Ivacaftor

-With this expansion, any variant that results in production of CFTR protein is now included in the indication for ALYFTREK and TRIKAFTA, reinforcing the impact these medicines have, regardless of the location of the variant in the CFTR protein- -Approximately 800 more people with CF in the US are now eligible for a CFTR modulator for the first time- BOSTON --(BUSINESS WIRE)--Apr. 1, 2026-- Vertex Pharmaceuticals Incorporated (Nasdaq: VRTX) today announced the U.S. Food and Drug Administration (FDA) has approved expanded use of ALYFTREK® (vanzacaftor/tezacaftor/deutivacaftor) for the treatment of people with cystic fibrosis (CF) ages 6 and older with a variant in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that is either responsive based on clinical and/or in vitro data or results in production of CFTR protein. Additionally, the U.S. FDA has also expanded the indication statement for TRIKAFTA® (elexacaftor/tezacaftor/ivacaftor and ivacaftor) in patients ages 2 and older. This label expansion was supported by clinical and/or in vitro data from 564 variants demonstrating response to ALYFTREK and 521 variants demonstrating response to TRIKAFTA. As such, approximately 800 more people with a clinical diagnosis of CF in the U.S. are now eligible for a medicine that treats the underlying cause of their disease for the first time. This extension means approximately 95% of people with CF in the U.S. are now eligible for treatment with a CFTR modulator. “This groundbreaking approval represents more than 20 years of innovation in CF, including testing over 600 variants in our laboratory, demonstrating clinical effects in large clinical trials, and studying younger people with CF so they can be treated as early as possible,” said Carmen Bozic , M.D., Executive Vice President, Global Medicines Development and Medical Affairs, and Chief Medical Officer at Vertex . “With this label expansion, any variant that results in production of CFTR protein is now included in the ALYFTREK and TRIKAFTA labels, validating that these medicines can restore CFTR function and provide clinical benefit to patients regardless of where in the CFTR protein a variant is located. We thank the CF community and investigators for their trust and look forward to bringing ALYFTREK and TRIKAFTA to more patients than ever before.” For more information on ALYFTREK or TRIKAFTA, patient assistance programs, or eligibility details, visit ALYFTREK.com, TRIKAFTA.com, VertexGPS.com or vertextreatments.com. IMPORTANT SAFETY INFORMATION WARNING: DRUG-INDUCED LIVER INJURY AND LIVER FAILURE Elevated transaminases have been observed in patients treated with ALYFTREK. TRIKAFTA can cause serious and potentially fatal drug-induced liver injury. Cases of liver failure leading to transplantation and death have been reported in both clinical trials and the postmarketing setting in patients with and without a history of liver disease taking TRIKAFTA, a fixed-dose combination drug containing elexacaftor (ELX), tezacaftor (TEZ), and ivacaftor (IVA), the same or similar active ingredients as ALYFTREK. Liver injury has been reported within the first month of therapy and up to 15 months following initiation of TRIKAFTA. Assess liver function tests (ALT, AST, alkaline phosphatase, and bilirubin) in all patients prior to initiating ALYFTREK or TRIKAFTA, then every month during the first 6 months of treatment, every 3 months for the next 12 months, and at least annually thereafter. Consider more frequent monitoring for patients with a history of liver disease or liver function test (LFT) elevations at baseline. Interrupt ALYFTREK or TRIKAFTA for significant elevations in LFTs or in the event of signs or symptoms of liver injury. Consider referral to a hepatologist. Follow patients closely with clinical and laboratory monitoring until abnormalities resolve. If resolved, resume treatment only if benefit is expected to outweigh risk. Closer monitoring is advised after resuming treatment. ALYFTREK or TRIKAFTA should not be used in patients with severe hepatic impairment (Child- Pugh Class C ). ALYFTREK or TRIKAFTA is not recommended in patients with moderate hepatic impairment (Child- Pugh Class B ). ALYFTREK or TRIKAFTA should only be considered when there is a clear medical need and benefit outweighs risk. If ALYFTREK is used, monitor patients closely. If TRIKAFTA is used, use with caution at a reduced dosage and monitor patients closely. WARNINGS AND PRECAUTIONS DRUG-INDUCED LIVER INJURY AND LIVER FAILURE Elevated transaminases have been observed in patients treated with ALYFTREK. TRIKAFTA can cause serious and potentially fatal drug-induced liver injury. Liver failure leading to transplantation and death has been reported in patients with and without a history of liver disease taking TRIKAFTA. Liver injury has been reported within the first month of therapy and up to 15 months following initiation of TRIKAFTA Assess LFTs in all patients prior to initiating ALYFTREK or TRIKAFTA, then every month during the first 6 months of treatment, every 3 months for the next 12 months, and at least annually thereafter. Consider more frequent monitoring for patients with a history of liver disease or LFT elevations at baseline, or a history of elevated LFTs with drugs containing ELX, TEZ, and/or IVA Interrupt ALYFTREK or TRIKAFTA in the event of signs or symptoms of liver injury, which may include: Significant elevations in LFTs (e.g., ALT or AST >5x the upper limit of normal (ULN) or ALT or AST >3x ULN with bilirubin >2x ULN) Clinical symptoms suggestive of liver injury (e.g., jaundice, right upper quadrant pain, nausea, vomiting, altered mental status, ascites) Consider referral to a hepatologist and follow patients closely with clinical and laboratory monitoring until abnormalities resolve. If resolved, and if benefit is expected to outweigh risk, resume treatment with close monitoring ALYFTREK and TRIKAFTA should not be used in patients with severe hepatic impairment, are not recommended in patients with moderate hepatic impairment, and should only be considered when there is a clear medical need and benefit outweighs risk. If ALYFTREK is used, monitor patients closely. If TRIKAFTA is used, use with caution at a reduced dosage and monitor patients closely Significant elevations in LFTs (e.g., ALT or AST >5x the upper limit of normal (ULN) or ALT or AST >3x ULN with bilirubin >2x ULN) Clinical symptoms suggestive of liver injury (e.g., jaundice, right upper quadrant pain, nausea, vomiting, altered mental status, ascites) HYPERSENSITIVITY REACTIONS, INCLUDING ANAPHYLAXIS Hypersensitivity reactions, including cases of angioedema and anaphylaxis, have been reported in the postmarketing setting for TRIKAFTA. If signs or symptoms of serious hypersensitivity reactions develop during treatment, discontinue ALYFTREK or TRIKAFTA and institute appropriate therapy. Consider benefits and risks to determine whether to resume treatment PATIENTS WHO DISCONTINUED OR INTERRUPTED ELX-, TEZ-, OR IVA-CONTAINING DRUGS DUE TO ADVERSE REACTIONS ALYFTREK There are no available safety data for ALYFTREK in patients who previously discontinued or interrupted treatment with drugs containing ELX, TEZ, or IVA due to adverse reactions. Consider benefits and risks before using ALYFTREK in these patients and if used, closely monitor for adverse reactions INTRACRANIAL HYPERTENSION (IH) IH has been reported in the postmarketing setting with TRIKAFTA, which contains the same or similar active ingredients as ALYFTREK. Clinical manifestations of IH include headache, blurred vision, diplopia, and potential vision loss; papilledema can be found on fundoscopy. If an unusual headache or visual disturbances occur during treatment, and IH is suspected, interrupt treatment and refer for prompt medical evaluation. Consider benefits and risks to determine whether to resume treatment. Patients should be monitored until IH resolution and for recurrence. Patients with elevated vitamin A levels may be at increased risk NEUROPSYCHIATRIC EVENTS, INCLUDING SUICIDAL THOUGHTS AND BEHAVIORS Serious neuropsychiatric events, including symptoms of anxiety, depression, suicidal ideation and behavior, and sleep disturbances, have been reported in the postmarketing setting in patients with and without a previous history of neuropsychiatric symptoms taking ALYFTREK or TRIKAFTA. Symptoms may occur within the first 3 months of treatment. Assess patients for baseline neuropsychiatric symptoms and monitor for new or worsening symptoms. Consider the benefits and risks to determine if treatment should be interrupted at symptom occurrence or resumed with symptom improvement DRUG INTERACTIONS Use With CYP3A Inducers Following concomitant use of strong or moderate CYP3A inducers with ALYFTREK, exposures of vanzacaftor, TEZ, and deutivacaftor were decreased, which may reduce ALYFTREK effectiveness. Concomitant use with strong or moderate CYP3A inducers is not recommended Exposure to IVA is significantly decreased and exposure to ELX and TEZ are expected to decrease with concomitant use of CYP3A inducers, which may reduce effectiveness of TRIKAFTA. Concomitant use with strong CYP3A inducers is not recommended Use With CYP3A Inhibitors Exposure to vanzacaftor, TEZ, and deutivacaftor or ELX, TEZ, and IVA are increased when used concomitantly with strong or moderate CYP3A inhibitors. The dose of ALYFTREK or TRIKAFTA should be reduced when used concomitantly with moderate or strong CYP3A inhibitors CATARACTS Non-congenital lens opacities have been reported in pediatric patients treated with TRIKAFTA, which contains IVA (similar to an active ingredient in ALYFTREK). Baseline and follow-up ophthalmological examinations are recommended in pediatric patients ADVERSE REACTIONS ALYFTREK Serious adverse reactions that occurred more frequently with ALYFTREK than with ELX/TEZ/IVA in 2 or more patients (≥0.4%) were influenza (1.5%), increased AST (0.4%), increased GGT (0.4%), depression (0.4%), and syncope (0.4%) The most common adverse reactions occurring in ≥5% of patients and at a frequency higher than ELX/TEZ/IVA by ≥1% were cough, nasopharyngitis, upper respiratory tract infection (URTI), headache, oropharyngeal pain, influenza, fatigue, increased ALT and AST, rash, and sinus congestion TRIKAFTA Serious adverse reactions that occurred more frequently in patients treated with TRIKAFTA compared to placebo included rash (1% vs <1%) and influenza (1% vs 0%) The most common adverse reactions occurring in ≥5% of patients treated with TRIKAFTA and at a rate higher than placebo by ≥1% were headache; URTI; abdominal pain; diarrhea; rash; increased ALT, blood creatine phosphokinase, AST, and blood bilirubin; nasal congestion; rhinorrhea; rhinitis; influenza; sinusitis; and constipation USE IN SPECIFIC POPULATIONS PEDIATRIC USE Safety and effectiveness have not been established for ALYFTREK in patients <6 years, nor for TRIKAFTA in patients <2 years. The use in children under these ages is not recommended Please see full Prescribing Information, including Boxed WARNING, for ALYFTREK and TRIKAFTA. About Cystic Fibrosis Cystic fibrosis (CF) is a rare, life-shortening genetic disease affecting more than 112,000 people, including approximately 97,000 people in the United States , Europe , Australia and Canada . CF is a progressive, multi-organ disease that affects the lungs, liver, pancreas, GI tract, sinuses, sweat glands and reproductive tract. CF is caused by a defective and/or missing CFTR protein resulting from certain mutations in the CFTR gene. Children must inherit two defective CFTR genes — one from each parent — to have CF, and these mutations can be identified by a genetic test. While there are many different types of CFTR mutations that can cause the disease, the vast majority of people with CF have at least one F508del mutation. CFTR mutations lead to CF by causing CFTR protein to be defective or by leading to a shortage or absence of CFTR protein at the cell surface. The defective function and/or absence of CFTR protein results in poor flow of salt and water into and out of the cells in a number of organs. In the lungs, this leads to the buildup of abnormally thick, sticky mucus, chronic lung infections and progressive lung damage that eventually leads to death for many patients. The median age of death is in the 30s, but with treatment, projected survival is improving. Learn more about the importance of sweat chloride (SwCl) in cystic fibrosis. Today Vertex CF medicines are treating over 75,000 people with CF across more than 60 countries on six continents. This represents approximately 2/3 of the diagnosed people with CF eligible for CFTR modulator therapy. About Vertex Vertex is a global biotechnology company that invests in scientific innovation to create transformative medicines for people with serious diseases and conditions. The company has approved therapies for cystic fibrosis, sickle cell disease, transfusion-dependent beta thalassemia and acute pain, and it continues to advance clinical and research programs in these areas. Vertex also has a robust clinical pipeline of investigational therapies across a range of modalities in other serious diseases where it has deep insight into causal human biology, including IgA nephropathy, neuropathic pain, APOL1-mediated kidney disease, primary membranous nephropathy, autosomal dominant polycystic kidney disease, type 1 diabetes, generalized myasthenia gravis, and myotonic dystrophy type 1. Vertex was founded in 1989 and has its global headquarters in Boston , with international headquarters in London . Additionally, the company has research and development sites and commercial offices in North America , Europe , Australia , Latin America and the Middle East . Vertex is consistently recognized as one of the industry's top places to work, including 16 consecutive years on Science magazine's Top Employers list and one of Fortune’s 100 Best Companies to Work For. For company updates and to learn more about Vertex 's history of innovation, visit www.vrtx.com or follow us on LinkedIn, Facebook, Instagram, YouTube and X. Special Note Regarding Forward-Looking Statements This press release contains forward-looking statements as defined in the Private Securities Litigation Reform Act of 1995, including, without limitation, statements made by Carmen Bozic , M.D., in this press release, statements regarding the anticipated benefits of ALYFTREK and TRIKAFTA, expectations regarding the eligible patient population, and expectations for patient access to ALYFTREK and TRIKAFTA. While Vertex believes the forward-looking statements contained in this press release are accurate, these forward-looking statements represent the company's beliefs only as of the date of this press release and there are a number of factors that could cause actual events or results to differ materially from those indicated by such forward-looking statements. Those risks and uncertainties include, among other things, that patients may not have access to ALYFTREK or TRIKAFTA on the anticipated timeline, and other risks listed under the heading “Risk Factors” in Vertex 's annual report and in subsequent filings filed with the Securities and Exchange Commission and available through the company's website at www.vrtx.com and www.sec.gov. You should not place undue reliance on these statements. Vertex disclaims any obligation to update the information contained in this press release as new information becomes available. (VRTX-GEN) View source version on businesswire.com: https://www.businesswire.com/news/home/20260401690804/en/ Vertex Pharmaceuticals Incorporated Investors: InvestorInfo@vrtx.com Media: mediainfo@vrtx.com or U.S. : 617-341-6992 or International: +44 20 3204 5275 Source: Vertex Pharmaceuticals Incorporated

表型驱动的反向靶点发现：First-in-class药物的核心创新源泉 【医药智能】靶点发现的主要技术方法：从传统到前沿、从实验驱动到AI赋能的全谱系方法 【医药智能】六大靶点发现技术适用场景及组合应用策略 一、核心定义与逻辑 表型驱动的反向靶点发现（Phenotype-driven Reverse Target Identification，也称表型药物发现PDD/靶点去卷积Target Deconvolution）是一种**“先观效果（表型），再溯机制（靶点）”**的创新药物研发范式，是First-in-class药物的最主要来源之一。 核心区别：PDD vs 传统靶点驱动 维度 表型驱动反向靶点发现（PDD） 传统靶点驱动发现（TDD） 研发逻辑 先找“能逆转疾病表型的分子”，再反向确定靶点 先找“疾病相关靶点”，再找“能作用于靶点的分子” 靶点状态 靶点未知/全新（可发现不可成药靶点） 靶点已知（通常已验证成药潜力） FIC产出率 极高（占2000-2008年FIC药物50%以上） 中低（多为me-too/me-better） 适用场景 复杂疾病、机制不明疾病、罕见病 机制清晰疾病、单基因疾病 核心挑战 靶点去卷积（确认分子作用的精确靶点） 靶点成药性验证（确认靶点可被药物干预） 二、完整流程（5大核心步骤） 1. 疾病表型模型构建（PDD起点） 构建疾病相关的、可量化的表型筛选模型，模拟人体疾病病理状态，如： •细胞水平：疾病相关细胞系、类器官、3D培养模型 •分子水平：转录组/蛋白组/代谢组扰动模型 •动物水平：基因编辑疾病模型、自发疾病模型 •患者水平：患者来源样本、类器官模型 关键要求：表型需具备疾病相关性、可测量性、可重复性，并能反映临床治疗终点。 2. 高通量表型筛选（Hit发现） 通过高通量筛选（HTS）、高内涵筛选（HCS）、虚拟筛选等技术，从化合物库（百万级）中筛选能特异性逆转疾病表型的活性分子（Hit），完全不预设靶点假设。 3. 靶点去卷积（核心环节） 这是PDD最关键、最具挑战性的步骤，通过多技术组合确定Hit分子的作用靶点，常用方法包括： 技术类型 代表方法 原理 适用场景 化学蛋白质组学 Drug Pull-down、TPP、LiP-MS 直接捕获与药物结合的蛋白质 小分子、可修饰化合物 功能基因组学 CRISPR-Cas9筛选、RNAi、shRNA 基因扰动后观察表型变化是否被药物逆转 所有分子类型 计算预测 反向虚拟筛选、AI模型（GPS）、知识图谱 基于结构/活性/多组学数据预测靶点 初步筛选、缩小候选范围 生物化学 酶活性测定、结合亲和力检测、竞争结合实验 直接验证分子与候选靶点的相互作用 已知候选靶点验证 多组学整合 转录组+蛋白组+代谢组联合分析 构建分子作用的通路网络，定位核心靶点 多靶点/复杂机制分子 核心标准：靶点确认需满足**“三证合一”**：①分子与靶点直接结合；②靶点扰动可模拟药物表型；③靶点过表达可逆转药物作用。 4. 靶点验证与机制解析 完成靶点因果性验证：在多种模型中确认干预该靶点确实能逆转疾病表型，明确分子-靶点-通路-表型的完整作用链，区分直接靶点与间接靶点。 5. 先导优化与临床转化 基于靶点信息优化分子，提升特异性、活性、成药性，进入临床前研究与临床试验，最终开发为First-in-class药物。 三、技术突破：AI赋能PDD新范式 1. 深度学习驱动表型筛选 如GPS平台（Gene Expression Profile Predictor on Chemical Structures），可仅通过化合物结构预测其诱导的全转录组扰动，筛选能逆转疾病转录组表型的分子，直接完成“表型筛选+初步机制解析”，大幅提升FIC发现效率。 2. 多组学整合靶点预测 结合单细胞测序、空间转录组、蛋白质组学数据，构建疾病分子网络，AI自动识别网络中的关键调控节点（潜在靶点），实现**“表型-网络-靶点”**的智能关联。 四、为何是FIC药物核心来源？核心优势 1. 突破“已知靶点”局限，发现全新机制 PDD能发现传统靶点驱动方法无法触及的全新靶点与信号通路，包括： •不可成药靶点（如蛋白-蛋白相互作用、无序蛋白） •多靶点协同作用机制 •细胞内复杂调控网络节点 2. 提高临床转化成功率 PDD筛选在疾病相关模型中进行，筛选结果更接近人体生理状态，临床前到临床转化成功率比传统方法高2-3倍。 3. 适配复杂疾病治疗需求 对多因素、多机制疾病（如肿瘤、神经退行性疾病、代谢疾病），PDD能找到同时调节多个病理环节的分子，实现更全面的治疗效果。 五、经典FIC成功案例 1. 来那度胺（Lenalidomide）——多发性骨髓瘤FIC药物 •表型起点：沙利度胺衍生物筛选中发现能抑制骨髓瘤细胞增殖的化合物 •靶点发现：反向确认作用于CRBN（Cereblon）E3泛素连接酶，诱导IKZF1/3降解 •创新价值：开创**蛋白降解靶向嵌合体（PROTAC）**药物先河，全球销售额超100亿美元 2. 依伐卡托（Ivacaftor）——囊性纤维化FIC药物 •表型起点：筛选能恢复CFTR突变体功能的小分子 •靶点发现：确认直接作用于CFTR蛋白，增强其通道活性 •创新价值：首个针对囊性纤维化根本病因的药物，后续开发三联疗法覆盖90%患者 3. 克立硼罗（Crisaborole）——特应性皮炎FIC药物 •表型起点：筛选能抑制炎症反应的小分子 •靶点发现：反向确定为磷酸二酯酶4（PDE4）抑制剂 •创新价值：首个非激素外用PDE4抑制剂，开创特应性皮炎治疗新路径 六、挑战与解决方案 1. 核心挑战 •靶点去卷积复杂性：多靶点作用、间接作用、脱靶效应 •机制解析耗时：传统方法需6-12个月确认靶点 •知识产权风险：靶点未知可能导致专利保护困难 2. 解决方案 •多技术组合：化学蛋白质组学+CRISPR筛选+计算预测，提高靶点确认准确性 •AI加速：深度学习模型预测靶点，缩短靶点解析时间至数周 •专利策略优化：同时保护分子结构、表型效果、作用机制，构建全面专利壁垒 七、总结：PDD与FIC的未来 表型驱动的反向靶点发现是First-in-class药物的核心创新引擎，尤其在AI技术赋能下，正迎来黄金发展期。它不仅能发现全新治疗靶点，更能将药物研发从“为已知靶点找分子”的同质化竞争，转向“为复杂疾病找正确干预策略”的源头创新，为未满足临床需求提供颠覆性解决方案。 一句话概括：PDD的本质是**“让疾病自己告诉我们该如何治疗”**，这正是First-in-class药物最宝贵的创新精神。 科学智能：在先进产业场景中构建“状态感知-实时认知-自主决策-精准执行-学习提升”的科学智能（Science_and_AI）；实现产业转型升级、DT驱动业务、价值创新创造的产业互联生态链。 先进产业+物理AI=科学智能 产业智能官：Science_and_AI 加入知识星球“产业智能研究院”：产业OT技术（自动化+机器人+工艺+精益）和新一代IT技术（云计算+物联网+区块链+大数据+人工智能）深度融合，在场景中构建“状态感知-实时认知-自主决策-精准执行-学习提升”的科学智能（Science_and_AI）；实现产业转型升级、DT驱动业务、价值创新创造的产业互联生态链。 科学智能（Science_and_AI）作为第四次工业革命的核心驱动力，将进一步释放历次科技革命和产业变革积蓄的巨大能量，并创造新的强大引擎；重构设计、生产、供应链和服务等经济活动各环节，形成从宏观到微观各领域的智能化新需求，催生新技术、新产品、新产业、新业态和新模式；引发经济结构重大变革，深刻改变人类生产生活方式和思维模式，实现社会生产力的整体跃升。 产业智能化技术分支用来的今天，从业者必须了解如何将科学智能（Science_and_AI）全面渗入整个公司、产品、业务等商业场景中，利用科学智能（Science_and_AI）形成数字化、网络化和智能化力量，实现行业的重新布局、企业的重新构建和焕然新生。 版权声明：产业智能官（ID：Science_and_AI）发表的文章，除非确实无法确认，我们都会注明作者和来源，涉权请联系协商解决，联系、投稿邮箱：wolongzy@qq.com