Genovate Biotechnology Co., Ltd.

TAIPEI, May 28, 2024 /PRNewswire/ -- Genovate Biotechnology Co., Ltd. (TPEx: 4130), a Taiwan-based specialty pharmaceutical company, today announced its plans to submit a New Drug Application (NDA) with the United States Food and Drug Administration (US FDA) for PMR, an investigational once daily extended-release form of cilostazol for the treatment of Intermittent Claudication, in the second half of 2025. In the written responses to the pre-NDA meeting package, the FDA confirmed that the clinical studies conducted are sufficient to support the submission of a marketing application under the 505(b)(2) regulatory pathway. The key study in the submission package, GBL23-001 (NCT06167265), is a randomized, fully replicate crossover study designed to evaluate the bioequivalence and within-subject variability between PMR 145 mg once daily and the immediate-release tablet of cilostazol 100 mg twice daily. This study is expected to be completed in mid-2024, and the top-line results have shown that the primary endpoints of the study were achieved, and the decision to submit the application was made following the successful outcome of study GBL23-001. Furthermore, Genovate has been improving the PMR formulation and its manufacturing processes in order to address additional FDA comments. All clinical study and manufacturing data are expected to be included in the final submission package. "We are pleased to share what we believe is an efficient regulatory pathway for PMR with the goal of bringing a new treatment option to the people who suffer from intermittent claudication and recurrence of cerebral infarction, from the US to the globe." said Chia-Chen Chu, General Manager of Genovate. About PMR (Cilostazol Extended-Release Tablets) PMR, a novel extended-release (ER) formulation of cilostazol, was designed to reduce the concentration-dependent side effects associated with immediate-release (IR) tablet form of cilostazol. Cilostazol is currently available in IR tablet form at 50 and 100 mg strengths administered twice daily. The IR formulation of cilostazol, marketed as Pletal® in the US (Pletaal® in Taiwan and other Asian countries), was first available in Japan in 1988 for the treatment of peripheral arterial diseases and the prevention of recurrence of cerebral infarction and later approved by the US FDA in 1999 for the treatment of intermittent claudication (IC). Cilostazol is a specific PDE III inhibitor that can cause reduced platelet aggregation and increased vasodilatation. Cilostazol showed good efficacy in preventing secondary strokes, notably reducing the rates of ischaemic stroke recurrence. Nevertheless, the results from eight placebo-controlled clinical trials indicated that 15.4% of patients withdrawn from cilostazol treatment were as a result of adverse reactions. Headache, palpitations, and diarrhea were the most frequently reported adverse reactions among these patients. These adverse reactions were attributable to the peak concentration of cilostazol. Genovate is developing an ER tablet form of cilostazol, PMR, to be administered once daily aiming to improve adherence and to reduce the side effects associated with the high peak-to-trough variation of the concentration of cilostazol IR. About Intermittent Claudication Peripheral arterial disease (PAD) affects over 200 million people globally and around 8.5 million Americans over the age of 40. PAD occurs as a result of the narrowing or blockade of blood vessels that carry blood from the heart to the legs. The main symptom of PAD observed in approximately 70% of patients is intermittent claudication (IC), a condition that presents as pain and cramping in the lower extremities (thigh, calf, hip and buttock muscles), as a result of limited blood flow. IC is commonly viewed as a signal of substantial atherosclerosis, suggesting a higher likelihood of heart attack or stroke. The symptoms of IC are intermittent, exacerbated when walking or during exercise, and are alleviated with rest, but reoccur when activity resume; as a result, IC can be very debilitating, drastically affecting the quality of life of those affected. In severe cases, IC may require surgical intervention, but in general, it can be treated and managed with a combinational approach including medication, life style changes that modify or eliminate risk factors, and exercise program. Drugs improving blood flow such as anti-clotting agents (aspirin), anti-hypertensives, statins, and phosphodiesterase (PDE) III inhibitors such as cilostazol are currently used to treat IC. About Genovate Biotechnology Co., Ltd. Genovate Biotechnology Co., Ltd. is a Taiwan-based, fully integrated specialty pharmaceutical company focusing on the new drug development in new formulation, new active ingredient, new treatment modality in cardiovascular, autoimmune, neurodegenerative, and liver diseases. Genovate is equipped with PIC/S GMP manufacturing, marketing, and distribution capabilities. Forward-Looking Statements All statements other than statements of historical facts contained in this press release are forward-looking statements, including statements regarding the timing of any regulatory process or ultimate approvals for PMR for the treatment of IC. These forward-looking statements speak only as of the date of this press release and are subject to a number of risks, uncertainties and assumptions, including the risks and uncertainties associated with the projected timeline of our NDA submission, whether FDA will agree with our interpretation of the data or the adequacy of data to support an NDA, the FDA's review of our NDA, market conditions, as well as risks and uncertainties inherent in Genovate's business. The events and circumstances reflected in the company's forward-looking statements may not be achieved or occur and actual results could differ materially from those projected in the forward-looking statements. Except as required by applicable law, the company does not plan to publicly update or revise any forward-looking statements contained herein, whether as a result of any new information, future events, changed circumstances or otherwise. SOURCE Genovate Biotech

2023年1月31日（北京时间），由复旦大学基础医学院王明伟、中国科学院上海药物研究所柳红和杨德华领衔的合作团队在Nature Communications在线发表了题为“Ligand recognition mechanism of the human relaxin family peptide receptor 4 (RXFP4)”的研究论文。该论文首次报道了人源松弛素/胰岛素样肽受体4（Relaxin family peptide receptor 4, RXFP4）分别结合内源性配体胰岛素样肽5（Insulin-like peptide 5, INSL5）、小分子RXFP4/RXFP3双激动剂Compound 4及小分子RXFP4选择性激动剂DC591053并与Gi蛋白形成复合物的高分辨率冷冻电镜结构，不仅阐明了INSL5独特的受体识别模式，而且揭示了Compound 4拟肽作用的关键位点和DC591053受体亚型选择性的分子机制。RXFP4为A类G蛋白偶联受体（G protein-coupled receptor, GPCR），2003年首见于人类基因组数据库1，2005年被证实为INSL5的内源性受体2。INSL5属于松弛素/胰岛素超家族，1999年Conklin等人在研究该超家族保守的B链半胱氨酸基序（Motif）时，通过检索人类表达序列标签（Expressed sequence tags, EST）数据库而被发现3，二者均高表达于结直肠组织。2015年，王明伟课题组通过对RXFP4的多年研究发现其配体INSL5既可促进小鼠胰岛瘤细胞MIN-6分泌胰岛素，又可提高小鼠肠系L细胞GLUTag释放胰高血糖素样肽-1（Glucagon-like peptide-1, GLP-1）的能力；动物实验亦证实INSL5可改善小鼠的血糖稳态4。此外，INSL5/RXFP4还参与调控能量代谢、食欲调节和肠道蠕动等生理功能5。由于INSL5是由A链和B链通过3个二硫键连接的多肽，化学合成非常困难；现有小分子配体数量稀少，诺华公司报道的Compounds 1、2、3和4均为RXFP4/RXFP3双激动剂6，特异性低，从而限制了对RXFP4生物效应的深入研究和相关新药的发现。2020年，王明伟/杨德华团队通过高通量筛选获得了特异性靶向RXFP4的小分子化合物JK17，并在此基础上经过结构优化改造得到了靶点特异性更佳的激动剂9-(S)-14b8。遗憾的是，上述两个化合物都存在活性弱、毒性大和溶解不易等问题。参与本论文研究的国际合作团队在利用大肠杆菌表达、高密度发酵和专有蛋白纯化技术批量生产INSL5的同时，通过化合物筛选和基于四氢异喹啉母核的结构优化改造，发现了非肽类RXFP4选择性激动剂DC591053（pEC50 = 7.24 ± 0.12），且在NanoBiT系连技术9的助推下获得了分别与上述三种不同配体结合、颗粒均一和性状稳定的 RXFP4–Gi蛋白复合物。他们借助中国科学院上海药物研究所的300 kV冷冻电镜所拍摄的清晰图像和后继单颗粒三维重构，成功解析了分辨率各自为3.19 Å、3.03 Å和2.75 Å的INSL5–RXFP4–Gi、Compound 4–RXFP4–Gi及DC591053–RXFP4–Gi三个复合物的分子结构（图1）。图1. RXFP4–Gi分别结合INSL5、Compound 4和DC591053的冷冻电镜结构。a，INSL5–RXFP4–Gi复合物结构；b，Compound 4–RXFP4–Gi复合物结构及Compound 4的化学结构；c，DC591053–RXFP4–Gi复合物结构及DC591053的化学结构。研究显示，RXFP4识别INSL5的方式不同于已报道的A类GPCR：INSL5 B链羧基末端的α-螺旋深入受体跨膜域（Transmembrane domain, TMD），而A链则覆盖正构位点从而维持配体的完整性和结构稳定性。特别是B链羧基末端的R23B与RXPF4上的E1002.63（右上标数字为Ballesteros–Weinstein编号10，用于确定TMD氨基酸的相对位置）形成盐桥，而W24B除了与T1213.32、Q2055.39和R2085.42等残基形成众多极性作用网络外，亦可与W972.60及H2997.43发生与受体激活密切关联的堆叠效应（图2）。人为突变E1002.63、T1213.32和R2085.42导致INSL5完全失活，破坏W972.60、Q2055.39和H2997.43等残基也不同程度地影响了RXFP4的活化。图2. RXFP4识别INSL5的结构基础。a，INSL5与RXFP4结合的整体示意图；b，INSL5的B链羧基末端R23B和W24B深入RXFP4的正构位点并形成多个极性相互作用；c-e，RXFP4胞外环参与INSL5的识别。非选择性激动剂Compound 4也能深入RXFP4的结合口袋，其胍基模拟INSL5的B链R23B与RXFP4上的E1002.63形成盐桥，而吲哚母核则模拟W24B的吲哚环与周围残基形成广泛的相互作用；该小分子配体对RXFP4的激活能力在发生W972.60、E1002.63、T1213.32与H2997.43等残基的突变后显著降低（图3a-b）。然而，选择性激动剂DC591053则展现与Compound 4迥异的结合方式，其马琳环占据RXFP4独特的配体结合口袋（图3c-d），在3.29、3.33、5.39、5.42和7.39等位点上（Ballesteros–Weinstein编号10）与RXFP3的氨基酸差异明显，与亚型选择性相关（图3e）。这个发现得到了功能性实验数据的支持：置换RXFP3和RXFP4上述同源位点的氨基酸，Compound 4对RXFP4突变体L1183.29S+V1223.33S的作用没有显著变化，但DC591053的效价却降低20.9倍；较之Compound 4，DC591053激活Q2055.39H和R2085.42K等RXFP4突变体的能力也受到更大影响。可以预期，这项成果将有助于深入研究RXFP4的生理功能和开发高效的的选择性RXFP4小分子激动剂，同时也有望提升人们对胰岛素超家族成员多元识别相关受体的认识。 图3. 小分子激动剂的拟肽作用及和DC591053选择性激活RXFP4的分子机制。a，Compound 4的结合口袋截面图；b，Compound 4与RXFP4的相互作用；c，DC591053特异性激活RXFP4；d，DC591053结合口袋截面图；e，小分子激动剂与受体相互作用模式示意。复旦大学基础医学院博士研究生陈彦、复旦大学基础医学院青年研究员周庆同和中国科学院上海药物所王江研究员为该论文的共同第一作者；复旦大学王明伟讲席教授、中国科学院上海药物研究所柳红研究员和杨德华研究员为该论文的共同通讯作者。合作者包括澳大利亚墨尔本大学Ross A.D. Bathgate教授、中国科学院上海药物所徐华强研究员和常州健亚生物科技有限公司沈纯博士等。该研究成果先后获得了国家自然科学基金委员会、国家科学技术部、国家卫生与健康委员会、中国科学院和上海市科学技术委员会等的经费资助。原文链接：https://doi.org/10.1038/s41467-023-36182-z（也可后台留邮箱，获取PDF版本）参考文献：Boels, K. & Schaller, H. C. Identification and characterisation of GPR100 as a novel human G-protein-coupled bradykinin receptor. Br J Pharmacol 140, 932-938 (2003)Liu, C. et al. INSL5 is a high affinity specific agonist for GPCR142 (GPR100). J Biol Chem 280, 292-300 (2005).Conklin, D. et al. Identification of INSL5, a new member of the insulin superfamily. Genomics 60, 50-56 (1999).Luo, X. et al. The insulinotrophic effect of insulin-like peptide 5 in vitro and in vivo. Biochem J 466, 467-473 (2015).Hechter, D. et al. Reviewing the physiological roles of the novel hormone-receptor pair INSL5-RXFP4: a protective energy sensor? J Mol Endocrinol 69, R45-R62 (2022).DeChristopher, B. et al. Discovery of a small molecule RXFP3/4 agonist that increases food intake in rats upon acute central administration. Bioorg Med Chem Lett 29, 991-994 (2019).Lin, G. Y. et al. High-throughput screening campaign identifies a small molecule agonist of the relaxin family peptide receptor 4. Acta Pharmacol Sin 41, 1328-1336 (2020).Lin, L. et al. Design, synthesis and pharmacological evaluation of tricyclic derivatives as selective RXFP4 agonists. Bioorg Chem 110, 104782 (2021).Xu, Y. et al. A distinctive ligand recognition mechanism by the human vasoactive intestinal polypeptide receptor 2. Nat Commun 13, 2272 (2022).Juan A. B. et al. Integrated methods for the construction of three-dimensional models and computational probing of structure-function relations in G protein-coupled receptors. 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