Ivacaftor deuterated

- Data presented on outcomes following treatment with CFTR modulators add to growing body of evidence that reduced level of sweat chloride is associated with improved clinical outcomes, particularly in younger people with cystic fibrosis - BOSTON --(BUSINESS WIRE)--Oct. 23, 2025-- Vertex Pharmaceuticals Incorporated (Nasdaq: VRTX) today announced the presentation of multiple abstracts demonstrating the clinical benefits of treatment with CFTR modulators, including the Company’s most recently approved medicine, ALYFTREK® (vanzacaftor/tezacaftor/deutivacaftor), at the North American Cystic Fibrosis Conference (NACFC) held from October 22-25 in Seattle, Washington . Several of the abstracts that will be presented at this year’s conference demonstrate that improvement in CFTR function, as measured by reduction in sweat chloride (SwCl), is associated with improved outcomes in people with cystic fibrosis (CF). ALYFTREK has shown greater reductions in sweat chloride compared to TRIKAFTA® (elexacaftor/tezacaftor/ivacaftor and ivacaftor) in Phase 3 trials, suggesting that ALYFTREK has the potential for even greater improvements in quality of life and other health-related outcomes. Data being presented on ALYFTREK and on correlation between lower SwCl and improved clinical outcomes with CFTR modulator treatment: “Decreased Pulmonary Exacerbations and Lower IV Antibiotic Usage Following Vanzacaftor/Tezacaftor/Deutivacaftor Treatment in People with CF with F508del-Minimal Function Genotypes” (Poster #868): Post-hoc analyses of two pivotal Phase 3 studies (SKYLINE 102 and SKYLINE 103) will be presented, showing that F580del/minimal function mutation (F/MF) subjects treated with ALYFTREK had lower rates of pulmonary exacerbations (PEx), PEx requiring hospitalization or IV antibiotics, and IV antibiotic use vs. F/MF subjects treated with TRIKAFTA. Friday, October 24,1:15–2:15 p.m. PDT. “Maximizing benefits with early CFTR modulator treatment: Lower sweat chloride is associated with improved clinical outcomes in children aged 6 to 11 years” (Poster #119): Data will be presented from a pooled analysis of data from participants in Phase 3 studies and open-label extension studies of CFTR modulators, including ALYFTREK. An analysis of three age cohorts (≥18 years, 12-17 years, and 6-11 years) with F/MF or F508del/F508del (F/F) mutations shows that participants who initiated therapy at a younger age achieved greater levels of CFTR function, as demonstrated by lower levels of SwCl. Among study participants in the 6-11 years cohorts, those that achieved lower SwCl levels experienced broad clinical benefits — as indicated by greater numerical improvements in lung function, respiratory symptoms, nutritional status and annual rates of PEx. Friday, October 24 , 12:15–1:15 p.m. PDT. “Changes in Sweat Chloride Concentrations Following CFTR Modulator Treatment and Association with Antibiotic Usage in Adolescents and Adults with Cystic Fibrosis” (Poster #120): Data will be presented from a pooled analysis of over 2,000 people with CF 12 years and older with F/MF or F/F genotypes who took part in Phase 3 clinical trials of CFTR modulators, including ALYFTREK. These data demonstrate that, following the initiation of treatment with CFTR modulators, achieving sweat chloride levels below the diagnostic threshold (<60 mmol/L) and normal levels (<30 mmol/L) was associated with reduced annual rates of IV and/or oral antibiotic usage compared to trial participants that reached higher levels of sweat chloride. Friday, October 24 at 1:15–2:15 p.m. PDT. Additional data being presented on Vertex’s other CFTR modulators, including three oral presentations: “Clinical characteristics and outcomes of people with cystic fibrosis with homozygous minimal function genotypes: Comparison to those with F508del/minimal function genotypes” (Oral & Poster #728), on Thursday, October 23 from 10:15 a.m. to 12:15 p.m. PDT and poster presentation on Friday, October 24 , at 1:15–2:15 p.m. PDT. “The lived experience & unmet needs of people with CF with genotypes not responsive to CFTR modulators: A mixed-methods study” (Oral & Poster #429), on Saturday, October 25 from 10:15 a.m. to 12:15 p.m. PDT and poster presentation on Friday, October 24 , at 12:15–1:15 p.m. PDT. “Impact of elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) on healthcare resource utilization (HCRU) over three years in LONGITUDE – a UK CF Registry observational study” (Oral & Poster #729), on Friday, October 24 , from 10:15 a.m. to 12:15 p.m. PDT and poster presentation on Friday, October 24 , at 12:15–1:15 p.m. PDT. “Baseline results from the NEMO Study: Psychometric evaluation of the Preschool Cystic Fibrosis Questionnaire-Revised in children with cystic fibrosis and caregivers in the United States and Australia” (Poster #529), will be presented at a Rapid Fire Poster Talk on Thursday, October 23 , at 1:30–2:20 p.m. PDT in Theater C Exhibit Hall, and poster presentation on Friday, October 24 , at 12:15–1:15 p.m. PDT. “Real-world outcomes in people with cystic fibrosis treated with elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) with up to four years of follow-up” (Poster #731), on Friday, October 24 , at 12:15–1:15 p.m. PDT. “Long-term effects of elexacaftor/tezacaftor/ivacaftor on clinical outcomes and quality of life among adolescents and adults aged 12+ with cystic fibrosis: Interim results from the TRAJECTORY Study” (Poster #739), on Friday, October 24 , at 12:15–1:15 p.m. PDT. “Impact of elexacaftor/tezacaftor/ivacaftor on clinical outcomes and quality of life in children with cystic fibrosis aged 6-11 years in the real-world setting” (Poster #734), on Friday, October 24 , at 1:15–2:15 p.m. PDT. About Cystic Fibrosis Cystic fibrosis (CF) is a rare, life-shortening genetic disease affecting more than 109,000 people, including 94,000 people in North America , Europe and Australia . 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 in more than 60 countries on six continents. This represents approximately 2/3 of the diagnosed people with CF eligible for CFTR modulator therapy. ALYFTREK AND TRIKAFTA INDICATIONS AND IMPORTANT SAFETY INFORMATION ALYFTREK is indicated for the treatment of cystic fibrosis (CF) in patients ≥6 years who have ≥1 F508del mutation or another responsive mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene.* TRIKAFTA is indicated for the treatment of CF in patients ≥2 years who have ≥1 F508del mutation in the CFTR gene or a mutation in the CFTR gene that is responsive based on clinical and/or in vitro data.* *If the patient’s genotype is unknown, an FDA-cleared CF mutation test should be used to confirm the presence of the indicated mutation(s) for the respective product. 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 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 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 neuropathic pain, APOL1-mediated kidney disease, IgA nephropathy, primary membranous nephropathy, autosomal dominant polycystic kidney disease, type 1 diabetes 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 15 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, as amended, including, without limitation, statements regarding expectations for the clinical benefits of ALYFTREK and the company’s other CFTR modulators, and expectations for the data presented at NACFC. 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 risks and uncertainties that could cause actual events or results to differ materially from those expressed or implied by such forward-looking statements. Those risks and uncertainties include, among other things, that data from the company's research and development programs may not support registration or further development of its potential medicines in a timely manner, or at all, due to safety, efficacy, and other risks listed under the heading “Risk Factors” in Vertex 's most recent annual report and subsequent quarterly reports filed with the Securities and Exchange Commission at www.sec.gov and available through the company's website at www.vrtx.com. You should not place undue reliance on these statements, or the scientific data presented. 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/20251023956256/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

被喻为“诺奖风向标”，备受瞩目的2025拉斯克奖（The Lasker Awards）于当地时间9月11日正式揭晓。2025年的拉斯克基础医学研究奖授予了马克斯·普朗克研究所的Dirk Görlich博士以及得克萨斯大学西南医学中心的Steven McKnight博士，表彰他们在揭示细胞内运输和细胞组织新原理方面的贡献。 临床医学研究奖授予了爱荷华大学的Michael Welsh博士、曾任职于Vertex Pharmaceuticals的Jesús González博士和Vertex Pharmaceuticals的Paul Negulescu博士，以表彰他们在囊性纤维化（CF）创新治疗药物开发的贡献。 医学科学特别成就奖则授予斯坦福大学医学院的Lucy Shapiro博士，以表彰她在生物医学领域55年的职业生涯中的学术、产业以及公共政策上的卓越贡献。 其中，临床医学研究奖的三名科学家为众多囊性纤维化患者带来了“改变命运”的治疗策略——三联疗法 Trikafta®。该药物能大幅减少感染发生次数和严重程度。从儿童或青少年时期开始接受该疗法的患者预计寿命接近正常人。本文将为大家介绍这些科学家为改善囊性纤维化患者的治疗格局，所做出的不懈努力。 图片来源：The Lasker Foundation 破解“死亡诅咒” 数个世纪以前，在欧洲的部分地区流传着这样一个说法：“当亲吻婴儿额头能尝到咸味时，那么他就受到了诅咒，很快就会死去。” 为何婴儿额头有咸味会让他们早早夭折呢？这在很长一段时间中都是一个未解之谜。 直到20世纪，“死亡诅咒”的真相才被逐步揭开。1938年，美国病理学家Dorothy Andersen博士首次描述了患儿胰腺的囊状扩张与纤维化，并提出“胰腺囊性纤维化”一词。在当时，大多数囊性纤维化患者无法活过幼儿期。随后，儿科病理学家Paul di Sant’Agnese发现囊性纤维化患儿汗液盐分显著增高，由此发明了汗液诊断法。直到20世纪80年代，加州大学圣地亚哥分校的Paul Quinton教授进一步揭示了汗液异常咸的根源：囊性纤维化患者的氯离子通道异常，这既会导致汗液含盐量过高，也使黏液过稠，阻塞肺部功能。 直到1989年，徐立之教授、Francis Collins教授、Jack Riordan教授组成的联合团队找到并命名了真正影响囊性纤维化发生的基因——囊性纤维化跨膜转运调节分子（CTFR）。研究表明，CFTR编码的蛋白负责氯离子与碳酸氢根的跨膜转运，维持黏液盐水平衡。而最常见的ΔF508 CFTR突变仅因缺失一个氨基酸，就使蛋白折叠异常，功能丧失。至此，囊性纤维化的疾病发生机制首次得到了完整的科学解释。一场拯救囊性纤维化患者的行动即将拉开序幕。 Welsh：阐明致命异常蛋白机制 当Michael Welsh博士还是医学院学生时，就对囊性纤维化研究产生了兴趣。他还记得自己见到的第一位囊性纤维化患者——这位患者是一名小女孩，她的预期寿命最多只有十几岁。当时的治疗通常包括使用抗生素，或者物理方式稀释肺部黏液。“我们尽了最大努力，但我也意识到，我们并没有从根本上改变这种疾病的进程，” Welsh博士表示。 当他看到徐立之教授等人的工作成果后，他开始考虑CFTR究竟发挥了哪些作用。他决定验证一个最简单的假设：CTFR本身就是一个氯离子通道。Welsh 博士在该蛋白质假定的跨膜结构域中生成了突变，并观察了这如何改变其对不同带负电荷离子的选择性。 ▲机制示意图（图片来源：参考资料[1]） 结果显示，该区域带正电荷的赖氨酸突变改变了CTFR对阴离子（包括氯离子）的选择性，这表明CTFR确实能够充当氯离子通道的作用。随后，他开始研究之前发现的最著名的ΔF508 CFTR突变。该突变体导致CTFR无法正常成熟，因此无法到达细胞膜。突变蛋白的通道开放能力也受到了损害。 然而令人惊讶的是，ΔF508 CFTR在青蛙和昆虫细胞中保留了部分功能。随后，Welsh博士回想起自己之前的研究工作，意识到研究人员通常在较低温度下培养青蛙细胞。因此，Welsh博士尝试将细胞冷却。结果ΔF508 CFTR不仅成熟并成功迁移到质膜上。这一变化甚至部分挽救了突变蛋白作为氯离子通道的功能。这告诉科学界，ΔF508 CFTR并没有被彻底摧毁，它或许是可以修复的，也能用药物来实现这一目的。 González：全新筛选技术奠定研发基础 这一发现点燃了研究者对囊性纤维化新疗法的探索热情。20世纪90年代，科学界开始尝试为这种致命疾病寻找治疗手段。当时，一项名为“组合化学”的技术刚刚兴起。这项技术使科学家能够快速合成大量分子，但研究人员缺乏高通量的手段进行候选药物筛选、来评估这些分子的功能。为了评估合成的分子能否纠正突变的CFTR功能，研究人员不得不依赖于膜片钳电生理学等低通量手段，筛选效率很低。 当时，Jesús González博士任职于Aurora Biosciences公司，这家初创公司由他在加州大学圣地亚哥分校的博士后导师、在2008年获得诺贝尔化学奖的钱永健教授共同创立。 图片来源：The Lasker Foundation 博士后期间，González博士曾与钱永健教授共同发明了一种可以检测膜电位变化的细胞膜染料。这种染料最初是用于研究神经元之间的通讯，但在Aurora Biosciences公司工作期间，González博士与团队赋予了这种染料新的应用场景——经过改造后，这种细胞膜染料能用来评估CFTR的功能。 这项被称作荧光共振能量转移（FRET）的技术，能够实时监测氯离子通道活性。研究人员用细胞质膜染料对细胞进行染色，随后用光照射，此时功能正常的CFTR会发出蓝光，而功能失调的CFTR则会发出橙光。这项技术让研究人员建立起高通量检测体系，得以在短时间内筛选上百万种化合物，大幅提高了筛选效率。 González博士领导的研究成果，将原本复杂难以验证的蛋白功能，转化为能够大规模检验的可视化指标，为后续的药物研发奠定了坚实基础。而在此基础上进一步推动药物研发的关键人物，则是另一位获奖者Paul Negulescu博士。 Negulescu：近25年探索改写患者结局 2001年，Vertex Pharmaceuticals收购了Aurora Biosciences公司，继续推进囊性纤维化的研究。领导这一项目的Negulescu博士也迎来了众多科研人才的加入，例如与他共同获得2024年生命科学突破奖的Fredrick Van Goor博士和Sabine Hadida博士就是其中的核心人员。 当时，研究团队提出了两种基于不同思路的治疗策略：一种是引导突变蛋白前往细胞膜的校正剂（corrector）；另一种是在蛋白抵达后，让其稳定发挥作用的增效剂（potentiator）。理想情况下，这两种分子的组合可以带来双管齐下的治疗效果。 2012年，FDA批准了首个针对囊性纤维化病因研发的药物ivacaftor（商品名Kalydeco）上市，用于治疗携带G551D突变的囊性纤维化患者。这款由Negulescu博士等人筛选出的分子（研发阶段名为VX-770）是一种增效剂，能靶向CFTR蛋白上G551D突变，帮助这些患者打开跨膜通道，恢复CFTR功能。 ivacaftor的问世为携带G551D突变的囊性纤维化患者带来了突破性疗法，不过对于更为常见的ΔF508突变个体，ivacaftor仍无能为力。这是因为ΔF508突变的CFTR蛋白未曾到达细胞膜，因此除了增效剂ivacaftor，研究团队还需要设计一款校正剂为突变蛋白导航。 基于这一思路，校正剂lumacaftor很快得以问世。2015年7月，囊性纤维化的第一种联合疗法Orkambi（ivacaftor/lumacaftor）获FDA批准上市，用于治疗6岁及以上拥有两个ΔF508突变拷贝的囊性纤维化患者。随后，研究人员用另一款校正剂tezacaftor与ivacaftor联合使用以提高疗效，新的组合疗法Symdeko在2018年获得FDA批准，用于治疗12岁以上携带两个ΔF508突变拷贝的囊性纤维化患者。 ▲药物筛选和研发示意图（图片来源：参考资料[1]） 此时，这些获批药物尚无法惠及仅有一个CFTR ΔF508基因拷贝的患者。但很快，Negulescu博士与合作者给出了答案。研究团队在tezacaftor基础上增加了第二种校正剂elexacaftor，两种校正剂作用于CFTR蛋白的不同部分，产生协同效应。最终，三联药物Trikafta（elexacaftor/tezacaftor/ivacaftor）在2019年获FDA批准，携带一个ΔF508突变的囊性纤维化患者也迎来了治疗药物。 2024年底， Vertex Pharmaceuticals的新一代CFTR调节剂组合Alyftrek（deutivacaftor/tezacaftor/vanzacaftor）获FDA批准上市，用于治疗6岁及以上、携带至少一个ΔF508突变或其他对这款新药有应答的CFTR基因突变的囊性纤维化患者。 这些药物的出现彻底改写了囊性纤维化的治疗格局。据拉斯克奖官网新闻稿，目前全球至少有10万名囊性纤维化患者，其中超过90%的人符合此类新疗法的适应条件，约有7.5万人正在接受治疗。这些科学家的研究成果，正让众多囊性纤维化患者重新获得正常、健康的日常生活，并期待和规划美好的未来。 更多潜在疗法在路上 如今，基于多种策略的囊性纤维化药物研发正在开展。一些团队正尝试借助mRNA疗法进一步帮助尚未受益的囊性纤维化患者。例如，ReCode Therapeutics公司的吸入式mRNA疗法通过脂质纳米颗粒（LNP）载体将疗法递送到肺部正确位置，表达功能性CFTR蛋白以治疗囊性纤维化。这款RCT2100疗法于今年3月获得FDA授予治疗囊性纤维化的孤儿药资格，已经进入临床开发阶段。此外，Arcturus Therapeutics公司开发的吸入式mRNA疗法ARCT-032已进入2期临床试验阶段，该疗法利用Arcturus的LUNAR脂质介导雾化平台递送CFTR mRNA抵达肺部，旨在表达功能性CFTR蛋白并减轻导致进行性肺部疾病的下游影响。 与此同时，多种其他疗法也蕴育了治疗囊性纤维化的潜力，相关临床研究正在进行。在反义寡核苷酸（ASO）疗法领域，SpliSense公司在研的ASO疗法SPL84旨在治疗CFTR基因中携带特定剪接突变的患者，目前2期临床试验正在开展。4D Molecular Therapeutics公司的候选基因疗法4D-710通过腺相关病毒载体A101，以气溶胶形式将疗法递送至肺部从而恢复CFTR表达，目前4D-710处于1/2期临床试验阶段，此前公布的中期数据展现出积极结果。此外，一些噬菌体疗法正在尝试治疗囊性纤维化患者的慢性肺铜绿假单胞菌感染。 CRDMO平台赋能新疗法研发 药明康德在成立至今的25年里，见证了重磅囊性纤维化疗法的诞生与发展，也携手全球合作伙伴，在这一领域贡献自己的力量。作为创新的赋能者，药明康德长期以来也在为此类疾病新疗法的开发提供各种服务，通过一体化、端到端的CRDMO业务模式，从早期药物发现和研究（R）、开发（D）到生产（M）都能为合作伙伴提供支持，助力更多突破性疗法造福病患。根据公开信息，在过去3年中，药明康德纤维化药物开发一体化平台助力全球合作伙伴向美国FDA/中国NMPA提交了超过40个纤维化药物相关的IND申请；药明康德测试业务平台的药性评价部也能为包括CFTR蛋白调节剂在内的各类药物的体内、体外药物代谢与药代动力学（DMPK）研究提供支持。 参考资料： [1] 2025 Lasker~DeBakey Clinical Medical Research Award. Retrieved September 12, 2025 from https://laskerfoundation.org/winners/combined-triple-drug-therapy-for-cystic-fibrosis/ [2] Triple-Drug Combination for Cystic Fibrosis Wins Lasker Award. Retrieved September 12, 2025 from https://www-the-scientist-com.libproxy1.nus.edu.sg/triple-drug-combination-for-cystic-fibrosis-wins-lasker-award-73442 [3] FDA Approves TRIKAFTA (elexacaftor/tezacaftor/ivacaftor and ivacaftor) to Treat the Underlying Cause of Cystic Fibrosis in People Ages 12 and Older Who Have at Least One F508del Mutation. Retrieved August 21, 2025 from https://www.businesswire.com/news/home/20191021005792/en [4] FDA approves new breakthrough therapy for cystic fibrosis. Retrieved August 21, 2025 from https://www.prnewswire.com/news-releases/fda-approves-new-breakthrough-therapy-for-cystic-fibrosis-300942263.html [5] ReCode Therapeutics Receives U.S. FDA Orphan Drug Designation for RCT2100 for the Treatment of Cystic Fibrosis. Retrieved August 21, 2025 from https://recodetx.com/recode-therapeutics-receives-u-s-fda-orphan-drug-designation-for-rct2100-for-the-treatment-of-cystic-fibrosis/ [6] Arcturus Therapeutics Announces Initiation of Dosing in Phase 2 Multiple Ascending Dose Studies for Cystic Fibrosis (CF) and Ornithine Transcarbamylase (OTC) Deficiency. Retrieved August 21, 2025 from https://ir.arcturusrx.com/news-releases/news-release-details/arcturus-therapeutics-announces-initiation-dosing-phase-2 [7] 4DMT Announces Update on Regulatory Interactions and Development Path for 4D-710 for Treatment of Cystic Fibrosis. Retrieved August 21, 2025 from https://ir.4dmoleculartherapeutics.com/news-releases/news-release-details/4dmt-announces-update-regulatory-interactions-and-development 欢迎转发到朋友圈，谢绝转载到其他平台。如有开设白名单需求，请在“学术经纬”公众号主页回复“转载”获取转载须知。其他合作需求，请联系wuxi_media@wuxiapptec.com。 免责声明：本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。 更多推荐 点个“在看”再走吧~