Intervertebral Disc Displacement

Despite some safety concerns, an FDA advisory committee on Friday voted 8 to 4 in favor of Japan-based Seikagaku’s condoliase injection for the treatment of radicular leg pain associated with lumbar disc herniation in adults. Much of the discussion centered on one of Seikagaku’s three clinical trials presented before the committee that failed on its primary endpoint and several secondary endpoints. Overall, the members of the FDA’s Anesthetic and Analgesic Drug Products Advisory Committee said the negative study should be weighed appropriately by the agency, and they raised short and long-term safety questions about the injection. Committee chair Brian Bateman of Stanford University School of Medicine, who voted against the injection, cautioned that the population in the negative, US-based study “might reflect the population that would ultimately use it.” He also noted several safety concerns, including that the drug has to be used in a setting that can treat anaphylaxis, and that those receiving the drug can be at risk of severe cutaneous adverse reactions (SCARs). Committee panelist Steven Schiff, professor of neurosurgery at Yale University, who voted in favor of condoliase, also raised concerns about larger numbers of people accessing it. “I could envision in the next years, a million people might get this therapy,” Schiff said, and if the prevalence of SCARs is about one in 1,000, as Seikagaku estimates, a few hundred cases of these life-threatening reactions in the US “might cause the FDA to think twice” about the approval. Michael Sprintz of Ethos Behavioral Health Group in Houston voted in favor of the injection but said he hopes the label will be appropriately narrow and ensure that those who receive it fail on the more commonly used therapies. Lumbar disc herniation can cause lower back or leg pain, but is typically resolved with existing medicines. About 20% to 50% of those in pain progress to surgery, Seikagaku said Friday. The company has presented condoliase as a less invasive alternative to surgery. About 29,000 patients have been treated with condoliase, first approved in Japan in 2018, the company said. Two of the studies were based in the US, but only one of those was positive. One key way that the two trials differed was that in the positive trial, the company used MRIs to find evidence of nerve impingement before administering the drug. But some of the panelists questioned if the MRI scans were the primary reason for the differences between the failed and positive studies. Schiff noted that the two US-based studies had very different populations and indications. And while he’s not surprised by the one failed study, he did ask: “How do you translate the success of the second study given the very rigorous inclusion and exclusion criteria? How does that get translated into approval?” DJ Kennedy of the Vanderbilt University Medical Center, who voted in favor of the drug, also said that the application of condoliase in the real world will likely be more similar to what occurred in the negative study, “unless there’s significant efforts to make that not the case.” But the experience of using the drug in Japan could be informative to the FDA in making its approval decision. ‘The longer term studies out of Japan are reassuring, maybe not completely sufficient, but they are reassuring,” Kennedy said.

Japan-based Seikagaku will face an FDA advisory committee on Friday, with the agency raising concerns ahead of the meeting regarding the efficacy of its condoliase injection for the treatment of radicular leg pain associated with lumbar disc herniation in adults. Ahead of the meeting of the Anesthetic and Analgesic Drug Products Advisory Committee, the FDA notes that one of the clinical trials failed on its primary endpoint. Overall, the agency sounded positive on an approval, noting in briefing documents released Wednesday that “the negative study may inform the benefit-risk assessment for specific populations who may be considered for treatment with condoliase if the product is approved.” One of the three clinical trials evaluated by the FDA did not meet its primary efficacy endpoint (change in worst leg pain from baseline to week 13), nor did it meet either of its two key secondary endpoints, including a pain outcome assessment after a year. The change from worst leg pain from baseline to week 52 slightly favored the control in the failed study, FDA said, but the difference was not statistically significant. The agency also noted that the study that failed likely did so because herniation resulting in symptomatic nerve impingement was not present in most of the patients enrolled, and that’s what the injection targets. The agency said that Seikagaku “performed a detailed analysis to explain the negative U.S. findings despite the positive findings in Study 1031 in Japan.” The company highlighted two key issues: 1) A majority of patients in the failed trial did not have definitive impingement of the nerve root by the disc herniation on an MRI. 2) Baseline back pain was significantly higher in the US study compared to the study in Japan. Two other Phase 3 clinical trials were positive, although one was conducted exclusively in Japan. And in both trials, nerve impingement conducive to condoliase treatment was confirmed by imaging, FDA said. Friday’s committee will have an up-or-down vote on the injection, with the question presented as, “Do the benefits of condoliase injection for treatment of radicular leg pain associated with confirmed nerve root impingement caused by lumbar disc herniation in adults with radicular leg pain outweigh the risks?” Seikagaku, which also markets an intra-articular injection for the treatment of knee osteoarthritis in the US, calls its condoliase injection an improvement on the current treatment landscape, because it does not require general anesthesia and is “less invasive to the patient than surgical treatment.”

*仅供医学专业人士阅读参考 今天早上一起来，北京温度突然降了不少，不过天倒是挺蓝的。往年一到冬天就开始忧心雾霾问题，这几年的整治还是蛮有效果，体感上好天气是越来越多了。 除了雾霾的主要污染源PM2.5，其实还有更多造成空气污染的成分，比如主要由交通工具燃油燃烧产生的二氧化氮（NO2），也是要为一系列疾病负起责任。 近期，北京大学、复旦大学、西安交通大学、牛津大学的联合科研团队在《柳叶刀·公共卫生》杂志发文，研究者们分析了来自中国嘉道理生物库的50余万中国人数据，发现长期二氧化氮暴露与多种疾病高风险存在正向关联。 二氧化氮年暴露量每升高10 μg/m³，分别与心血管疾病、呼吸道疾病、肌肉骨骼病、精神行为障碍发生风险升高4%、3%、11%、12%有关。 论文题图 不得不说，相较PM2.5，二氧化氮的危害程度在人们心中是低不少的。就看《全球疾病、伤害和风险因素负担研究》（GBD），PM2.5被列为全球疾病负担的主要贡献者，而二氧化氮只被认为是哮喘的可归因因素。 那么事实如何呢？ 研究者们调取了最大规模的中国人队列嘉道理生物库，结合卫星记录、气象参数、人口分布和道路网格等数据，将二氧化氮浓度的分析精度定位到了1km × 1km的小地块，并对二氧化氮暴露和参与者的医疗数据进行匹配分析。 最终纳入分析的有512709名参与者，中位基线年龄52岁，59%为女性，44.1%为城市居民。参与者在2005年-2008年期间的年平均二氧化氮暴露量，第一四分位数为19 μg/m³，第四分位数为41.1 μg/m³，超过99.96%的参与者暴露量高于10 μg/m³。 分析结果显示，二氧化氮暴露量较高的参与者往往居住在城市地区，家庭收入较高，有饮酒习惯，使用清洁燃料，同时PM2.5暴露量也更高。 在嘉道理生物库的10个调查地点之间，二氧化氮暴露水平差异挺大，不过总的来说，二氧化氮暴露在2005年-2013年之间有一个显著的增加，随后略有下降，在整个随访期间二氧化氮水平是上升的。 不同地点的年二氧化氮暴露 在所有疾病大类中，二氧化氮暴露与精神行为障碍、心血管、呼吸和肌肉骨骼病之间存在显著的关联，调整PM2.5后正向关联性更明显。 二氧化氮与疾病大类的关系 研究者进一步分析了12种特定的疾病，发现二氧化氮与高血压、下呼吸道感染、关节病、脊椎病、椎间盘疾病、缺血性心脏病、缺血性卒中和哮喘存在正相关。 二氧化氮与12种特定疾病的关系 此外，分析发现，精神行为障碍中，男性参与者的相关性较女性更强，而女性参与者与肌肉骨骼病的相关性更强。 从机制上来说，二氧化氮是一种反应性气体，可被呼吸道上皮吸收，产生活性氮/活性氧/氧化脂质分子，从而增加局部和全身的炎症、促进氧化应激。这可能导致呼吸免疫功能受损和动脉粥样硬化、高血压风险增加，这都是心肺疾病的风险因素。全身炎症可能引起自身免疫反应，与肌肉骨骼病风险增加有关。此外，二氧化氮还参与激素调节和内分泌紊乱，可能与精神行为障碍、肌肉骨骼病和内分泌疾病风险的升高有关。 参考资料： [1]Xia X, Meng X, Liu C, Guo Y, Li X, Niu Y, Lam KBH, Wright N, Kartsonaki C, Chen Y, Yang L, Du H, Yu C, Sun D, Lv J, Chen J, Yang X, Gao R, Wu S, Kan H, Chan KH, Li L, Chen Z; China Kadoorie Biobank Study Group. Associations of long-term nitrogen dioxide exposure with a wide spectrum of diseases: a prospective cohort study of 0·5 million Chinese adults. Lancet Public Health. 2024 Dec;9(12):e1047-e1058. doi: 10.1016/S2468-2667(24)00264-0. PMID: 39643329; PMCID: PMC11626078. 本文作者丨代丝雨