Infliximab

Centocor位于宾夕法尼亚州的Malvern市，成立于1979年，创始人是电气工程师Michael Wall和病毒与免疫学家Hilary Koprowski。虽然Centocor早在1999年就与强生合并，但是提及biotech的发展史，它却是不可缺失的元素。Centocor不仅是单抗药物的先驱，还为初创型biotech公司开创了全新的发展模式。Centocor与众不同的地方是巧妙地利用科学技术带来的商业机会，并通过“借鸡生蛋”的方式建立起了产品管线，让公司以最快的速度实现了盈利。 一、Centocor的诞生 1973年，基因工程技术问世，这项诺奖级的技术催生出一类全新的公司——生物技术（biotech）公司。基因泰克公司（Genentech）被视为biotech的开端，该公司成立于1976年，旨在利用基因重组技术开发和商业化创新药。然而在基因工程技术问世之后的两年里，又出现了另一项诺奖级的生物技术——杂交瘤技术，而Centocor就是最早开发该技术的公司之一。 Michael Wall是一位毕业于麻省理工学院的电气工程师，早年在电气行业工作。上世纪60年代中期，Wall从电气行业转行到了生物行业，成立了Flow Laboratories。1969年，Wall将该公司卖给了General Research Corp，但Wall继续为General Research运营了10年。在此期间，Flow主要生产和销售细胞发酵相关的产品，这使Wall对生物技术行业产生了浓厚的兴趣。Centocor的另一位创始人Hilary Koprowski是Wistar研究所的所长，著名的病毒与免疫学家。Koprowski是最早研究单克隆抗体（单抗）的科学家之一，于1978年获得了两项制造单抗的重要专利。他本想将那两项专利授权给勃林格殷格翰（BI），但经过大半年的拉锯谈判，BI并没有买下专利权益。这让Koprowski很恼火，于是才有了自己组建公司的想法。最终，Koprowski决定与Wall合作，于1979年5月在费城组建了Centocor。 基于实验室长期的研究，Koprowski坚信Centocor很快就能开发出诊断性的单克隆抗体。Centocor之所以选择开发诊断类产品，是因为诊断性产品的开发难度和开发周期远小于治疗性产品。尽管如此，治疗性产品也被纳入了公司的远期发展规划。在公司成立后不久，Ted Allen和Hubert Schoemaker先后加入了公司，他们的到来为毫无市场开发经验和产品设计经验的Centocor起到了至关重要的作用。 二、借鸡生蛋 与众多初创型biotech公司一样，缺钱是永远无法回避的话题。在公司成立之初，Wall利用他的个人影响力到处找投资。1979-1981年间，Centocor通过私募股票筹集了约700万美元，但这点钱对一个公司而言简直是杯水车薪，Centocor如想存活与发展，必须快速产生收益，而合作是该公司成功的秘诀。 虽然当今的初创型biotech都会努力地建立合作，但在70年代并不是这样。当时的biotech几乎都是风险投资资助下的内部研究——从候选分子发现、产品开发到上市后的生命周期管理都是在自己的实验室完成，而Centocor是最早打破这种“in - house”研发模式的biotech。在长达20年的时间里，Centocor一共推出了10个产品，而这些产品全部来自于授权引进。就如Schoemaker后来回忆的那样，从外部引进项目比自己从头开发要便宜的多。因为广泛的合作， Centocor在1984年实现了微盈利，而与Centocor同一时期成立的基因泰克、安进、Biogen却还在为“年底的揭不开锅”而发愁。 由于Koprowski的关系，Wistar研究所成为Centocor的首个合作伙伴。1979年，Centocor与该研究所签署了三项许可协议，以2.5万美元的首付款外加4%~6%的衍生产品销售额提成为代价，获得了4项专利。为了便于合作，Centocor还与Wistar建立了开创性的联盟机制，这极大地增加了合作的灵活性。1980年，《Bayh - Dole法案》获得通过，该法案为美国政府资助的学术成果转化提供了指导，非常有利于科研合作的达成。随后的几年里，Centocor又与Scripps临床和研究基金会、麻省总医院等知名科研机构达成合作，“廉价”地引进了大量的项目。到1990年时，与Centocor建立合作的研究机构数量达到了80多个。 除了产品开发方面的合作，Centocor也试图通过建立销售端的合作，以节省市场开发成本和渠道建设成本。当时的诊断市场规模约为20亿美元，产品均以化学合成的小分子为基础，竞争较为激烈，而且主要的市场份额被雅培、罗氏、华纳-兰伯特等巨头控制。这些巨头都基于自己的专有诊断设备开发了独立的检测和结果分析体系，测试试剂、分析方法互不兼容。因此，Centocor开发的以单抗为基础的诊断方法，不仅不会被视为竞争对手，还可能成为争相拉拢的合作对象——有助于他们推出新产品打破市场格局。为了建立合作，Centocor在产品设计时就做到了与巨头们的诊断系统兼容。1981年，雅培成为了该公司的首个合作伙伴。次年，Centocor的首个产品获批上市。随着获批产品的不断增加，Centocor广泛与诊断公司建立了合作，不仅授权他们销售和使用试剂盒，还允许他们基于Centocor生产的抗体二次开发产品。 正如当初商业规划的那样，Centocor很快就迎来了自己的产品。1982年，FDA批准了Centocor的狂犬病诊断试剂，这使得该公司成功IPO。1983 -1986年间，Centocor又成功推出了一款乙肝诊断产品和四款癌症相关的诊断产品。由于当时美国和诸多发达国家都要求在输血前进行乙肝筛查，这使得Centocor的乙肝检测试剂盒成为了爆品。另外，四款癌症诊断产品的表现同样不俗，到1990年，Centocor已经占领了全球四分之一以上的癌症抗体检测市场。 三、造影剂的沉浮 1982年，Centocor推出了首个产品，这使得该公司成功IPO，募集到资金约2100万美元。1983年，Centocor又推出了两款诊断产品，由于销售表现不错，在1984年实现了微盈利。随着获批产品的不断增加，Centocor的营收从1985年的2000万美元迅速增长至1989年的7200万美元。 然而进入壁垒越低的赛道越容易发生内卷，随着技术的不断成熟，越来越多的企业进入了赛道，他们基于市售的抗体很快就能开发出诊断产品，到1983年时，美国已有上百家企业布局了抗体诊断技术，仅获批上市的产品就有20多个，处于研发阶段的产品更是数不胜数。为此，Centocor不得不考虑开辟新赛道。1985年，Centocor新开设了造影剂部门，并开始研发三种针对癌症和心血管系统疾病的造影剂。当时的分析师认为单抗造影剂市场将快速发展，仅癌症和心血管系统疾病的潜在市场将在1988年达到三到四亿美元。1986年，Centocor再次进行了公开募股，为了获得投资者的认可，Centocor对外宣称很快就能推出造影剂产品。1989年8月，Centocor用于心血管系统疾病诊断的造影剂Myoscint在欧洲获批上市，趁此机会，该公司又一次公开募股。 虽然Centocor向投资者兑现了“很快推出产品”的承诺，但销售表现远不及预期。早在1987年，就有金融分析师预测Centocor的心血管造影剂的年销售额有望达到3-4亿美元，但在此后的20年里，全球单抗类造影剂的市场规模一直也没能超过1亿美元。虽然单抗的确是很好的靶向造影工具，但体内代谢时间过长，这大幅延缓了影像读取和诊断结果的获得时间，不仅如此，当时市面上已有对患者伤害更小、结果更精准的诊断产品，这意味着Myoscint刚上市就被淘汰了。不过该产品也并非一无是处，Myoscint可以很好地识别心脏移植后的排斥反应和心肌炎，后来被超适应症用于心脏移植后排斥反应的监测。 尽管Myoscint在欧洲的销售表现不佳，但Centocor仍不肯放弃，努力挣扎着将Myoscint推向美国和日本市场。由于申报资料的问题，Myoscint屡次被撤回，直到1996年才最终获得FDA批准。同年，日本也批准了该产品。不过这些似乎都是无畏的挣扎，该产品还是因为销售不理想而在1999年退市。 三、冒险之旅 尽管70年代末期已经诞生了多家biotech，但大多都是利用基因工程技术合成人体激素，如胰岛素、生长激素、代谢酶等，这些药物的安全有效性都是已知的，主要解决的是发酵工艺的问题，而单抗是此前人类从未接触过的一类物质，大部分人并不知晓它们的潜在用途，况且以当时的技术做出来的鼠源单抗有非常强的免疫原性，疗效差而不良反应大，离商业化非常遥远。然而Centocor作为能最早生产单抗的公司，单抗治疗也被纳入到长期战略，为了解决当时单抗存在的问题，Centocor很早就布局的单抗的人源化研究。 说实在的，在当时的人们看来，这是一种纯粹的冒险，不过世界上从来不缺探险者，Centocor很快就找到了战略合作伙伴。1980年，FMC corporation同意出资1240万美元与Centocor成立合资公司（JV），以研究单克隆抗体的人源化。经过几年的努力，研究取得了巨大的进展，而且做出了候选分子。然而在初见苗头之时，Centocor放弃了合作。1986年，Centocor用137万股买断了JV公司人源化抗体的独家权益，又从加州大学引进了另一种人源化抗体HA-1A（ebacumab）。到1988年，Centocor的研究团队开发出了30多个单抗分子，并计划提交12个分子的临床试验申请（IND）。 Ebacumab是一种针对革兰阴性菌所致败血症的药物，当时的美国，每年有10万人死于这种疾病，如果开发成功，有望成为一款年销售额达10-15亿美元的产品，而Centocor也有望因此一步登天——成为一家大型制药公司。小规模的临床试验初步证明了该产品的安全有效性，让Wall和Schoemaker雄心勃勃，他们认为诊断业务产生的利润和技术合作收入能够推动Centocor在2000年前后发展成默沙东一样的制药巨头——默沙东是当时的全球第一大制药公司。一开始，他们还坚持通过JV的形式打造这项业务，但在某华尔街咨询顾问的“煽动”下，让他们产生了肥水不流外人田的想法。为了独自开发产品，Centocor在1986-1992年间进行了9次股权或债务融资，筹集资金达5亿美元。而这些钱几乎都用在了临床试验、荷兰工厂建设和销售队伍建设上。 1991年2月，《新英格兰医学杂志》发表了ebacumab的三期临床试验结果——ebacumab治疗组的败血症患者数量比对照组减少了39%，死亡率下降了47%。随后不久，欧洲率先批准了该药物。同年9月，FDA疫苗和相关生物制品顾问委员会也建议批准该产品上市，而Centocor也做好了上市前的准备。然而人红是非多，在ebacumab即将上市之际，Centocor被竞争对手Xoma Corporation起诉专利侵权——Xoma从加州大学的另一分校区引进了一款相同靶点的单抗（edobacomab），但这是一款鼠源单抗，在Xoma和辉瑞的共同推进下，edobacomab已领先ebacumab几个月提交了上市申请。为了抵抗ebacumab的竞争，Xoma联合辉瑞向Centocor发起了专利战。一开始，Schoemaker想通过和解的方式解决问题，但当时的业务总裁兼首席运营官James Wavle认为和解会导致交叉授权，进而引起收益减少。最终，因为贪婪，ebacumab功亏一篑——Centocor不但没能赢下官司，还被迫公开了有关ebacumab试验设计和结果分析的信息，而这些信息正好又为竞争对手的“吹毛求疵”提供了依据。 专利战引起了轩然大波，并招来越来越多的质疑。美国独立卫生院（NIH）的科学家发现ebacumab在动物试验中不但无法预防败血症，而且还有致命风险。几乎在同一时期，该产品也引起了欧洲医生的质疑。一是药物定价过高，二是没有显著的临床获益。随着质疑声的不断增多，FDA也引起了重视，但这种情况下，Centocor还试图通过向FDA施加压力以尽快获得药物的批准。最终，Centocor在1992年4月迎来了坏消息，FDA以“需要更多临床数据”为由，拒绝批准ebacumab (Centoxin)。 四、艰难的翻身之战 1990年，ebacumab的临床开发接近尾声，而Centocor也为这款具有重磅炸弹潜质的新药做足了上市前的准备。一方面，该公司在欧洲建设了工厂，以满足欧洲市场的正常供货，另一方面，该公司还招募了大量的市场和营销人员，以快速形成推广和铺货能力。因为这些能力的建设，公司的员工总数从几百人暴增至1500人。因为ebacumab的失败，这些资源再无用武之地，反而成为沉重的财务负担。为了及时止损，Wall在ebacumab被拒绝批准之后，迅速推动了公司重组。前前后后裁掉了三分之二的员工，Hubert Schoemaker接任了董事长，David Holveck接任了CEO。Wall离开了董事会，公司从此失去了创始人的元素。 虽然遭遇了巨大挫折，但Centocor还没到穷途末路的地步。一方面FDA拒绝批准ebacumab的原因是临床证据不足，这也就是说该产品还有挽救的希望，另一方面，该公司管线里还有多个药物，而且ReoPro（阿西单抗）已经进入到三期临床试验。一切都要大量的资金，然而彼时的Centocor已在ebacumab上烧了数亿美元，而且股价因该产品的失败而暴跌，Wall和Schoemaker收到了大量的投资者诉讼。为了起死回生，Centocor只能想其他办法融资。 在Centocor的危急关头，礼来成了雪中送炭者。在ebacumab被FDA拒绝后不久，礼来与该公司达成了战略合作。礼来用5000万美元现金收购了Centocor 5%的股份，并同意另支付5000万美元用于继续开发ebacumab，如果ebacumab开发失败，则继续支付2500万美元用于支持阿西单抗的开发，而作为回报，礼来将获得阿西单抗和ebacumab的销售权益。在礼来的资金支持下，1992年7月，Centocor又对ebacumab开展了一项三期临床试验，但因为设计方面的缺陷，该试验在1993年宣告失败。同年，ebacumab在欧洲停止销售，Centocor步入了至暗的时刻，财务报表上也出现了资不抵债，净资产为-1919万美元。 1993年，ebacumab宣告彻底失败，原本预想的重磅炸弹，仅在1992年销售了一个完整财年，销售额也仅为1255万美元。Ebacumab的失败对Schoemaker等人造成了巨大的打击。不过俗话说，永远不要把全部的鸡蛋放在同一个篮子里，因为Centocor还有其他药物。在礼来的帮助下，阿西单抗于1994年同时获得了欧盟和美国的批准，Centocor的股价也因此而快速反弹。随着阿西单抗销售额的快速增长，Centocor在1997年再次实现了盈利，净利润为1113万美元。 除了礼来，Centocor还与先灵葆雅、史克必成等企业建立了合作，到1998年底，Centocor已经拥有4大上市的治疗药物——ReoPro（阿西单抗）、Retavase（瑞替普酶）、Panorex（edrecolomab）和Remicade（英夫利昔单抗），年销售额达到了3.17亿美元，此外还有多个项目处于不同的临床试验开发阶段。为了发展治疗药物，Centocor将诊断业务单独拆分，并逐渐剥离，成为一家纯粹的制药公司。 五、Centocor带来的启示 在形势一片大好之际，Centocor却仅以49亿美元的价格卖给了强生，不得不让人惋惜，但导致这种结果的原因是多重的。第一，Centocor与多家公司有专利纠纷，而这些纠纷几乎都是在项目授权时就埋下了“祸根”；第二，跨世纪期间，制药行业非常“动荡”，像Centocor那样既有产品、又有技术，而且非常具成长潜力的公司绝对是制药巨头争相追逐的对象，与其被强行兼并，不如主动找“靠山”，至少还能保持独立运营；第三，或许是屡次挫折让Schoemaker等人的雄心不再，他们认为Centocor没有足够的资金持续支持烧钱的研发，也没有足够的产能和销售能力将产品的市场价值最大化；第四，董事会已经没有创始人元素，是一个纯市场化的公司，创业时的那份“情怀”早已不再；第五，Schoemaker低估了英夫利昔单抗的发展潜力；第六，“收购”其实是合并，1999年底，强生通过用4500万股交换Centocor的7100万股完成合并，而Centocor以子公司的身份独立运营。后来，强生安排Centocor与另一家子公司Ortho Biotech合并为Centocor Ortho，而该公司是强生制药业务快速增长的主要驱动力。 虽然因为被强生收购而消失在历史的长河，但Centocor在biotech的发展史上始终是不可磨灭的一笔。Centocor的成长之路为后人留下了以下几点启示： 启示一：商业机会的识别与定位。Centocor是最早布局单抗的公司之一，被后人称为单抗领域的先驱，但该公司并没有一开始就布局单抗治疗，而是选择了诊断。由于诊断产品研发更简单、更容易获得批准，这让该公司实现了快速盈利。 启示二：开创性地打破了in - house的研发模式。Centocor商业模式是从外部拿项目，用很低的成本就从各科研机构授权到大量的候选药物，这使得该公司的研发费用较低，烧钱速度与程度远不及基因泰克、安进等biotech公司。 启示三：Centocor成功的一大秘诀是一有机会就募股，而不是在缺钱的情况下才融资。在公司的高光时刻，往往只需要稀释很少的股份就能筹集到大量的资金，而这些钱可以用于扩大产品管线或企业规模，以换取更多的净现值。 启示四：处理好与利益相关者的关系。Centocor之所以多次遭受危机，一是没处理好与竞争对手的关系，导致了Xoma的专利诉讼，而该诉讼是ebacumab “翻船”的导火索；二是没有处理好客户的关系，因定价过高而导致了医生的质疑和支付部门的抵制，而这些是推动ebacumab遭遇滑铁卢的关键原因；三是没处理好与FDA的关系，使得药物迟迟不被批准，除了ebacumab，Myoscint也经历了相似的问题。 参考文献略 相关阅读——另一家Michael Wall创办的著名公司：制剂创新巨头Alkermes的发家故事：万里长城不是一朝一夕建立起来的 本文节选自新版《跨国药企成功启示录》，任何媒体、公众号、网站转载本文都会被起诉侵权。作者：魏利军，北京药眼信息咨询有限公司创始人，著有《跨国药企成功启示录》、《仿制药企兴衰启示录》和《制药企业的战略与产品管线》，从事产品线规划、产品立项和战略策划相关的工作十余年，担任过多个企业的产品战略顾问。如对本文有建议或发行内容有错误，请不吝赐教，作者微信Voyager88

Celltrion USA has expanded access to ZYMFENTRA ® (infliximab-dyyb), the first and only FDA-approved subcutaneous (SC) infliximab, to a significant share of the U.S. market The availability of ZYMFENTRA will support greater patient access and choice while helping to drive greater affordability to patients and health care systems JERSEY CITY, N.J., Oct. 31, 2024 /PRNewswire/ -- Celltrion USA announced today that, through continued partnership with key PBMs and health plans, the company has expanded access to ZYMFENTRA ® (infliximab-dyyb), the first and only U.S. Food and Drug Administration (FDA)-approved subcutaneous infliximab. With these partnerships Celltrion has now secured comprehensive access across the US health care system. ZYMFENTRA has attained access to a significant share of the U.S. market, providing an increase in availability to patients and prescribers. This achievement reflects unmet needs of patients, providers and payers, as well as Celltrion USA's ability to deliver on our strong heritage of supply, manufacturing and commitment to biologics. "Our extensive engagement with PBMs and health plans from the outset have led to the comprehensive expanded access for ZYMFENTRA in a short time frame," said Thomas Nusbickel, Celltrion USA Chief Commercial Officer (CCO). "This achievement underscores ZYMFENTRA's unique and innovative therapeutic advantages, and we look forward to expanding our outreach to deliver its treatment benefits to as many patients in the U.S. as possible." ZYMFENTRA was approved by the FDA in October 2023 through the Biologics License Application (BLA) under the 351 (a) pathway of the Public Health Service Act (a "stand-alone" BLA). ZYMFENTRA is the first FDA-approved subcutaneous infliximab for the treatment of moderately to severely active ulcerative colitis and moderately to severely active Crohn's disease. About Celltrion USA Celltrion USA is Celltrion's U.S. subsidiary established in 2018. Headquartered in New Jersey, Celltrion USA is committed to expanding access to innovative biologics to improve care for U.S. patients. Celltrion currently has five biosimilars approved by the U.S. FDA: INFLECTRA® (infliximab-dyyb), TRUXIMA® (rituximab-abbs), HERZUMA® (trastuzumab-pkrb), VEGZELMA® (bevacizumab-adcd), and YUFLYMA®(adalimumab-aaty) as well as a novel biologic ZYMFENTRA®. Celltrion USA will continue to leverage Celltrion's unique heritage in biotechnology, supply chain excellence, and best-in-class sales capabilities to improve access to high-quality biopharmaceuticals for U.S. patients. For more information, please visit: . About ZYMFENTRA® (infliximab-dyyb) [1] ZYMFENTRA is a prescription medicine used as an injection under the skin (subcutaneous injection) by adults for the maintenance treatment of: moderately to severely active ulcerative colitis following treatment with an infliximab product given by intravenous infusion (IV), moderately to severely active Crohn's disease following treatment with an infliximab product given by intravenous infusion (IV). ZYMFENTRA blocks the action of tumor necrosis factor-alpha (TNF-alpha), a protein that can be overproduced in response to certain diseases and cause the immune system to attack normal, healthy parts of the body. ZYMFENTRA® (infliximab-dyyb) was approved by the FDA through the Biologics License Application (BLA) under the 351 (a) pathway of the Public Health Service Act (a "stand-alone" BLA). ZYMFENTRA is considered a new biologic with a first-approved subcutaneous administration form and thus will be under patent protection for its dosage form by 2037 and for its route of administration by 2040. Indication and Important Safety Information ZYMFENTRA is a prescription medicine indicated in adults for maintenance treatment of: Moderately to severely active Crohn's disease following treatment with an infliximab product administered intravenously. Moderately to severely active ulcerative colitis following treatment with an infliximab product administered intravenously. It is not known if ZYMFENTRA is safe and effective in children under 18 years of age. What is the most important information I should know about ZYMFENTRA? SERIOUS INFECTIONS Patients treated with ZYMFENTRA are at increased risk for developing serious infections involving various organ systems and sites that may lead to hospitalization or death. Discontinue ZYMFENTRA if a patient develops a serious infection or sepsis. Reported infections include: Active tuberculosis (TB), including reactivation of latent TB. Patients frequently presented with disseminated or extrapulmonary disease. Patients should be tested for latent TB before and during treatment with ZYMFENTRA. Treatment for latent infection should be initiated prior to treatment with ZYMFENTRA. Invasive fungal infections, including histoplasmosis, coccidioidomycosis, candidiasis, aspergillosis, blastomycosis, and pneumocystosis. Patients may present with disseminated, rather than localized, disease. Empiric anti-fungal therapy should be considered in patients at risk for invasive fungal infections who develop severe systemic illness. Bacterial, viral, and other infections due to opportunistic pathogens, including Legionella and Listeria. The risks and benefits of treatment with ZYMFENTRA should be carefully considered prior to initiating therapy in patients with chronic or recurrent infection. Closely monitor patients for the development of signs and symptoms of infection during and after treatment with ZYMFENTRA, including the possible development of TB in patients who tested negative for latent TB infection prior to initiating therapy. Risk of infection may be higher in patients greater than 65 years of age, patients with comorbid conditions and/or patients taking concomitant immunosuppressant therapy. In clinical trials, other serious infections observed in patients treated with infliximab included arthritis bacterial, pneumonia, and urinary tract infection. MALIGNANCIES Malignancies, some fatal, have been reported in children, adolescents, and young adults treated with TNF blockers, including infliximab products. Approximately half of these cases were lymphomas, including Hodgkin's and non-Hodgkin's lymphoma. The other cases represented a variety of malignancies, including rare malignancies that are usually associated with immunosuppression and malignancies that are not usually observed in children and adolescents. The malignancies occurred after a median of 30 months after the first dose of therapy. Most of the patients were receiving concomitant immunosuppressants. Post-marketing cases of hepatosplenic T-cell lymphoma, a rare type of T-cell lymphoma, have been reported in patients treated with TNF blockers, including infliximab products. These cases have had a very aggressive disease course and have been fatal. The majority of reported cases have occurred in patients with Crohn's disease or ulcerative colitis, and most were in adolescent and young adult males. Almost all of these patients had received treatment with azathioprine or 6-mercaptopurine concomitantly with a TNF blocker at or prior to diagnosis. Carefully assess the risks and benefits of treatment with ZYMFENTRA, especially in these patient types. In clinical trials of all TNF blockers, more cases of malignancies were observed compared with controls and the expected rate in the general population. In clinical trials of some TNF blockers, including infliximab products, more cases of other malignancies were observed compared with controls. As the potential role of TNF blocker therapy in the development of malignancies is not known, caution should be exercised when considering treatment of patients with a current or a past history of malignancy. Melanoma and Merkel cell carcinoma have been reported in patients treated with TNF blocker therapy, including infliximab products. Periodic skin examination is recommended for all patients, particularly those with risk factors for skin cancer. CONTRAINDICATIONS ZYMFENTRA is contraindicated in patients with a previous severe hypersensitivity reaction to infliximab-dyyb, other infliximab products, any of the inactive ingredients of ZYMFENTRA or any murine proteins (severe hypersensitivity reactions have included anaphylaxis, hypotension, and serum sickness). HEPATITIS B VIRUS REACTIVATION TNF blockers, including infliximab products, have been associated with reactivation of hepatitis B virus (HBV) in patients who are chronic carriers. Some cases were fatal. Patients should be tested for HBV infection before initiating ZYMFENTRA. For patients who test positive, consult a physician with expertise in the treatment of hepatitis B. Exercise caution when prescribing ZYMFENTRA for patients identified as carriers of HBV, and monitor closely for active HBV infection during and following termination of therapy with ZYMFENTRA. Discontinue ZYMFENTRA in patients who develop HBV reactivation and initiate antiviral therapy with appropriate supportive treatment. Exercise caution when considering resumption of ZYMFENTRA, and monitor patients closely. HEPATOTOXICITY Hepatobiliary disorders, including acute liver failure, jaundice abnormal hepatic function, hepatic steatosis, hepatitis, hepatotoxicity, hyperbilirubinemia, and non-alcoholic fatty liver, have been reported in patients receiving infliximab products post-marketing. Some cases were fatal or required liver transplant. Aminotransferase elevations were not noted prior to discovery of liver injury in many cases. Patients with symptoms or signs of liver dysfunction should be evaluated for evidence of liver injury. If jaundice and/or marked liver enzyme elevations (eg, ≥5 times the upper limit of normal) develop, ZYMFENTRA should be discontinued, and a thorough investigation of the abnormality should be undertaken. CONGESTIVE HEART FAILURE Cases of worsening congestive heart failure (CHF) and new onset CHF have been reported with TNF blockers. Some cases had a fatal outcome. In several exploratory trials of other TNF blockers in the treatment of CHF, there were greater proportions of TNF-blocker-treated patients who had CHF exacerbations requiring hospitalization or increased mortality. ZYMFENTRA has not been studied in patients with a history of CHF and ZYMFENTRA should be used with caution in patients with CHF. HEMATOLOGIC REACTION Cases of leukopenia, neutropenia, thrombocytopenia, and pancytopenia (some fatal) have been reported. The causal relationship to infliximab-product therapy remains unclear. Exercise caution in patients who have ongoing or a history of significant hematologic abnormalities. Advise patients to seek immediate medical attention if they develop signs and symptoms of blood dyscrasias or infection. Consider discontinuation of ZYMFENTRA in patients who develop significant hematologic abnormalities. HYPERSENSITIVITY AND OTHER ADMINISTRATION REACTIONS In post-marketing experience, serious systemic hypersensitivity reactions (including anaphylaxis, hypotension, and serum sickness) have been reported following administration of infliximab products. If an anaphylactic or other clinically significant hypersensitivity reaction occurs, institute appropriate therapy and discontinue ZYMFENTRA. INJECTION SITE REACTIONS In clinical studies, localized injection-site reactions were reported following administration of ZYMFENTRA. If a clinically significant injection-site reaction occurs, institute appropriate therapy and discontinue ZYMFENTRA. NEUROLOGIC REACTIONS Agents that inhibit TNF have been associated with central nervous system (CNS) manifestation of systemic vasculitis, seizure, and new onset or exacerbation of CNS demyelinating disorders, including multiple sclerosis and optic neuritis, and peripheral demyelinating disorders, including Guillain-Barré syndrome. Exercise caution when considering ZYMFENTRA in patients with these disorders and consider discontinuation if these disorders develop. RISK OF INFECTION WITH CONCURRENT ADMINISTRATION OF OTHER BIOLOGICS PRODUCTS Serious infections and neutropenia have been reported with concurrent use of ZYMFENTRA with other immunosuppressive biological products. The concurrent use of ZYMFENTRA with other immunosuppressive biological products used to treat UC and CD may increase the risk of infection and is not recommended. RISK OF ADDITIVE IMMUNOSUPPRESSIVE EFFECTS FROM PRIOR BIOLOGICAL PRODUCTS Consider the half-life and mode of action of prior biological products to avoid unintended additive immunosuppressive effects when initiating ZYMFENTRA. AUTOIMMUNITY Treatment with TNF blockers may result in the formation of autoantibodies and in the development of a lupus-like syndrome. Discontinue ZYMFENTRA treatment if symptoms of a lupus-like syndrome develop. VACCINATIONS AND USE OF LIVE VACCINES/THERAPEUTIC INFECTIOUS AGENTS Prior to initiating ZYMFENTRA, update vaccinations in accordance with current vaccination guidelines. Live vaccines or therapeutic infectious agents should not be given with ZYMFENTRA due to the possibility of clinical infections, including disseminated infections. At least a 6-month waiting period following birth is recommended before the administration of any live vaccine to infants exposed in utero to ZYMFENTRA. ADVERSE REACTIONS In clinical trials with ZYMFENTRA, the most common adverse reactions occurring in ≥3% of ZYMFENTRA -treated patients included site reactions, COVID-19, anemia, arthralgia, infection site reaction, increased alanine aminotransferase and abdominal pain for UC, and COVID-19, headache, upper respiratory tract infection, injection site reaction, diarrhea, increased blood creatine phosphokinase, arthralgia, increased alanine aminotransferase, hypertension, urinary tract infection, neutropenia, dizziness and leukopenia for CD. Please click for Full U.S. Prescribing Information. Globally, prescribing information varies; refer to the individual country product label for complete information. For further information please contact: Celltrion Global PR Team [email protected] SOURCE Celltrion USA WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED