A randomized, double-blind, placebo-controlled dose escalation study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of single (intravenous infusion) and multiple (continuous intravenous infusion over 7 days) doses of KNS366 in healthy adult participants

开始日期2023-01-10

申办/合作机构

Kynos Therapeutics Ltd.初创企业

100 项与 KNS-366 相关的临床结果

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100 项与 KNS-366 相关的转化医学

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100 项与 KNS-366 相关的专利（医药）

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项与 KNS-366 相关的文献（医药）

2024-12-01·Biochemical and Biophysical Research Communications

Maternal immune activation induces neurodevelopmental impairments of adult offspring through alterations in tryptophane-kynurenine pathway in the placenta

Article

作者: Mouri, Akihiro ; Saito, Kuniaki ; Fujigaki, Suwako ; Niijima, Moe ; Fujigaki, Hidetsugu ; Kunisawa, Kazuo ; Nabeshima, Toshitaka ; Hasegawa, Masaya ; Kim, Hyoung-Chun ; Yamamoto, Yasuko ; Teshigawara, Tomoaki ; Kubota, Hisayoshi

Maternal immune activation (MIA) is recognized as one of the significant environmental risk factors for neuropsychiatric disorders such as schizophrenia in adult offspring. However, the pathophysiological mechanisms remain unknown. The tryptophan (TRP)-kynurenine (KYN) pathway, influenced by inflammation, may be implicated in the pathophysiology of neuropsychiatric disorders. We investigated whether abnormal behaviors in adult offspring could be induced by MIA through alterations in the TRP-KYN pathway. MIA increased not only IL-6 expression in the placenta but also reactive oxygen species (ROS) levels in both the placenta and fetal brain and disrupted cortical layering in the fetal brain. We observed increased levels of 3-hydroxykynurenine (3-HK), a metabolite with oxidative stress properties, in both the placenta and fetal brain. In the knockout mice of kynurenine 3-monooxygenase (KMO), the enzyme responsible for 3-HK production, MIA failed to induce the abnormal behaviors in adult offspring. Notably, RO-618048, a KMO inhibitor that does not cross the blood-brain barrier (BBB), also blocked MIA-induced abnormal behaviors in adult offspring, reduced not only increased IL-6 expression in the placenta but also ROS levels in both the placenta and fetal brain, and prevented abnormal cortical development in the fetal brain. These findings suggest that MIA-induced abnormal behaviors in adult offspring may result from the increase in 3-HK levels through activation of KMO. Therefore, KMO is an attractive target for the prevention of neuropsychiatric disorders associated with MIA.

2024-05-01·Heliyon

Identification of potent inhibitors of kynurenine-3-monooxygenase from natural products: In silico and in vitro approaches

Article

作者: Toumi, Mohammed Esseddik ; Derardja, Imene ; Pérez-Sánchez, Horacio ; Boudah, Abdennacer ; Jasmin, Luc ; Carmena-Bargueño, Miguel ; Rebai, Redouane

Existing inhibitors of kynurenine-3-monooxygenase (KMO) have side effects and poorly cross the blood-brain barrier. Therefore, the discovery of new molecules targeting KMO isnecessary.This study aims to develop a novel therapeutic drug targeting KMO using computational methods and experimental validation of natural compounds.The results of our study show that the top four compounds, namely, 3'-Hydroxy-alpha-naphthoflavone exhibited the best docking scores with KMO (-10.0 kcal/mol), followed by 3'-Hydroxy-ss-naphthoflavone (-9.9 kcal/mol), genkwanin (-9.2 kcal/mol) and apigenin(-9.1 kcal/mol) respectively. Molecular dynamics was used to assess the stability of the primary target, KMO, and inhibitor complexes. We found stable interactions of 3'-Hydroxy-ss-naphthoflavone and apigenin with KMO up to 100 ns. Further, kinetic measurements showed that 3'-Hydroxy-alpha-naphthoflavone and 3'-Hydroxy-ss-naphthoflavone induce competitive inhibition with a good IC₅₀ activity (15.85 ± 0.98 μM and 18.71 ± 0.78, respectively), while Genkwanin and Apigenin exhibit non-competitive inhibition mechanism (21.61 ± 0.97 μM and 24.14 ± 1.00 μM, respectively).Drug-likeness features and ADME analysis features also showed that the top four compounds could be used as potential candidates to replace the synthetic KMO inhibitor drugs with known side effects and poor brain-blood barrier penetration.

2023-12-18·Angewandte Chemie International Edition

Pre‐intercalation of Ammonium Ions in Layered δ‐MnO₂ Nanosheets for High‐Performance Aqueous Zinc‐Ion Batteries

Article

作者: Zheng, Yaqi ; Yao, Haixin ; Lou, Xiong Wen David ; Yu, Le ; Yu, Huan ; Li, Nian Wu ; Luan, Deyan ; Li, Sheng

AbstractLayered manganese dioxide is a promising cathode candidate for aqueous Zn‐ion batteries. However, the narrow interlayer spacing, inferior intrinsic electronic conductivity and poor structural stability still limit its practical application. Herein, we report a two‐step strategy to incorporate ammonium ions into manganese dioxide (named as AMO) nanosheets as a cathode for boosted Zn ion storage. K+‐intercalated δ‐MnO2 nanosheets (KMO) grown on carbon cloth are chosen as the self‐involved precursor. Of note, ammonium ions could replace K+ ions via a facile hydrothermal reaction to enlarge the lattice space and form hydrogen‐bond networks. Compared with KMO, the structural stability and the ion transfer kinetics of the layered AMO are enhanced. As expected, the obtained AMO cathode exhibits remarkable electrochemical properties in terms of high reversible capacity, decent rate performance and superior cycling stability over 10000 cycles.

项与 KNS-366 相关的新闻（医药）

2024-05-01

·药明康德

基因疗法关键指标临床结果积极；治疗多种癌症，靶向5种KRAS突变的疫苗进入临床…… | 一周盘点

▎药明康德内容团队编辑本期看点1. 治疗杜氏肌营养不良的候选基因疗法GNT0004在1/2/3期临床试验中展现治疗潜力，治疗后第8周时最高有85%的肌纤维表达微肌营养不良蛋白，治疗后第12周时关键生物标志物肌酸磷酸激酶的水平下降了50%-87%。2. 治疗1型脊髓性肌萎缩症的基因疗法EXG001-307在给药后三个月就使患者的头部控制有所改善，11个月时患者无需外部辅助就能保持坐姿。3. 用于治疗抗精神病药引起的体重增加（AIWG）的候选疗法RDX-002能够使服用抗精神病药的患者的餐后甘油三酯降低约82%，并显著抑制其体重的增加。4. 靶向5种KRAS常见突变的治疗性癌症疫苗HB-700的IND申请获得了FDA的许可。药明康德内容团队整理GNT0004：公布1/2/3期临床试验的初步数据由Genethon与伦敦大学皇家霍洛威学院团队和巴黎肌肉研究所合作开发的候选基因疗法GNT0004的1/2/3期临床试验的初步数据积极。GNT0004是一种基于腺相关病毒8（AAV8）载体的基因疗法，含有一个缩短但功能正常的DMD基因（hMD1），编码杜氏肌营养不良患者缺乏的蛋白质——肌营养不良蛋白。hMD1转基因由Spc5.11启动子驱动，可在骨骼肌和心肌等关键组织中表达。截至目前，已有5名年龄在6至10岁之间的患者接受了GNT0004治疗，其中2名患者接受了第一剂量水平的治疗，3名患者接受了第二剂量水平的治疗。初步的安全性和药效学结果表明，GNT0004与免疫预防治疗相结合具有良好的耐受性，在微肌营养不良蛋白表达和功能改善方面也有疗效。接受第二剂量水平的患者在注射GNT0004后的第8周时，免疫组化检测结果显示，最高有85%的肌纤维表达微肌营养不良蛋白（平均54%；范围15%-85%），并重建了肌营养不良蛋白相关蛋白质复合体。这种表达与每个肌纤维核中的转基因拷贝数量显著相关，最高可达2.4（平均1.2；范围0.4-2.4）。治疗后第12周时，患者肌肉损伤的生物标志物肌酸磷酸激酶的水平下降了50%-87%（平均74%）。此外，队列2中首位患者的一年疗效结果积极，NorthStar门诊评估量表（NSAA）得分明显改善，其他功能评估（10米步行测试和起立能力）也呈现出积极的趋势。EXG001-037：公布1/2期临床试验的初步数据Exegenesis Bio公司公布了其用于治疗1型脊髓性肌萎缩症的重组AAV基因疗法EXG001-307的1/2期临床试验的疗效和安全性数据。EXG001-307具有独特的AAV设计，包括一个新颖的pro-NS启动子，与目前可用的基因疗法相比，可在目标脊髓组织中实现高表达，并减少在肝脏和心脏这类非目标组织中的表达。此次公布的结果显示，EXG001-307低剂量组患者在用药3至6个月后实现了头部控制，在用药11个月后无需外部辅助即可保持坐姿。中剂量组中的首位患者在用药3个月后就能在辅助下保持坐姿。安全性方面，EXG001-307具有高耐受性，无剂量限制性毒性，无>2级试验品相关严重不良事件，无>1级转氨酶或心肌酶升高。RDX-002：公布1b期临床试验数据Response Pharmaceuticals公司公布了其用于治疗抗精神病药引起的体重增加的潜在“first-in-class”候选疗法RDX-002的1b期临床试验的初步结果。RDX-002是一种强效、选择性和肠道特异性的小分子甘油三酯微粒体转移蛋白（MTP）抑制剂，旨在降低餐后体内甘油三酯和胆固醇的含量。RDX-002正在开发中，可作为服用非典型抗精神病药物患者的辅助治疗药物，也可作为临床上体重增加和/或不良代谢变化普遍存在的其他情况下的潜在治疗药物。此次公布的结果显示，在为期两周的开放标签试验中，RDX-002队列中的受试者达到了主要疗效终点，即餐后甘油三酯有所降低。接受奥氮平（一种与AIWG相关的高效抗精神病药物）治疗的受试者在第8天时与第1天相比，餐后甘油三酯的平均AUC增加了54%（p=0.009），并在第15天保持升高。而奥氮平+RDX-002治疗组在第15天时与第8天相比，餐后甘油三酯的平均AUC下降了81.6%（p<0.001）。此外，接受奥氮平单药治疗的受试者在治疗的第一周和第二周体重明显增加，而接受奥氮平+RDX-002治疗的患者在第二周时体重没有明显变化。安全性方面，RDX-002的耐受性良好，不良反应主要限于轻度至中度消化道反应，研究期间没有发生严重不良反应或与治疗相关的停药。HB-700：IND申请获得FDA许可HOOKIPA Pharma公司宣布，其用于治疗KRAS突变癌症的新型治疗性疫苗HB-700的IND申请已获得美国FDA的许可。HB-700旨在通过靶向这些疾病中最常见的五种KRAS突变（G12D、G12V、G12R、G12C和G13D），治疗KRAS突变的肺癌、结直肠癌、胰腺癌和其他癌症。与单一突变抑制剂相比，该候选疫苗有望使更多患者受益。RB-ADSC：1期临床试验完成首例患者输注Regeneration Biomedical公司宣布，其用于治疗轻度至中度阿尔茨海默病患者的自体Wnt激活脂肪来源干细胞（RB-ADSC）的1期临床试验已完成首例患者输注。RB-ADSC是Wnt激活的脂肪源性干细胞，取自患者自身的脂肪组织。采集后，干细胞在体外进行培养和扩增，筛选出Wnt表达的干细胞，然后通过植入位于头皮下，可直接进入大脑的一个侧脑室的Ommaya储存器重新输回患者体内。在两种动物模型中的研究结果表明，注入脑室系统的干细胞会自行分布到大脑实质中。此外，没有观察到炎症、脑脊液循环受阻或其他安全信号。VCN-01：公布1期临床试验数据Theriva Biologics公司公布了其在研溶瘤腺病毒疗法VCN-01在眼内视网膜母细胞瘤患者（9人）中进行两次玻璃体内注射的安全性和耐受性。VCN-01是一种溶瘤腺病毒，旨在选择性地在肿瘤细胞内积极复制，并降解肿瘤基质（一种在癌症治疗中重要的物理和免疫抑制屏障）。此次公布的结果显示，玻璃体内注射VCN-01显示出良好的抗肿瘤活性，似乎不会改变视网膜功能。4名患者的症状有明显改善。截至目前，3名患者避免了眼球摘除术，其中一名患者的眼球在随访4年后仍得以保留。安全性方面，VCN-01玻璃体内给药的耐受性良好，最常报告的治疗相关不良反应为1级或2级。在评估期间，没有出现剂量限制性毒性反应，也没有出现≥3级的眼部或全身毒性反应。注射VCN-01后观察到一定程度的眼部炎症和相关浑浊。通过局部和全身使用抗炎药物，炎症能够得到控制，玻璃体混浊在某些情况下也能够得到改善。ONC-841：IND申请获得FDA许可OncoC4公司宣布，美国FDA已经批准了其用于治疗实体瘤的SIGLEC 10阻断抗体ONC-841的IND申请。SIGLEC 10是一种免疫检查点，可抑制先天性和适应性免疫细胞的激活。ONC-841通过抑制SIGLEC 10，阻止癌细胞的免疫逃逸。支持IND申请的临床前研究表明，ONC-841能改善肿瘤浸润T细胞的功能，增强对癌细胞的吞噬能力。其他体内和异种移植肿瘤模型显示，使用ONC-841治疗后，对癌细胞的免疫排斥反应增强了。ONC-841单药治疗的安全性、药代动力学和临床活性的1期临床试验的初步数据预计将于2025年下半年公布。ALTO-101：公布1期临床试验数据Alto Neuroscience公司公布了其用于治疗精神分裂症相关认知障碍（CIAS）的新型PDE4抑制剂ALTO-101的1期研究的积极结果。ALTO-101采用专有的透皮给药（transdermal formulation）系统，旨在提供稳定的浓度，以提高药物的安全性、耐受性和药代动力学。在1期临床试验中，ALTO-101表现出了脑渗透性、强大的中枢神经系统相关的药效学效应，并且在治疗相关剂量范围内耐受性良好。此次公布的研究结果表明，与口服给药相比，ALTO-101通过透皮给药系统给药时具有良好的耐受性和更好的药代动力学。透皮制剂的药物暴露水平明显高于口服给药的全身暴露水平，并且透皮制剂的血浆浓度在服药后的第2天（24-48小时）内依然保持稳定。此外，透皮制剂大大降低了通常与PDE4抑制剂相关的不良反应。接受口服给药的患者有40%出现了头晕，并有20%的患者出现了恶心，而接受透皮给药的患者只有7.1%出现了头晕，没有患者出现恶心。该公司计划在2024年上半年启动一项概念验证研究，评估ALTO-101在CIAS患者中的疗效，预计在2025年下半年获得初步数据。 ▲ALTO-101口服制剂和透皮制剂的药代动力学曲线（图片来源：参考资料[11]）KNS366：公布1期临床试验数据Kynos Therapeutics公司公布了其用于治疗急性和慢性炎症性疾病的小分子犬尿氨-3-单加氧酶（KMO）抑制剂KNS366的积极1期临床试验数据。KMO是一种在色氨酸代谢的犬尿氨酸途径中起关键作用的酶，能将犬尿氨酸转化为3-HK。通过抑制KMO的活性，KNS366可降低升高的3-HK，从而防止炎症期间出现的过度的组织损伤和免疫系统失调。此次公布的结果显示，所有剂量的KNS366都是安全的，而且该分子显示出极佳的耐受性。药效学指标清楚地表明，KNS366是一种强效的KMO酶抑制剂，代谢产物3-HK的大幅减少证明了它具有很强的抑制作用。▲欲了解更多前沿技术在生物医药产业中的应用，请长按扫描上方二维码，即可访问“药明直播间”，观看相关话题的直播讨论与精彩回放参考资料（可上下滑动查看）[1] Ocugen Announces Dosing Completion of Subjects with Geographic Atrophy in Cohort 2 of Phase 1/2 ArMaDa Clinical Trial of OCU410—A Modifier Gene Therapy. Retrieved April 22, 2024, from https://www.globenewswire.com/news-release/2024/04/19/2866086/0/en/Ocugen-Announces-Dosing-Completion-of-Subjects-with-Geographic-Atrophy-in-Cohort-2-of-Phase-1-2-ArMaDa-Clinical-Trial-of-OCU410-A-Modifier-Gene-Therapy.html[2] GC녹십자, ‘산필리포증후군’ 약물 “美 IND 신청” . Retrieved April 24, 2024, from http://www.biospectator.com/view/news_view.php?varAtcId=21741[3] Kynos Therapeutics announces positive top-line results from the first-in-human Phase I study of its KMO inhibitor, KNS366, demonstrating safety, tolerability and target engagement. Retrieved April 24, 2024, from https://www.globenewswire.com/news-release/2024/04/22/2866623/0/en/Kynos-Therapeutics-announces-positive-top-line-results-from-the-first-in-human-Phase-I-study-of-its-KMO-inhibitor-KNS366-demonstrating-safety-tolerability-and-target-engagement.html[4] Krystal Biotech Announces First Patient Dosed in Phase 1 Clinical Trial of Inhaled KB707 for the Treatment of Locally Advanced or Metastatic Solid Tumors of the Lung. Retrieved April 24, 2024, from https://ir.krystalbio.com/news-releases/news-release-details/krystal-biotech-announces-first-patient-dosed-phase-1-clinical-0[5] Centessa Pharmaceuticals Announces Open IND for ORX750; Proof-of-Concept Data in Sleep-Deprived Healthy Volunteers Planned for 2H 2024. Retrieved April 24, 2024, from https://investors.centessa.com/news-releases/news-release-details/centessa-pharmaceuticals-announces-open-ind-orx750-proof-concept[6] Enlivex Announces Dosing of First Two Patients in its Randomized, Controlled Phase I/II Trial Evaluating Allocetra™ in Patients with Knee Osteoarthritis. Retrieved April 24, 2024, from https://www.globenewswire.com/en/news-release/2024/04/22/2866825/0/en/Enlivex-Announces-Dosing-of-First-Two-Patients-in-its-Randomized-Controlled-Phase-I-II-Trial-Evaluating-Allocetra-in-Patients-with-Knee-Osteoarthritis.html[7] Neurogene Announces Upcoming Presentation of Safety Data from Phase 1/2 Trial of NGN-401 Gene Therapy for Rett Syndrome at ASGCT Meeting. Retrieved April 24, 2024, from https://www.businesswire.com/news/home/20240422214954/en[8] Response Pharmaceuticals’ Drug Candidate for the Treatment of Antipsychotic-Induced Weight Gain (AIWG) Achieves Primary Endpoint in Phase 1b Clinical Trial. Retrieved April 24, 2024, from https://www.businesswire.com/news/home/20240423868454/en[9] Theriva™ Biologics Announces Positive Topline Data from Investigator Sponsored Phase 1 Trial of Intravitreal VCN-01 in Pediatric Patients with Refractory Retinoblastoma. Retrieved April 24, 2024, from https://www.globenewswire.com/news-release/2024/04/23/2867520/0/en/Theriva-Biologics-Announces-Positive-Topline-Data-from-Investigator-Sponsored-Phase-1-Trial-of-Intravitreal-VCN-01-in-Pediatric-Patients-with-Refractory-Retinoblastoma.html[10] OncoC4 Announces FDA Clearance of IND Application for Novel SIGLEC 10 Immune Checkpoint Inhibitor ONC-841 for Solid Tumors. Retrieved April 24, 2024, from https://www.globenewswire.com/news-release/2024/04/23/2867588/0/en/OncoC4-Announces-FDA-Clearance-of-IND-Application-for-Novel-SIGLEC-10-Immune-Checkpoint-Inhibitor-ONC-841-for-Solid-Tumors.html[11] Alto Neuroscience Announces Positive Phase 1 Results for ALTO-101, a Novel PDE4 Inhibitor in Development for Schizophrenia. Retrieved April 24, 2024, from https://www.businesswire.com/news/home/20240423861340/en[12] Regeneration Biomedical Doses First Patient in a First-in-Human Phase I Clinical Trial of Stem Cell Therapy delivered directly into the brain of Patients with Alzheimer’s Disease. Retrieved April 24, 2024, from https://pipelinereview.com/regeneration-biomedical-doses-first-patient-in-a-first-in-human-phase-i-clinical-trial-of-stem-cell-therapy-delivered-directly-into-the-brain-of-patients-with-alzheimers-disease/[13] ITM, Helmholtz Munich and University Hospital Münster Announce First Patient Dosed in Phase I Investigator-Initiated Glioblastoma Trial. Retrieved April 24, 2024, from https://www.globenewswire.com/news-release/2024/04/23/2867438/0/en/ITM-Helmholtz-Munich-and-University-Hospital-M%C3%BCnster-Announce-First-Patient-Dosed-in-Phase-I-Investigator-Initiated-Glioblastoma-Trial.html[14] First Clinical Trial Results of Gene Therapy (GNT0004) for Duchenne Muscular Dystrophy Presented at International Myology 2024 Congress. Retrieved April 24, 2024, from https://www.businesswire.com/news/home/20240423774806/en[15] HOOKIPA Pharma Announces FDA Clearance of its Investigational New Drug Application for HB-700 for the Treatment of KRAS-Mutated Cancers. Retrieved April 24, 2024, from https://www.globenewswire.com/news-release/2024/04/24/2868480/0/en/HOOKIPA-Pharma-Announces-FDA-Clearance-of-its-Investigational-New-Drug-Application-for-HB-700-for-the-Treatment-of-KRAS-Mutated-Cancers.html[16] Gain Therapeutics Announces Positive Results from the Single Ascending Dose (SAD) Part of the Phase 1 Clinical Trial of GT-02287, a Novel GCase-Targeting Small Molecule Therapy for GBA1 Parkinson’s Disease. Retrieved April 24, 2024, from https://www.globenewswire.com/news-release/2024/04/24/2868696/0/en/Gain-Therapeutics-Announces-Positive-Results-from-the-Single-Ascending-Dose-SAD-Part-of-the-Phase-1-Clinical-Trial-of-GT-02287-a-Novel-GCase-Targeting-Small-Molecule-Therapy-for-GB.html[17] Arrowhead Pharmaceuticals Initiates Phase 1/2a Study of ARO-CFB for Treatment of Complement Mediated Kidney Disease. Retrieved April 24, 2024, from https://www.businesswire.com/news/home/20240424663343/en[18] Hanmi Enters into Clinical Trial Collaboration and Supply Agreement with MSD to Evaluate BH3120 in Combination with KEYTRUDA® (pembrolizumab). Retrieved April 24, 2024, from https://www.prnewswire.com/news-releases/hanmi-enters-into-clinical-trial-collaboration-and-supply-agreement-with-msd-to-evaluate-bh3120-in-combination-with-keytruda-pembrolizumab-302125355.html[19] Insilico Medicine receives IND approval from FDA for novel MAT2A inhibitor ISM3412. Retrieved April 24, 2024, from https://www.eurekalert.org/news-releases/1042535[20] PEP-Therapy and Institut Curie Announce First Patients Dosed in Phase Ib Clinical Trial Evaluating PEP-010 in Ovarian and Pancreatic Cancers. Retrieved April 24, 2024, from extension://emelgiiiemoiljnmikcgbmjkapalgcme/assets/pdf-viewer/web/viewer.html?file=https%3A%2F%2Fpep-therapy.com%2Fwp-content%2Fuploads%2F2024%2F04%2F20240417-PR-First-patients-Phase-Ib-vf.pdf[21] Exegenesis Bio to Present 9-Patient Data from a Phase 1/2 Clinical Trial of EXG001-307, a Novel rAAV Gene Therapy for Spinal Muscular Atrophy (SMA) Type 1: Improved Head Control and Sitting Without External Assistance. Retrieved April 24, 2024, from https://www.businesswire.com/news/home/20240425546173/en/免责声明：药明康德内容团队专注介绍全球生物医药健康研究进展。本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。版权说明：本文来自药明康德内容团队，欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。转载授权请在「药明康德」微信公众号回复“转载”，获取转载须知。分享，点赞，在看，聚焦全球生物医药健康创新

基因疗法临床申请临床结果临床研究疫苗

2024-04-22

·BioSpace

Kynos Therapeutics announces positive top-line results from the first-in-human Phase I study of its KMO inhibitor, KNS366, demonstrating safety, tolerability and target engagement

EDINBURGH, United Kingdom, April 22, 2024 (GLOBE NEWSWIRE) -- Kynos Therapeutics Ltd, a clinical-stage biotechnology company developing first-in-class small molecule kynurenine 3-monooxygenase (KMO) inhibitors for acute and chronic inflammatory disorders, today announces the key findings from the first-in-human Phase I trial of its lead drug candidate, KNS366. KMO is an enzyme that acts at a key point in the kynurenine pathway of tryptophan metabolism, converting kynurenine into 3-hydroxykynurenine (3-HK). By inhibiting KMO activity, KNS366 is designed to reduce elevated 3-HK in order to prevent excess tissue damage and dysregulation of the immune system occurring during inflammation. The Phase I study of KNS366 was a randomized, double-blind, placebo-controlled dose escalation study evaluating the safety, tolerability, pharmacokinetics, and pharmacodynamics of single and multiple doses of KNS366 in healthy adult participants. During the multiple dose part, KNS366 was administered over seven days. All doses of KNS366 were safe and the molecule showed excellent tolerability. Pharmacodynamic measures clearly demonstrated KNS366 is a potent inhibitor of the KMO enzyme, with a high level of inhibition achieved as demonstrated by a substantial reduction in the enzyme product 3-HK. Kynos Therapeutics founder and CSO Damian Mole said, “The headline data from this Phase I study have demonstrated KNS366 is safe and well tolerated at exposures that resulted in a high level of KMO enzyme inhibition. Information from the study, including pharmacodynamic measures, enables the selection of doses for future clinical studies in patients. To our knowledge, this is the first time a KMO inhibitor has been administered across multiple days resulting in sustained KMO inhibition in humans. We are, therefore, also able to generate information on the biological pathways impacted by this mechanism in humans, through an ongoing exploratory biomarker analysis as a valuable tool to inform further clinical development.” Kynos Therapeutics CEO Jonathan Savidge said, “The successful completion of this Phase I study is a significant milestone for Kynos and the results provide an excellent basis for further development of KNS366. The full analysis of the wealth of data from the study will generate invaluable information on this first-in-class mechanism to enable optimization of the further clinical development pathway. We appreciate the funding contribution from Innovate UK to conduct this important clinical trial.” About Kynos Therapeutics – Kynos Therapeutics is a clinical-stage private company developing an innovative pipeline of first-in-class kynurenine 3-monooxygenase (KMO) inhibitors. KMO plays a major role in the regulation of inflammation, acting at the interface between inflammation, immunity and metabolism, and inhibition of KMO has therapeutic potential in both acute inflammatory conditions such as acute kidney injury and acute pancreatitis and in chronic immuno-inflammatory disorders. Spun out from the University of Edinburgh, Kynos leverages a decade of drug discovery research on KMO inhibitors originally co-developed through a collaboration between GSK and the University of Edinburgh and now exclusively licensed to Kynos. Based in Edinburgh, UK, the company is backed by founding investor Epidarex Capital as well as IP Group plc and Scottish Enterprise with additional non-dilutive funding from Innovate UK. Follow us on LinkedIn - For further information please contact: At the Company Jonathan Savidge, CEO, Kynos Therapeutics E: admin@kynostx.com Media enquiries: Sue Charles, Charles Consultants T: +44 (0)7968 726585 E: sue@charles-consultants.com

临床1期

2024-04-22

·Outsourcing Pharma

Edinburgh's Kynos Therapeutics reveals significant findings from trial of leading drug candidate

The company has unveiled significant findings from its first-in-human phase 1 trial of KNS366, its leading drug candidate. The trial focused on assessing the safety, tolerability, pharmacokinetics, and pharmacodynamics of single and multiple doses of KNS366 in healthy adult participants. KMO, an enzyme pivotal in the kynurenine pathway of tryptophan metabolism, plays a crucial role in converting kynurenine into 3-hydroxykynurenine (3-HK). By inhibiting KMO activity, KNS366 aims to mitigate elevated 3-HK levels, thereby averting excessive tissue damage and immune system dysregulation during inflammation. According to the results, all doses of KNS366 were deemed safe and exhibited excellent tolerability. Moreover, pharmacodynamic measures showcased KNS366's potency as a KMO enzyme inhibitor, with a notable reduction in the enzyme product 3-HK. Dr. Damian Mole, is the founder and chief scientific officer (CSO) of Kynos Therapeutics, told OSP about the significance of the phase 1 data. He said: “The headline data from this phase I study have demonstrated KNS366 is safe and well tolerated at exposures that resulted in a high level of KMO enzyme inhibition. Information from the study, including pharmacodynamic measures, enables the selection of doses for future clinical studies in patients.” Kynos says this phase 1 trial represents a crucial step forward in advancing KNS366 as a potential therapeutic option for inflammatory disorders. With promising safety and efficacy profiles, KNS366 holds promise for future clinical studies aimed at addressing unmet medical needs in patients with acute and chronic inflammatory conditions. googletag.cmd.push(function () { googletag.display('text-ad1'); }); Jonathan Savidge, CEO of Kynos Therapeutics, is optimistic about the trial's outcomes: He said: “The successful completion of this Phase I study is a significant milestone for Kynos and the results provide an excellent basis for further development of KNS366. The full analysis of the wealth of data from the study will generate invaluable information on this first-in-class mechanism to enable the optimization of the further clinical development pathway. We appreciate the funding contribution from Innovate UK to conduct this important clinical trial.” Manifesting across various bodily systems, chronic inflammatory diseases encompass afflictions affecting the digestive system, joints, skin, respiratory tract, and internal organs. While these conditions lack a definitive cure, treatment strategies typically involve the administration of nonsteroidal anti-inflammatory drugs (NSAIDs), disease-modifying antirheumatic drugs (DMARDs), and lifestyle interventions. Although incurable, effective management of symptoms and complications through tailored treatment regimens remains pivotal in enhancing the quality of life for individuals grappling with chronic inflammatory diseases. Chronic inflammatory diseases encompass a diverse array of conditions characterized by persistent inflammation within the body. These diseases can extend their reach beyond localized inflammation to affect vital organs, including segments of the digestive tract, the cardiovascular system, and the respiratory system. Certain inflammatory disorders, such as specific forms of arthritis, may manifest with additional complications, including vision impairment.

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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


ASN2019	N/A	肾移植排斥反应 Kynurenine 3-monooxygenase (KMO) \| indoleamine 2,3-dioxygenase (IDO)	-	Kynurenine 3-Monooxygenase	構範選願製醖蓋獵獵鏇(蓋膚顧艱壓憲廠夢餘廠) = The addition of 3HK completely restored E-cadherin and TJP1 expression 繭遞積鹹餘鏇襯製製網 (餘鬱醖獵鹹積鏇鹹夢範 ) 更多	积极	2019-11-05
ASN2018	N/A	肾移植排斥反应 IDO \| KYnurinase \| KYamiotransferase II ... 更多	-	Kynurenine 3-Monooxygenase	齋艱鏇憲膚餘鑰餘淵廠(遞鑰顧窪範鬱繭簾膚鑰) = 3HK inhibited proliferation of active Tcells and promoted Tcell injury and death. The same and higher concentrations of 3HK had no effect on cortical Epi and Endo cells 範願鹽鹹鹽製艱顧襯顧 (鑰糧範鹹鹹構簾範繭獵 )	积极	2018-10-23
ASN2018	N/A	肾移植排斥反应 IDO \| KYnurinase \| KYamiotransferase II ... 更多	-	Kynurenine 3-Monooxygenase		积极	2018-10-23