expected cash to be received upon the close of the VOWST sale and related installment payments due in 2025, and ongoing transaction-related obligations, the Company expects to fund operations into the fourth quarter of 2025. Absent the VOWST sale, the Company expects to fund operations into the fourth quarter of 2024. Conference Call InformationSeres’ management will host a conference call today, August 13, 2024, at 8:30 a.m. ET. The conference call may be accessed by calling 1-800-715-9871 (international callers dial 1-646-307-1963) and referencing the conference ID number 4877586. To join the live webcast, please visit the “Investors and News” section of the Seres website at www.serestherapeutics.com. A webcast replay will be available on the Seres website beginning approximately two hours after the event and will be archived for at least 21 days. INDICATION AND IMPORTANT SAFETY INFORMATION FOR VOWSTINDICATIONVOWST (fecal microbiota spores, live-brpk) is indicated to prevent the recurrence of Clostridioides difficile infection (CDI) in individuals 18 years of age and older following antibacterial treatment for recurrent CDI (rCDI). Limitation of Use: VOWST is not indicated for treatment of CDI. IMPORTANT SAFETY INFORMATION WARNINGS AND PRECAUTIONS Transmissible infectious agents: Because VOWST is manufactured from human fecal matter, it may carry a risk of transmitting infectious agents. Report any infection that is suspected to have been transmitted by VOWST to Aimmune Therapeutics, Inc. at 1-833-246-2566. Potential presence of food allergens: VOWST may contain food allergens. The potential to cause adverse reactions due to food allergens is unknown. ADVERSE REACTIONS The most common adverse reactions (reported in ≥5% of participants) were abdominal distension (31.1%), fatigue (22.2%), constipation (14.4%), chills (11.1%) and diarrhea (10.0%). To report SUSPECTED ADVERSE REACTIONS, contact Aimmune Therapeutics at 1-833-AIM-2KNO (1-833-246-2566), or the FDA at 1-800-FDA-1088, or visit www.fda.gov/MedWatch. DRUG INTERACTIONS Do not administer antibacterials concurrently with VOWST. Please see Full Prescribing Information and Patient Information About SER-155 The SER-155 composition is designed to prevent GI-derived infections and resulting bloodstream infections, enhance epithelial barrier integrity, and induce immune tolerance responses, to reduce the incidence of GvHD. SER-155 is being evaluated in a Phase 1b placebo-controlled study in patients undergoing allo-HSCT. SER-155 is a consortium of bacterial species selected and optimized using Seres’ reverse translation discovery and development platform technologies. The design incorporates biomarker data from human clinical data, nonclinical human cell-based assays and in vivo disease models. SER-155 has received FDA Fast Track Designation. About Seres Therapeutics  Seres Therapeutics, Inc. (Nasdaq: MCRB) is a commercial-stage company focused on improving patient outcomes in medically vulnerable populations through novel live biotherapeutics. Seres led the successful development and approval of VOWST™, the first FDA-approved orally administered microbiome therapeutic. The Company is evaluating SER-155 in a Phase 1b study in patients receiving allo-HSCT. SER-155 is designed to prevent GI-derived infections and resulting bloodstream infections, enhance epithelial barrier integrity and induce immune tolerance responses to reduce the incidence of GvHD. The Company is also advancing additional cultivated oral microbiome therapeutic candidates for medically vulnerable populations, including those with chronic liver disease, cancer neutropenia and solid organ transplants. For more information, please visit www.serestherapeutics.com. Important Additional Information About the Transaction and Where to Find It This communication is being made in respect of the proposed transaction involving Seres Therapeutics, Inc., a Delaware corporation (“Seres”) and Société des Produits Nestlé S.A., a société anonyme organized under the laws of Switzerland (“SPN”). Seres intends to file a proxy statement and other relevant documents with the Securities and Exchange Commission (the “SEC”) in connection with a special meeting of Seres’ stockholders for purposes of obtaining, stockholder approval of the proposed transaction. The definitive proxy statement will be sent or given to the stockholders of Seres and will contain important information about the proposed transaction and related matters. INVESTORS AND STOCKHOLDERS OF SERES ARE URGED TO READ THE DEFINITIVE PROXY STATEMENT AND OTHER RELEVANT MATERIALS CAREFULLY AND IN THEIR ENTIRETY WHEN THEY BECOME AVAILABLE BECAUSE THEY WILL CONTAIN IMPORTANT INFORMATION ABOUT SERES AND THE PROPOSED TRANSACTION. Investors may obtain a free copy of these materials (when they are available) and other documents filed by Seres with the SEC at the SEC’s website at www.sec.gov or from Seres at its website at ir.serestherapeutics.com. Participants in the Solicitation Seres and certain of its directors, executive officers and other members of management and employees may be deemed to be participants in soliciting proxies from its stockholders in connection with the proposed transaction. Information regarding the persons who may, under the rules of the SEC, be considered to be participants in the solicitation of Seres’ stockholders in connection with the proposed transaction will be set forth in Seres’ definitive proxy statement for its stockholder meeting at which the proposed transaction will be submitted for approval by Seres’ stockholders. You may also find additional information about Seres’ directors and executive officers in Seres’ Annual Report on Form 10-K for the fiscal year ended December 31, 2023, which was filed with the SEC on March 5, 2024, Seres’ Definitive Proxy Statement for its 2024 annual meeting of stockholders, which was filed with the SEC on March 5, 2024, and in subsequently filed Current Reports on Form 8-K and Quarterly Reports on Form 10-Q. Forward-Looking Statements This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. All statements contained in this press release that do not relate to matters of historical fact should be considered forward-looking statements, including statements about the financial terms, timing and completion of the sale of VOWST assets to Nestlé Health Science; the receipt of future payments and the use of proceeds of the transaction; the timing and results of our clinical studies and data readouts; future product candidates, development plans and commercial opportunities; operating plans and our future cash runway; our ability to generate additional capital; our planned strategic focus; anticipated timing of any of the foregoing and other statements which are not historical fact. These forward-looking statements are based on management’s current expectations. These statements are neither promises nor guarantees, but involve known and unknown risks, uncertainties and other important factors that may cause our actual results, performance or achievements to be materially different from any future results, performance or achievements expressed or implied by the forward-looking statements, including, but not limited to, the following: (1) we have incurred significant losses, are not currently profitable and may never become profitable; (2) our need for additional funding; (3) our history of operating losses; (4) the restrictions in our debt agreement; (5) our novel approach to therapeutic intervention; (6) our reliance on third parties to conduct our clinical trials and manufacture our product candidates; (7) the competition we will face; our ability to protect our intellectual property; (8) our ability to retain key personnel and to manage our growth; (9) the occurrence of any event, change or other circumstance that could give rise to the termination of the Purchase Agreement; (10) our failure to obtain stockholder approval for the proposed transaction or to satisfy any of the other conditions to the completion of the proposed transaction; (11) the effect of the announcement of the proposed transaction on our ability to retain and hire key personnel and maintain relationships with our customers, suppliers, advertisers, partners and others with whom we do business, or on our operating results and businesses generally; (12) the risks associated with the disruption of management’s attention from ongoing business operations due to the proposed transaction and the obligation to provide transition services; (13) our failure to receive the installment payments or the milestone payments in the future; (14) the significant costs, fees and expenses related to the proposed transaction; (15) the uncertainty of impact of the 50/50 profit or loss sharing arrangement on our reported results and liquidity; (16) the risk that the proposed transaction will not be completed within the expected time period or at all; and (17) we may not be able to realize the anticipated benefits of the proposed transaction. These and other important factors discussed under the caption “Risk Factors” in our Quarterly Report on Form 10-Q filed with the Securities and Exchange Commission (SEC) on May 8, 2024, and our other reports filed with the SEC could cause actual results to differ materially from those indicated by the forward-looking statements made in this press release. Any such forward-looking statements represent management’s estimates as of the date of this press release. While we may elect to update such forward-looking statements at some point in the future, we disclaim any obligation to do so, even if subsequent events cause our views to change. These forward-looking statements should not be relied upon as representing our views as of any date subsequent to the date of this press release. SERES THERAPEUTICS, INC. CONDENSED CONSOLIDATED BALANCE SHEETS(unaudited, in thousands, except share and per share data) June 30, December 31, 2024 2023 Assets Current assets: Cash and cash equivalents $71,232 $127,965 Collaboration receivable - related party 18,601 8,674 Inventories 52,997 29,647 Prepaid expenses and other current assets 6,435 9,124 Total current assets 149,265 175,410 Property and equipment, net 17,794 22,457 Operating lease assets 103,282 109,793 Restricted cash 9,873 8,185 Restricted investments — 1,401 Other non-current assets (1) 41,517 41,354 Total assets $321,731 $358,600 Liabilities and Stockholders’ Deficit Current liabilities: Accounts payable $4,809 $3,641 Accrued expenses and other current liabilities (2) 86,356 80,611 Operating lease liabilities 9,195 6,677 Deferred income - related party 7,922 7,730 Total current liabilities 108,282 98,659 Long term portion of note payable, net of discount 102,494 101,544 Operating lease liabilities, net of current portion 100,936 105,715 Deferred revenue - related party 95,364 95,364 Warrant liabilities — 546 Other long-term liabilities 1,729 1,628 Total liabilities 408,805 403,456 Commitments and contingencies (Note 15) Stockholders’ deficit: Preferred stock, $0.001 par value; 10,000,000 shares authorized at June 30, 2024 and December 31, 2023; no shares issued and outstanding at June 30, 2024 and December 31, 2023 — — Common stock, $0.001 par value; 360,000,000 shares authorized at June 30, 2024 and 240,000,000 shares authorized at December 31, 2023; 151,633,922 and 135,041,467 shares issued and outstanding at June 30, 2024 and December 31, 2023, respectively 152 135 Additional paid-in capital 964,012 933,244 Accumulated other comprehensive loss — — Accumulated deficit (1,051,238) (978,235)Total stockholders’ deficit (87,074) (44,856)Total liabilities and stockholders’ deficit $321,731 $358,600 [1] Includes $38,877 as of June 30, 2024 and December 31, 2023, of milestones related to the construction of the Company's dedicated manufacturing suite at BacThera AG, or Bacthera. Such amounts will form part of the right-of-use asset upon lease commencement.[2] Includes related party amounts of $43,075 and $28,053 at June 30, 2024 and December 31, 2023, respectively (see Note 17, Related Party Transactions). SERES THERAPEUTICS, INC.CONDENSED CONSOLIDATED STATEMENTS OF OPERATIONS AND COMPREHENSIVE LOSS (INCOME)(unaudited, in thousands, except share and per share data) Three Months EndedJune 30, Six Months EndedJune 30, 2024 2023 2024 2023 Revenue: Collaboration revenue - related party$— $126,473 $— $125,951 Total revenue — 126,473 — 125,951 Operating expenses: Research and development expenses 17,875 46,792 $39,577 90,761 General and administrative expenses 16,059 28,051 $31,525 50,521 Collaboration (profit) loss sharing - related party (2,589) 2,106 $(171) 5,713 Total operating expenses 31,345 76,949 $70,931 146,995 (Loss) income from operations (31,345) 49,524 $(70,931) (21,044)Other income (expense): Interest income 1,230 1,726 $2,878 2,758 Interest expense (3,447) (3,187) $(8,110) (5,135)Other income (expense) 692 (1,511) $3,160 (1,201)Total other expense, net (1,525) (2,972) $(2,072) (3,578)Net (loss) income$(32,870) $46,552 $(73,003) $(24,622)Net (loss) income per share attributable to common stockholders, basic$(0.22) $0.36 $(0.49) $(0.19)Net (loss) income per share attributable to common stockholders, diluted$(0.22) $0.36 $(0.49) $(0.19)Weighted average common shares outstanding, basic 151,514,597 127,713,486 148,808,089 126,793,342 Weighted average common shares outstanding, diluted 151,514,597 129,844,931 148,808,089 126,793,342 Other comprehensive (loss) income: Unrealized (loss) income on investments, net of tax of $0 — (2) — 10 Currency translation adjustment — (1) — 1 Total other comprehensive (loss) income — (3) — 11 Comprehensive loss (income)$(32,870) $46,549 $(73,003) $(24,611) Investor and Media Contact:  IR@serestherapeutics.com Carlo Tanzi, Ph.D.Kendall Investor Relationsctanzi@kendallir.com