Conjunctivitis, Acute Hemorrhagic

IVC2024第四届核酸疫苗与创新型疫苗论坛议程曝光点击图片查看，大会火热进行中，明天继续：（扫码立即领取限量免费参会入场券）疫苗的定义疫苗是将病原微生物(如细菌、病毒等)及其代谢产物，经过人工减毒、灭活或利用基因工程等方法制成的用于预防传染病的自动免疫制剂。疫苗保留了病原菌刺激动物体免疫系统的特性。当动物体接触到这种不具伤害力的病原菌后，免疫系统便会产生一定的保护物质，如免疫激素、活性生理物质、特殊抗体等;当动物再次接触到这种病原菌时，动物体的免疫系统便会依循其原有的记忆，制造更多的保护物质来阻止病原菌的伤害。国内传染病发病情况2017年，甲乙类传染病发病率222.1/10万，死亡率1.4/10万。发病数前5位的病种依次为病毒性肝炎、肺结核、梅毒、淋病、细菌性和阿米巴性痢疾，占甲乙类传染病发病总数的92.8%；死亡数前5位的病种依次为艾滋病、肺结核、病毒性肝炎、狂犬病、人感染H7N9禽流感，占甲乙类传染病报告死亡总数的98.8%。2017年，丙类传染病发病率287.5/10万,死亡率0.01/10万。发病数前5位的病种依次为手足口病、其他感染性腹泻病、流行性感冒、流行性腮腺炎和急性出血性结膜炎，占丙类传染病发病总数的99.8%；死亡数较多的病种依次为手足口病、流行性感冒和其他感染性腹泻病，占丙类传染病报告死亡总数的100％。疫苗的免疫反应疫苗的分类我国疫苗主要分为一类疫苗和二类疫苗。北京市第一类疫苗（2014-2016年）15种A群C群脑膜炎球菌多糖疫苗、A群脑膜炎球菌多糖疫苗、冻干水痘减毒活疫苗（应急接种用）、脊髓灰质炎减毒活疫苗糖丸、脊髓灰质炎灭活疫苗、甲型肝炎灭活疫苗、流感病毒裂解疫苗（老人和学生用）、麻疹腮腺炎风疹联合减毒活疫苗、麻疹风疹联合减毒活疫苗、麻疹减毒活疫苗、吸附白喉破伤风联合疫苗、吸附无细胞百日咳白喉破伤风联合疫苗、乙型脑炎减毒活疫苗、重组乙型肝炎疫苗、双价肾综合征出血热疫苗（应急接种用）北京市第二类疫苗（2016年）19种23价肺炎球菌多糖疫苗、A、C群脑膜炎球菌多糖结合疫苗、ACYW135群脑膜炎球菌多糖疫苗、b型流感嗜血杆菌结合疫苗、冻干人用狂犬病疫苗、冻干水痘减毒活疫苗、脊髓灰质炎灭活疫苗、甲型肝炎灭活疫苗、甲型乙型肝炎联合疫苗、口服轮状病毒活疫苗、狂犬免疫球蛋白、流感病毒裂解疫苗、麻疹腮腺炎风疹联合减毒活疫苗、森林脑炎灭活疫苗（专业人员用）、无细胞百白破b型流感嗜血杆菌联合疫苗、吸附无细胞百白破灭活脊髓灰质炎和b型、流感嗜血杆菌（结合）联合疫苗、乙型脑炎灭活疫苗、重组B亚单位/菌体霍乱疫苗、重组乙型肝炎疫苗国内疫苗市场仍由一类疫苗为主导，由国家财政拨款购买，集中采购，下游需求比较稳定。二类疫苗市场主要由民营企业主导，毛利高、市场化竞争程度高。民营企业占比60%左右、国企占比在30%左右、外企占比在10%左右。一类疫苗与二类疫苗的批签发量比例约为：3：2疫苗新规国家规定2019年12月1日开始施行《中华人民共和国疫苗管理法》；疫苗法的实施，会带来哪些机会呢？在《疫苗管理法》中，有几点内容值得重点关注。疫苗上市流程疫苗生产流程疫苗生产原料是生物体，类似生物药，生产过程中难以控制变异可能；质量控制严格，要求10000级洁净室，100000级洁净室；疫苗主要针对健康人群及婴幼儿，因此疫苗的安全性、有效性、可控性、一致性要求比一般药品还要高。疫苗行业产业链疫苗行业的上游一般包括临床、流行病研究机构、基础研究机构或企业，还包括参与疫苗研发、生产的设备、培养基、化学试剂和药包材等制造企业疫苗行业的下游为符合国家相关法规的合格经销商、代理商，实施疾病预防和控制工作的各级疾控中心、医院、接种点最终端为普通消费者上市前的质量控制手段——批签发制度流通制度——一票制疫苗行业上游-疫苗供应主力军我国官方的疫苗生产历史从1919年北洋政府中央防疫处的建立开始；新中国成立后，国家分别在北京、上海、武汉、长春、兰州、成都、昆明成立生物制品研究所；2017年，七大所占据了国内疫苗批签发量的52%疫苗行业中游-疫苗的流通一类疫苗属于国家强制接种，由政府在省级平台统一采购，由生产企业直接配送至终端CDC。二类疫苗的采购在疫苗新规之后，纳入省级集中招标平台，生产企业只能通过省级交易平台将疫苗销售给县疾控中心,同时需要直接或者委托配送，配送环节要求全程冷链运输，疫苗流通全部实现一票制。疫苗行业下游-疫苗接种及接种群体2017年，专业公共卫生机构中，疾病预防控制中心3457个，总的机构人员数为19.1万人，其中：省级31个、市(地)级412个、县(区、县级市)级2773个。二类疫苗不属于强免范围，可自愿选择打或不打。凡是收费的疫苗都需要签名认可，方可接种。疫苗行业发展的驱动力驱动力一：疫苗品种驱动力二：接种人数疫苗行业特点特点一：疫苗行业无论从全球市场还是公司角度都是品种驱动型，都具有上市时的起步销售额较大（起步都在2亿美金以上）、年均复合增速在7%-10%的特点。疫苗技术代际的大跨越需要多学科的发展和支持，一般需要30-40年左右的时间完成积累，同一品类疫苗的再次创新和技术升级需要10-15年的时间，因此疫苗市场的竞争格局相对稳定新的重磅炸弹都是从技术和工艺积累颇深的企业里孕育而生。因此，疫苗行业具有较高的准入门槛和技术壁垒。超级重磅品种推动或是持续不断的多品类推陈出新，造就了辉瑞或GSK的巨头地位。特点二：特点三：疫苗品种规模的大小具有DT和ET的特点，即Disease Talks & Effectiveness Talks，发病率决定了赛道的宽度，效果（技术和工艺）决定了赛道的高度。发病率越高且疾病进展危害越大的疾病其疫苗市场规模也越大；疫苗保护率不能超过现有疫苗或保护率提升不明显，都不能成为真正的重磅品种。各疾病发病特点的差异，决定了疫苗市场的结构趋于“积木式”，而工艺和技术的积累又具有连续性，因而大品种只会从积累深厚的企业中诞生。疫苗与创新药现金流模式的差异经疫苗的消费属性不同于药品，大部分疫苗完成接种后不存在再次接种的必要，而一些重磅药品需要终生服药，因此药品对价格的敏感度会更高，随着价格下降其渗透率会提升、产品生命周期会延长。重磅疫苗不仅起始销售额远高于药品，而且会在上市早期纳入部分国家的计划免疫体系内，在10-15年内迅速达到销售峰值，直至新一代的疫苗出现，其销售额会快速回落，其疫苗的产品替代性较药品更加明显。对于测算若干年后某疫苗市场规模最关键的变量为渗透率，而渗透率的决定因素为是否纳入计划免疫范围、疾病的危害性和疫苗的有效性。全球疫苗市场格局全球疫苗市场高度集中。近年来，四大疫苗巨头（葛兰素史克、赛诺菲、默沙东、辉瑞）合计销售额占比维持在全球市场总额的80%以上。全球疫苗市场规模前瞻研究院数据预测：2018年全球疫苗市场规模约494亿美元。受全球对疫苗接种日益增加的需求、政府及国际机构的支持以及研发新疫苗的驱动，预计全球疫苗市场规模将于2030年达到1000亿美元，年复合增速为6.6％。中国疫苗行业现状国内疫苗行业同样有高准入、高投入、高周期、高收益、高毛利特征，是典型的“五高”行业。高准入壁垒、高研发投入和长耗时、生产的周期性，共同导致了行业的高成本，抬高了整个行业的门槛。我国疫苗市场目前整体规模偏小，2017年，国内疫苗市场规模达到250亿，占全球438亿美元的市场总额较小（8%），远小于我国人口占世界人口的比例（18%）近几年没有重磅产品出现，行业增长较慢，急需有重磅品种冲击市场。中国疫苗市场规模2017年中国疫苗市场规模253亿元，2013-2017年CAGR为6.2%其中，一类苗市场37亿，2013-2017年CAGR为-16.3%二类苗市场217亿，2013-2017年CAGR为14.9%灼识咨询预测：2030年我国疫苗市场规模1009亿元，CAGR为11.2%其中，一类苗市场33亿，2018-2030年CAGR为-0.8%二类苗市场976亿，2018-2030年CAGR为12.3%中国疫苗行业总结中国疫苗行业发展前景一类疫苗发展前景整体上看，国内规划免疫计划下的国家采购行为决定了一类苗的市场空间弹性有限。二类疫苗发展前景二类苗为可选消费品，其属性决定了产品的升级和丰富能够刺激市场的扩大，支付能力和更多的需求反过来促进品种的升级。目前，二类苗的竞争力一方面是安全性、顺应性上对传统一类苗的升级替代；另外是满足未被一类苗覆盖的新疾病领域。联合疫苗、多价苗、新型疫苗，这将是未来疫苗行业发展的重要方向。中国疫苗行业投资趋势一类疫苗投资空间一类疫苗由国家统一控制，免费供应，国家定价、政府招标采购的模式，定价低、毛利低。所以一类疫苗基本上处于垄断竞争的微利状态。一类苗基本由国企垄断，受制政策导向严重，市场化程度极低，基本不存在可预见的投资空间。二类疫苗投资空间国内二类疫苗赚钱能力极强，但由于疫苗属于国家管制商品，受限于政策，并不是完全由市场把控。二类苗行业竞争激烈，疫苗企业的销售费用均占到营收40%以上，国内疫苗企业在销售费率上有增无减。外资企业技术成熟、资金雄厚，品种多样性；国内二类疫苗竞争上优势不明显。只有自身技术过硬、销售能力强、资本雄厚的公司才会有机会成为中国的疫苗寡头。疫苗行业投资逻辑“短期看品种”，无论是整体疫苗市场还是公司的收入结构，都具有品种导向性，站在当下或面对未来，欲打造中国的“GPSM”需要有重磅品种面世或储备才具备持续成长性。监管趋严会使得市场集中度提高、“二八原则”也将在中国市场突显，强者恒强的逻辑将逐渐得到验证。“长期看工艺和技术”，具备产能和规模优势的企业，且工艺、技术持续积累的企业才有可能孕育新的品种，兼顾质控与创新。由于技术和工艺的延续性，除了看现有和即将上市的品种，从专利角度即可大致判断生产企业对于未来品种的储备和工艺积累的完成度。疫苗上市公司-智飞生物重庆智飞生物成立于1995年，2010年在深交所上市，是我国第一家在创业板上市的民营疫苗企业。主营业务为疫苗、生物制品的研发、生产、销售、推广、配送以及进口疫苗的代理销售等。智飞生物以代理疫苗起家，直销比例维持在 70%-80%。公司销售人员合计1792人，典型销售型企业。2007年开始，智飞生物自主研发的产品陆续上市，公司从疫苗代理企业逐渐转型为代理和自主研发同步发展的企业。股权结构男，1953年出生，桂林医学院大专学历，副主任医师，中国国籍；曾任广西灌阳县卫生防疫站副站长、广西计划免疫科、生物制品管理科科长、总经理等职务，现任智飞生物董事长、总经理，重庆市江北区人大代表。财务表现公司AC-Hib疫苗步入高速放量期，代理产品四价、九价HPV疫苗销售态势非常良好，五价口服轮状病毒疫苗获批，微卡报产，将与EC诊断试剂盒形成肺结核“诊断筛查+预防+治疗”全产品链布局，企业未来前景广阔。自研及代理产品核心产品——AC-Hib三联疫苗（自研）多联苗替代单苗的趋势势不可挡，替代效应逐渐显现。AC结合疫苗和Hib疫苗批签发量逐渐下降。AC-Hib三联苗于2014年上市，2015年正式销售，2018年销量约640万支，收入10亿元左右。财务预测：根据太平洋证券研究院预测，按照现有市场及替代效率，符合增长率25%计算，预计2022年AC-Hib三联苗销售将达到峰值，即1000万支，收入21亿人民币，贡献10亿净利润。需要注意！！！公司AC-Hib 疫苗于 2014 年 4 月 2 日获得原国家食品药品监督管理总局的药品注册批件（批件号：2014S00240），批准该产品注册，并颁发了药品批准文号（国药准字 S20140003），批准文号有效期5年。而2019年4月1日正是有效到期日。截止目前，公司还未拿到再注册批件，该产品从4月份开始已停产，目前无任何准确消息。核心产品——HPV疫苗（代理）人乳头状瘤病毒（HPV）是一种男女均可能感染的通过性传播、皮肤密切接触传播病毒，临床证明，99.7%的宫颈癌都是 HPV 感染所引起，不仅如此，85-90%的肛门癌、70-75%的阴道癌、30%的 外阴癌也与 HPV 感染密切相关目前，全球共有3种HPV疫苗。据智库推算，预计2020年我国HPV疫苗市场超过300亿。2017年5月，智飞获得默沙东的四价疫苗的独家代理销售权，2018年5月，获得默沙东的九价疫苗的独家代理销售权。公告显示，双方协议约定的 HPV 疫苗综合基础采购额为：2019年55.07亿元、2020年83.3亿元、2021年（6月30日前）41.65亿元。简单计算即可得出，未来3年，智飞生物从默沙东采购的HPV疫苗金额将达到180.02亿元。这也就是说，智飞生物的主营业务收入3年间，仅HPV基础采购就足以贡献180亿元营收，毛利近90亿元（50%的毛利率），净利润在50亿左右（净利润率28%），每年17亿，每股多增加1.4元的业绩，即便按照30倍的市盈率，新增股价近42元，接近翻倍。假设一：由于 GSK 批准的年龄段为 9~25 岁，且由于其产品为 2 价，我们认为其未来占比会很低，故暂不考虑2价疫苗的市场假设二：到 2023 年，5年左右时间存量，3亿左右的适龄人群累计接种率提高到10%（已知：我国HPV适龄人群免疫覆盖率约1%，远低于发达国家的60%-80%）假设三：5年时间内，国内外暂无可替代产品或者优化产品出现财务预测：默沙东HPV疫苗2019~2023 年销售量分别为 880 万支、1350 万支、1800 万支、2100 万支、2300 万支，4 价和 9 价 HPV 价格分别为 798 元/支和 1298 元/支，按照平均价1000元测算，则2019年~2023年HPV销售额分别为88亿、135亿、180亿、210亿和230亿元。其他重点产品——五价轮状疫苗人类轮状病毒(HRV)是导致全球儿童急性重症腹泻的主要原因，每年约有52.5万名五岁以下儿童死于腹泻病；全球90%的人类轮状病毒感染来源于G1P[8]、G2P[4]、G3P[8]、G4P[8]和G9P[8]五种病毒株，G1P[8]型最常见。市场情况：国内上市疫苗有两种，一是默沙东的五价轮状病毒疫苗RotaTeq，一是我国兰州的单价轮状病毒疫苗罗威特；智飞生物获得默沙东口服五价轮状病毒疫苗的独家代理权五价轮状疫苗作为远优于已有疫苗的品种，能迅速替代已有疫苗（已有疫苗销售近10亿）预测：未来2-3年内，疫苗每年贡献收入超20亿在研管线及进度在研重磅产品-母牛分枝杆菌疫苗结核病是由结核分枝杆菌引起的慢性传染病，可侵及许多脏器，80%发生在肺部，是全球前10位死因之一；市场情况：对于预防结核病市场尚无有效的疫苗，已有的卡介苗只对儿童重症结核病和严重肺外结核病具有保护作用，不能预防原发性感染 (首次感染结核杆菌)，更重要的是不能预防肺部潜伏感染(隐性感染)；2018年4月，智飞的母牛分枝杆菌疫苗(结核感染人群用)申请新药生产注册获得受理，并于2018年6月正式纳入优先审评。8部门联合印发《遏制结核病行动计划(2019—2022 年)》假设一：按照1500万新生儿数量测算，则对应小学、初中、高中、大学(本科+研究生) 新生入学人数在 5300万左右；假设二：到2023年覆盖新生入学人数为20%，即1060万人，结核杆菌感染率 18%的比例，即筛查出结核杆菌携带者191万人，假设接种率60%；假设三：按照目前的6 支/人份，300元/支；预测：未来2-3年内，结核疫苗每年贡献收入超10亿，利润超4亿在研重磅产品-重组结核杆菌融合蛋白（诊断试剂）产品进度：与公司母牛分枝杆菌疫苗同步研发，该产品于2013年8月开展III期临床，并于2018年9月申请新药生产注册获得受理。诊断试剂市场情况：世界卫生组织 2014及2017版《潜伏结核感染管理指南》建议使用γ -干扰 素释放试验(IGRA)或结核菌素皮试(PPD)检测结核潜伏感染，而前者操作复杂、价格昂贵不适合大规模人群筛查和贫困地区使用，后者难以鉴别卡介苗接种与结核杆菌感染特异性差异。二级市场表现市盈率（简称P/E或PER），也称“本益比”、“股价收益比率”或“市价盈利比率（简称市盈率）”。是衡量企业估值的重要指标。三家企业对比发现，智飞生物的市盈率（动）及市盈率（TTM）均最低。自身对比，智飞生物的市盈率处于历史低点。净资产收益率是衡量一家企业是否赚钱的重要的指标。代表企业的净资产有多少是转化为了公司利润。三家企业在近三年的净资产收益率总体是一个上升的趋势。随着智飞生物这两三年自研疫苗和代销疫苗业绩的大幅增长，ROE净值和增速都是最大的。其次，对ROE进行分解，来看其盈利是靠什么因素驱动的。净资产收益率=营业净利润率*总资产周转率*权益乘数；营业净利润率=净利润/营业收入；利润空间总资产周转率=营业收入/资产总额；赚钱快慢权益乘数=1/（1-负债总额/资产总额）；杠杆高低一家企业的经营情况好不好，赚了多少钱，除了看营业收入、净利润等利润表的数据外，更重要的要看现金流量表。这是体现企业的钱流向了哪里，花在什么地方；钱回来了多少，都是什么钱。很多时候看现金流量表的重要性要超过利润表，后者只是结果，而前者是内在逻辑。经营现金流净值为正，说明公司通过开展业务能够收回现金，可以不断再投入;投资现金流净值为负，说明公司有多余现金可以进行对外投资;筹资现金流净值为负，说明公司有多余现金可以对外支付利息、现金分红;因此，公司近两年的现金流健康。智飞生物最近两年的经营现金流净额和净利润的比值均小于1，且有所下降。说明其经营现金流的增速，赶不上净利润的增速。营业成本大幅增长：其营业成本的增加主要为代理生物制品的采购成本。2016-2018年，营业成本中采购成本由2.25%增加到96.54%。营业收入大幅增长：其营业收入的增加主要为代理二类苗的收入。2016-2018年，营业收入中二类苗的代理收入由0.66%增加到74.36%。营业成本增速显著大于营业收入增速综上，2017年开始，智飞生物业务类型转变，其代理销售为主的业务模式不同于可比公司的自研销售，因此，毛利率的变化趋势也不相同。这不但不影响智飞生物的ROE和其他三家一样逐年大幅上涨。相反，其净利润的增速，远远大于净资产的增速，ROE持续稳步走高。企业运营能力主要看两个指标：应收账款周转天数、存货周转天数，这两个指标主要体现企业应收账款变现速度和存货变现速度。从上表可以看出，智飞的应收账款周转天数和存货周转天数近三年大幅缩短。相比其他三家来看，其存货变现速度和应收账款回现速度在逐渐加快，具有显著优势。说明公司的资产运转效率高。总结ENDIVC2024第四届核酸疫苗与创新型疫苗论坛议程曝光点击图片查看，大会火热进行中，明天精彩继续：戳这里，阅读原文立即领取免费参会入场券

Pictured: A person with an irritated gut/Taylor Tieden for BioSpace Twenty-two years ago, a molecule called TL1A was first discovered and isolated. Today, after two decades of research, therapeutics to calm its activity may usher in a new era for the treatment of immune-mediated diseases like inflammatory bowel disease, psoriasis and rheumatoid arthritis. TL1A (tumor necrosis factor-like cytokine 1A) is part of the tumor necrosis factor (TNF) superfamily, a group of cell-signaling molecules that have potent effects on immune function and which have led to anti-TNF antibodies such as AbbVie’s blockbuster Humira (adalimumab). Against this backdrop, two monoclonal antibodies targeting TL1A spurred major biopharma acquisitions in 2023. In June, Merck completed the purchase of Prometheus Biosciences for $10.8 billion. The company’s lead asset, PRA-023—now MK-7240—has shown clinical evidence of “best-in-class” potential for treating inflammation and scarring in the inflammatory bowel diseases (IBD) ulcerative colitis and Crohn’s disease, Nature reported. Then in October, Roche paid $7.1 billion for Roivant subsidiary Televant Holdings and its anti-TL1A antibody RVT-3101, also for IBD. That same month, Sanofi and Teva Pharmaceuticals announced a collaboration worth a potential $1.5 billion to co-develop TEV-’574, a TL1A inhibitor currently in Phase IIb clinical trials for IBD. Stephan Targan, executive director of the F. Widjaja Inflammatory Bowel Institute of Cedars-Sinai, Los Angeles, and colleagues carried out much of the research into TL1A and developed the antibody Prometheus purchased. After giving the keynote presentation about TL1A at the Crohn’s & Colitis Congress earlier this month, Targan told BioSpace, “I have never had an audience response like that. There’s a big buzz about this in our field.” What’s All the Excitement About? In an April 2023 note shared with BioSpace, Jefferies analyst Michael Yee wrote that there is a “high unmet need” in IBD. Current treatment options are limited and with modest benefit, Yee explained. Driving part of the excitement around TL1A inhibitors is the hope that they can break the “efficacy ceiling that we see even with the best drugs out there,” Aileen Pangan, a rheumatologist and therapeutic area head of immunology clinical research at Merck, told BioSpace. “We are not getting the remission rates we’d like. And even after remission, there is a considerable loss of response over time, requiring patients to switch to another drug. . . . Some patients may have to try two or three different drugs before they find one that works. We are simply not where we want to be.” In December 2022, Prometheus announced positive results from two 12-week Phase IIa studies of PRA-023, ARTEMIS-UC and APOLLO-CD, in patients with moderate to severe ulcerative colitis and Crohn’s disease who had failed other therapies. In the ARTEMIS study, 26.5% of patients reached the primary endpoint of clinical remission compared to 1.5% of those on placebo. And in APOLLO-CD, a 49.1% clinical remission rate was achieved, compared with a 16% historical placebo rate. Targan called the results “huge,” highlighting the durability of the treatment as a significant improvement over existing treatments. “The therapeutics available today might offer a 20% increase [in remission] over placebo over a 12-week trial, but at the end of a year, only 40% are maintained. That means, of the entire population of Crohn’s sufferers, a given biologic may offer an 8% remission.” But with Merck’s TL1A inhibitor, he said, “Initial remission rates may be over 50% and durability over time could be as high as 90%,” for an overall remission rate of 45%. “That’s never been seen before.” Similarly, Roche’s RVT-3101 showed positive results in the Phase IIb TUSCANY-2 study in moderate-to-severe ulcerative colitis. The results, released in June 2023, led to clinical remission in 36% of patients after 56 weeks of treatment, with endoscopic improvement reaching 50%. Enabling Targeted Treatment These new antibodies could perform very well in targeted patient populations, Targan said, thanks to a novel diagnostic tool that uses genetic testing as well as other genomic markers to inform physicians about how well the molecule will work in a specific patient. “Right now, physicians and patients have to go through trial-and-error steps before they find the right drug,” he explained. But certain genetic variations, called risk alleles, increase the likelihood the patient will respond to the drug. “Risk alleles are very significantly associated with increased expression of TL1A over time,” Targan said. “I predict the Phase III trials will show people doing very well if their diagnostic tests show a strong genetic association with the presence of the TL1A molecule.” He added that he believes the new companion diagnostic will also identify those patients who will see a durable response. He compared this companion diagnostic, which is yet to be approved by the FDA, to those used in oncology, where “to find out what you need to treat a tumor, you evaluate the characteristics of the tumor.” Pangan said the power of this diagnostic was evident in Prometheus’ Phase II trial. In the ARTEMIS-UC study, all trial participants were tested with the complementary diagnostic and stratified according to the result. Of the 135 enrolled patients, 32 were positive for a SNP-based signature that includes the TL1A risk alleles (16 were on placebo and 16 received the antibody), and a greater proportion who were positive for risk alleles or other biomarkers achieved remission with the antibody compared to those who were negative, Pangan shared. Merck has embarked on a global Phase III trial that will enroll over 1,000 patients. “If we can identify the population that is most likely to get into remission with this antibody, we can help patients and physicians everywhere,” she said. Biotech entrepreneur Andrew Pannu told BioSpace that the biomarker-driven approach being taken by both Merck and Roche reflects a belief that these biomarkers will credibly predict responders and that this will help with reimbursement efforts in a “fairly crowded market.” Beyond IBD TL1A inhibitors also hold potential in other autoimmune diseases. In a 2022 summary review article published in Frontiers, TL1A was found to be was abnormally expressed in IBD, as well as in rheumatoid arthritis, psoriasis, primary biliary cirrhosis, systemic lupus erythematosus and ankylosing spondylitis. And, as the molecule binds to activated fibroblasts, targeting TL1A might offer another novel benefit: the reversal of fibrosis and scarring. “In a lot of our work in animals, we found that, lo and behold, TL1A inhibitors could reverse scarring,” Targan said. That could have applications for strictures in Crohn’s disease—although anti-TL1A drugs can’t ‘fix’ already formed strictures, they might help keep them from forming or re-forming after surgical intervention, he said. TL1A inhibitors might also be helpful in other diseases where fibrosis and scarring are significant such as systemic sclerosis and primary sclerosing cholangitis, Targan noted. And Merck is currently conducting a Phase II study looking at fibrosis in systemic sclerosis associated with interstitial lung disease. Lee also noted the potential durability and success of the class. “Data could get even better over time given the anti-fibrotic potential of TL1A inhibitors,” he wrote in the April 2023 investor note. “Of course, I’m prejudiced,” Targan said, “but I’ve been around a long time. I’ve been working on inflammatory bowel disease for half a century now, and I do believe TL1A inhibitors will be transformational for many immune-mediated diseases.” Jill Neimark is a freelance science writer based in Macon, Georgia. Reach her at jillneimark.com.

– Reported strong efficacy and favorable safety results for PRA023 in ARTEMIS-UC and APOLLO-CD Phase 2 Studies – – Prometheus intends to advance PRA023 into Phase 3 studies for UC and CD in 2023 – – Initiated a third Phase 2 of PRA023 into SSc-ILD, demonstrating pipeline-in-a-product candidate potential for the program – – Expanded clinical pipeline with advancement of PRA052, a potentially first-in-class monoclonal antibody blocking CD30L, into Phase 1 – – Strong cash position of >$700M following full completion of recent financing – SAN DIEGO, Feb. 28, 2023 (GLOBE NEWSWIRE) -- Prometheus Biosciences, Inc. (Nasdaq: RXDX), a clinical-stage biotechnology company pioneering a precision medicine approach for the discovery, development, and commercialization of novel therapeutics for the treatment of immune-mediated diseases, today reported financial results for the quarter and full-year ended December 31, 2022 and highlighted recent corporate progress. "2022 was a momentous year for Prometheus and the IBD community, highlighted by the positive readout in both PRA023 Phase 2 studies in UC and CD, which we believe set a new standard in IBD by combining high efficacy and favorable safety results,” said Mark McKenna, Chairman and CEO of Prometheus Biosciences. “We continue to believe that PRA023 is a potential best-in-class and first-in-class therapeutic candidate for IBD and we intend on carrying this momentum into 2023 by advancing PRA023 into Phase 3 studies.” FOURTH QUARTER AND FULL-YEAR 2022 AND RECENT CORPORATE HIGHLIGHTS CORPORATE HIGHLIGHTS Reported positive results for PRA023 in both ARTEMIS-UC Phase 2 and APOLLO-CD Phase 2a studies. Prometheus reported topline results from the initial cohort of its ARTEMIS-UC Phase 2 trial and results from its APOLLO-CD Phase 2a trial of PRA023, demonstrating strong efficacy and favorable safety results in both studies in the context of very severe and refractory patient populations. The company plans to advance to Phase 3 trials in both UC and CD this year. Prometheus’ Phase 2 ARTEMIS-UC clinical trial was a 12-week, double-blind, placebo-controlled, randomized study to evaluate the efficacy and safety of PRA023 in patients with moderate-to-severely active UC who have failed conventional or advanced therapy. PRA023 met the primary and all ranked secondary endpoints including clinical, endoscopic, histologic, and patient-reported outcome measures in the initial cohort (Cohort 1) of the trial. 68/68 (100%) of PRA023-treated patients completed the Cohort 1 study, compared to 60/67 (89.6%) in the placebo group. The topline results were as follows: 26.5% of patients on PRA023 reached the primary endpoint of clinical remission (per modified Mayo Score), compared to 1.5% on placebo, for a placebo-adjusted clinical remission rate of 25.0% on the primary endpoint (p<0.0001)36.8% of patients on PRA023 reached the secondary endpoint of endoscopic improvement (Mayo endoscopy subscore of ≤ 1), compared to 6.0% on placebo, for a placebo-adjusted endoscopic improvement rate of 30.8% on the secondary endpoint (p<0.0001)All secondary endpoints met with statistical significancePRA023 was well tolerated with no safety signal identifiedCohort 1 interim analysis suggests a trend towards increased PRA023 response in CDx+ patients over all comers with clinical remission of 37.5% in Dx+ patients, compared with 25.0% for all-comers Prometheus’ Phase 2a APOLLO-CD clinical trial was a 12-week open-label study that enrolled 55 patients with moderate-to-severely active CD with endoscopically active disease who had failed conventional or biologic therapy. The study enrolled a highly refractory patient population with 70.9% of patients previously treated with at least one biologic therapy and 52.7% treated with two or more biologic therapies. The results were as follows: 26.0% of patients on PRA023 achieved endoscopic response (p=0.002 compared to 12% prespecified historical placebo rate)49.1% of patients on PRA023 achieved clinical remission (p<0.001 compared to 16% prespecified historical placebo rate)PRA023 was well tolerated in subjects with moderately-to-severely active CD with no safety signal identifiedPRA023 showed a significant impact on multiple markers of inflammation and fibrosis Expanded therapeutic investigation of PRA023 into SSc-ILD, a rare autoimmune disorder. Prometheus initiated its third Phase 2 study of PRA023, ATHENA-SSc-ILD, targeting both key fibrotic and inflammatory pathways for the treatment of SSc-ILD. PRA023 received Fast Track Designation from the US Food and Drug Administration (FDA) for the treatment of SSc-ILD. Systemic Sclerosis (SSc) is a rare autoimmune disorder characterized by progressive fibrosis of the skin and internal organs thought to result from inflammation and chronic immune activation. Lung involvement (SSc-ILD) is the leading cause of morbidity and mortality for individuals with the disorder. SSc-ILD has been largely irreversible with current therapeutic strategies focused on slowing progression of the disorder. Topline results from the Phase 2 study are expected in 1H 2024. Advanced second precision program, PRA052, into Phase 1. Prometheus received IND clearance from the FDA and initiated a Phase 1 trial in normal healthy volunteers (NHVs) for PRA052, a potential first-in-class monoclonal antibody blocking CD30 ligand (CD30L). CD30L is a costimulatory molecule that has been implicated in inflammatory bowel disease (IBD) by genetic, preclinical, and human translational data. Prometheus is also developing a companion diagnostic candidate designed to select potential responders for this program. Results from the Phase 1 NHV study are expected in 4Q 2023. Completed upsized $550M public offering of common stock. Prometheus completed an upsized public offering of common stock following the release of its Phase 2 data on PRA023, with net proceeds to the company of approximately $520 million. UPCOMING ANTICIPATED MILESTONES AND EVENTS ARTEMIS-UC expansion cohort (Cohort 2) results – 2Q 2023Initiation of registrational studies for PRA023 in UC and CD – 2023R&D Day Presentation – 2H 2023PRA052 Phase 1 NHV results– 4Q 2023IND submission for PR1100 – 4Q 2023 FOURTH QUARTER AND FULL-YEAR 2022 FINANCIAL RESULTS Cash, Cash Equivalents and Short-Term Investments. As of December 31, 2022, Prometheus had cash, cash equivalents and short-term investments of $695.8 million, compared to $257.3 million at the end of 2021. The increase is primarily due to raising approximately $470.5 million in net proceeds through an upsized underwritten public offering of common stock in Q4 2022. Subsequent to the end of the year, Prometheus raised approximately $50.1 million in additional net proceeds through the exercise of the underwriters’ option to purchase additional shares. Collaboration Revenue. Revenue was $0.7 million for the three months ended December 31, 2022, compared to $1.0 million for the three months ended December 31, 2021 and $6.8 million for the full year 2022 compared with $3.1 million for the full year 2021. The fluctuations were primarily due to revenue generated from Prometheus’ collaboration with Dr. Falk Pharma GmbH. Research and Development (R&D) Expenses. Research and development expenses were $29.9 million for the three months ended December 31, 2022 compared to $23.6 million for the three months ended December 31, 2021 and $112.8 million for the full year 2022 compared with $62.4 million for the full year 2021. The increases in R&D expenses were primarily due to advancement of PRA023 in global Phase 2 clinical trials and PRA052 into Phase 1 clinical trials, as well as advancing our other development programs. General and Administrative (G&A) Expenses. General and administrative expenses were $12.0 million for the three months ended December 31, 2022 compared to $7.4 million for the three months ended December 31, 2021 and $39.7 million for the full year 2022 compared with $28.5 million for the full year 2021. The increases were primarily due to an increase in headcount and stock-based compensation expense. About Prometheus Biosciences Prometheus Biosciences, Inc. is a clinical-stage biotechnology company pioneering a precision medicine approach for the discovery, development, and commercialization of novel therapeutics for the treatment of immune-mediated diseases. The Company’s target discovery engine, Prometheus360™, combines proprietary machine learning-based analytical approaches with one of the world’s largest gastrointestinal bioinformatics databases to identify novel therapeutic targets and develop therapeutic candidates to engage those targets. The company’s lead candidate, PRA023, is a humanized IgG1 monoclonal antibody (mAb) that has been shown to block the tumor necrosis factor (TNF)-like ligand 1A (TL1A), a target associated with both intestinal inflammation and fibrosis. Prometheus is developing PRA023 for the treatment of immune-mediated diseases including ulcerative colitis (UC), Crohn’s Disease (CD), and systemic sclerosis-associated interstitial lung disease (SSc-ILD). Prometheus plans to advance PRA023 into Phase 3 trials in UC and CD later this year. Forward Looking Statements Prometheus cautions readers that statements contained in this press release regarding matters that are not historical facts are forward-looking statements. These statements are based on the company’s current beliefs and expectations. Such forward-looking statements include, but are not limited to statements regarding: the potential of PRA023 to improve IBD treatment and to be both a first-in-class and best-in-class anti-TL1A mAb; the potential of PRA052 to be a first-in-class mAb blocking CD30L; the timing of results from Cohort 2 of the ARTEMIS-UC trial, topline results from the ATHENA-SSc-ILD trial, and results from the Phase 1 NHV study of PRA052; plans to advance PRA023 into Phase 3 trials in UC and CD, including the timing thereof; plans to submit an IND for PR1100, including the timing thereof; plans to develop diagnostic candidates; and the potential of Prometheus’ diagnostic candidates to identify potential responders. The inclusion of forward-looking statements should not be regarded as a representation by Prometheus that any of its plans will be achieved. Actual results may differ from those set forth in this press release due to the risks and uncertainties inherent in our business, including, without limitation: topline results Prometheus reports are based on preliminary analysis of key efficacy and safety data, and such data may change following a more comprehensive review of the data related to the clinical trial and such topline data may not accurately reflect the complete results of a clinical trial; Prometheus’ approach to the discovery and development of precision medicines based on Prometheus360™ is unproven; interim results of a clinical trial do not predict final results and the clinical outcomes may materially change following more comprehensive reviews of the data, as follow-up on the outcome of any particular patient continues and as more patient data become available, including from Cohort 2 of the ARTEMIS-UC trial; potential delays in the commencement, enrollment and completion of clinical trials and preclinical studies; the results of clinical trials are not necessarily predictive of future results; Prometheus’ dependence on third parties in connection with product manufacturing, research and preclinical and clinical testing; Prometheus’ ability to develop companion diagnostics for its therapeutic product candidates; unexpected adverse side effects or inadequate efficacy of its product candidates that may limit their development, regulatory approval and/or commercialization, or may result in recalls or product liability claims; planned future trials of PRA023 may not support regulatory registration; regulatory developments in the United States and foreign countries; Prometheus’ ability to maintain undisrupted business operations due to the COVID-19 pandemic, including delaying or otherwise disrupting its preclinical studies, clinical trials, manufacturing and supply chain; and other risks described in the company’s prior press releases and filings with the Securities and Exchange Commission (SEC), including under the heading “Risk Factors” in Prometheus’ most recent annual report on Form 10-K and any subsequent filings with the SEC. You are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date hereof, and Prometheus undertakes no obligation to update such statements to reflect events that occur or circumstances that exist after the date hereof. All forward-looking statements are qualified in their entirety by this cautionary statement, which is made under the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. Prometheus Biosciences, Inc.Condensed Consolidated Statements of Operations and Comprehensive Loss(unaudited)(in thousands, except share and per share data) Three Months Ended Twelve Months Ended December 31, December 31, 2022 2021 2022 2021 Collaboration revenue$653 $1,037 $6,809 $3,129 Operating expenses: Research and development 29,942 23,564 112,848 62,427 General and administrative 12,041 7,417 39,739 28,505 Total operating expenses 41,983 30,981 152,587 90,932 Loss from operations (41,330) (29,944) (145,778) (87,803)Other income (expense), net 2,566 26 4,026 (2,392)Net loss$(38,764) $(29,918) $(141,752) $(90,195)Other comprehensive loss: Unrealized gain (loss) on marketable securities, net 22 — (429) — Comprehensive loss (38,742) (29,918) (142,181) (90,195)Net loss per share, basic and diluted$(0.90) $(0.77) $(3.49) $(2.88)Weighted average shares outstanding - basic and diluted 42,950,876 38,916,838 40,617,465 31,334,154 Prometheus Biosciences, Inc.Condensed Consolidated Balance Sheets (in thousands)(unaudited) December 31, 2022 December 31, 2021Assets Cash and cash equivalents$292,423 $257,254 Short-term investments 403,329 — Other current assets 12,399 8,129 Total current assets 708,151 265,383 Other assets 32,622 2,418 Total assets$740,773 $267,801 Liabilities and Stockholders' Equity Current liabilities$22,817 $16,442 Long-term liabilities 41,988 16,204 Total liabilities 64,805 32,646 Total stockholders' equity 675,968 235,155 Total liabilities and stockholders' equity$740,773 $267,801 Contacts:Noel KurdiVP Investor Relations and Communications(646) 241-4400nkurdi@prometheusbiosciences.com Media contact:Juniper PointAmy Conrad(858) 914-1962media@prometheusbiosciences.com