A Multicenter, Open Label Study to Evaluate Tolerability and Efficacy of Orally Administered ENT-01 for the Treatment of Parkinson's Disease Dementia.

This study will be conducted as a multi-center, open label study in the US. There will be 40 patient to receive the active investigational product.

开始日期2024-03-01

申办/合作机构

Enterin, Inc.

NCT04483479

/ Terminated临床2期

A Multicenter, Non-Randomized, Open-Label Study to Evaluate the Safety and Efficacy of Orally Administered ENT-01 in Improving Constipation and Neurologic Symptoms in Patients With Parkinson's Disease and Constipation Over a 14-week Period

This study will be conducted as an open-label safety follow-on to a multi-center, double-blind, randomized study. All subjects who participated in the randomized study will be offered participation in this unblinded, single-arm, safety study. Approximately 50 subjects will be entered into the study and ENT-01 will be administered daily in escalating doses followed by a fixed dose for 12 weeks. Each subject will participate for approximately 20 weeks; dosing duration will be approximately 14 weeks.

开始日期2020-07-30

申办/合作机构

Enterin, Inc.

NCT03781791

/ Completed临床2期

A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Multiple Dose Study to Evaluate Safety, Tolerability and Efficacy of Orally Administered ENT-01 for the Treatment of Parkinson's Disease-Related Constipation (KARMET)

This study will be conducted as a multi-center, randomized, double-blind, placebo-controlled study. Approximately 72 patients will be randomized 3:1 to treatment or placebo, with approximately 54 patients allocated to receive the active investigational product and approximately 18 patients allocated to receive placebo.
- Study Update-
Amendment 3 - In this amendment, an additional 80 patients (approximately) will be randomized 1:1 to treatment or placebo (double-blind) with approximately 40 subjects allocated to each group.

开始日期2018-12-10

申办/合作机构

Enterin, Inc.

100 项与 Kenterin 相关的临床结果

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100 项与 Kenterin 相关的转化医学

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100 项与 Kenterin 相关的专利（医药）

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107

项与 Kenterin 相关的文献（医药）

2025-12-31·JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY

Identification of chemical scaffolds for targeting ubiquitin-specific protease 11 (USP11) through high-throughput virtual screening

Article

作者: Kim, Hong-Rae ; Hurh, Sunghoon ; Lee, Hobin ; Logan, Derek T. ; Hwang, Jong-Ik ; Kang, Soomin ; Yoon, Jihwan

USP11 is a promising therapeutic target implicated in Alzheimer's disease and various cancers; however, no specific inhibitors are currently available, with the only known inhibitor being mitoxantrone, which primarily targets topoisomerase II. To identify novel chemical starting points, we conducted high-throughput virtual screening using a USP11 homology model. Screening over 600,000 compounds yielded five structurally distinct hits with significant inhibitory activity. Biochemical validation highlighted two promising scaffolds: benzoxadiazole derivatives and pyrrolo-phenylamidine analogues, both demonstrating structure-dependent inhibition and tractable SAR profiles. Docking studies further characterised their binding modes, supporting their potential for optimisation. Hydroxyphenyl hydrazone analogues raised PAINS-related concerns, while compounds such as squalamine were deprioritized due to weak binding affinity and structural complexity. Overall, this study provides valuable scaffolds and mechanistic insights that can inform future development of potent, selective USP11 inhibitors.

2025-09-01·FOOD CHEMISTRY

The aroma evolution in lotus (Nelumbo nucifera Gaertn.) seed juice: A comprehensive analysis of processing and low-temperature storage effects

Article

作者: Jiang, Xiangfu ; Lu, Xu ; Zhou, Taoyi ; Mao, Sirui ; Lei, Qiuming ; Zheng, Baodong ; Huang, Zhanhong ; Zhou, Fuzhen ; Ma, Shuang

Lotus seed juice has significant potential in the plant-based beverage market owing to its distinctive flavor. However, its sensory quality is significantly influenced by processing and storage conditions. This study examined the effects and underlying mechanisms of fresh squeezing, sterilization, and refrigeration at 4 °C (for 1-6 months) on the aroma profile of lotus seed juice using an electronic nose, gas chromatography-ion mobility spectrometry (GC-IMS), and non-targeted metabolomics. Sterilization processes resulted in vanilla, mint, and ammonia-like flavors due to the accumulation of hexanal, pentanal, and pyrrolidine. One month of refrigeration enhanced fruity and minty flavors, attributed to increased acetone and 6-ethyl acetate-D from fatty acid oxidation and esterification, respectively. However, prolonged refrigeration (six months) introduced undesirable alcoholic and pungent off-flavors caused by slow oxidative degradation (such as 2-propanol and 1-hydroxy-2-propanone). These findings provide valuable insights for improving the preservation methods and quality control strategies for plant-based beverages.

2025-02-13·JOURNAL OF PHYSICAL CHEMISTRY B

Interaction of Squalamine with Lipid Membranes

Article

作者: Ulrich, Anne S. ; Afonin, Sergii ; Kohlmeyer, Annika ; Meng, Beibei ; Guschtschin-Schmidt, Nadja ; Grage, Stephan L.

Squalamine is an aminosterol from dogfish shark which has drawn attention, besides its antimicrobial activity, as a drug candidate in the treatment of Parkinson's disease due to its ability to prevent binding of α-synuclein to lipid membranes. To get insight into the mode of action of this steroid, we studied the influence of squalamine on lipid bilayers and whether it could inhibit the binding of a model peptide. Solid-state ¹⁹F NMR of labeled [KIGAKI]₃ indicated that, indeed, this peptide no longer binds as a flexible chain to the bilayer in the presence of squalamine. When the cationic squalamine was added to lipid vesicles containing phosphatidylglycerol lipids, the aminosterol was found in differential scanning calorimetry and solid-state ³¹P NMR experiments to lower the gel-to-fluid phase transition and cause the phase separation of domains enriched in anionic lipids. Squalamine had only a little influence on ²H NMR relaxation and on the order parameters of the chains. These findings indicate that the aminosterol does not affect the molecular mobility of the hydrophobic core of the bilayer; hence, it does not insert into the membrane, nor causes thinning as found for molecules inserting in the headgroup region. On the other hand, squalamine was found to interact with lipid headgroups through electrostatic interactions, as seen by solid-state ²H NMR on headgroup-labeled lipids. Furthermore, ³¹P NMR showed that squalamine shifted the lamellar-to-hexagonal phase transition of phosphatidylethanolamine lipids to higher temperatures, indicating a preference for positively curved membranes. Altogether, our experiments indicate a strong interaction of the cationic squalamine with lipid headgroups, in particular with anionic lipids. This affinity for membranes is strong enough to efficiently displace cationic polypeptides, confirming the proposed action mechanism in Parkinson treatment. Notably, supported by ¹H-¹H NOESY experiments, it was found that squalamine does not insert into the bilayer, but rather acts as facial amphiphile binding to the membrane surface. The binding to membranes may be envisaged in the form of oligomeric or micellar assemblies, which can disrupt the membrane at high concentrations, thereby explaining the antimicrobial and antifungal activities of squalamine.

项与 Kenterin 相关的新闻（医药）

2026-05-22

·生物通

综述：帕金森病药物治疗的最新进展

帕金森病（Parkinson’s disease, PD）是一种常见神经退行性疾病，由错误折叠α-突触核蛋白（α-synuclein）扩散及主要累及多巴胺能神经元的上行性神经变性驱动，导致进行性黑质纹状体功能障碍及其他通路受损。其临床诊断以运动迟缓、静止性震颤、肌强直为核心运动特征，常伴随多种非运动症状。本文综述PD药物治疗的最新进展，重点关注近期获批药物、新型给药模式及处于临床开发晚期的候选药物。药理多巴胺替代仍是控制PD运动症状对症治疗的核心手段。左旋多巴（levodopa）仍被视为对症疗效的金标准，但多数患者长期使用后会出现疗效波动及药物诱导的运动障碍。因此，优化左旋多巴的持续递送是研发重点。新型制剂与给药方式包括口服缓释（extended-release, ER）左旋多巴（IPX203）、吸入用左旋多巴粉雾剂，以及经皮下（foslevodopa/foscarbidopa, ND0612）或空肠泵（左旋多巴[恩他卡朋]卡比多巴肠凝胶）的输注治疗。此外，具有与左旋多巴等效疗效的多巴胺激动剂阿扑吗啡已有多种皮下及舌下给药制剂，用于治疗PD运动波动。新型多巴胺激动剂亦取得进展，选择性多巴胺D1/D5受体部分激动剂tavapadon在早期PD单药治疗及合并运动波动患者的左旋多巴辅助治疗中均显示出疗效。儿茶酚-O-甲基转移酶（catechol-O-methyltransferase, COMT）抑制剂opicapone的早期使用证据也在更新。这一不断丰富的药物库中，越来越多靶向非多巴胺能通路的药物正在涌现，金刚烷胺（amantadine）治疗左旋多巴诱导的运动障碍及运动波动的对症疗效证据持续增加。除肉毒毒素制剂获批治疗流涎外，过去数年针对PD广泛非运动症状的研发尚未转化为新的PD特异性获批药物。PD症状在早期至中期通常可得到满意控制，但疾病的进展性不可避免导致功能残疾加重，凸显了对疾病修饰治疗的迫切未满足需求。尽管目前尚无确凿证据证明任何在研方案具有疾病修饰疗效，研究人员总结了近期晚期临床试验证据，聚焦于胰高血糖素样肽1（glucagon-like peptide 1, GLP1）受体激动剂、葡萄糖脑苷脂酶（glucocerebrosidase, GBA）通路靶向策略、富含亮氨酸重复激酶2（leucine-rich repeat kinase 2, LRRK2）抑制，以及基于α-突触核蛋白的治疗方案。引言帕金森病是全球第二大神经退行性疾病，2021年全球患病人数约1180万，且是增长最快的神经退行性疾病，预计2050年将增至2520万。其诊断基于运动迟缓、静止性震颤、肌强直三大核心运动特征，晚期还可出现冻结步态、姿势不稳、跌倒、构音障碍、吞咽困难等症状，是导致残疾的关键驱动因素。非运动症状涵盖睡眠障碍、自主神经功能紊乱、淡漠、抑郁及认知功能障碍，是影响患者生活质量的主要负担来源。 PD运动症状的药物治疗以药理多巴胺替代为核心，左旋多巴疗效最优，但长期治疗受限于疗效波动与运动障碍的发生，这推动了多巴胺能策略的持续优化，包括改善左旋多巴药代动力学与递送方式、研发新型多巴胺激动剂及各类辅助疗法。非多巴胺能药物如金刚烷胺及抗胆碱能药作用有限，前者仍是唯一有效治疗左旋多巴诱导运动障碍的药物。晚期PD以药物难治性运动与非运动症状为主要特征，迫切需要疾病修饰治疗。本文聚焦PD对症治疗与疾病修饰治疗的在研药物进展，排除手术、基因与细胞治疗及非药物干预。检索方法本叙述性综述通过检索PubMed筛选截至2026年3月的原创论文与综述，纳入近5年内获批或处于临床开发晚期的药物，同时检索2025年国际三大会议摘要及ClinicalTrials.gov平台在研试验。 PD运动症状的治疗药物多巴胺能药物药理多巴胺替代仍是PD运动症状管理的核心支柱，左旋多巴联合多巴脱羧酶抑制剂（dopa decarboxylase inhibitor, DDCI）仍为对症疗效金标准。现有常规多巴胺能药物可有效控制多数患者长期运动症状，但在疗效、安全性、耐受性及预防长期运动并发症方面仍存在未满足需求。除P2B001外，本文未纳入单胺氧化酶B（monoamine oxidase B, MAO-B）抑制剂相关内容。新型左旋多巴制剂与递送缓释左旋多巴延长左旋多巴半衰期以减少运动波动、延长“开”期的研究已开展数十年。IPX066是首个口服缓释左旋多巴/卡比多巴（levodopa/carbidopa, LD/CD）复方制剂，Ⅲ期试验显示较即刻释放制剂减少每日“关”期1.2小时，于10年前获美国食品药品监督管理局（Food and Drug Administration, FDA）批准。IPX203是一种新型口服速释/缓释复方胶囊，含4:1比例的LD/CD，速释组分30分钟内达峰，缓释组分维持稳态浓度达4.6小时以上，Ⅲ期试验显示较即刻释放制剂每日“开”期增加0.53小时、“关”期减少0.48小时，2024年获FDA批准用于PD治疗。其他口服递送策略如口腔微型泵DopaFuse?、夜间给药制剂CLE-600及延迟脉冲释放制剂CP-012均处于早期开发阶段。非口服按需制剂口服左旋多巴吸收受吞咽障碍、胃排空延迟、肠道竞争转运等因素干扰，变异性大。吸入用左旋多巴CVT-301（Inbrija?）采用粉雾剂肺递送，15分钟起效，30分钟达峰，Ⅲ期试验显示84 mg剂量较安慰剂显著改善“关”期运动评分，欧盟与美国分别于2019年、2018年批准其用于“关”期按需治疗。其他鼻用、吸入剂型处于早期临床阶段。左旋多巴输注持续静脉输注因需中心静脉置管及大剂量液体负荷未被常规应用。左旋多巴卡比多巴肠凝胶（levodopa carbidopa intestinal gel, LCIG）经经皮内镜下胃造瘘空肠给药，Ⅲ期试验显示较安慰剂减少“关”期1.9小时，真实世界研究减少约4小时，并可降低运动障碍严重程度。左旋多巴恩他卡朋卡比多巴肠凝胶（levodopa entacapone carbidopa intestinal gel, LECIG）在配方中加入COMT抑制剂，生物利用度更高，所需输注体积更小，已在部分国家上市。皮下输注避免了肠凝胶的有创性与管路负担。Foslevodopa/foscarbidopa是前体药物，经碱性磷酸酶快速转化为左旋多巴/卡比多巴，水溶性显著提高，Ⅲ期试验显示24小时输注较安慰剂增加“良好开”期1.75小时，2022年获欧洲药品管理局（European Medicines Agency, EMA）批准，2024年获FDA批准用于晚期PD运动波动。ND0612是另一种皮下输注用LD/CD溶液，Ⅲ期BouNDless试验显示较口服LD/CD增加“良好开”期1.7小时，2026年2月获EMA人用药品委员会正面意见。DIZ102利用酸性pH提高溶解度与皮肤耐受性，处于Ⅰ期临床阶段。新型多巴胺激动剂及新制剂传统非麦角类多巴胺激动剂疗效确切，但日间嗜睡与冲动控制障碍风险限制了应用。Tavapadon是选择性长效多巴胺D1/D5受体部分激动剂，Ⅲ期TEMPO-1、TEMPO-2试验证实其作为早期PD单药可显著改善MDS-UPDRSⅡ+Ⅲ评分，TEMPO-3试验显示作为左旋多巴辅助治疗可增加“良好开”期1.1小时，已完成Ⅲ期开发。Glovadalen是D1受体正向别构调节剂，Ⅱ期ATLANTIS试验达到主要终点，显著降低每日“关”期时长。阿扑吗啡是唯一疗效与左旋多巴相当的多巴胺能药物，传统皮下注射与输注在欧洲应用多年，2025年获FDA批准用于美国市场。舌下可溶性双层膜剂2020年获FDA批准，Ⅲ期试验显示30分钟显著改善“关”期运动评分，但因局部黏膜刺激与停药率较高，目前在美国已退市。其他在研方案包括低剂量普拉克索与雷沙吉兰固定复方P2B001，Ⅲ期试验显示非劣于常规剂量普拉克索且安全性更优；每周一次肌注罗替高汀缓释微球LY03003完成Ⅲ期试验；多巴胺D3受体拮抗剂mesdopetamⅡ期试验未达主要终点，但次要终点显示可改善运动障碍评分，计划推进Ⅲ期开发。 COMT抑制剂的新数据长效COMT抑制剂opicapone于2016年、2020年分别获EMA与FDA批准用于“剂末现象”。近期ADOPTION项目显示，在早期运动波动患者中加用50 mg opicapone较增加100 mg左旋多巴可多减少45分钟每日“关”期。EPSILON研究显示，在无运动并发症的PD患者中早期加用opicapone，76周内可延缓MDS-UPDRSⅢ评分恶化且不增加运动并发症风险。非多巴胺能药物治疗PD运动症状治疗左旋多巴诱导运动障碍的非多巴胺能药物金刚烷胺通过拮抗N-甲基-D-天冬氨酸（N-methyl-D-aspartate, NMDA）谷氨酸受体发挥抗运动障碍作用，缓释制剂Gocovri?于2017年获FDA批准该适应症。PREMANDYSK试验探索早期联用金刚烷胺能否降低运动障碍发生率，18个月时用药组发病率显著低于安慰剂组，但洗脱期后差异消失，未证实其保护作用。 5-羟色胺1A受体激动剂NLX-112在Ⅱa期试验中显著改善运动障碍评分且不加重帕金森症状。磷酸二酯酶10A（phosphodiesterase 10A, PDE10A）选择性抑制剂CPL500036的Ⅱ期试验显示良好的抗运动障碍与抗帕金森疗效，支持进一步开发。治疗运动波动的非多巴胺能药物缓释金刚烷胺除抗运动障碍外，还可减少“关”期时长。腺苷A2A受体拮抗剂伊曲茶碱（istradefylline）在日本与美国获批用于改善运动波动。抗癫痫药唑尼沙胺（zonisamide）在日本获批作为左旋多巴辅助治疗改善运动波动。G蛋白偶联受体6（G-protein coupled receptor 6, GPR6）反向激动剂solengepras的Ⅱ期试验显示150 mg剂量可减少“关”期1.3小时，Ⅲ期试验正在进行。 PD非运动症状的治疗药物非运动症状是PD长期残疾的关键驱动因素，但有效药物仍十分有限。肉毒毒素注射治疗流涎已在全球多地获批。针对过度日间嗜睡、直立性低血压、认知障碍的在研项目多数已终止。5-羟色胺2A受体激动剂psilocybin治疗PD抑郁、μ-阿片受体部分激动剂pimavanserin治疗冲动控制障碍、乙酰胆碱M1受体正向别构调节剂TAK-071改善认知、夜间皮下阿扑吗啡输注改善失眠、口服ENT-01改善便秘、米拉贝隆（mirabegrone）治疗膀胱过度活动症、合成大麻素类似物nabilone改善非运动症状等方面均有Ⅱ期试验证据，但尚未形成新的获批药物。疾病修饰治疗目前尚无被证实可延缓PD进展的疾病修饰药物，在研方向集中在四大领域。 GLP1受体激动剂流行病学研究显示GLP1受体激动剂可降低糖尿病患者的PD发病风险。Exenatide早期Ⅱ期试验显示可延缓运动症状进展，但近期Ⅲ期试验未达主要终点。Lixisenatide的Ⅱ期试验显示12个月时可改善“开”期运动评分，但其他GLP1受体激动剂的大型Ⅲ期试验均未获得阳性结果。遗传型PD的靶向治疗 GBA1突变是PD最常见遗传亚型，靶向葡萄糖脑苷脂酶活性的分子伴侣ambroxol、变构调节剂BIA-28-6156处于临床开发阶段；底物还原疗法venglustat虽证实靶点结合但未改善临床进展。LRRK2 G2019S突变是最常见的致病突变，LRRK2激酶抑制剂DNL201（BIIB122）已完成Ⅰ/Ⅱ期试验，正在开展针对LRRK2突变携带者的BEACON试验及不筛选基因型的大规模LUMA试验。靶向α-突触核蛋白病理 c-Abl激酶抑制剂nilotinib、vodobatinib、risvodetinib及小分子聚集抑制剂minzasolmin均未在Ⅱ期试验中显示明确疗效。被动免疫疗法中，抗α-突触核蛋白单抗prasinezumab的PASADENA试验未达主要终点，但预设亚组显示可延缓快速进展患者的运动恶化，PADOVA试验在基线使用左旋多巴的患者中观察到获益信号，已启动Ⅲ期PARAISO试验。主动免疫疗法如UB-312、PD01A、PD03A已完成Ⅰ期试验，证实安全性与免疫原性，ACI-7104正开展Ⅱ期VacSYn试验。结论 PD是目前少数拥有高效对症药物的神经退行性疾病。左旋多巴仍是金标准，新型口服缓释、吸入、皮下输注制剂显著改善了长期治疗的运动并发症。多巴胺能药物研发正向高选择性、低风险方向推进，非多巴胺能药物仍较匮乏。晚期PD的药物难治性症状与疾病修饰治疗的空缺仍是最大挑战。随着基于α-突触核蛋白的生物分期系统逐步建立，未来有望实现更早干预甚至预防性试验，最终实现延缓或阻止疾病进展的目标。

2025-11-27

·知乎专栏

帕金森病药物研发如火如荼，现有临床试验都有哪些？

我国65岁以上患病人群有近200万人，随着PD发病呈现年轻化趋势，预计到2030年我国PD患病人数预计将达500万，约占全球半数以上，成为全球PD病人数量最多的国家。随着中国人口老年化时代的到来，中国帕金森病药物的市场需求也越来越大，帕金森病用药已成为国内药企追逐的热点，赛道已经慢慢变得拥挤。2005年至2030年各国帕金森病患者的分布情况。覆盖人口超过世界上50个国家和西方前五大人口国家。2005 100%=410万人口2030 100%=870万人口由于PD病人中脑黑质多巴胺（DA）能神经元的选择性丢失，导致纹状体神经末梢释放的DA耗竭，引起了静止性震颤、肌僵直和运动迟缓等为主要表现的临床运动症状，并伴有嗅觉减退、胃肠功能障碍、心血管功能障碍、睡眠障碍和神经认知障碍等非运动症状。帕金森病药物治疗的三大症状和特色目前，PD的临床治疗包括药物和手术两类，其策略主要是解决DA能神经元丢失引起的DA减少及相应功能丧失的问题。FDA批准的抗PD药物约25~30个（表1），包括：①补充外源性DA，如含有左旋多巴制剂的美多芭、多巴丝肼等；②DA受体激动剂，如呲贝地尔等药物；③DA递质酶代谢的抑制剂，如司来吉兰、雷沙吉兰等；④促进内源性DA释放，如金刚烷胺等；⑤抗胆碱能药物，如苯海索等。手术方法主要有两种，神经核毁损术和脑深部电刺激术（DBS）。表1. FDA批准上市的PD治疗药物截止到2020年，中总共包括145项治疗帕金森病药物治疗I-III期有效临床试验。在这些试验中，37项（26%）为I期，14项（10%）为I期/II期，61项（42%）为II期，5项（3%）为II期/III期，28项（19%）为III期。在145项试验中，57项（39%）是疾病改善治疗（DMT）试验，88项（61%）是对症治疗（ST）试验。在疾病改善治疗试验中，30项（53%）处于II期，而只有3项（5%）处于III期。36项（41%）对症治疗试验处于II期，其余的在II期和III之间。表2汇总了中按治疗类别划分的有效PD药物临床试验不同阶段的数量。表2. 截至2020年1月21日，按治疗类别划分的有效PD药物试验数量在145个临床试验评估的药物中，有49种药物（21 DMT/28 ST）在I期进行评估，60种药物（28 DMT/32 ST）在II期进行评估，III期有22种药物（3 DMT/19 ST）。截至2020年，在网站上公布的PD药物试验中的药物（按阶段、DMT/ST和治疗类别分类）。我们重点分析处于临床III期的试验，总共在28项III期试验中研究了22种不同的药物（见下图）。在这些试验中，有3项试验（占11％）是疾病改善治疗（DMT）试验。这些DMT试验包括艾塞那肽（一种GLP-1R激动剂），灵芝（一种真菌提取物）和美金刚（一种NMDA受体拮抗剂，正在评估其抑制α-synuclein细胞间传递能力）的评估。III期试验中有25项（89%）是对症治疗（ST）的药物。其中16项试验是多巴胺能症状缓解试验，评估了11种不同的多巴胺能症状缓解剂，包括3个涉及阿朴吗啡的试验和2个涉及他达帕酮的试验；加上沙芬酰胺、IPX203（卡比多巴左旋多巴缓释胶囊）、Accordion pill（左旋多巴/卡比多巴）和APL-130277（阿朴吗啡舌下贴膜）。剩下的9项试验是非多巴胺能症状缓解试验，评估了6种非多巴胺能症状缓解剂，包括3项口服去甲肾上腺素再摄取抑制剂安普雷西汀的试验。III期临床试验的治疗类别（截至2020年，）尽管现有药物显示出了延缓疾病进展的作用，但目前几乎所有可用的帕金森病治疗本质上均为对症治疗，疾病改善治疗的效果一般。而且经典的抗PD治疗会带来一些如运动并发症的不良反应和耐药性，故临床上仍有大量需求未满足。越来越多的新靶点和新疗法随着对PD了解的深入和技术的进步而涌现出来。1. 靶向α-synucleinα-突触核蛋白靶点（α-synuclein,α-syn）是一种位于神经元突出前末端，由140个氨基酸组成的蛋白质，它的突变、聚集和过度积累与许多神经退行性疾病密切相关。α-syn是第一个被确定与帕金森相关的有基因突变的蛋白，减少其产生能够减缓或阻止疾病进展。目前全球有17个以α-syn为靶点开发的药物，其中7个处于临床I期，3个处于临床II期。处于临床2期的3个药物中，有两个是单克隆抗体药物，分别是由罗氏开发的Cinpanemab，以及百健开发的Prasinezumab，另外一个是小分子药物，是由Enterin公司开发的小分子抑制剂Kenterin。2. 靶向LRRK2富亮氨酸重复激酶2（Leucine-richrepeat kinase 2，LRRK2）在人类是由PARK8基因编码的一个酶，LRRK2基因中的激酶激活突变是遗传的PD的最常见遗传原因。以LRRK2为靶点开发的抗PD药物共有4个，其中2个处于临床I期，1个处于临床II期。研发进度最快处于临床II期阶段的药物，是由百健和Ionis合作研发的反义寡核苷酸药物ION-859，它与LRRK2的mRNA结合并介导其降解，使LRRK2蛋白维持在较低水平。3. 干细胞治疗干细胞治疗的思路便是向大脑中移植新的神经细胞，来替代原有损伤或凋亡的细胞来产生新的多巴胺。用于PD治疗的干细胞来源多样，如胚胎干细胞（embryonic stem cells，ESCs）、神经干细胞（neuralstem cells，NSCs）、间充质干细胞（mesenchymal stem cells，MSCs）、诱导多功能干细胞等（induced pluripotent stem cells，iPSCs），不同类型的干细胞在治疗PD的过程中展现出了各自的优缺点。在中共查询到有28个干细胞疗法治疗PD的临床试验，目前在研的干细胞治疗PD的临床试验涵盖了ESCs、NSCs、MSCs与iPSCs，为PD的治疗与康复带来了希望。在 145项临床试验中，有17项（12%）是在中国境内开展。当前，国内致力于PD新药研发的药企，主要有山东绿叶、英科新创、北京中元恒康生物、东阳光药、江苏康缘、石家庄以岭、浙江春禾医药、中科院药物所、军科院毒物所等等；产品大都处于临床I期，品种数量及进展十分火爆。除了原创药物研发，国内多家药企如石药集团，福达制药、益生源药业、白云山医药、爱大制药均有PD仿制药上市。其中普拉克索在国内样本医院抗帕金森药市场占比达到43%，除了石药集团，还有其它14家国内药企提出盐酸普拉克索片/缓释片的上市申请，竞争十分激烈。随着我国人口老龄化加剧，PD作为老年性疾病随着年龄增大其发病率逐渐上升，病人身心健康受损严重，社会和家庭经济负担显著增大。预防PD的发生，开发有效的药物，延缓疾病进程，制定有效的治疗策略是减轻各项负担的最有效措施。虽然在临床开发的多个阶段中有很多治疗方法应用于PD，但将疾病改善治疗引入PD临床应用的过程仍然充满挑战。临床试验过程的改进可能会加快对疾病改善治疗和对症治疗的评估，国内制药企业对PD药物研发的热情高涨，我们期待着有更多的药物和疗法可用于PD患者。参考文献：1. McFarthing, Kevin et al. “Parkinson's Disease Drug Therapies in the Clinical Trial Pipeline: 2020.” Journal of Parkinson's diseasevol. 10,3 (2020): 757-774.2. Li G, Ma J, Cui S, et al. Parkinson’s disease in China: a forty-year growing track of bedside work[J]. Translational neurodegeneration, 2019, 8(1): 1-9.3.Lamonaca G,Volta M. Alpha-Synuclein and LRRK2 in Synaptic Autophagy: Linking EarlyDysfunction to Late-Stage Pathology in Parkinson’s Disease[J]. s, 2020,9(5): 1115.业务联系电话：010-61251566邮箱：tdcs@qianchengjx.com

上市批准临床3期临床2期

2023-06-24

·GlobeNewswire-Health Care

Enterin Presents Data Demonstrating Strong Benefit of ENT-03 on Body Weight, Adiposity and Blood Glucose Vs. Semaglutide in a Diet Induced Obesity Mouse Model

Data presented at the American Diabetes Association 83rd Scientific SessionsPHILADELPHIA, June 24, 2023 (GLOBE NEWSWIRE) -- Enterin Inc., a privately held, Philadelphia-based, clinical-stage biopharmaceutical company pioneering novel treatments for neurodegenerative and metabolic diseases, presented in vivo data demonstrating benefit on body weight, adiposity and blood glucose of ENT-03 compared to semaglutide in an obese, diabetic animal model, with persistence of benefit on weight beyond treatment. The data were presented at the American Diabetes Association’s (ADA) 83rd Scientific Sessions in San Diego. “ENT-03 differs profoundly from the GLP-1 agonists both with respect to its pharmacology and mechanism of action,” said Michael Zasloff, M.D., Ph.D., Scientific Director of the Medstar Georgetown Transplant Institute, Co-Founder and Chief Scientific Officer of Enterin and senior author of the paper. “We believe ENT-03 can add a new dimension to the management of Type 2 diabetes and obesity.” ENT-03 is a novel, endogenous, centrally acting mammalian aminosterol with Protein Tyrosine Phosphatase 1B (PTP1B) inhibitory activity, which normalizes glucose and causes weight loss by acting on brain circuits that regulate energy and metabolism. In obese, diabetic mice, ENT-03 rapidly lowers blood glucose, reduces food intake and adiposity, eliminates liver fat, and improves liver function. The study presented today compared the effects of subcutaneously administered ENT-03 to semaglutide on blood glucose, adiposity, and body weight over a 10-week treatment period in a diet-induced obesity (DIO) mouse model. Within one-to-two weeks of treatment with ENT-03, DIO mice exhibit a rapid and substantial fall in blood glucose, out of proportion to the loss of weight. In contrast, in semaglutide treated DIO mice, glucose falls in proportion to weight loss. Weight loss continues smoothly in the ENT-03 treatment group over the 10-week period, plateauing at lean body weight, and blood glucose remains in the normoglycemic range. In contrast, the effects of semaglutide on both weight loss and blood glucose begin to diminish between four and six weeks after initiation of treatment, since both body weight and blood glucose increase despite continued dosing. Within several days following the end of the 10-week treatment period, the semaglutide group exhibited a sharp rebound in food intake and body weight and by five weeks approached the body weight of the untreated obese mice. In contrast, ENT-03 treated animals maintained the lower weight and the reduced food intake, with no evidence of rebound in either. Body fat, which decreased significantly in both groups during treatment, increased at a faster rate in the semaglutide group post-treatment compared with the ENT-03 group. Results can be found online at www.enterininc.com and at https://diabetesjournals.org/diabetes/article/72/Supplement_1/854-P/149928/854-P-ENT-03-a-Centrally-Acting-Endogenous. “Weight loss during treatment with ENT-03 is progressive, profound and outlasts the treatment period for prolonged periods, which suggests that a neuroregenerative process might be taking place,” said Denise Barbut, M.D., F.R.C.P., Co-Founder, President, and Chief Medical Officer of Enterin and first author of the paper. Phase 1 studies in obese and diabetic subjects are currently in progress (IND155001). Results of the first-in-human, randomized, double-blind, single ascending dose study involving approximately 49 subjects with obesity with or without Type 2 diabetes are expected to be available in the fourth quarter of 2023. ENT-03 is Enterin’s second compound in clinical trials. The first compound, ENT-01, has completed a successful randomized Phase 2b study in patients with Parkinson’s disease (https://www.acpjournals.org/doi/10.7326/M22-1438). About Enterin Inc. Enterin Inc. is the first company to develop novel compounds that repair the dysfunctional gut-brain axis in patients with neurodegenerative diseases. Enterin Inc. is pioneering the medical community’s understanding of the link between infections, dysfunction of the enteric nervous system (ENS) and the onset and progression of neurodegenerative disease. Enterin’s lead compound, ENT-01, displaces membrane-bound alpha-synuclein (αS) aggregates from nerve cells in the ENS and improves neural signalling between the gut and the brain. Enterin Inc. has completed a large, randomized Phase 2b clinical trial in patients with Parkinson’s disease. The study met all the endpoints. Preparations for Phase 3 studies are currently underway. The second compound, ENT-03, increases insulin sensitivity by acting at the level of the brain. It is being developed for the treatment of diabetes, obesity, and Alzheimer’s disease. For more information, please visit www.enterininc.com. Company contact:Katherine WolfChief Financial Officerk.wolf@enterininc.com

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适应症	最高研发状态	国家/地区	公司	日期
便秘	临床2期	美国	Enterin, Inc.	2018-12-10
功能性便秘	临床2期	美国	Enterin, Inc.	2018-12-10
帕金森病	临床2期	美国	Enterin, Inc.	2018-12-10
帕金森病所致痴呆	临床1期	美国	Enterin, Inc.	2024-03-01
痴呆	临床1期	美国	Enterin, Inc.	-
精神障碍	临床1期	美国	Enterin, Inc.	-
多系统萎缩	临床申请	美国	Enterin, Inc.	2023-05-31
自闭症	临床前	美国	Enterin, Inc.	2025-04-01

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT04483479 (Rollover, CTgov)	临床2期	便秘 \| 帕金森病	27	Active Investigational Treatment ENT-01	鬱繭艱顧夢壓淵繭鏇製 = 淵餘鹽膚衊範艱壓夢糧遞窪鬱獵艱膚積壓襯夢 (積觸構廠觸選襯廠觸衊, 鑰選顧糧艱糧願簾簾夢 ~ 獵鹹顧鬱窪願構蓋鬱鹹) 更多	-	2024-03-19
NCT03781791 (KARMET, CTgov)	临床2期	功能性便秘 \| 便秘 \| 帕金森病	151	Active Investigational Treatment ENT-01 (Active Treatment)	鑰鏇壓蓋鑰繭鏇積製衊 = 顧範鹽壓鹹憲顧範願獵願衊鑰鹹築觸齋醖醖鏇 (窪襯糧構願蓋襯簾鬱築, 構觸願廠簾網獵鬱網蓋 ~ 鬱壓醖鏇憲鏇選淵網簾) 更多	-	2023-12-04
				Placebo Treatment (Placebo Treatment)	鑰鏇壓蓋鑰繭鏇積製衊 = 願築衊鹹獵遞網醖範鹽願衊鑰鹹築觸齋醖醖鏇 (窪襯糧構願蓋襯簾鬱築, 襯蓋願遞鏇築鹹獵選觸 ~ 艱齋憲鏇遞選顧憲艱餘) 更多
NCT03781791 (Pubmed)	临床2期	帕金森病	150	ENT-01	窪鬱遞淵壓構構獵簾憲(鹽齋蓋鏇範鏇獵廠襯鑰) = 鬱淵願襯齋艱襯壓積繭簾鏇積襯糧壓鏇顧襯夢 (壓獵糧獵積遞鬱遞願鬱 ) 更多	积极	2022-11-08
				Placebo	窪鬱遞淵壓構構獵簾憲(鹽齋蓋鏇範鏇獵廠襯鑰) = 齋齋壓觸憲鏇鏇製簾積簾鏇積襯糧壓鏇顧襯夢 (壓獵糧獵積遞鬱遞願鬱 ) 更多