Tafamidis

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.

最近心血管领域的里程碑和催化有点多。早前，恒瑞医药与默沙东就旗下Lp(a)口服小分子HRS-5346以2亿美元首付款+17.7亿里程碑及销售分成达成授权协议，让人看到了国产心血管领域创新分子亦能拿下大的BD。3月底，AZ在美国心脏病学会（ACC）年会公布了口服PCSK9抑制剂AZD0780的2b期数据同样也令人振奋，其在12周内实现了约50%的LDL - C（低密度脂蛋白胆固醇）降低，该药物无需空腹即可服用。接下来的两个月，最令投资者关注的莫过于两大心血管领域“新秀”BridgeBio Pharma和Alnylam Pharmaceuticals一季度的成绩单，这涉及到转甲状腺素蛋白淀粉样变性心肌病（ATTR-CM）这一大市场的全球竞争格局变革。01ATTR-CM大市场转甲状腺素蛋白淀粉样变性心肌病（ATTR-CM）是一种由转甲状腺素蛋白（TTR）错误折叠引发的致命性心肌病，TTR原以四聚体形式稳定存在负责转运甲状腺素和视黄醇结合蛋白，但在基因突变、炎症或衰老等因素作用下，四聚体解离成单体并错误折叠形成淀粉样纤维，错误折叠TTR蛋白在心肌间质沉积会导致心肌增厚、舒张功能受限，最终进展为心力衰竭。ATTR-CM又可以分为遗传型（hATTR-CM）、野生型（wtATTR-CM），前者由于与TTR基因突变相关，发病年龄更早，严重程度更高；后者患病率会随着年龄的增长，更多见于60岁以上男性。ATTR-CM患者生存质量较低，同时生存率较低，存在较大的未满足临床需求。一方面，数据显示全球约有5万名hATTR患者，20-30万名wtATTR患者，以wtATTR为例mOS在诊断后大概也就是43-57个月，且75%患者对现有治疗应答不佳；另一方面，ATTR可能引起多种不良反应，例如心衰、呼吸困难、虚弱、知觉丧失等，且治疗通常需要延续一生，疾病负担较重。据报道，中国ATTR-CM患者数可能达到27万，诊断率不足1%，这意味着还有大量患者未被诊断。据Intellia Therapeutics预计，全球ATTR-CM药物市场预计到2028年将达到约120亿美元，可见这个“罕见病”的市场潜力巨大。在2017年以前，全球治疗ATTR-CM的方案和手段非常有限，仅能通过肝脏移植或者使用在部分国家获批的氯苯唑酸进行治疗。2019年辉瑞的口服TTR稳定剂Tafamidis获批，才将ATTR-CM治疗药物的市场潜力充分发挥，2024年录得33.21亿美元销售额，位列辉瑞十大销售药物之一。TTR稳定剂为通过稳定TTR四聚体结构，抑制其解离为致病单体，延缓淀粉样蛋白沉积；在Tafamidis的III期ATTR-ACT研究显示，治疗30个月后，全因死亡率降低30%，心血管相关住院率降低32%。Tafamidis作为老一代的TTR稳定剂，其仍存在一定的不足。一方面，其对hATTR（变异型）患者疗效有限，ATTR-ACT研究中hATTR亚组全因死亡率未显著降低；另一方面，其起效较慢，需要长期用药才能降低死亡率和住院率，同时有一定胃肠道副作用（最常见为腹泻）。02三雄争霸随着BridgeBio的新一代口服TTR稳定剂Acoramidis在2024年11月获批、Alnylam的RNAi疗法Vutrisiran在2025年3月获批，海外机构预计未来ATTR-CM治疗药物市场将呈现“三强争霸”的局面。瑞银在采访的一位管理超过1000位ATTR-CM患者的心脏病专家在访谈中预计，随着两款新药物的上市，2025年底前ATTR-CM新增患者病例开具厨房的比例各占三分之一，而到2026年底可能达到2:2:1的比例（Acoramidis：Vutrisiran：Tafamidis）。两款新获批药物有何独特之处？BridgeBio的Acoramidis与辉瑞的Tafamidis一样均为TTR稳定剂，其改善了Tafamidis存在的起效慢、对变异型患者疗效有限的不足，同时更大幅度的降低了患者的全因死亡率和心血管相关住院风险。据公司口径，Acoramidis是一种近完全 （≥90%） 转甲状腺素蛋白 （TTR） 稳定剂。Acoramidis的ATTRibute-CM三期研究显示，接受Acoramidis治疗的患者3个月内就出现显著的心血管获益，包括降低全因死亡率和心血管相关住院风险等；在30个月时，Acoramidis组患者的心血管相关住院事件减少了42%，心血管住院事件的累积频率降低了50%，在变异型和野生型患者均展现出疗效。在ACC 大会另一项Acoramidis壁报显示，无论是接受安慰剂治疗ATTR-CM患者还是接受安慰剂和Tafamidis治疗的患者，Acoramidis均显著增加了血清TTR水平；相反，将Tafamidis添加到Acoramidis中并未显示血清TTR水平进一步增加，这一结果也反映了Acoramidis潜在Me better的属性。Alnylam的Vutrisiran与辉瑞、BridgeBio两款口服稳定剂的机制截然不同，是一种化学修饰的siRNA，能够特异性靶向TTR的mRNA使其在肝脏中的催化降解，通过降解TTR mRNA减少血清中TTR蛋白的水平，从而减少了TTR淀粉样蛋白在组织中的沉积，达到从上游层面解决问题的目的。在Vutrisiran治疗ATTR-CM的HELIOS-B三期研究中，接受Vutrisiran治疗的患者在36个月内将死亡和心脏相关事件的风险降低了28%。延长至42个月的随访期内，总人群的死亡风险降低了36%。（上述三款药物对比）从两款迭代的疗效和安全性上看，Acoramidis在起效时间和心血管控制事件层面均具备不错的优势，并且价格与Tafamidis相当，患者转化相对好；而Vutrisiran则是在更长的随访期展现了不错的生存获益，同时海外部分临床医生给予了很高的评价。03值得关注的同赛道管线全球范围来看，参与ATTR-CM药物研发竞争的选手不少，但前述的TTR稳定剂、siRNA疗法均代表了目前的主流思路，这里不得不提的还有一种新型思路：体内基因编辑疗法。这一领域颇具代表性的药物为Intellia Therapeutics的NTLA-2001，该药通过脂质纳米颗粒LNP向患者肝脏细胞递送CRISPR/Cas9基因编辑系统，靶向永久性地敲除TTR基因，减少血清中TTR蛋白的生成，这也从理论上看到了治愈ATTR-CM的希望。NTLA-2001的一期临床数据显示，接受1.0mg/kg剂量组的6名患者血清TTR蛋白水平下降了93%，并且在治疗后2-12个月的随访期，患者的TTR水平持续保持下降。该药物的早期临床治疗效果十分显著，不过其在多发性神经疾病的临床中不良反应率较高，安全性需要进一步在大样本的三期临床数据中观察验证。放眼国内，目前针对ATTR-CM研发进度较前的创新管线为倍特药业的siRNA药物BPR-30221616注射液（刚进入临床，全球第二款针对该疾病的siRNA药物）、尧唐生物的体内基因编辑药物YOLT-201（已有IIT数据，进入注册临床），两者分别追随Alnylam和Intellia的路线，未来值得期待。抛开ATTR-CM适应症赛道不谈，心血管创新药物存在广阔的机会。两款PCSK9单抗2023年全球销售近30亿美元，AZ通过研发口服药物AZD0780改善患者依从性，同样默沙东MK - 0616也是该策略下的竞品，部分海外机构更是给出了50亿美元的市场机会预测。同样针对降低动脉粥样硬化性心血管疾病（ASCVD）风险的，Lp(a)靶点药物显然也存在巨大的机会，恒瑞、石药相关分子均达成了不俗的对外授权，这类药物未来极有可能将与PCSK9药物联用，探索更大市场的可能性。当然，除上面提到这些之外还有不少的潜力靶点，包括调控甘油三酯代谢的ANGPTL3/4、可改善心肌肥厚的GDF-15/MSTN（肌肉生长抑制素）等，以及可聚焦难治的射血分数保留型心衰（HFpEF）开发药物等。结语：心血管药物的传奇之旅还在延续，ATTR-CM这样的“罕见病”都能让BridgeBio、Alnylam这样的中大型Biotech绽放出耀眼的价值光芒，它的每一个细分赛道机会，都值得我们重视。识别微信二维码，添加抗体圈小编，符合条件者即可加入抗体圈微信群！请注明：姓名+研究方向！本公众号所有转载文章系出于传递更多信息之目的，且明确注明来源和作者，不希望被转载的媒体或个人可与我们联系(cbplib@163.com)，我们将立即进行删除处理。所有文章仅代表作者观点，不代表本站立场。