Fitusiran

ChenFJMU团队编辑（原创）思语湖畔QuoteThe only way to do great work is to love what you do. If you haven’t found it yet, keep looking. Don’t settle. — Steve JobsFDA新药速递【25年3月】看点FDA于2025年3月批准2款新药，分别为用于治疗体重至少为40 kg的12岁及以上女性由微生物引起的无并发症尿路感染（uUTI）患者的三氮杂苊类抗生素Blujepa；用于常规预防或减少12 岁及以上患有血友病 A/B 儿童和成人患者出血发作频率的抗凝血酶（AT）降低疗法Fitusiran。01 近三十年首款——GSK的“First-in-class”药物Blujepa开创uUTI抗菌新疗法。02 重磅预防——全球第七款siRNA药物Fitusiran获批，用于血友病A/B出血发作，每两月皮下注射一次！细说FDA新药【25年3月】（ChenFJMU）Blujepa，01Blujepa（Gepotidacin，吉泊达星），由英国制药公司葛兰素史克研发，于2025年3月25日获得FDA的批准。Gepotidacin用于治疗由特定敏感微生物引起的儿科患者和成年女性的单纯性尿路感染（uUTIs），这些微生物包括大肠杆菌、肺炎克雷伯菌、弗氏柠檬酸杆菌复合菌、腐生葡萄球菌和粪肠球菌。uUTIs是女性最常见的感染之一，患者对新型口服抗生素（尤其是对产生耐药的尿路感染病原体）的治疗需求仍未得到满足。作为近三十年来首个具有新型作用机制的口服抗生素， Blujepa的获批为反复感染和对现有治疗耐药上升的患者提供了新选择。此外，全球获FDA批准用于治疗uUTI的药物还有多款，包括两款传统抗菌药物（Nitrofurantoin，呋喃妥因和Ciprofloxacin，环丙沙星）以及2024年获批的Pivya（Pivmecillinam，吡美西林）和Orlynvah（Sulopenem etzadroxil/Probenecid，舒洛培南和丙磺舒）。FDA批准用于治疗uUTI的药物（ChenFJMU原创）注：ChenFJMU原创，转载需要标注出处！【结构与剂型处方】Blujepa片剂含有活性成分Gepotidacin，这是一种抑制细菌DNA回旋酶和拓扑异构酶IV的三氮杂苊抗菌剂，化学名称为（R）-2-((4-(((3，4-二氢-2H-吡喃并[2，3-c]吡啶-6-基)甲基)氨基)哌啶-1-基)甲基)-1，2-二氢-3H，8H-2a，5，8a-三氮杂苊-3，8-二酮甲磺酸盐二水合物，分子式为C24H28N6O3●CH4O3S●2H2O，分子量为580.66。化学结构如下：每片Blujepa口服片剂含有750 mg Gepotidacin（相当于910.7 mg无水Gepotidacin甲磺酸盐）。非活性成分包括：二氧化硅胶体、交联羧甲基纤维素钠、硬脂酸镁、微晶纤维素、聚乙二醇、聚乙烯醇、滑石、二氧化钛和黄铁氧化物。【作用机制】Gepotidacin是一种新型三氮杂苊烯类口服抗生素，通过抑制细菌的II型拓扑异构酶（包括细菌DNA拓扑异构酶II（促旋酶）和拓扑异构酶IV），来抑制细菌DNA复制而发挥良好的杀菌作用。这种独特的结合位点和作用机制使其对大多数目标病原体（如大肠杆菌和腐生葡萄球菌）具有活性，包括对现有抗生素耐药的菌株。经时间杀伤研究证实，Gepotidacin对病原体具有杀菌活性。体外研究表明，在最低抑菌浓度（MIC）为5倍的情况下，Gepotidacin对大肠杆菌的抗生素后作用为1.8~2.2 h，对肺炎克雷伯菌的作用为1~6.6 h，对奇异杆菌的作用为1.4~3 h，对弗氏梭菌的作用为1.5~2.6 h，对腐生链球菌的作用为2.7~4.3 h，对粪肠球菌的作用为1.2~2.7 h。Gepotidacin的作用机制（Tiffany C, et al. Clin Transl Sci. 2022; 15: 2251-2264.）【药效学及药代动力学】药效学：动物感染和体外药代动力学-药效学（PK-PD）模型显示，24 h游离药物AUC与MIC之比是预测Gepotidacin抗菌疗效的PK-PD指数。药代动力学：除非另有说明，否则下表中以平均值（标准偏差[SD]）总结Gepotidacin的药代动力学特性。特殊人群用药：1、孕妇：尚无关于孕妇使用Gepotidacin评估重大出生缺陷、流产或其他不良母体或胎儿结果的药物相关风险的可用数据。2、哺乳期：尚无关于人乳中存在Gepotidacin、其对母乳喂养儿童或产奶量的影响的数据。根据对哺乳期小鼠的研究，其可能会转移到乳汁中。3、儿童患者：尚未确定Gepotidacin对12岁以下或体重低于40 kg的儿童患者的安全性和有效性。4、老年患者：未观察到65岁以上老年患者与年轻成人患者之间在Gepotidacin的安全性或有效性方面存在总体差异，但不能排除一些老年人的更大敏感性。5、肝功能损伤患者：轻度或中度肝功能损害（Child-Pugh分级A/B）的患者无需调整剂量，严重肝功能损害患者避免使用。6、肾功能损伤患者：轻度或中度肾功能损害（轻度：eGFR 60至89 mL/min；中度：eGFR 30至59 mL/min）的患者无需调整剂量，严重肾功能损害患者避免使用。【非临床毒理学】Gepotidacin尚未进行长期致癌性研究，在动物研究中未发现该药影响生育能力。但在人类外周血淋巴细胞的体外微核试验和L5178Y小鼠淋巴瘤试验中呈阳性，在大鼠体内微核试验或彗星试验中呈阴性。基于证据的总体权重，其不太可能具有基因毒性。【临床研究】在2项多中心、双盲、双模拟、随机非劣效性（NI）试验中（试验1 EAGLE-2[NCT04020341]，N=1531和试验2 EAGLE-3[NCT04187144]，N=1605）对Gepotidacin的安全性进行了评估，受试者为12岁及以上患有uUTI的儿童患者和成年女性。试验共招募3136名患者，比较了Gepotidacin（1500 mg，每日两次）与呋喃妥因（100 mg，每日两次）在治疗uUTI上的有效性和安全性。研究的主要终点是在第10至13天的治愈检验期（TOC）访视中，达到临床和微生物学应答的患者比例。这两项试验中，Gepotidacin在治疗患uUTI的成年女性（≥40 kg）及大于12岁青少年患者（≥40 kg）时，与当前标准治疗之一呋喃妥因相比具有非劣效性。在EAGLE‑2研究中，Gepotidacin的治疗成功率为50.6%（162/320），活性对照组为47.0%（135/287），提高了4.3%（95%CI：-3.6～12.1）；其中临床成功率相近（65.6% vs 65.2%），微生物学成功率提高5.2%（72.5% vs 67.6%）。在EAGLE‑3研究中，Gepotidacin与活性对照组相比， Gepotidacin组治疗成功率为58.5%（162/277），活性对照组为43.6%（115/264），提高了14.6%（95%CI：6.4～22.8），表现出优效性；其中临床成功率提高4.4%（67.9% vs 63.3%），微生物学成功率提高15.0%（72.2% vs 57.2%）。【用药指南】往期回顾编辑：廖源榕排版：周纯情补充和审核：陈昌买推送：ChenFJMU（欢迎个人转发分享，企业及其他公众号需授权后转载，并注明出处！）

The pairing of two Bristol Myers Squibb immunotherapies is now permitted for the first-line treatment of two types of gastrointestinal cancers, after regulatory decisions handed out this past week that convert the accelerated approval status of the drug combination to full FDA approval in both indications. The drugs, Opdivo and Yervoy, belong to the class of medicines called checkpoint inhibitors. On April 8, the FDA approved use of this drug combination for adults and children age 12 and older whose colorectal cancer has metastasized or cannot be removed by surgery. The cancer must also be microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR), references to biomarkers that indicate the stability of DNA in a tumor. The regulatory submission was based on the results of an open-label Phase 3 test that compared the Opdivo/Yervoy combination to either Opdivo alone or chemotherapy. Results showed the immunotherapy combination led to a 38% reduction in the risk of disease progression or death compared to Opdivo monotherapy, and by 79% compared to chemo, both in the first-line setting. The study is ongoing to assess secondary measures, including overall survival. BMS said it will continue working with study investigators to present these data and longer-term follow-up results in the future. Sponsored Post Changes in Nurse Staffing Answer Clinician Demands The ongoing nursing shortage facilitates high turnover rates since nurses know they won’t have difficulties finding new jobs. In order to retain and attract staff, it’s in a facility’s best interest to understand what nurses want. By Tomasz Rezik On April 11, the FDA approved the combination of Opdivo and Yervoy for treating advanced cases of hepatocellular carcinoma. In the pivotal test in this indication, the drug combination led to median overall survival of 23.7 months. The comparator arm, in which patients received standard of care drugs sorafenib or levantinib, median overall survival was 20.6 months. At three years, the drug combination showed an overall survival rate of 38% versus 24% in the comparator arm. FDA approval of Opdivo plus Yervoy in hepatocellular carcinoma follows the European Commission’s early March approval of the drug combination in this indication. There’s plenty of news on the regulatory front. Here’s a recap of other recent highlights: New and Expanded Regulatory Approvals —Argenx drug Vyvgart Hytrulo received an additional approval for dosing of the product via a prefilled syringe. The drug, supplied in vials, previously received FDA approvals for the autoimmune conditions chronic inflammatory demyelinating polyneuropathy and generalized myasthenia gravis. Analysts say prefilled syringes bring patients a more convenient dosing option while giving Argenx the opportunity to get more market share by penetrating into earlier lines of therapy. Sponsored Post Understanding EGPA: The Role of Eosinophils and Advancements in Treatment Options FASENRA® (benralizumab) injection, for subcutaneous use, 30 mg is indicated for the treatment of adult patients with eosinophilic granulomatosis with polyangiitis (EGPA). FASENRA provides a treatment option for HCPs to consider when managing this challenging disease. By FASENRA, Sponsored Content —Amgen’s Uplizna expanded its label to include the treatment of immunoglobulin G4-related disease (IgG4-RD), an immune-mediated inflammatory disorder that can affect multiple organs. The regulatory decision makes the intravenously infused antibody the first FDA-approved treatment for this rare and chronic disease. Uplizna was first approved in 2020 as a treatment for neuromyelitis optica spectrum disorder. —Bayer’s Viktrakvi now has full FDA approval for the treatment of NTRK gene fusion-positive solid tumors in adults and children without a known acquired resistance mutation. The drug received accelerated approval in this indication in 2018. —AstraZeneca and Daiichi Sankyo welcomed European Union approval of Datroway as a treatment for metastatic breast cancer that is HR positive and HER2 negative. Datroway received FDA approval in the same indication in January. The drug is an antibody drug conjugate designed to target the cancer protein TROP2. —Novartis drug atrasentan, brand name Vanrafia, was awarded accelerated approval as a new treatment for the kidney disorder immunoglobulin A nephropathy (IgAN). The drug is an oral small molecule designed to block the endothelin A receptor. It’s one of two IgAN nephropathy drugs that came via the $3.2 billion acquisition of Chinook Therapeutics in 2023. Novartis’s internal IgAN research yielded the complement inhibitor Fabhalta, which received accelerated approval in this indication last summer. —Speaking of Fabhalta, that Novartis drug expanded its label to include C3 glomerulopathy, making the twice-daily pill the first approved treatment for this rare kidney disorder. Fabhalta is a small molecule designed to block the complement protein C3. It was first approved in 2023 as a treatment for the rare blood disorder paroxysmal nocturnal hemoglobinuria. —Sanofi received FDA approval for fitusiran, brand name Qfitlia, as a treatment for both hemophilia A and B. The drug leverages RNA interference to lower levels of AT, a protein that inhibits blood clotting. The approval covers the treatment of adults and children age 12 and older with or without inhibitors, which are antibodies that can develop in hemophilia patients, making it more difficult to control bleeding. By contrast, new Pfizer drug Hympavzi is approved only for hemophilia A and B patients without inhibitors while Sanofi’s Alhemo is approved only for hemophilia A and B patients with inhibitors. —Blockbuster AstraZeneca cancer immunotherapy Imfinzi landed European Union approval for the treatment of limited-stage small cell lung cancer. This new approval is based on Phase 3 results showing a 27% reduction in the risk of death compared to a placebo. The FDA approved Imfinzi for this indication last December. —Imfinzi also added perioperative treatment of muscle invasive bladder cancer to its list of FDA-approved indications. The newest FDA nod covers use of the drug in combination with chemotherapy before surgery to remove the bladder, followed by Imfinzi as an adjuvant monotherapy. In the pivotal study supporting this new indication, results showed a 32% reduction in the risk of cancer recurrence and a 25% reduction in the risk of death compared to neoadjuvant chemotherapy alone. —The European Commission approved Pfizer vaccine Abrysvo for protection against respiratory syncytial virus (RSV). The regulatory decision expands the vaccine’s approval to adults ages 18 to 59. European regulators initially approved the vaccine in 2023 for preventing lower respiratory tract disease in adults age 60 and older. Abrysvo won FDA approval the same year. —The FDA expanded approval of Novartis’s Pluvicto to include use as an earlier line of treatment — after anti-androgen drugs and before chemotherapy — for PSMA-positive metastatic castration-resistant prostate cancer (mCRPC). Pluvicto was initially approved in 2022 for PSMA-positive mCRPC that has already been treated with an anti-androgen drug and chemotherapy. Novartis said this expansion is important because about half of patients do not live long enough to receive a second-line treatment. —Exelixis cancer drug Cabometyx expanded its FDA-approved uses to advanced cases of pancreatic neuroendocrine tumors (pNET) and extra-pancreatic neuroendocrine tumors (epNET). The approval covers adults and children age 12 and older. Cabometyx is a small molecule designed to block enzymes that support cancer growth. The drug was first approved in 2016 for advanced renal cell carcinoma. —GSK landed FDA approval for Blujepa, an oral antibiotic developed to treat uncomplicated urinary tract infections. While drugs are already available for these infections, they can become resistant to treatment. Blujepa is designed to block two enzyme targets key to bacterial DNA replication, an approach intended to lower the potential for drug resistance. —The European Commission approved Capvaxive, a pneumococcal vaccine developed by Merck to protect against the 21 Streptococcus pneumoniae serotypes that lead to the majority of cases of invasive pneumococcal disease including eight that are not covered by any other available pneumococcal vaccine. The European regulatory decision covers adults age 18 and older. Capvaxive received FDA approval last July. —Alynlam Pharmaceuticals drug Amvuttra received FDA approval for treating cardiomyopathy caused by transthyretin amyloidosis (ATTR). The RNA interference drug was first approved in 2022 for the treatment of polyneuropathy caused by ATTR. In the cardiomyopathy indication, it will compete with Pfizer’s Vyndaqel and Vyndamax, which are established as the standard of care, as well as Attruby, a BridgeBio Pharma drug that received FDA approval last fall. —Bristol Myers Squibb’s Breyanzi received European Commission approval for relapsed or refractory follicular lymphoma. The CAR T-therapy received accelerated FDA approval in this indication last May. —Geron Corporation’s Rytelo received European Commission approval for the treatment of transfusion-dependent anemia caused by lower-risk myelodysplastic syndrome, a progressive type of blood cancer. The intravenously infused drug is the first telomerase inhibitor to reach the market. Rytelo landed FDA approval last June. —Neffy, an epinephrine nasal spray that ARS Pharmaceuticals developed to treat allergic reactions to insect bites, medications, and food, expanded its FDA approval to include patients weighing 15 to 30 kilograms (about 33 to 60 pounds). The product’s initial approval last year covered its use in patients weighing 30 kg or more. —Roche subsidiary Genentech received FDA approval for tenecteplase, brand name TNKase, as a treatment for acute ischemic stroke in adults. Genentech said TNKase is the first stroke medicine approved by the FDA in nearly 30 years. It’s the second approved indication for the clot-busting drug. The FDA approved it in 2000 for treating acute myocardial infarction. —A Neurotech Pharmaceuticals cell and gene therapy administered via a surgical implant received FDA approval for the treatment of macular telangectasia type 2. The therapy, brand name Encelto, is the first approved treatment for this rare vision-loss disorder. Regulatory Setbacks —The FDA missed the April 1 regulatory decision target date for Novavax’s Covid-19 vaccine. Politico reported the holdup was due to the intervention of Sara Brenner, the FDA’s principal deputy commissioner, who asked for more data. Novavax said it has responded to all of the FDA’s information requests and believes the application is ready for approval based on the submitted Phase 3 data. Novavax’s protein-based vaccine initially received FDA emergency use authorization in 2022, a status that it retained under amended authorizations in 2023 and last year, both times for new formulas that covered the prevalent variants at the time. Full FDA approval would put the vaccine on par with the approved messenger RNA vaccines marketed by Pfizer and Moderna. Novavax’s Covid-19 vaccine will be co-commercialized with Sanofi under a partnership announced last year. —Roche paused European clinical tests of the Duchenne muscular dystrophy gene therapy Elevidys, the pharmaceutical giant said in a letter to the World Duchenne Organization. The move follows Sarepta Therapeutics’ recent report of a liver failure-associated patient death. Roche said the European Medicines Agency asked for a clinical hold on four studies until the inquiry into the cause of death is complete. Under a 2019 deal with Sarepta, Roche holds rights to Elevidys outside of the U.S. —For the second time, the FDA has rejected Aldeyra Therapeutics drug reproxalap as a treatment for dry eye disease. The agency turned down an application for the drug in 2023. According to Aldeyra, the FDA’s latest complete response letter said the new drug application failed to demonstrate efficacy. The regulator asked the company to run at least one more clinical trial. Among the concerns raised by the FDA is differences in baseline scores, which may have affected interpretation of trial results. Aldeyra said results from two ongoing studies are expected later in the current quarter, potentially paving the way for a mid-year resubmission of the application. —The European Medicines Agency refused marketing authorization for Eli Lilly Alzheimer’s disease drug Kisunla. Safety was the main reason cited, particularly the brain inflammation and bleeding that is a known complication risk associated with all drugs in the same class of Alzheimer’s medicines. The agency said the drug’s benefits were not enough to outweigh the potentially fatal safety risks. The FDA approved Kisunla last July. —In other Alzheimer’s drug news, Eisai again failed to persuade Australia’s drugs regulator to register Leqembi. The pharma company had asked the Therapeutics Goods Administration (TGA) to reconsider its October 2024 decision to not register the drug in Australia. Eisai’s request for reconsideration covered a narrower indication, but Eisai said the TGA did not agree that safety has been established for these patients.