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Lecanemab's Path Forward: Navigating the Future of Alzheimer's Treatment in Europe Amidst the EMA's Rejection. 莱卡单抗的前进之路:在欧洲药品管理局(EMA)的反对声中探索欧洲阿尔茨海默氏症治疗的未来。
IF 3.9 3区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2025-02-01 Epub Date: 2024-11-02 DOI: 10.1007/s40120-024-00675-w
Alessandro Martorana, Chiara Giuseppina Bonomi, Martina Gaia Di Donna, Caterina Motta

Lecanemab (Leqembi©, Biogen), a humanized anti-amyloid-beta monoclonal antibody, has been approved for early-stage Alzheimer's disease (AD) in several countries, including the US and Japan. However, the European Medicines Agency (EMA) recently issued a negative opinion on its marketing authorization, reflecting concerns over the clinical value and manageability of anti-amyloid treatments. This decision highlights the ongoing disconnect between research advancements and clinical practice, where the focus on biological markers over tangible clinical improvements remains contentious. Despite promising biological effects, lecanemab's clinical outcomes have been modest, raising questions about its therapeutic role. The EMA's refusal underscores the need to address doubts surrounding the real-world effectiveness and safety of such treatments, especially concerning amyloid-related imaging abnormalities (ARIAs), a common side effect observed in clinical trials. The recent approval of lecanemab by the UK's Medicines and Healthcare products Regulatory Agency, despite the National Institute for Health and Care Excellence's rejection on cost-effectiveness grounds, further fuels the debate on the feasibility of anti-amyloid therapies. This commentary emphasizes the importance of real-world data on lecanemab's impact on cognitive decline, daily functioning, and side-effect management. As the global clinical use of lecanemab increases, continuous and standardized reporting on its outcomes is crucial for guiding future regulatory decisions and for potentially bridging the gap between research and practice in AD treatment.

Lecanemab(Leqembi©,百健公司)是一种人源化抗淀粉样蛋白-β单克隆抗体,已在美国和日本等多个国家获批用于早期阿尔茨海默病(AD)的治疗。然而,欧洲药品管理局(EMA)最近对其上市授权发表了负面意见,反映出对抗淀粉样蛋白治疗的临床价值和可管理性的担忧。这一决定凸显了研究进展与临床实践之间持续存在的脱节,在临床实践中,对生物标志物的关注超过了对实际临床改善的关注,这一点仍然存在争议。尽管lecanemab的生物效应前景看好,但其临床疗效并不显著,这让人们对它的治疗作用产生了疑问。欧洲医学管理局(EMA)的拒绝突出表明,有必要解决围绕此类治疗的实际有效性和安全性的疑问,尤其是关于淀粉样蛋白相关成像异常(ARIAs)的疑问,这是在临床试验中观察到的常见副作用。尽管英国国家健康与护理卓越研究所以成本效益为由拒绝批准 lecanemab,但英国药品与保健品监管局最近还是批准了该药,这进一步加剧了有关抗淀粉样蛋白疗法可行性的讨论。这篇评论强调了莱卡尼单抗对认知能力下降、日常功能和副作用控制影响的真实世界数据的重要性。随着莱卡奈单抗在全球临床应用的增加,对其结果进行持续和标准化的报告对于指导未来的监管决策以及缩小AD治疗研究与实践之间的差距至关重要。
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引用次数: 0
Development and Validation of a Novel Classification System and Prognostic Model for Open Traumatic Brain Injury: A Multicenter Retrospective Study. 开放性创伤性脑损伤的新型分类系统和预后模型的开发与验证:一项多中心回顾性研究。
IF 3.9 3区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2025-02-01 Epub Date: 2024-11-04 DOI: 10.1007/s40120-024-00678-7
Yuhui Chen, Li Chen, Liang Xian, Haibing Liu, Jiaxing Wang, Shaohuai Xia, Liangfeng Wei, Xuewei Xia, Shousen Wang

Introduction: Open traumatic brain injury (OTBI) is associated with high mortality and morbidity; however, the classification of these injuries and the determination of patient prognosis remain uncertain, hindering the selection of optimal treatment strategies. This study aimed to develop and validate a novel OTBI classification system and a prognostic model for poor prognosis.

Methods: This retrospective study included patients with isolated OTBI who received treatment at three large medical centers in China between January 2020 and June 2022 as the training set. Data on patients with OTBI collected at the Fuzong Clinical Medical College of Fujian Medical University between July 2022 and June 2023 were used as the validation set. Clinical parameters, including clinical data at admission, radiological and laboratory findings, details of surgical methods, and prognosis were collected. Prognosis was assessed through a dichotomized Glasgow Outcome Scale (GOS). A novel OTBI classification was proposed, categorizing patients based on a combination of intracranial hematoma and midline shift observed on imaging, and logistic regression analyses were performed to identify risk factors associated with poor prognosis and to investigate the association between the novel OTBI classification and prognosis. Finally, a nomogram suitable for clinical application was established and validated.

Results: Multivariable logistic regression analysis identified OTBI classification type C (p < 0.001), a Glasgow Coma Scale score (GCS) ≤ 8 (p < 0.001), subarachnoid hemorrhage (SAH) (p = 0.004), subdural hematoma (SDH) (p = 0.011), and coagulopathy (p = 0.020) as independent risk factors for poor prognosis. The addition of the OTBI classification to a model containing all the other identified prognostic factors improved the predictive ability of the model (Z = 1.983; p = 0.047). In the validation set, the model achieved an area under the curve (AUC) of 0.917 [95% confidence interval (CI) = 0.864-0.970]. The calibration curve closely approximated the ideal curve, indicating strong predictive performance of the model.

Conclusions: The implementation of our proposed OTBI classification system and its use alongside the other prognostic factors identified here may improve the prediction of patient prognosis and aid in the selection of the most suitable treatment strategies.

导言:开放性创伤性脑损伤(OTBI)与高死亡率和高发病率有关;然而,这些损伤的分类和患者预后的确定仍不确定,阻碍了最佳治疗策略的选择。本研究旨在开发并验证一种新型 OTBI 分类系统和预后不良的预后模型:这项回顾性研究将 2020 年 1 月至 2022 年 6 月期间在中国三家大型医疗中心接受治疗的孤立性 OTBI 患者作为训练集。福建医科大学福宗临床医学院在 2022 年 7 月至 2023 年 6 月期间收集的 OTBI 患者数据作为验证集。收集的临床参数包括入院时的临床数据、放射学和实验室检查结果、手术方法详情以及预后。预后通过二分格拉斯哥预后量表(GOS)进行评估。研究人员提出了一种新的 OTBI 分类法,根据影像学观察到的颅内血肿和中线移位的组合对患者进行分类,并进行了逻辑回归分析,以确定与不良预后相关的风险因素,并研究新的 OTBI 分类法与预后之间的关联。最后,建立并验证了适合临床应用的提名图:结果:多变量逻辑回归分析确定了 OTBI 分型 C 型(p 结论:我们提出的 OTBI 分型可用于临床应用:实施我们提出的 OTBI 分类系统,并将其与其他预后因素结合使用,可改善对患者预后的预测,有助于选择最合适的治疗策略。
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引用次数: 0
The Impact of Migraine on the Whole Life Course of Patients: Results from the OVERCOME (Japan) 2nd Study. 偏头痛对患者整个生命过程的影响:来自日本攻克第二次研究的结果
IF 3.9 3区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2025-02-01 Epub Date: 2024-12-21 DOI: 10.1007/s40120-024-00690-x
Daisuke Danno, Shiho Suzuki, Tsubasa Takizawa, Ryotaro Ishii, Masayuki Hamakawa, Yoshinori Tanizawa, Satoshi Osaga, Mika Komori

Introduction: The impact of migraine on patients' lives, including challenges they face before getting access to appropriate medical management, is not well understood. The ObserVational survey of the Epidemiology, tReatment, and Care Of MigrainE [OVERCOME (Japan)] 2nd study was conducted to provide information regarding burden and experience with migraine throughout the life course.

Methods: This cross-sectional, population-based, nationwide online survey was conducted in adults with or without migraine. The migraine group reported their headache features and experiences in medical management since headache onset. Migraine's burden and impact were assessed with various PRO instruments. Migraine and non-migraine groups reported their experiences in life events and answered questions on self-esteem. Subgroup analyses by the number of monthly headache days (MHD) were performed.

Results: The migraine group (n = 19,590) was numerically younger [mean (SD) age 40.5 (13.1) years vs. 53.1 (17.8) years] and included more females (68.8% vs. 52.1%) than the non-migraine group (n = 2219). The migraine group had mean (SD) 3.5 (5.2) MHDs; 24.2-56.7% had moderate-to-very severe disease burden per various PRO instruments. Headaches started when respondents with migraine were 17.8 years old; 86.7% started over-the-counter medications at 19.4 years of age. Only 46.4% self-reported migraine diagnosis by a physician and 25.1% received an oral preventive drug, almost a decade after headache onset. Up to 16.8% reported poor support/lack of understanding from either teachers or parents during school life. The migraine group had numerically more frequent job changes and divorce, and lower self-esteem, than the non-migraine group. Across assessments, increased MHDs tended to worsen outcomes.

Conclusion: Migraine affected many individuals from an early stage, but timely support and medical intervention were insufficient. This may negatively impact important life events, cause long-term impairment, and decrease self-esteem. Hence, improving the social understanding and medical environment for migraine to provide timely support is essential.

引言:偏头痛对患者生活的影响,包括他们在获得适当的医疗管理之前面临的挑战,还没有得到很好的理解。偏头痛的流行病学、治疗和护理观察性调查[克服(日本)]第2项研究旨在提供有关偏头痛在整个生命过程中的负担和经历的信息。方法:这项横断面、以人群为基础的全国性在线调查是在有或没有偏头痛的成年人中进行的。偏头痛组报告了他们的头痛特征和自头痛发作以来的医疗管理经验。用各种PRO仪器评估偏头痛的负担和影响。偏头痛组和非偏头痛组报告了他们的生活经历,并回答了有关自尊的问题。按每月头痛天数(MHD)进行亚组分析。结果:偏头痛组(n = 19,590)比非偏头痛组(n = 2219)更年轻[平均(SD)年龄40.5(13.1)岁对53.1(17.8)岁],女性(68.8%对52.1%)更多。偏头痛组平均(SD)为3.5 (5.2)mhd;24.2-56.7%的患者有中度至非常严重的疾病负担。偏头痛患者开始头痛的年龄为17.8岁;86.7%的儿童在19.4岁时开始服用非处方药。只有46.4%的人在头痛发作近十年后接受了医生的偏头痛诊断,25.1%的人接受了口服预防药物。多达16.8%的学生表示在学校生活中得不到老师或家长的支持或理解。与非偏头痛组相比,偏头痛组换工作和离婚的频率更高,自尊也更低。在整个评估中,mhd的增加往往会使结果恶化。结论:偏头痛患者多为早期发病,但缺乏及时的支持和医疗干预。这可能会对重要的生活事件产生负面影响,造成长期损害,并降低自尊。因此,提高对偏头痛的社会认识和医疗环境,及时提供支持是至关重要的。
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引用次数: 0
Clinical Pharmacokinetics of Atogepant in Healthy Japanese and White Adults. atgeagent在健康日本人和白人成人中的临床药代动力学。
IF 3.9 3区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2025-02-01 Epub Date: 2025-01-04 DOI: 10.1007/s40120-024-00699-2
Ramesh R Boinpally, Brian McNamee

Introduction: Atogepant is a calcitonin gene-related peptide receptor antagonist approved for the preventive treatment of migraine in adults in the USA, EU, and several other countries. The objectives of this study were to evaluate the pharmacokinetics (PK) and dose proportionality of atogepant in healthy Japanese participants, evaluate the safety and tolerability of atogepant in Japanese participants, and explore the differences in the PK and safety of atogepant in Japanese vs white participants.

Methods: A total of 50 participants (40 Japanese and 10 white) were enrolled into five cohorts; Japanese cohorts were randomized in a 4:1 ratio to atogepant (10 mg, 30 mg, or 60 mg daily dosing and 60 mg twice daily) or placebo. The white participants were randomized to atogepant (60 mg twice daily) or placebo. Doses were administered on day 1 and days 3-8, with those on days 1 and 8 administered after an overnight fast.

Results: In Japanese participants, atogepant exposure increased with dose, and there was no accumulation with once-daily dosing and minimal (~ 20%) accumulation with twice-daily dosing. Atogepant steady-state exposure appeared to be marginally lower in Japanese participants compared with white participants and was well tolerated. There were no treatment-related adverse events, serious adverse events, clinically significant changes in vital signs, or signs of suicidal ideation or behaviors.

Conclusion: Atogepant exposure increased with dose in healthy Japanese participants and was well tolerated within the dose range tested.

atoggepant是一种降钙素基因相关肽受体拮抗剂,在美国、欧盟和其他几个国家被批准用于成人偏头痛的预防性治疗。本研究的目的是评价同聚剂在健康日本受试者中的药代动力学(PK)和剂量比例,评价同聚剂在日本受试者中的安全性和耐受性,并探讨同聚剂在日本与白人受试者中的PK和安全性差异。方法:50名参与者(40名日本人,10名白人)被分为5个队列;日本队列以4:1的比例随机分配给联合剂(每日10mg、30mg或60mg,每日两次60mg)或安慰剂。白人参与者被随机分配到atgeagent组(60毫克,每日两次)或安慰剂组。第1天和第3-8天给药,第1天和第8天给药,禁食一夜后给药。结果:在日本参与者中,增毒剂暴露量随剂量增加而增加,每日一次给药时没有积累,每日两次给药时最小(约20%)积累。与白人受试者相比,日本受试者的抗凝止剂稳态暴露似乎略低,并且耐受性良好。无治疗相关不良事件、严重不良事件、临床显著生命体征改变、自杀意念或行为的迹象。结论:在健康的日本参与者中,抗氧剂暴露量随剂量增加而增加,并且在试验剂量范围内耐受性良好。
{"title":"Clinical Pharmacokinetics of Atogepant in Healthy Japanese and White Adults.","authors":"Ramesh R Boinpally, Brian McNamee","doi":"10.1007/s40120-024-00699-2","DOIUrl":"10.1007/s40120-024-00699-2","url":null,"abstract":"<p><strong>Introduction: </strong>Atogepant is a calcitonin gene-related peptide receptor antagonist approved for the preventive treatment of migraine in adults in the USA, EU, and several other countries. The objectives of this study were to evaluate the pharmacokinetics (PK) and dose proportionality of atogepant in healthy Japanese participants, evaluate the safety and tolerability of atogepant in Japanese participants, and explore the differences in the PK and safety of atogepant in Japanese vs white participants.</p><p><strong>Methods: </strong>A total of 50 participants (40 Japanese and 10 white) were enrolled into five cohorts; Japanese cohorts were randomized in a 4:1 ratio to atogepant (10 mg, 30 mg, or 60 mg daily dosing and 60 mg twice daily) or placebo. The white participants were randomized to atogepant (60 mg twice daily) or placebo. Doses were administered on day 1 and days 3-8, with those on days 1 and 8 administered after an overnight fast.</p><p><strong>Results: </strong>In Japanese participants, atogepant exposure increased with dose, and there was no accumulation with once-daily dosing and minimal (~ 20%) accumulation with twice-daily dosing. Atogepant steady-state exposure appeared to be marginally lower in Japanese participants compared with white participants and was well tolerated. There were no treatment-related adverse events, serious adverse events, clinically significant changes in vital signs, or signs of suicidal ideation or behaviors.</p><p><strong>Conclusion: </strong>Atogepant exposure increased with dose in healthy Japanese participants and was well tolerated within the dose range tested.</p>","PeriodicalId":19216,"journal":{"name":"Neurology and Therapy","volume":" ","pages":"399-412"},"PeriodicalIF":3.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11762053/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142927511","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
TEC-ADHERE: Real-World Persistence and Adherence on Dimethyl Fumarate in Patients with Relapsing-Remitting Multiple Sclerosis in the French OroSEP Patient-Support Program. TEC-ADHERE:法国 OroSEP 患者支持计划中复发缓解型多发性硬化症患者对富马酸二甲酯的实际坚持和依从性。
IF 3.9 3区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2025-02-01 Epub Date: 2024-11-11 DOI: 10.1007/s40120-024-00674-x
Pierre Labauge, Alain Créange, Thibault Moreau, Jocelyne Nouvet-Gire, Bernard Pedespan, Olivier Heinzlef, Nathalie Texier, Marilyn Gros, Catherine Marti, Marta Ruiz, Mikel Martinez, Giovanni Castelnovo

Introduction: Treatment persistence and adherence are essential for achieving therapeutic goals in patients with multiple sclerosis (MS). OroSEP is an independent patient-support program (PSP) in France for patients with relapsing-remitting MS (RRMS) receiving oral disease-modifying therapies.

Methods: TEC-ADHERE (NCT04221191; 08/19/2019-09/15/2022) was a prospective, non-interventional, phase 4 study to assess the effect of OroSEP on persistence and adherence to dimethyl fumarate (DMF; Tecfidera™) in patients with RRMS. Outcomes were compared for patients in OroSEP versus non-OroSEP patients who received their neurologists' standard of care (SoC). Patients initiated DMF at month 0 (M0); follow-up visits occurred at M3 and M6. Primary outcome was persistence at M6. Secondary outcomes included persistence at M1 and M3, adherence at M6 (Girerd questionnaire), anxiety (Generalized Anxiety Disorder Assessment), patient satisfaction at M6 (Treatment Satisfaction Questionnaire for Medication), patient and neurologist satisfaction with OroSEP participation, and adverse events (AEs).

Results: Per-protocol population included 341 patients (OroSEP, n = 135; SoC, n = 206). Persistence was similar for OroSEP vs SoC (M6, 75.9% vs 76.6%; M1, 96.0% vs 92.4%; M3, 85.5% vs 89.0%). At M6, mean adherence was higher for OroSEP (5.4) vs SoC (4.7; p < 0.0001), and good adherence (Girerd score = 6) was achieved by more OroSEP patients (55.7%) than SoC patients (29.6%; p < 0.01). Mean anxiety scores were lower in the OroSEP group than in the SoC group at baseline (7.1 vs 8.8; p = 0.02) and M6 (3.4 vs 6.1; p < 0.001). Mean satisfaction scores at M6 were higher for OroSEP (77.4) vs SoC (64.2; p < 0.01). Most neurologists (n = 11/14) agreed that OroSEP helped improve adherence. Treatment-related AEs occurred in 62 (36.3%) OroSEP patients and 76 (42.9%) SoC patients; most common were flushing, diarrhea, hot flush, and abdominal pain.

Conclusion: These outcomes support the value of PSPs in encouraging adherence, alleviating anxiety, improving patient satisfaction, and supporting patients to be more independent in managing MS.

Trial registration: ClinicalTrials.gov identifier, NCT04221191.

导言:坚持治疗是多发性硬化症(MS)患者实现治疗目标的关键。OroSEP是法国一项独立的患者支持计划(PSP),针对接受口服改变病情疗法的复发性缓解型多发性硬化症(RRMS)患者:TEC-ADHERE(NCT04221191;08/19/2019-09/15/2022)是一项前瞻性、非干预性的4期研究,旨在评估OroSEP对RRMS患者坚持和依从富马酸二甲酯(DMF;Tecfidera™)的影响。研究比较了OroSEP患者与非OroSEP患者接受神经科医生标准护理(SoC)的结果。患者在第0个月(M0)开始使用DMF;在M3和M6进行随访。主要结果是 M6 时的持续性。次要结果包括:M1和M3时的持续性、M6时的依从性(Girerd问卷)、焦虑(广泛性焦虑症评估)、M6时的患者满意度(药物治疗满意度问卷)、患者和神经科医生对参与OroSEP的满意度以及不良事件(AEs):按协议人群包括 341 名患者(OroSEP,135 人;SoC,206 人)。OroSEP与SoC的坚持率相似(M6,75.9% vs 76.6%;M1,96.0% vs 92.4%;M3,85.5% vs 89.0%)。在 M6 阶段,OroSEP 的平均依从性(5.4)高于 SoC(4.7;P 结论:这些结果支持了 PSP 的价值:这些结果支持了PSP在鼓励患者坚持治疗、减轻焦虑、提高患者满意度以及支持患者更独立地管理多发性硬化症方面的价值:试验注册:ClinicalTrials.gov 标识符,NCT04221191。
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引用次数: 0
Caregiver Global Impression Observations from EMBARK: A Phase 3 Study Evaluating Delandistrogene Moxeparvovec in Ambulatory Patients with Duchenne Muscular Dystrophy. EMBARK:评估Delandistrogene Moxeparvovec在杜氏肌肉萎缩症非卧床患者中的应用的3期研究》护理人员全球印象观察。
IF 3.9 3区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2025-02-01 Epub Date: 2024-11-26 DOI: 10.1007/s40120-024-00685-8
Craig M McDonald, Jacob S Elkins, Sai Dharmarajan, Katherine Gooch, Teofil Ciobanu, Claire J Lansdall, Alexander P Murphy, Fiona McDougall, Eugenio M Mercuri, Ivana Audhya

Introduction: Duchenne muscular dystrophy (DMD) is a rare, progressive, debilitating neuromuscular disease. The early childhood onset and debilitating nature of the disease necessitate decades of caretaking for most patients. Caregivers have a critical role in evaluating patients' physical functioning and/or response to treatment. Using DMD-specific caregiver-reported scales, the impact of delandistrogene moxeparvovec gene therapy on caregivers' perceived change in patient disease status or severity was evaluated using the Caregiver Global Impression of Change and Severity (CaGI-C and CaGI-S, respectively).

Methods: In the Phase 3 randomized, double-blind, placebo-controlled trial (EMBARK; NCT05096221), the CaGI-C at week 52 and change from baseline to week 52 in CaGI-S were evaluated in a post hoc analysis. The CaGI-C assesses caregivers' impressions of change in DMD symptoms, physical ability, ability to perform daily activities, and overall health. The CaGI-S evaluates current severity of DMD symptoms, physical ability, ability to perform activities of daily living, and overall health. Data were evaluated using multi-domain responder index (MDRI) and ordinal regression analyses.

Results: MDRI analyses across all four CaGI-C items yielded a treatment difference of 1.7 (95% confidence interval [CI]: 0.90-2.5) favoring delandistrogene moxeparvovec; a treatment difference of 1.1 (95% CI 0.30-1.9) was observed for the CaGI-S favoring delandistrogene moxeparvovec. After adjusting for age, ordinal regression analysis showed a nominally significant increase in the odds of achieving a better rating for delandistrogene moxeparvovec-treated patients on all four CaGI-C items (≥ 3.8-fold increase). After adjusting for baseline severity and age, ordinal regression analysis showed a nominally significant increase in the odds of improvement on all four CaGI-S items (≥ 2.2-fold increase).

Conclusion: These exploratory findings captured by caregiver-reported outcomes add to the totality of evidence that supports the clinical benefits of delandistrogene moxeparvovec for patients with DMD.

Trial registration number: ClinicalTrials.gov identifier, NCT05096221.

简介杜兴氏肌肉萎缩症(DMD)是一种罕见的进行性神经肌肉疾病。该病早在儿童时期就已发病,并使人衰弱,因此大多数患者需要数十年的护理。护理人员在评估患者的身体功能和/或对治疗的反应方面起着至关重要的作用。利用 DMD 特异性照护者报告量表,使用照护者对疾病变化和严重程度的总体印象(分别为 CaGI-C 和 CaGI-S)评估了 delandistrogene moxeparvovec 基因疗法对照护者感知到的患者疾病状态或严重程度变化的影响:在 3 期随机、双盲、安慰剂对照试验(EMBARK;NCT05096221)中,对第 52 周的 CaGI-C 和 CaGI-S 从基线到第 52 周的变化进行了事后分析评估。CaGI-C 评估护理人员对 DMD 症状、体能、日常活动能力和整体健康变化的印象。CaGI-S 评估当前 DMD 症状的严重程度、体能、日常生活能力和总体健康状况。采用多域反应指数(MDRI)和序数回归分析对数据进行评估:对所有四个CaGI-C项目的MDRI分析结果显示,治疗差异为1.7(95%置信区间[CI]:0.90-2.5),倾向于delandistrogene moxeparvovec;CaGI-S的治疗差异为1.1(95%置信区间0.30-1.9),倾向于delandistrogene moxeparvovec。在对年龄进行调整后,序数回归分析显示,在所有四个CaGI-C项目上,接受delandistrogene moxeparvovec治疗的患者获得较好评分的几率均有明显增加(≥3.8倍)。在对基线严重程度和年龄进行调整后,序数回归分析表明,所有四项CaGI-S项目的改善几率均有名义上的显著增加(≥2.2倍):这些由护理人员报告结果得出的探索性发现,为支持delandistrogene moxeparvovec对DMD患者的临床益处的全部证据提供了补充:试验注册号:ClinicalTrials.gov标识符,NCT05096221。
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引用次数: 0
Safety, Tolerability and Pharmacokinetic-Pharmacodynamic Relationship of NX210c Peptide in Healthy Elderly Volunteers: Randomized, Placebo-Controlled, Double-Blind, Multiple Ascending Dose Study. NX210c肽在健康老年志愿者中的安全性、耐受性和药动学-药效学关系:随机、安慰剂对照、双盲、多次递增剂量研究
IF 3.9 3区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2025-02-01 Epub Date: 2024-12-21 DOI: 10.1007/s40120-024-00691-w
Annette Janus, Daniël Dumas, Juliette Le Douce, Sébastien Marie, Giuseppe Pasculli, Pauline Bambury, Sighild Lemarchant, Philip Kremer, Yann Godfrin

Introduction: Blood-brain barrier (BBB) integrity is fundamental to brain homeostasis, enabling control of substance exchange and safeguarding neurons against harmful toxins, pathogens, and immune cells that lead to dysregulation and inflammation involved in ageing and neurodegenerative diseases (NDD). The cyclized peptide NX210c is a thrombospondin type 1 repeat analogue derived from subcommissural organ-spondin. It exerts beneficial effects in animal models of NDD owing to its effects on neurons and endothelial cells. NX210c demonstrated a good safety profile in a single ascending dose phase 1a clinical study. The present multiple ascending dose phase 1b study was performed to evaluate the tolerability and pharmacological effects of repeated doses of NX210c in healthy elderly (age: > 55 years) volunteers.

Methods: This was a randomized, placebo-controlled, double-blind study (EudraCT No. 2022-002868-76), investigating safety/tolerability, pharmacokinetics, and pharmacodynamics (including blood and cerebrospinal fluid biomarkers). Participants received 5 or 10 mg/kg NX210c or placebo (10-min infusion) thrice weekly for 4 weeks in an ascending dose fashion. Follow-up was conducted 2 weeks after last dosing.

Results: The investigation included 29 participants. No serious adverse events were recorded and all adverse events were mild. Dedicated central nervous system testing did not reveal neurotoxicity. Biomarker evaluation showed a statistically significant reduction in blood claudin-5 and a trend toward reduction of blood homocysteine. In silico data modelling revealed salient pharmacokinetic-pharmacodynamic relationships, including reduction of claudin-5, neurofilament light chain, and SPARC-like protein 1 release, and degradation of homocysteine.

Conclusion: Multiple doses of NX210c exhibited a good safety profile, showed non-cumulative pharmacokinetics, and exerted pharmacodynamic effects on biomarkers linked to BBB integrity. The effects of NX210c on claudin-5 and biomarkers influencing BBB integrity-and the overarching brain protection it offers-provide a novel therapeutic strategy targeting an underlying driver of neurodegenerative conditions for which disease-modifying treatments are limited or not available.

血脑屏障(BBB)完整性是大脑稳态的基础,能够控制物质交换,保护神经元免受有害毒素、病原体和免疫细胞的侵害,这些有害毒素、病原体和免疫细胞会导致衰老和神经退行性疾病(NDD)中的失调和炎症。环化肽NX210c是一种凝血反应蛋白1型重复类似物,来源于关节下器官反应蛋白。由于其对神经元和内皮细胞的作用,在NDD动物模型中发挥了有益的作用。NX210c在单次递增剂量的1a期临床研究中显示出良好的安全性。本研究进行了多次递增剂量1b期研究,以评估健康老年人(年龄:55岁)志愿者重复给药NX210c的耐受性和药理作用。方法:这是一项随机、安慰剂对照、双盲研究(EudraCT No. 2022-002868-76),研究安全性/耐受性、药代动力学和药效学(包括血液和脑脊液生物标志物)。参与者接受5或10 mg/kg NX210c或安慰剂(输注10分钟),每周3次,持续4周,剂量递增。末次给药后2周随访。结果:调查对象29人。无严重不良事件记录,所有不良事件均为轻度。专门的中枢神经系统测试未显示神经毒性。生物标志物评估显示,血claudin-5有统计学意义的降低,血同型半胱氨酸有降低的趋势。计算机数据模型揭示了显著的药代动力学-药效学关系,包括cladin -5、神经丝轻链和sparc样蛋白1释放的减少,以及同型半胱氨酸的降解。结论:多剂量NX210c具有良好的安全性,表现出非累积药代动力学,并对血脑屏障完整性相关的生物标志物发挥药效学作用。NX210c对影响血脑屏障完整性的cludin -5和生物标志物的影响,以及它提供的总体脑保护,为神经退行性疾病的潜在驱动因素提供了一种新的治疗策略,这种疾病的改善治疗是有限的或不可用的。
{"title":"Safety, Tolerability and Pharmacokinetic-Pharmacodynamic Relationship of NX210c Peptide in Healthy Elderly Volunteers: Randomized, Placebo-Controlled, Double-Blind, Multiple Ascending Dose Study.","authors":"Annette Janus, Daniël Dumas, Juliette Le Douce, Sébastien Marie, Giuseppe Pasculli, Pauline Bambury, Sighild Lemarchant, Philip Kremer, Yann Godfrin","doi":"10.1007/s40120-024-00691-w","DOIUrl":"10.1007/s40120-024-00691-w","url":null,"abstract":"<p><strong>Introduction: </strong>Blood-brain barrier (BBB) integrity is fundamental to brain homeostasis, enabling control of substance exchange and safeguarding neurons against harmful toxins, pathogens, and immune cells that lead to dysregulation and inflammation involved in ageing and neurodegenerative diseases (NDD). The cyclized peptide NX210c is a thrombospondin type 1 repeat analogue derived from subcommissural organ-spondin. It exerts beneficial effects in animal models of NDD owing to its effects on neurons and endothelial cells. NX210c demonstrated a good safety profile in a single ascending dose phase 1a clinical study. The present multiple ascending dose phase 1b study was performed to evaluate the tolerability and pharmacological effects of repeated doses of NX210c in healthy elderly (age: > 55 years) volunteers.</p><p><strong>Methods: </strong>This was a randomized, placebo-controlled, double-blind study (EudraCT No. 2022-002868-76), investigating safety/tolerability, pharmacokinetics, and pharmacodynamics (including blood and cerebrospinal fluid biomarkers). Participants received 5 or 10 mg/kg NX210c or placebo (10-min infusion) thrice weekly for 4 weeks in an ascending dose fashion. Follow-up was conducted 2 weeks after last dosing.</p><p><strong>Results: </strong>The investigation included 29 participants. No serious adverse events were recorded and all adverse events were mild. Dedicated central nervous system testing did not reveal neurotoxicity. Biomarker evaluation showed a statistically significant reduction in blood claudin-5 and a trend toward reduction of blood homocysteine. In silico data modelling revealed salient pharmacokinetic-pharmacodynamic relationships, including reduction of claudin-5, neurofilament light chain, and SPARC-like protein 1 release, and degradation of homocysteine.</p><p><strong>Conclusion: </strong>Multiple doses of NX210c exhibited a good safety profile, showed non-cumulative pharmacokinetics, and exerted pharmacodynamic effects on biomarkers linked to BBB integrity. The effects of NX210c on claudin-5 and biomarkers influencing BBB integrity-and the overarching brain protection it offers-provide a novel therapeutic strategy targeting an underlying driver of neurodegenerative conditions for which disease-modifying treatments are limited or not available.</p>","PeriodicalId":19216,"journal":{"name":"Neurology and Therapy","volume":" ","pages":"357-377"},"PeriodicalIF":3.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11762061/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142872565","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Sex Differences in Parkinson's Disease: A Narrative Review. 帕金森病的性别差异:一个叙述性的回顾。
IF 3.9 3区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2025-02-01 Epub Date: 2024-12-04 DOI: 10.1007/s40120-024-00687-6
Carlo Cattaneo, Javier Pagonabarraga

Sex differences in epidemiology, clinical features, and therapeutical responses are emerging in several movement disorders, even though they are still not widely recognized. Parkinson's disease (PD) is not an exception: men and women suffering from PD have different levels of disability. Research has been performed using multiple databases and scientific journals; this review summarizes the available evidence on sex differences in PD regarding epidemiology, risk factors, genetics, clinical phenotype, social impact, and therapeutic management. The role of hormones in determining such differences is also briefly discussed. The results confirm the existence of differences between men and women in PD; women have a higher risk of developing disabling motor complications and non-motor fluctuations compared to men, while men have a higher risk of developing cognitive impairment, postural instability, and gait disorders. Improving our knowledge in these differences may result in the implementation of strategies for disease-tailored treatment and management.

在一些运动障碍中,流行病学、临床特征和治疗反应方面的性别差异正在出现,尽管它们尚未得到广泛认识。帕金森病(PD)也不例外:患有PD的男性和女性有不同程度的残疾。利用多个数据库和科学期刊进行了研究;本文综述了PD在流行病学、危险因素、遗传学、临床表型、社会影响和治疗管理等方面的性别差异。还简要讨论了激素在决定这些差异中的作用。结果证实了男性和女性在PD方面存在差异;与男性相比,女性患致残性运动并发症和非运动波动的风险更高,而男性患认知障碍、姿势不稳定和步态障碍的风险更高。提高我们对这些差异的认识可能导致实施针对疾病的治疗和管理战略。
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引用次数: 0
Clinical Study of Limosilactobacillus reuteri for the Treatment of Children with Chronic Tic Disorders/Tourette Syndrome: A Mid-Term Efficacy Evaluation. 罗伊氏乳酸杆菌治疗儿童慢性抽动障碍/抽动秽语综合征的临床研究:中期疗效评价
IF 3.9 3区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2025-02-01 Epub Date: 2024-12-19 DOI: 10.1007/s40120-024-00693-8
Yan Liang, Lin Wan, Guanglei Wang, Huimin Yan, Jing Zhang, Xinting Liu, Ziyan Zhang, Gang Zhu, Guang Yang

Introduction: Gut microbiota plays an important role in tic disorders (TDs); however, clinical research on probiotics for chronic TDs treatment is lacking. We aimed to investigate the effectiveness of probiotics, hypothesizing that their clinical efficacy is comparable to that of clonidine in treating chronic TDs.

Methods: Patients were randomly assigned to receive either Limosilactobacillus reuteri or clonidine transdermal patch treatment for 8 weeks while maintaining their existing treatment. The Yale Global Tic Severity Scale (YGTSS); Swanson, Nolan, and Pelham-IV Scale (SNAP-IV); and Child Behavior Check List (CBCL) scores were assessed before and after treatment.

Results: We matched the patients in both groups for age, sex, age at onset, and tic type. A significant improvement in YGTSS scores was observed in both groups (p = 0.024). The improvement in attention deficits on the SNAP-IV scale was similar between the two groups, with no significant difference (p = 0.465). For hyperactivity disorder, after matching patients in both groups for age, sex, age at onset, tic type, and Children's Yale-Brown Obsessive Compulsive Scale (CY-BOCS) scores, a significant difference in improvement was observed between the groups (p = 0.010), with the probiotics group showing greater improvement (0.3 ± 0.58 vs. 0.1 ± 0.50). At 9 weeks, social ability on the CBCL scale increased by 3.2 ± 6.26 from baseline in the probiotics group and by 0.6 ± 4.07 in the clonidine group, with a significant difference between the two (p = 0.049). Although there was no significant difference in behavioral problems between the two groups (p = 0.347), the trend of improvement was more pronounced in the probiotics group than in the clonidine group (12.7 ± 25.86 vs. 8.4 ± 13.15).

Conclusion: The mid-term efficacy evaluation demonstrated that L. reuteri, when added to the treatment of children with chronic TDs, was more effective in improving tic symptoms than clonidine transdermal patch treatment. Additionally, it provided moderate improvement in hyperactivity symptoms.

Trial registration: chictr.org.cn (registration numbers ChiCTR2200056708, ChiCTR2200056578).

肠道菌群在抽动障碍(TDs)中起重要作用;然而,益生菌治疗慢性TDs的临床研究缺乏。我们的目的是研究益生菌的有效性,假设它们在治疗慢性td方面的临床疗效与可乐定相当。方法:患者在维持原有治疗的基础上,随机接受罗伊氏乳酸杆菌或可乐定透皮贴剂治疗8周。耶鲁全球抽搐严重性量表(YGTSS);Swanson, Nolan和Pelham-IV量表(SNAP-IV);治疗前后儿童行为检查表(CBCL)评分。结果:我们匹配了两组患者的年龄、性别、发病年龄和抽动类型。两组患者YGTSS评分均有显著改善(p = 0.024)。两组在SNAP-IV量表上的注意缺陷改善情况相似,差异无统计学意义(p = 0.465)。对于多动障碍,在匹配两组患者的年龄、性别、发病年龄、抽搐类型和儿童耶鲁-布朗强迫症量表(CY-BOCS)评分后,观察到两组患者的改善有显著差异(p = 0.010),其中益生菌组的改善更大(0.3±0.58比0.1±0.50)。第9周时,益生菌组和可乐定组的CBCL社交能力分别比基线提高了3.2±6.26和0.6±4.07,两者差异有统计学意义(p = 0.049)。虽然两组患者的行为问题无显著性差异(p = 0.347),但益生菌组的改善趋势明显高于可乐定组(12.7±25.86比8.4±13.15)。结论:中期疗效评价表明,联合应用罗伊氏乳杆菌治疗儿童慢性TDs,改善抽动症状的效果优于可乐定透皮贴剂治疗。此外,它还能适度改善多动症症状。试验报名:chictr.org.cn(注册号ChiCTR2200056708, ChiCTR2200056578)。
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引用次数: 0
Burden of Myasthenia Gravis in the Czech Republic: Analysis of the Nationwide Patient Registry. 捷克共和国重症肌无力的负担:全国患者登记的分析。
IF 3.9 3区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2025-02-01 Epub Date: 2024-12-04 DOI: 10.1007/s40120-024-00682-x
Stanislav Voháňka, Aleš Tichopád, Magda Horáková, Jana Junkerová, Michala Jakubíková, Jiří Piťha, Michaela Týblová, Daniela Vlažná, Katarína Breciková, Jacek Cudny, Petr Hájek

Introduction: The main goal of this study was to describe the Czech population of patients with MG in terms of demographics, disease characteristics, management approaches, and treatment trends.

Methods: We selected all patients, both incident and prevalent, who were enrolled in the Czech MyReg registry between August 24, 2015 and November 19, 2021. For the descriptive analysis, all patients enrolled in the registry, regardless of their date of diagnosis or date of enrolment, were included. We analyzed the following disease-related endpoints: myasthenia gravis composite (MGC) score, forced vital capacity (FVC), and Myasthenia Gravis Foundation of America (MGFA) clinical classification.

Results: The incidence showed a consistent increasing trend from 0.62 to 3.13. The mean MGC score was 5.0 (median 4.0, 95% CI 4.7, 5.3) representing mild form of MG. The difference in FVC from the predicted value in patients during and without myasthenic crisis was 58.93% (95% CI 37.27, 80.59) and 75.93% (95% CI 74.87, 77.00), respectively. We identified 70 patients (5.0%) with refractory MG, of whom 58.6% were female. The MGFA classifications in those with refractory vs. non-refractory disease was as follows: IIa 21.8% vs 23.2%, IIb 45.3% vs 33.6%, and IIIb 14.1% vs 4.6%, respectively.

Conclusion: Our analysis shows that the incidence of MG is increasing in the Czech Republic and that patients with refractory disease, of whom up to 58% are female, have a higher burden of disease than non-refractory patients.

本研究的主要目的是描述捷克MG患者的人口统计学、疾病特征、管理方法和治疗趋势。方法:我们选择了2015年8月24日至2021年11月19日期间在捷克MyReg注册中心登记的所有患者,包括发病和流行患者。对于描述性分析,所有入组的患者,无论其诊断日期或入组日期,均被纳入。我们分析了以下疾病相关终点:重症肌无力复合(MGC)评分、用力肺活量(FVC)和美国重症肌无力基金会(MGFA)临床分型。结果:发病率从0.62上升到3.13,呈持续上升趋势。平均MGC评分为5.0(中位数4.0,95% CI 4.7, 5.3),代表轻度MG。有肌无力危像和无肌无力危像患者的FVC与预测值的差异分别为58.93% (95% CI 37.27, 80.59)和75.93% (95% CI 74.87, 77.00)。我们发现70例难治性MG患者(5.0%),其中58.6%为女性。难治性和非难治性疾病的MGFA分类如下:IIa 21.8% vs 23.2%, IIb 45.3% vs 33.6%, IIIb 14.1% vs 4.6%。结论:我们的分析表明,MG在捷克共和国的发病率正在增加,难治性疾病患者(其中高达58%为女性)的疾病负担高于非难治性患者。
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