Sasineprocel

Parkinson’s disease (PD) is entering a pivotal phase. For decades, treatment has centred on dopamine replacement to manage motor symptoms. That approach remains foundational and commercially important. However, scientific advances are shifting the field toward biologically defined subtypes, biomarker-guided development, and therapies designed to slow or alter disease progression. 帕金森病（PD）正处于一个关键阶段。几十年来，治疗主要集中于通过多巴胺替代来管理运动症状。这种方法仍然是基础且具有商业重要性。然而，科学进展正在推动该领域向生物定义的亚型、基于生物标志物的开发以及旨在减缓或改变疾病进展的疗法转变。The next era of competition will not be defined solely by improved symptom control, but by the ability to demonstrate measurable impact on underlying neurodegeneration. . 下一个竞争时代将不仅仅由症状控制的改善来定义，而是由展示对潜在神经退行性病变的可衡量影响的能力来定义。Globally, PD is the fastest-growing major neurodegenerative disorder. Prevalence is projected to more than double by 2050, reaching an estimated 25 million people, largely driven by ageing populations. Clinically, PD is characterised by bradykinesia (slowness of movement), accompanied by tremor and/or rigidity. 全球范围内，帕金森病是增长最快的大型神经退行性疾病。预计到2050年，患病率将增加一倍以上，达到约2500万人，主要原因是人口老龄化。临床上，帕金森病的特征是运动迟缓（动作缓慢），伴随震颤和/或僵硬。Over time, postural instability, cognitive impairment, sleep disturbances, constipation, depression, and autonomic dysfunction frequently emerge. Approximately 10%–15% of cases are linked to genetic mutations such as LRRK2 or GBA1, though most cases are considered sporadic. . 随着时间的推移，姿势不稳、认知障碍、睡眠障碍、便秘、抑郁和自主神经功能障碍等症状经常出现。大约10%-15%的病例与LRRK2或GBA1等基因突变有关，尽管大多数病例被认为是散发性的。Biologically, PD is marked by the accumulation of misfolded alpha-synuclein protein within neurons. These aggregates form Lewy bodies, disrupt cellular trafficking, impair mitochondrial function, and activate inflammatory pathways, ultimately leading to the loss of dopamine-producing neurons in the substantia nigra. 生物学上，帕金森病的特征是神经元内错误折叠的α-突触核蛋白的积累。这些聚集体形成路易小体，破坏细胞运输，损害线粒体功能，并激活炎症通路，最终导致黑质中多巴胺能神经元的丧失。Dopamine depletion drives the classical motor symptoms. While diagnosis remains primarily clinical, the field is increasingly moving toward biologically defined disease frameworks using molecular biomarkers. This shift is important for research and future therapy selection, though symptomatic treatment remains the dominant clinical reality today. . 多巴胺耗竭驱动了典型的运动症状。虽然诊断仍然主要是临床性的，但该领域正越来越多地朝着使用分子生物标志物的生物学定义疾病框架发展。这种转变对于研究和未来的治疗选择很重要，尽管对症治疗仍然是当前主要的临床现实。Current standard: Advancing symptomatic control 当前标准：推进症状控制Dopamine replacement with levodopa continues to anchor PD treatment. However, long-term oral levodopa use is associated with motor fluctuation periods when medication effect wears off (“OFF” time) and dyskinesias (involuntary movements). As a result, much of current innovation focuses on stabilising dopaminergic stimulation, rather than introducing entirely new mechanisms. . 左旋多巴的多巴胺替代疗法仍然是帕金森病治疗的核心。然而，长期口服左旋多巴会导致药效减退时的运动波动期（“关闭”时间）和异动症（不自主运动）。因此，当前的许多创新集中在稳定多巴胺能刺激上，而不是引入全新的机制。One major advancement is continuous subcutaneous levodopa delivery. Recently approved and late-stage systems such as Vyalev (ABBV-951) and ND0612 provide steady infusion of levodopa throughout the day. Continuous delivery reduces peaks and troughs in plasma levels, thereby decreasing OFF time and smoothing motor control. 一项重要的进展是持续的皮下左旋多巴输注。近期获批和处于后期阶段的系统，如Vyalev（ABBV-951）和ND0612，能够提供全天候稳定的左旋多巴输注。持续输注减少了血浆水平的峰值和低谷，从而减少关闭时间并使运动控制更加平稳。Strategically, these platforms compete on convenience, device design, and pharmacokinetic stability, rather than molecular novelty, representing meaningful quality-of-life improvements for patients with advanced disease. . 从战略上讲，这些平台在便利性、设备设计和药代动力学稳定性方面展开竞争，而不是分子新颖性，这代表了对晚期疾病患者生活质量的显著改善。Another area of differentiation is receptor-selective dopamine agonism. Traditional dopamine agonists stimulate multiple receptor subtypes and are associated with neuropsychiatric adverse effects, including impulse control disorders. Tavapadon, a selective D1/D5 partial agonist, aims to provide motor benefit with improved tolerability by targeting specific receptor subtypes. 另一个差异化领域是受体选择性多巴胺激动作用。传统的多巴胺激动剂会刺激多种受体亚型，并伴有神经精神方面的不良反应，包括冲动控制障碍。Tavapadon是一种选择性的D1/D5部分激动剂，旨在通过靶向特定的受体亚型，在提供运动获益的同时改善耐受性。This reflects a broader movement toward precision modulation of dopaminergic tone, rather than broad stimulation. . 这反映了一种更广泛的运动，即对多巴胺能张力进行精确调节，而不是广泛刺激。Adjunctive therapies that reduce OFF time such as COMT inhibitors, MAO-B inhibitors, and adenosine A2A antagonists also remain important components of combination regimens. Across the symptomatic landscape, the competitive axis is increasingly defined by durability of effect, reduction in fluctuations, and simplification of treatment regimens. . 减少关闭时间的辅助疗法，如COMT抑制剂、MAO-B抑制剂和腺苷A2A拮抗剂，仍然是联合治疗方案中的重要组成部分。在症状治疗领域，竞争的关键越来越由效果的持久性、波动性的减少以及治疗方案的简化所定义。Despite this progress, symptomatic optimisation alone is unlikely to transform long-term disease trajectory. As delivery systems mature, differentiation based purely on motor benefit may plateau, intensifying focus on therapies that address the underlying biology of neurodegeneration. 尽管取得了这些进展，但仅靠症状优化不太可能改变疾病的长期发展轨迹。随着递送系统的成熟，单纯基于运动益处的差异化可能会达到平台期，从而更加聚焦于针对神经退行性病变潜在生物学机制的治疗方案。The shift toward disease modification 向疾病修饰的转变Disease-modifying therapies (DMTs) aim to slow neuronal loss, rather than simply compensate for dopamine deficiency. In PD, this represents a major scientific and regulatory challenge, as progression is gradual and heterogeneous. There are still no regulatory-approved DMTs for PD, however, multiple programmes are aiming to generate the kind of long-duration data that demonstrates a slowing of disease progression. . 疾病修饰治疗（DMTs）旨在减缓神经元损失，而不仅仅是补偿多巴胺的缺乏。在帕金森病（PD）中，这代表着一个重大的科学和监管挑战，因为疾病的进展是渐进且异质的。目前尚无监管机构批准的PD疾病修饰治疗，然而，多个项目正致力于生成能够证明疾病进展减缓的长期数据。Therapeutic modalities span monoclonal antibodies, small-molecule kinase inhibitors, substrate reduction therapies, and gene therapies. The leading biological targets include: 治疗方式涵盖了单克隆抗体、小分子激酶抑制剂、底物减少疗法和基因疗法。主要的生物靶点包括：• Alpha-synuclein aggregation: preventing or clearing toxic protein clumps • α-突触核蛋白聚集：预防或清除有毒蛋白质团块 • LRRK2 signalling: modulating kinase activity linked to genetic and sporadic PD • LRRK2信号传导：调节与遗传性和散发性帕金森病相关的激酶活性 • Glucocerebrosidase (GBA1) dysfunction: addressing lysosomal impairment • 葡糖脑苷脂酶 (GBA1) 功能障碍：解决溶酶体损伤问题• Neuroinflammation and mitochondrial dysfunction: reducing secondary drivers of degeneration 神经炎症和线粒体功能障碍：减少退化的次要驱动因素Despite multiple late-stage failures of anti-alpha-synuclein antibodies in PD, continued investment in immunotherapies and aggregation inhibitors reflects sustained confidence in alpha-synuclein biology. Among the most advanced programmes, prasinezumab is a monoclonal antibody targeting the C-terminus of aggregated alpha-synuclein, designed to neutralise extracellular species and limit cell-to-cell spread. 尽管抗α-突触核蛋白抗体在帕金森病的多个后期试验中失败，但对免疫疗法和聚集抑制剂的持续投资反映了对α-突触核蛋白生物学的持续信心。在最先进的项目中，prasinezumab 是一种单克隆抗体，靶向聚集的α-突触核蛋白的C端，旨在中和细胞外物质并限制细胞间传播。Exidavnemab (BIIB054) selectively binds soluble alpha-synuclein aggregates, which are believed to represent the most neurotoxic conformations. Together, these agents are viewed as important bellwethers for whether targeting extracellular or propagating alpha-synuclein can translate into measurable slowing of clinical decline in PD. . Exidavnemab（BIIB054）选择性结合可溶性α-突触核蛋白聚集体，这些聚集体被认为是最具神经毒性的构象。这些药物共同被视为重要的风向标，用以判断靶向细胞外或传播中的α-突触核蛋白是否能够转化为可测量的帕金森病临床衰退减缓。In parallel, active immunisation strategies are emerging. ACI-7104.056, an alpha-synuclein vaccine, is designed to stimulate a patient’s own immune system to generate a sustained, polyclonal antibody response against pathological alpha-synuclein species. Early clinical data has demonstrated favourable safety and tolerability, along with robust antibody generation and evidence of target engagement, supporting continued development. 与此同时，主动免疫策略正在兴起。ACI-7104.056 是一种 α-突触核蛋白疫苗，旨在刺激患者自身免疫系统产生针对病理性 α-突触核蛋白的持续多克隆抗体反应。早期临床数据表明其具有良好的安全性和耐受性，同时能够强有力地生成抗体并显示出靶点结合的证据，支持进一步开发。If successful, vaccination could offer a more durable and potentially scalable approach to modifying alpha-synuclein pathology compared with passive antibody therapies. . 如果成功，与被动抗体疗法相比，疫苗接种可能提供一种更持久且潜在可扩展的方法来改变α-突触核蛋白病理。Several late-stage trials are expected to report results between 2025 and 2027, marking the first true test of biological disease modification in PD. 预计在2025年至2027年间，将有几项晚期试验报告结果，这标志着帕金森病生物学疾病修饰的首次真正测试。Regenerative and restorative approaches 再生与修复方法Beyond slowing progression, a longer-term ambition is functional restoration by rebuilding or stabilising dopaminergic circuitry, rather than merely protecting what remains. These strategies move beyond classical disease modification and instead aim to replace lost neurons, enhance their survival, or directly correct underlying genetic drivers of degeneration. . 除了减缓疾病进展，更长远的目标是通过重建或稳定多巴胺能回路来实现功能恢复，而不仅仅是保护现存的神经元。这些策略超越了传统的疾病修饰方法，旨在替换丢失的神经元、增强其存活能力，或直接纠正导致退化的潜在遗传驱动因素。Cellular replacement strategies are leading the regenerative push in PD. Bemdaneprocel, the most advanced cell therapy in clinical development, uses induced pluripotent stem cell (iPSC)-derived dopaminergic neurons implanted into the putamen to restore physiologic dopamine production, with the aim of durable engraftment and sustained functional benefit. 细胞替代策略正在引领帕金森病（PD）的再生医学发展。Bemdaneprocel 是临床开发中最先进的细胞疗法，利用诱导多能干细胞 (iPSC) 衍生的多巴胺能神经元植入壳核，以恢复生理性的多巴胺生成，旨在实现持久的移植效果和持续的功能改善。In contrast, ANPD001 takes a personalised, autologous approach, generating dopaminergic neurons from a patient’s own induced pluripotent stem cells to potentially minimise immune rejection and reduce the need for chronic immunosuppression. Both approaches seek not just symptomatic relief, but structural rebuilding of dopaminergic circuitry. . 相比之下，ANPD001 采用个性化的自体方法，从患者自身的诱导多能干细胞生成多巴胺能神经元，以尽可能减少免疫排斥并降低对长期免疫抑制的需要。这两种方法不仅寻求症状缓解，还致力于多巴胺能回路的结构重建。Complementing cell therapy, gene- and RNA-based strategies aim to enhance neuronal resilience or correct underlying molecular drivers. AB-1005 delivers glial-derived neurotrophic factor (GDNF) via an adenoviral vector to promote dopaminergic neuron survival, while PR001 targets GBA1-associated PD through gene replacement to restore lysosomal function. 补充细胞治疗，基于基因和RNA的策略旨在增强神经元的适应能力或纠正潜在的分子驱动因素。AB-1005通过腺病毒载体递送胶质细胞源性神经营养因子（GDNF）以促进多巴胺能神经元的存活，而PR001则通过基因替代靶向GBA1相关帕金森病，以恢复溶酶体功能。At the RNA level, ION464 is an antisense oligonucleotide designed to reduce alpha-synuclein protein production upstream. Together, these programmes reflect a shift toward biologic stabilisation, and potentially partial restoration, of neural networks, moving beyond chronic pharmacologic management toward targeted, durable intervention. . 在RNA水平上，ION464是一种反义寡核苷酸，旨在减少上游的α-突触核蛋白生产。这些项目共同反映了一种向生物稳定以及潜在的部分神经网络恢复的转变，超越了长期的药物管理，朝着有针对性、持久的干预迈进。These strategies attempt not merely to delay decline, but to restore dopaminergic circuitry. While still early and surgically intensive, they represent a potential paradigm shift from chronic pharmacologic management to biologic stabilisation or partial reversal of deficits. 这些策略不仅试图延缓衰退，还旨在修复多巴胺能回路。尽管目前仍处于早期阶段且手术强度较大，但它们代表了从慢性药物治疗向生物稳定或部分逆转功能缺损的潜在范式转变。Biomarkers as enablers of DMT development 生物标志物作为DMT开发的推动者Historically, PD diagnosis and trial enrolment have relied on clinical criteria. The emergence of alpha-synuclein seed amplification assays (SAAs) is beginning to change that paradigm. These assays detect misfolded alpha-synuclein in cerebrospinal fluid, sometimes before motor symptoms manifest. In 2024, the FDA issued a Letter of Support encouraging their use for clinical trial enrichment, though they are not yet validated as surrogate endpoints. . 历史上，帕金森病（PD）的诊断和试验入组依赖于临床标准。阿尔法突触核蛋白种子扩增测定（SAAs）的出现开始改变这一模式。这些检测方法能够在脑脊液中检测到错误折叠的阿尔法突触核蛋白，有时甚至在运动症状出现之前就能发现。2024年，美国食品药品监督管理局（FDA）发布了一封支持信，鼓励将这些检测用于临床试验的富集，尽管它们尚未被验证为替代终点。Other biomarker tools include: 其他生物标志物工具包括：• DAT-SPECT imaging: assessing dopaminergic neuron integrity • DAT-SPECT成像：评估多巴胺能神经元完整性 • Neurofilament light chain (NfL): a blood-based marker of neuronal injury 神经丝轻链 (NfL)：一种基于血液的神经元损伤标志物• Genetic markers: such as LRRK2 or GBA1 mutations, enabling targeted enrolment • 基因标记：如LRRK2或GBA1突变，能够实现针对性招募• Skin biopsy assays: detecting peripheral synuclein deposition 皮肤活检分析：检测周围突触核蛋白沉积Biomarkers serve three main functions: earlier detection, biologically defined patient stratification, and measurement of drug–target interaction. Their integration is essential for reducing trial heterogeneity and potentially shortening development timelines. However, regulatory validation of progression biomarkers remains a key bottleneck. . 生物标志物有三个主要功能：早期检测、生物学定义的患者分层以及药物-靶点相互作用的测量。它们的整合对于减少试验异质性和潜在缩短开发时间至关重要。然而，进展生物标志物的监管验证仍然是一个关键瓶颈。Strategic outlook 战略展望In the near term, continuous levodopa systems and receptor-selective agents will intensify competition within symptomatic management, improving consistency, tolerability, and convenience areas of clear clinical value. 短期内，持续左旋多巴系统和受体选择性药物将加剧症状管理领域的竞争，提高一致性、耐受性和便利性，这些方面具有明确的临床价值。Over the next decade, however, leadership in PD will likely depend on demonstrating credible disease modification. Success will require biomarker-defined enrolment, long-duration studies, and regulatory acceptance of mechanistic endpoints. Health systems may also need to invest in diagnostic infrastructure to support earlier identification and precision treatment pathways. . 然而，在未来十年中，PD 的领导地位可能取决于能否证明可信的疾病修饰效果。成功将需要通过生物标志物定义的入组、长时间的研究以及监管机构对机制终点的认可。卫生系统可能还需要投资于诊断基础设施，以支持早期识别和精准治疗路径。Together, this positions Parkinson’s disease as an evolving field, from a syndrome managed through dopamine replacement to a biologically characterised condition with an emerging disease-modifying pipeline. Symptomatic innovation remains essential, but the ultimate transformation will hinge on preserving neurons, slowing progression, and potentially restoring function. . 这使得帕金森病成为一个不断发展的领域，从通过多巴胺替代治疗的综合征转变为一种生物学上明确特征且具有新兴疾病修饰疗法的状况。症状创新仍然至关重要，但最终的转变将取决于保护神经元、减缓疾病进展，并有可能恢复功能。About the author 关于作者Ivo Carre, PhD, is a senior business analyst at Lifescience Dynamics in London, with a doctorate in Neuroscience from the UKDRI and over two years of biopharma consulting experience. He has supported various clients across several indications, including oncology, neurology, and rare diseases, with expertise in competitive intelligence, market research, and market access.. 伊沃·卡雷博士是伦敦生命科学动态公司的高级业务分析师，拥有英国痴呆症研究所神经科学博士学位，并具有两年以上的生物制药咨询经验。他为多个适应症的客户提供了支持，包括肿瘤学、神经病学和罕见病领域，专长于竞争情报、市场研究和市场准入。