Riociguat

为打造全球ADC/RDC未来产业高地，成都医学城拟于2024年4月18日-19日举办首届未来XDC新药大会！大会以“共创偶联药物产业未来”为主题，由同写意策划，安排一场主论坛和九场主题论坛，邀请“政、产、学、研、金、媒”各领域专家，通过“成果发布、主题演讲、热点对话、表彰颁奖、展览展示”五位一体的多元化的组织形式，迸发更多XDC产业新科技、新业态、新模式，构建XDC产业全新生态，触摸医药产业未来脉动。市值并非万能的。对于一家生物制药上市公司而言，考虑到投资者的专业知识、情绪等因素，市值涨跌很有可能与业务的实际发展相背离。 不过，更多时候，市值的风向标作用确有其事。市值越高，往往意味着药企可以做越多的事情，例如增发。特别是面临资本寒冬，当IPO窗口收紧、VC趋于保守，拥有稳健募资途径的公司，赢面无疑大出数成。 2024年的交易并购活动风潮，也能从市值上进行理解。有目共睹，专利悬崖问题削弱了市场对MNC的信心，然而体量优势为后者保留了不少倒手腾挪的空间。 大体上说，在生物制药行业走出低谷之际，关注那些市值排名前列的上市公司，将是把握创新机会的一条线索。截至4月5日，市值突破千亿美元的药企共计14家。其中，1000亿到2000亿美元阵营最为庞大，占比超过一半。而在5000亿美元档位之上，仅有诺和诺德、礼来两家巨头身影。 不论是什么成就了这份名单里的公司，在2024年以后的行业发展中，它们或许都将发挥重要作用。1再生元：1035亿美元 再生元2023年的财报中，Dupixent创收115.9亿美元，同比增长了7.8%，但净利润却下降了8.9%。今年2月，再生元跨入千亿美元市值药企俱乐部，目前市值约为1035亿美元。 用于治疗眼部疾病的Eylea正面临着竞争和专利挑战，安进和三星生物等公司推出生物仿制药，尽管如此，该药在2023年仍取得57.2亿美元的销售额。随着2023年第三季度稍晚推出延长给药间隔的新品Eylea HD，再生元有望保持该药的市场主导地位。 另外，与赛诺菲共同销售的Dupixent一直是再生元的重要收入来源，这款产品主要针对特应性皮炎和哮喘等一系列免疫疾病。 2023年，Dupixent创收115.9亿美元，同比增长33%。今年1月，FDA批准Dupixent用于治疗1岁及以上患有嗜酸性粒细胞性食管炎的儿童。这使它成为该领域首个针对儿童的治疗药物，有望进一步增加其销售额。 FDA最近还接受了再生元关于linvoseltamab治疗复发难治性多发性骨髓瘤的BLA，预计8月8月做出监管审批决定。 2BMS：1040亿美元 凭借1040亿美元的市值，BMS近期进入了市值千亿美元的药企俱乐部。2023年，BMS的总收入为450亿美元。 BMS的业务重点横跨癌症、心血管、免疫和纤维化治疗，其战略重点是利用收购来加强其产品组合，并解决迫在眉睫的专利悬崖问题。自去年12月以来，BMS已宣布完成三项主要收购，它们旨在提高BMS的杠杆率，确保公司达到或超过在2025年后的指导目标。 其中，BMS用140亿美元买下Karuna，由此获得治疗精神分裂症和阿尔茨海默病的新型药物KarXT，增强其神经科学产品组合。 今年1月，对Mirati的收购也宣告完成。这项交易将已商业化的肺癌药物Krazati（adagrasib）引入BMS的产品管线，此外还有几项前景看好的临床资产正在开发。次月，RayzeBio正式并入BMS，带来基于锕的放射性药物平台，包括一款领先的实体瘤药物RYZ101。 在内部开发方面，CAR-T细胞疗法Abecma前线治疗三级暴露的复发难治性多发性骨髓瘤（RR MM）患者，在1月获得CHMP的支持意见。随后，ODAC也以8比3的投票结果，认可Abecma用于相对前线治疗RR MM的获益。 3Vertex：1050亿美元 Vertex在2023财年的营收为99亿美元，最新市值为1050亿美元，也跻身千亿美元市值药企俱乐部。 2023年对这家Biotech来说是重要的一年，核心产品Casgevy在美国、英国、沙特阿拉伯王国和巴林成功步入商业化。这不仅是公司的里程碑，也是整个CGT的里程碑。 事实上，Casgevy是首个获得批准的基于CRISPR的基因编辑疗法。今年2月，EC同意附条件批准Casgevy上市。然而，这款划时代产品未来的问题仍然没有答案，因为每名患者的治疗费用高达220万美元，关于报销的讨论仍在进行中。 Vertex的产品线中不乏颇具前景的疗法，包括VX-522，一种治疗囊性纤维化（CF）的CFTR（囊性纤维化跨膜传导调节因子）mRNA疗法，正在进行I期试验；VX-548，一种治疗急性和神经性疼痛的非阿片类药物，正在进行III期试验，一个多月前取得了积极结果；Exa-cel，针对镰状细胞病和输血依赖性β-地中海贫血，正在进行II/III期试验。 其他值得关注的项目包括：针对1型糖尿病的VX-880和VX-264，正在进行I/II期试验；针对癌症的VX-970和VX-803/VX-984，正在进行早期试验。 该公司的最近战略举措，包括与龙沙合作建造细胞疗法生产设施，以支持其1型糖尿病细胞疗法产品组合的开发和商业化。 4赛诺菲：1096亿美元 总部位于法国巴黎的赛诺菲，2023年营收468亿美元（431亿欧元）。当前，这家MNC的市值为1096亿美元。 2023年10月，赛诺菲宣布下调2024年利润预期，作为其“全力致胜”战略的一部分，随后公司股价下跌19%。利润预期降低的原因是研发投入增加，赛诺菲计划剥离消费者护理部门，更加聚焦药物研究。该公司放弃了2025年的营业利润率目标，更强调长期盈利能力。 这一战略转移是其专注于癌症、罕见病和糖尿病药物的一部分努力。赛诺菲还计划为创新进行大量研发投资和成本节约。 2024年的最新进展表明，赛诺菲正在努力扩大其生物技术领域的版图。该公司投资了一家处于临床阶段的Biotech Graviton，并获得FDA对Dupixent治疗儿童嗜酸性食管炎的监管批准。此外，赛诺菲还以17亿美元收购Inhibrx及其药物开发项目INBRX-101。 合作是赛诺菲战略的一个重要方面，涉及肿瘤学、免疫学和数字健康等多个领域。这方面的动态，包括与Exscientia关于新型小分子的项目合作、与ABLBio共同开发帕金森等α-突触核蛋白疾病疗法、与黑石生命科学推动CD38单抗临床开发、与Seagen探索ADC领域等。 5安进：1447亿美元 跨国药企安进2023年营收282亿，同比增长7%，目前市值1447亿美元。其业务涉及心血管疾病、肿瘤/血液学、骨骼健康、炎症、肾脏病和神经系统疾病等多个领域。 今年1月，安进与英伟达合作，涉足药物发现方面的生成式AI模型。公告显示，安进旨在借助世界上最大的人类数据集之一推进药物研发，使用英伟达的DGX SuperPOD来深入了解人类多样性、疾病特异性生物标志物和精准医学模型。 安进的另一个关键举措，是收购了Horizon，标志着其在罕见病药物领域的重大扩张。这项对价高达278亿美元的收购，为安进的产品组合带来了一系列罕见炎症性疾病的先进疗法，包括治疗甲状腺眼病的Tepezza、治疗慢性痛风的Krystexxa和治疗神经性脊髓炎视网膜频谱障碍的Uplizna。 在当前大热的肥胖症领域，安进正加速追赶礼来、诺和诺德。最近，Nature发布的一篇研究，讨论了安进新型疗法AMG133（maridebart cafraglutide，MariTide），该疗法结合GIPR拮抗剂和GLP-1类似物，在减重和改善代谢方面显示出不错的前景。 文章指出，AMG133在肥胖小鼠和猕猴的临床前研究中证明了其有效性，在肥胖症患者中进行的I期临床进一步证实其潜力。 6辉瑞：1510亿美元 因与BioNTech合作开发mRNA疫苗，辉瑞一度重回MNC营收排行榜首位。但现在，它不得不着眼于COVID-19产品组合之外的未来。这家药企的最新市值高达1510亿美元。 2023年，辉瑞的财务业绩反映了其产品需求的变化情况，尤其是Paxlovid和Comirnaty随着进入传统商业市场而面临收入的大幅下降。尽管如此，辉瑞在其他领域的销售额仍实现了增长，例如RSV疫苗Abrysvo在美国的收入，以及2022年第四季度因收购Biohaven获得的Nurtec ODT（欧洲市场商品名Vydura）和Oxbryta的全球收入。 上述这转变凸显了辉瑞向更多元化产品组合发展的战略支点。这家药企的产品种类繁多，可治疗的疾病包括心血管、代谢和疼痛、妇女健康、癌症、炎症、免疫疾病和罕见病。 为巩固其在COVID-19产品之外的增长，近年辉瑞开展一系列巨额交易：以430亿美元收购Seagen，增强其癌症治疗产品组合；以116亿美元收购Biohaven，扩大其偏头痛治疗选择；以54亿美元收购Global Blood，将镰状细胞病治疗药物Oxbryta纳入其产品线。 此外，辉瑞还提出成本削减计划，旨在到2024年底至少节省35亿美元。 7阿斯利康：1646亿美元 阿斯利康总部位于英国剑桥，2023年的总营收为458亿美元。阿斯利康市值达1646亿美元，是英国最重要的制药公司。 阿斯利康的产品组合丰富多样，包括生物制剂、处方药和疫苗。它在肿瘤学领域的努力尤为突出，Enhertu等药物在多种HER2表达的晚期实体瘤中疗效显著。此外，该公司还致力于呼吸系统和心血管疾病等领域，有170多种处于不同开发阶段的管线药物。 交易方面，这家巨头在去年1月完成了对Neogene的收购，加强其在细胞疗法和精准医疗方面的能力。2023年，阿斯利康总共推动了3起新的并购，单纯的管线交易也不少。到今年1月，它最新相中的BD对象是安锐生物。 多年来，阿斯利康一直对中国表现出浓厚的兴趣。2月，它宣布完成对亘喜生物的收购，这是其在中国的首次收购，但肯定不是最后一次。完成该笔收购后不久，阿斯利康就在行业活动上宣布，其第五个战略中心将落户上海。 而监管审批上，2023年初，EC批准Enhertu用于治疗HER2低表达的转移性乳腺癌。今年1月，FDA授予Enhertu针对HER2阳性转移性实体瘤患者的优先审查权。 8诺华：1881亿美元 作为一家总部位于瑞士巴塞尔的全球医疗保健巨头，诺华目前市值为1881亿美元。2023年，它的营收为454亿美元，同比增长8%，净利润也有显著提高。 该公司的产品组合包括治疗癌症、心血管疾病、皮肤病、神经系统疾病、眼科和呼吸系统疾病、血液病、实体瘤、免疫系统疾病和感染的药物。 跟不少MNC类似，诺华通过重大收购和合作，扩大了其产品组合和市场影响力。今年2月，诺华宣布以29亿美元收购MorphoSys，旨在增强其治疗癌症和其他疾病的能力。 此外，同样发生在2月的里程碑，还包括诺华与Erasca就MEK抑制剂Trametinib达成了两项临床试验合作和供应协议；诺华旗下Xolair获得FDA批准，成为首款用于治疗患有一种或多种食物过敏儿童和成人的药物。 9罗氏：2026亿美元 总部位于瑞士巴塞尔的罗氏，2023年营收为663亿美元（587亿瑞士法郎），净利润为140亿美元（124亿瑞士法郎）。当前，这家巨头的市值为2026亿美元。 罗氏的制药部门致力于治疗一系列疾病，包括癌症、心血管疾病、中枢神经系统疾病、皮肤病、乙型和丙型肝炎、艾滋病、炎症和自身免疫性疾病。同时，该公司的诊断部门提供大量体外诊断解决方案，涉及心脏病学、血液学、传染病学、肿瘤学等多个领域。 药品组合方面，罗氏推出了诸如Herceptin、Avastin、Rituxan和Actemra等重磅炸弹，它们极大地支撑了罗氏的业绩。专门针对乳腺癌的Herceptin一直是罗氏主要的收入来源。而罗氏的诊断部门进一步巩固了其市场地位，为包括癌症和心血管疾病在内的各种适应症，提供广泛的工具和检测手段。 今年1月，罗氏与中国的Biotech宜联生物签署了一项许可协议，加入ADC竞争行列。仅两天后，这家瑞士公司又和MOMA达成超20亿美元的合作，以获得后者知识库平台使用权，探索促进癌细胞生长和存活的新型药物靶点。 由于去年COVID-19产品销售额下滑，利润下降，罗氏将在其产品开发部门裁员345人，占该部门员工总数的6%。 10艾伯维：3010亿美元 2023年财年，艾伯维营收为543亿美元，净利润为48.6亿美元。当前，其市值达到3010亿美元。 艾伯维的战略重点包括免疫学（主要药物有Humira、Skyrizi和Rinvoq）和肿瘤学（主要治疗药物有Imbruvica和Venclexta）。2月，该公司将Skyrizi和Rinvoq在2027年的销售额预测提高到270亿美元，反映其对两款产品潜力的乐观态度。这一调整，正值艾伯维迫切希望抵消其重磅炸弹Humira销售额下滑之际。 除核心领域外，艾伯维还积极开展战略合作与收购，以加强其研发管线。例如，同样在2月，该公司宣布与Tentarix合作，开发用于肿瘤学和免疫学的具有条件控制活性的多特异性生物制剂。而此前稍早，艾伯维完成对Immunogen的101亿美元收购。 在监管方面这家MNC也取得里程碑式的进展，包括其偏头痛药物Aquipta去年8月获得EC批准。 11默沙东：3242亿美元 同比增长了1.4%后，默沙东2023年的营收突破至601亿美元。它市值为3242亿美元。 默沙东的产品范围涉及心血管、癌症、免疫疾病、传染病、呼吸系统疾病和糖尿病等治疗领域。制药部门的主要创收产品，包括Keytruda、Bridion、Adempas、Lagevrio、Belsomra、Simponi和Januvia，以及Gardasil和Pneumovax 23等疫苗。 为扩充其肿瘤学产品组合，默沙东已开展多项合作。1月，该公司与LAVA签署协议，评估Keytruda与LAVA-1207联合治疗难治性转移性抗性前列腺癌患者的效果。此外，默沙东还宣布与Unnatural Products联手，开发针对肿瘤治疗靶点的大环类候选药物。 1月，默沙东透露，将以约6.8亿美元的价格收购Harpoon，进一步加强其肿瘤治疗能力。在重磅炸弹Keytruda专利即将到期之际，此举是默沙东实现收入来源多元化战略的一部分。 12强生：3672亿美元 强生2023年收入为852亿美元，同比增长6.5%，目前市值高达3672亿美元。 去年，这家巨头剥离了OTC与保健业务，仅剩下创新药和医疗科技（器械和设备）两大业务。制药部门产品覆盖免疫疾病、癌症、神经系统疾病、传染病、心血管疾病和代谢疾病等；医疗器械领域包括心血管、整形外科、神经血管护理、普通外科、视力保健等。 强生与Pharmacyclics的合作，使其在2月获得FDA对Imbruvica口服混悬液制剂用于成人患者的批准。此外，强生Nipocalimab获得FDA突破性疗法认定，治疗有高风险出现严重新生儿溶血病的孕妇。 3月，强生Rybrevant与化疗的组合疗法获得FDA批准，用于非小细胞肺癌患者的一线治疗。这项批准是基于III期PAPILLON研究，结果表明，与单独化疗相比，该组合显著降低疾病进展或死亡风险。 13诺和诺德：5623亿美元 诺和诺德总部位于丹麦巴格韦尔德，专注于糖尿病、肥胖症、罕见病治疗。这家药企的财务表现强劲，2023年收入大幅增长至337亿美元。当前，它的市值高达5623亿美元。 2023年是GLP-1类药物蓬勃发展的一年，诺和诺德与礼来共同成为焦点。诺和诺德的Wegovy和Ozempic需求量巨大，这些药物的上市时间早于礼来的同类产品。诺和诺德还收购了Catalent的三家灌装工厂，以提高其产量，在供应上获得超越竞争对手的战略优势。 尽管GLP-1类药物面临着前所未有的需求，但这种并购情况仍不常见，此举或许会激发行业的类似举措。这可能也不是诺和诺德在这个方向上的唯一举措。 诺和诺德还在加速产品适应的扩张。2023年8月，司美格鲁肽在III期临床中被证实，可使超重或肥胖成人发生重大不良心血管事件的风险降低20%。另外，诺和诺德也深入到MASH治疗的研究。 14礼来：7456亿美元 如果说最接近万亿美元俱乐部药企，那答案一定是礼来。目前，它的市值自去年一路飙升，目前已经达到7456亿美元。 2023年，礼来以20%的同比增速，将营收拉高至341.24亿美元。该公司产品组合的一大亮点，是其在糖尿病治疗方面的重大贡献，包括Basaglar、Humalog和Trulicity等产品。礼来还通过Zepbound，在肥胖症治疗领域取得了长足进步。 肿瘤学领域，这家巨头推出了Alimta和Verzenio等治疗药物。除此以外，礼来还开发了从类风湿性关节炎（Olumiant）到偏头痛预防（Emgality）等各种疾病的治疗方法，展现其多样化的产品。 礼来与Incyte、BI、罗氏等公司建立了多项战略合作关系。2024年，礼来与AI公司Isomorphic签订协议，为各种靶点确定小分子疗法，以增强其药物研发能力。 展望未来，礼来需要找到应对GLP-1类药物热潮的解决方案，并提高Zepbound的产量。虽然礼来处于有利地位，但这一领域的竞争也很激烈，不仅是近身的Ozempic和Wegovy，还有未来可能出现来自安进的MariTide。参考文献：1.Fourteen 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OPSYNVI ® combines two proven treatments with established efficacy and safety profiles into one tablet to be taken once daily, offering an option that helps to support the implementation of clinical guideline recommendations for early use of combination therapy.1 The comprehensive PAH portfolio at Johnson & Johnson now includes treatments that address all three foundational and guideline-recommended pathways for this rare, progressive disease.2 Approval is based on the results from the pivotal Phase 3 A DUE study, which met its co-primary endpoints, demonstrating significant pulmonary hemodynamic improvement.1 RARITAN, N.J., March 22, 2024 /PRNewswire/ -- Johnson & Johnson today announced that the U.S. Food and Drug Administration (FDA) has approved OPSYNVI® – a single-tablet combination of macitentan, an endothelin receptor antagonist (ERA), and tadalafil, a phosphodiesterase 5 (PDE5) inhibitor – for the chronic treatment of adults with pulmonary arterial hypertension (PAH, World Health Organization [WHO] Group I) and WHO functional class (FC) II-III.1 OPSYNVI ® may be used in patients with PAH who are treatment-naïve or who are already on an ERA, PDE5 inhibitor or both. OPSYNVI ® may be used in patients who are currently treated concomitantly with stable doses of macitentan 10 mg and tadalafil 40 mg (20 mg x 2) as separate tablets.1 PAH is a rare, progressive and life-threatening blood vessel disorder characterized by the constriction of small pulmonary arteries and elevated blood pressure in the pulmonary circulation that eventually leads to right heart failure.2 An estimated 500 to 1,000 new cases of PAH are diagnosed each year in the U.S., classifying the disease as a rare condition.3 The 2022 European Society of Cardiology (ESC) / European Respiratory Society (ERS) clinical guidelines recommend initial combination therapy of an ERA and a PDE5 inhibitor for patients with idiopathic PAH, heritable drug-associated PAH, or PAH-associated with connective tissue disease without cardiopulmonary comorbidities at low or intermediate risk.2 "Clinical guidelines recommend treating patients with initial and sequential dual-combination therapy, regardless of risk at initial diagnosis and follow-up. Historically, this required patients to take multiple pills because no single-tablet combination therapy targeting two or more pathways was available," said Kelly Chin, M.D., Professor of Internal Medicine and Director of the Pulmonary Hypertension Program at UT Southwestern Medical Center, and an investigator in the A DUE study.* "As administration of macitentan and tadalafil together are commonly prescribed for initial therapy for PAH, the introduction of a single tablet combining both is promising for clinicians treating patients as it may help bridge the gap between clinical guidelines and everyday clinical practice, while offering a patient-friendly approach to support initial combination therapy and rapid escalation for the appropriate patients." The FDA's approval of OPSYNVI ® is based on the results from the pivotal Phase 3 A DUE study, in which OPSYNVI ® demonstrated greater reduction in Pulmonary Vascular Resistance (PVR) after 16 weeks versus tadalafil or macitentan monotherapy. OPSYNVI ® has a Boxed Warning due to the risk of embryo-fetal toxicity and requires female patients to enroll in the Macitentan-Containing Products Risk Evaluation and Mitigation Strategy (REMS) program.1 With the approval, Johnson & Johnson now offers a PAH portfolio addressing all three foundational and guideline-recommended pathways – nitric oxide, endothelin, and prostacyclin. "People with PAH often live with the burden of taking many pills each day, which can pose challenges," said James F. List, M.D., Ph.D., Global Therapeutic Area Head, whose team oversees a portfolio of programs including Pulmonary Hypertension at Johnson & Johnson. "We're thrilled to bring this single-tablet combination therapy to patients, as it has the potential to optimize disease management and fulfill a significant unmet need in supporting recently updated treatment guidelines that call for initial or early combination treatment." About OPSYNVI®1 OPSYNVI ® is a combination of macitentan, an endothelin receptor antagonist (ERA), and tadalafil, a phosphodiesterase 5 (PDE5) inhibitor indicated for the chronic treatment of pulmonary arterial hypertension (PAH, WHO Group I) in adult patients of WHO functional class (FC) II-III. Individually, macitentan reduces the risk of clinical worsening events and hospitalization, and tadalafil improves exercise ability. About the A DUE Study1,4 The A DUE study was a double-blind, randomized, active-controlled, multi-center, adaptive, parallel-group study designed to compare the efficacy and safety of OPSYNVI ® to macitentan and tadalafil monotherapies in adult patients with PAH (WHO FC II or III). The three-arm trial enrolled patients from across 76 sites in 16 countries/territories worldwide who were treatment-naïve or on a stable dose of an endothelin receptor antagonist (ERA), or a phosphodiesterase 5 (PDE5) inhibitor, for at least three months. The primary endpoint was change from baseline in PVR at the end of double-blind treatment at 16 weeks and was considered met if macitentan and tadalafil fixed-dose combination (FDC) treatment was superior to both monotherapies. Following the treatment period, patients transitioned to the open-label treatment period for 24 months. INDICATION OPSYNVI® is the combination of macitentan and tadalafil indicated for the chronic treatment of adults with pulmonary arterial hypertension (PAH, WHO Group I and WHO Functional Class [FC] II-III). Individually, macitentan reduces the risk of clinical worsening events and hospitalization, and tadalafil improves exercise ability. IMPORTANT SAFETY INFORMATION CONTRAINDICATIONS Pregnancy: OPSYNVI® may cause fetal harm when administered to a pregnant woman and is contraindicated in females who are pregnant. If OPSYNVI® is used during pregnancy, advise the patient of the potential risk to a fetus. Hypersensitivity: OPSYNVI® is contraindicated in patients with a history of a hypersensitivity reaction to macitentan, tadalafil, or any component of the product. Concomitant Organic Nitrates: OPSYNVI® is contraindicated in patients who are using any form of organic nitrate, either regularly or intermittently. Do not use nitrates within 48 hours of the last dose of OPSYNVI®. Concomitant Guanylate Cyclase (GC) Stimulators: OPSYNVI® is contraindicated in patients using GC stimulators such as riociguat. WARNINGS AND PRECAUTIONS Embryo-fetal Toxicity and Macitentan-Containing Products REMS: Due to the risk of embryo-fetal toxicity, OPSYNVI® is available for females only through a restricted program called the Macitentan-Containing Products REMS Program. For females of reproductive potential, exclude pregnancy prior to initiation of therapy, ensure use of acceptable contraceptive methods, and obtain monthly pregnancy tests. Notable requirements of the Macitentan-Containing Products REMS Program include: Prescribers must be certified with the program by enrolling and completing training. All females, regardless of reproductive potential, must enroll in the Macitentan-Containing Products REMS Program prior to initiating OPSYNVI®. Male patients are not enrolled in the REMS. Females of reproductive potential must comply with the pregnancy testing and contraception requirements. Pharmacies must be certified with the program and must only dispense to patients who are authorized to receive OPSYNVI®. Hepatotoxicity ERAs have caused elevations of aminotransferases, hepatotoxicity, and liver failure. In the double-blind arm of the A DUE study, the incidence of elevated aminotransferases >3 x ULN was 1.0%, and >8 x ULN was 1.0% for OPSYNVI®. In the combined double-blind/open-label arm, the incidence was 3.4% and 1.1%, respectively. Discontinuations for hepatic adverse events in the double-blind and combined double-blind/open-label arms study for OPSYNVI® were 0.9% and 2.2%, respectively. Obtain liver enzyme tests prior to initiation of OPSYNVI® and repeat during treatment as clinically indicated. Advise patients to report symptoms suggesting hepatic injury (nausea, vomiting, right upper quadrant pain, fatigue, anorexia, jaundice, dark urine, fever, or itching). If clinically relevant aminotransferase elevations occur, or if elevations are accompanied by an increase in bilirubin >2 x ULN, or by clinical symptoms of hepatotoxicity, discontinue OPSYNVI®. Consider re-initiation of OPSYNVI® when hepatic enzyme levels normalize in patients who have not experienced clinical symptoms of hepatotoxicity. Do not initiate OPSYNVI® in patients with elevated aminotransferases (> 3 x ULN) at baseline. Patients with severe hepatic cirrhosis (Child-Pugh Class C) have not been studied; therefore, avoid use of OPSYNVI®. Hypotension OPSYNVI® has vasodilatory properties that may result in transient decreases in blood pressure. Prior to prescribing OPSYNVI®, physicians should carefully consider whether patients with underlying cardiovascular disease could be adversely affected by such vasodilatory effects. Patients with pre-existing hypotension, autonomic dysfunction, or left ventricular outflow obstruction, may be particularly sensitive to the actions of vasodilators. Hemoglobin Decrease Decreases in hemoglobin concentration and hematocrit have occurred following administration of other ERAs and were observed in clinical studies with OPSYNVI® and OPSUMIT®. These decreases occurred early and stabilized thereafter. In the placebo-controlled study of OPSUMIT® in PAH, OPSUMIT® 10 mg caused a mean decrease in hemoglobin from baseline to up to 18 months of about 1.0 g/dL compared to no change in the placebo group. A decrease in hemoglobin to below 10.0 g/dL was reported in 8.7% of the OPSUMIT® 10 mg group and in 3.4% of the placebo group. Similar results were observed in the trial with OPSYNVI®. Decreases in hemoglobin seldom require transfusion. Initiation of OPSYNVI® is not recommended in patients with severe anemia. Measure hemoglobin prior to initiation of treatment and repeat during treatment as clinically indicated. Worsening Pulmonary Veno-Occlusive Disease (PVOD) Since there are no clinical data on administration of OPSYNVI® tablets to patients with veno-occlusive disease, administration of OPSYNVI® tablets to such patients is not recommended. Should signs of pulmonary edema occur when OPSYNVI® tablets are administered, the possibility of associated PVOD should be considered. If confirmed, discontinue OPSYNVI®. Visual Loss and Hearing Impairment Non–arteritic anterior ischemic optic neuropathy (NAION), a cause of decreased vision, including permanent loss of vision, has been reported postmarketing in temporal association with the use of phosphodiesterase type 5 (PDE5) inhibitors, including tadalafil. Most, but not all, of these patients had underlying anatomic or vascular risk factors for development of NAION. Use of OPSYNVI® in patients with known hereditary degenerative retinal disorders, including retinitis pigmentosa, is not recommended. Cases of sudden decrease or loss of hearing, which may be accompanied by tinnitus and dizziness, have been reported in patients taking tadalafil. Fluid Retention Peripheral edema and fluid retention are known clinical consequences of PAH and known effects of ERAs, and heart failure has been reported in patients taking OPSYNVI®. In the clinical study of OPSYNVI® in PAH, the incidence of peripheral edema/fluid retention was 20.6% in the active-controlled and 17.3% in the double-blind/open-label arm. Patients with underlying left ventricular dysfunction may be at particular risk for developing significant fluid retention after initiation of ERA treatment. Monitor for signs of fluid retention after OPSYNVI® initiation. If clinically significant fluid retention develops, evaluate the patient to determine the cause, such as OPSYNVI® or underlying heart failure, and the possible need to discontinue OPSYNVI®. Combination With Other PDE5 Inhibitors Tadalafil, a PDE5 inhibitor and a component of OPSYNVI®, is also indicated for erectile dysfunction. Instruct patients taking OPSYNVI® tablets not to take other PDE5 inhibitors. Decreased Sperm Counts and Prolonged Erection Macitentan may have an adverse effect on spermatogenesis. Counsel men about potential effects on fertility. There have been reports of prolonged erections greater than 4 hours and priapism (painful erections greater than 6 hours in duration) for PDE5 inhibitors like tadalafil. Patients with conditions that might predispose them to priapism, or in patients with anatomical deformation of the penis are at an increased risk. Patients who have an erection lasting greater than 4 hours, whether painful or not, should seek emergency medical attention. ADVERSE REACTIONS The most common adverse reactions (occurring in ≥ 10% of the OPSYNVI®-treated patients) from the double-blind study data were edema/fluid retention (21%), anemia (19%), and headache/migraine (18%). The incidence of treatment discontinuations due to adverse events among patients receiving OPSYNVI® in the double-blind phase of the study was 8%. The most frequent adverse reactions leading to discontinuation were anemia and hemoglobin decreased (2% grouped) and peripheral edema and peripheral swelling (2% grouped). DRUG INTERACTIONS Nitrates: Administration of nitrates within 48 hours after the last dose of OPSYNVI® is contraindicated. Strong CYP3A4 Inducers: Strong inducers of CYP3A4, such as rifampin, significantly reduce macitentan exposure. Use of OPSYNVI® with strong CYP3A4 inducers should be avoided. Strong CYP3A4 Inhibitors: Concomitant use of strong CYP3A4 inhibitors like ketoconazole, increases exposure to both macitentan and tadalafil. Avoid concomitant use of OPSYNVI® with strong CYP3A4 inhibitors such as ritonavir, ketoconazole and itraconazole. Use other PAH treatment options when strong CYP3A4 inhibitors are needed. Moderate Dual or Combined CYP3A4 and CYP2C9 Inhibitors: Concomitant use of moderate dual inhibitors of CYP3A4 and CYP2C9 such as fluconazole, is predicted to increase macitentan exposure approximately 4-fold. Avoid concomitant use of OPSYNVI® with moderate dual inhibitors of CYP3A4 and CYP2C9 (such as fluconazole and amiodarone). Concomitant treatment of both a moderate CYP3A4 inhibitor and moderate CYP2C9 inhibitor with OPSYNVI® should be avoided. Alpha-Blockers: PDE5 inhibitors, including tadalafil, and alpha-adrenergic blocking agents are both vasodilators with blood-pressure lowering effects. Therefore, the combination of OPSYNVI® and doxazosin is not recommended. Antihypertensives: PDE5 inhibitors, including tadalafil, are mild systemic vasodilators. Small reductions in blood pressure occurred following coadministration of tadalafil with selected antihypertensive medications compared with placebo. Alcohol: Substantial consumption of alcohol in combination with OPSYNVI® can increase the potential for orthostatic signs and symptoms, including increase in heart rate, decrease in standing blood pressure, dizziness, and headache. USE IN SPECIFIC POPULATIONS Pregnancy OPSYNVI® is contraindicated during pregnancy. Macitentan, a component of OPSYNVI®, may cause embryo-fetal toxicity, including birth defects and fetal death, when administered to a pregnant female. If the patient becomes pregnant while taking this drug, advise the patient of the risk to a fetus. Lactation There are no data on the presence of tadalafil, macitentan, and/or their metabolites in human milk, the effects on the breastfed infant, or the effect on milk production. Because of the potential for serious adverse reactions in breastfed infants from OPSYNVI®, advise women not to breastfeed during treatment with OPSYNVI®. Females and Males of Reproductive Potential Pregnancy Testing: Verify the pregnancy status of females of reproductive potential prior to initiating OPSYNVI®, monthly during treatment and one month after stopping treatment with OPSYNVI®. The patient should contact her physician immediately for pregnancy testing if onset of menses is delayed or pregnancy is suspected. If the pregnancy test is positive, the physician and patient must discuss the risks to her, the pregnancy, and the fetus. Contraception: Female patients must choose one highly effective form of contraception (intrauterine devices [IUD]), contraceptive implants or tubal sterilization) or a combination of methods (hormone method with a barrier method or two barrier methods) during treatment with OPSYNVI® and for 1 month after treatment with OPSYNVI®. If a partner's vasectomy is the chosen method of contraception, a hormone or barrier method must be used along with this method. Male Infertility: Based on findings in animals, macitentan may impair fertility in males of reproductive potential. There have been no studies evaluating the effect of tadalafil on fertility in men or women. Pediatric Use The safety and efficacy of OPSYNVI® in children has not been established. Renal Impairment The use of OPSYNVI® is not recommended in patients undergoing dialysis. Avoid use of OPSYNVI® in patients with severe renal impairment (creatinine clearance 15-29 mL/min). Hepatic Impairment OPSYNVI® must not be initiated in patients with severe hepatic impairment, or clinically significant elevated hepatic aminotransferases (> 3 × ULN). Please read Important Safety Information and full Prescribing Information , including Boxed WARNING, for OPSYNVI ® . About Johnson & Johnson At Johnson & Johnson, we believe health is everything. Our strength in healthcare innovation empowers us to build a world where complex diseases are prevented, treated, and cured, where treatments are smarter and less invasive, and solutions are personal. Through our expertise in Innovative Medicine and MedTech, we are uniquely positioned to innovate across the full spectrum of healthcare solutions today to deliver the breakthroughs of tomorrow, and profoundly impact health for humanity. Learn more at or at . Follow us at @JanssenUS and @JNJInnovMed. Janssen Research & Development, LLC and Actelion Pharmaceuticals US, Inc., are both Johnson & Johnson companies. *Dr. Chin was compensated for her participation on the steering committee for the A DUE study. Cautions Concerning Forward-Looking Statements This press release contains "forward-looking statements" as defined in the Private Securities Litigation Reform Act of 1995 regarding product development and the potential benefits and treatment impact of OPSYNVI ®. The reader is cautioned not to rely on these forward-looking statements. These statements are based on current expectations of future events. If underlying assumptions prove inaccurate or known or unknown risks or uncertainties materialize, actual results could vary materially from the expectations and projections of Janssen Research & Development, LLC; Actelion Pharmaceuticals US, Inc., and/or Johnson & Johnson. Risks and uncertainties include, but are not limited to: challenges and uncertainties inherent in product research and development, including the uncertainty of clinical success and of obtaining regulatory approvals; uncertainty of commercial success; competition, including technological advances, new products and patents attained by competitors; challenges to patents; changes in behavior and spending patterns of purchasers of health care products and services; changes to applicable laws and regulations, including global health care reforms; and trends toward health care cost containment. A further list and descriptions of these risks, uncertainties and other factors can be found in Johnson & Johnson's Annual Report on Form 10-K for the fiscal year ended December 31, 2023, including in the sections captioned "Cautionary Note Regarding Forward-Looking Statements" and "Item 1A. Risk Factors," and in Johnson & Johnson's subsequent Quarterly Reports on Form 10-Q and other filings with the Securities and Exchange Commission. Copies of these filings are available online at , or on request from Johnson & Johnson. None of Janssen Research & Development, LLC, Actelion Pharmaceuticals US, Inc. nor Johnson & Johnson undertakes to update any forward-looking statement as a result of new information or future events or developments. 1. OPSYNVI® Prescribing Information. Titusville, NJ: Actelion Pharmaceuticals US, Inc. 2. Humbert M, Kovacs G, Hoeper MM, et al. 2022 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J. 2022;43(38):3618-3731. 3. American Lung Association, PAH, 23.10.2020, "Learn About Pulmonary Arterial Hypertension", lung.org, . 4. Grünig E, et al. JACC. 2024; 83(4): 473-484. DOI:10.1016/j.jacc.2023.10.045. Media Contact: Shelly Orlacchio Phone: +1 717-471-3888 [email protected] Investor Contact: Raychel Kruper [email protected] SOURCE Johnson & Johnson