11月2日 - 诺华公司一款实验性心脏药物在大型试验中最近失败，引发心脏病专家和投资者对一个广为接受的观点的质疑：降低一种名为脂蛋白(a)的基因决定的胆固醇载体水平，可以改善心脏健康。
Nov 2 - The recent failure of a Novartis experimental heart drug in a large trial raised questions among cardiologists and investors about the widely held idea that reducing levels of a genetically set cholesterol carrier called lipoprotein(a) can improve heart health.
医生表示，即将公布的试验细节将揭示，针对这种血液颗粒（通常称为Lp(a)，或“LP little a”）的药物，是否可能是心脏病预防领域的下一个重大突破，还是这种脂肪颗粒仅仅是风险指标，而非病因。
Doctors say the upcoming release of trial details will shed light on whether drugs that target the blood particle, commonly referred to as Lp(a), or "LP little a," might be the next big breakthrough in heart disease prevention, or whether the fatty particle is merely an indicator of risk, rather than a cause.
该药物名为pelacarsen，由诺华公司和Ionis Pharmaceuticals开发，已被证明可将血液中Lp(a)水平降低80%，但未能在试验中转化为降低心脏病发作和中风风险。
The drug, pelacarsen, developed by Novartis and Ionis Pharmaceuticals, has been shown to lower blood levels of Lp(a) by 80%, but that failed to translate into a lower heart attack and stroke risk in the trial.
大约20%的人携带指示肝脏产生这种额外粘性胆固醇颗粒的基因，尽管由此产生的血液水平各不相同。非裔或南亚裔人群的发病率更高。
Around 20% of people have genes that instruct their liver to produce the extra-sticky cholesterol particle, although resulting blood levels vary. Incidence is higher for people of African or South Asian ancestry.
与会在动脉中沉积脂肪和斑块的标准“坏”胆固醇LDL不同，Lp(a)水平不受饮食、运动或生活方式改变的影响。
Unlike standard "bad" LDL cholesterol that deposits fat and plaque in the arteries, Lp(a) levels are not affected by diet, exercise, or lifestyle changes.
根据美国心脏协会的数据，心脏病是美国的主要死亡原因，每年导致近百万人死亡。
Heart disease is the leading cause of death in the United States, killing nearly a million people annually, according to the American Heart Association.
pelacarsen试验的完整详细结果将于周六在芝加哥的美国心脏协会年度科学会议上公布。一切都将取决于试验是否仅仅错过了“统计显著性”——这意味着药物有积极影响，但不足以达到研究目标——是否毫无影响，甚至更糟，产生了负面影响。
Full detailed results of the pelacarsen trial will be presented on Saturday in Chicago at the AHA's annual scientific meeting. Much will hinge on whether the trial narrowly missed being "statistically significant" – meaning the drug had a positive impact, but not enough to meet the study's goal – had no impact, or even worse, had a negative effect.
“如果根本没有任何信号，那将真正削弱该领域任何进一步的热情，”达拉斯UT西南医学中心心脏病专家、该研究的调查人员Parag Joshi博士说。
"If there are no signals at all, then that will really dampen any further enthusiasm for the space," said Dr. Parag Joshi, a cardiologist at UT Southwestern Medical Center in Dallas and an investigator on the study.
其他制药商正在针对Lp(a)开发依赖不同机制的实验性药物。安进的奥帕西兰和礼来的莱波迪兰已被证明可将Lp(a)水平降低约95%。安进的III期结果预计将于2028年初公布，而礼来的结果预计将于2029年公布。
Other drugmakers are targeting Lp(a) with experimental drugs that rely on different mechanisms. Amgen's olpasiran and Eli Lilly's lepodisiran have been shown to lower Lp(a) levels by around 95%. Amgen's Phase 3 results are expected in early 2028, while Lilly's are expected in 2029.
这些研究的设计与诺华的试验不同，包括只招募Lp(a)水平高于许多参加诺华试验患者的患者。安进首席医疗官保罗·伯顿表示，他将关注AHA会议上的数据，但“我们相信我们拥有一种具有差异化的分子”。医生们的疑问 心脏病专家已经使用Lp(a)血液检测来评估个人患心脏病的遗传风险。美国心脏协会和美国心脏病学会今年早些时候发布了新指南，建议所有成年人至少在一生中检测一次Lp(a)。
Those studies are designed differently than the Novartis trial, including enrolling only patients with higher Lp(a) levels than many who took part in the Novartis trial. Paul Burton, Amgen's chief medical officer, said he will be monitoring the data at the AHA meeting, but "we believe we have a differentiated molecule." DOCTORS' QUESTIONS Cardiologists already use Lp(a) blood tests to assess an individual's inherited risk for heart disease. The AHA and the American College of Cardiology earlier this year issued new guidelines for all adults to have their Lp(a) measured at least once in their lifetime.
“当我看到有早发性心脏病家族史的人时，有95%的可能性是由LP little a引起的，”海肯萨克大学医学中心心脏病专家纳撒尼尔·莱博威茨博士说，他参与制定了这些指南。
"When I see someone with a family history of premature heart disease, there is a 95% chance it's going to be from LP little a," said Dr. Nathaniel Lebowitz, a cardiologist at Hackensack University Medical Center, who helped draw up the guidelines.
诺华此前表示，III期佩拉卡森试验未能实现显著降低死亡、心脏病发作、中风以及为恢复阻塞血管血流而进行的血管重建手术这一复合终点的主要目标。该消息导致其股价下跌16%。
Novartis had said that the Phase 3 pelacarsen trial did not meet its main goal of significantly reducing the risk of a composite of death, heart attack, stroke and need for revascularization procedures to restore blood flow in blocked blood vessels. The news contributed to a 16% share price drop.
这家瑞士制药商拒绝进一步评论。该试验的首席研究员、克利夫兰诊所的史蒂文·尼森博士表示，在试验结果公布之前他无法发表评论。
The Swiss drugmaker declined to comment further. The trial's lead investigator, Dr. Steven Nissen of the Cleveland Clinic, said he was unable to comment until after the trial presentation.
医生们指出，一些因素可能影响了研究结果，包括将中风列为复合终点的一部分，尽管研究表明Lp(a)与中风之间的关系尚不明确。
Doctors pointed to a handful of factors that could have influenced the study results, including the inclusion of stroke as part of the composite endpoint even though studies have shown an unclear relationship between Lp(a) and stroke.
UT西南医学中心的乔希表示，他最想看到的是心脏病发作和血管重建手术发生率的数据。
UT Southwestern's Joshi said he is most interested to see the data for rates of heart attack and revascularization.
诺华的试验首次测试了每月80毫克的剂量。此前的中期试验测试了每月最高60毫克剂量以及每周20毫克剂量。
The Novartis trial tested a monthly dose of 80 milligrams for the first time. A previous midstage trial tested a highest monthly dose of 60mg as well as a weekly 20mg dose.
“一种可能性是，也许出现了（患者）脱落。他们从未一次性研究过该剂量，”纽约市锡奈富斯特心脏医院代谢与脂质主任罗伯特·罗森森博士表示，并指出剂量与患者对药物的耐受性有关。
"One possibility is that maybe there were (patient) dropouts. They never studied that dose all at once," said Dr. Robert Rosenson, director of metabolism and lipids at Mount Sinai Fuster Heart Hospital in New York City, noting that dosage is linked to patient tolerance of the drug.
除了佩拉卡森或安慰剂，试验中的患者还接受了降低低密度脂蛋白的他汀类药物以及更强效的PCSK9胆固醇药物，如安进公司的瑞帕莎，后者已被证明可将Lp(a)降低约25%左右的较为温和的幅度。
In addition to pelacarsen or a placebo, patients in the trial were treated with LDL-lowering statins and more potent PCSK9 cholesterol drugs like Amgen's Repatha, which has been shown to lower Lp(a) by a more modest 25% or so.
医生表示，在显示大幅降低低密度脂蛋白有益的研究之后，PCSK9药物的使用已显著增长。
Doctors said use of PCSK9 drugs has grown significantly following studies showing the benefit of dramatic LDL lowering.
“在无法消除Lp(a)的情况下，我们一直在更积极地降低低密度脂蛋白，”莱博维茨说。“如果这种策略在风险降低方面有效，那会怎样？”罗森森表示，在2019年启动的试验中，病情恶化的参与者可能被使用了PCSK9药物。
"In the absence of being able to get rid of LP little a, we've been driving down LDL much more aggressively," Lebowitz said. "What if that strategy works in terms of risk reduction?" Participants whose condition worsened during the trial, which was launched in 2019, were likely put on PCSK9s, Rosenson said.
“这是否抵消了风险，还是说不？这是我心中真正重大的问题之一，”他说。
"Did that offset the risk or not? That is one of the really big questions that I have," he said.