Serelaxin

WATERTOWN, Mass., Dec. 03, 2024 (GLOBE NEWSWIRE) -- Tectonic Therapeutic, Inc. (NASDAQ: TECX) (“Tectonic”) a clinical stage biotechnology company focused on the discovery and development of therapeutic proteins and antibodies that modulate the activity of G-protein coupled receptors (“GPCRs”), today announced it will host a virtual key opinion leader (KOL) event on Thursday, December 12, 2024 from 4:00 PM to 6:00 PM ET. To register, click here. Key opinion leaders will include John R. Teerlink, MD, FHFSA (University of California San Francisco) and Raymond L. Benza, MD, FACC, FAHA, FACP (Icahn School of Medicine at Mount Sinai), who will discuss the unmet medical need and current treatment landscape for patients with Group 2 Pulmonary Hypertension due to Heart Failure with Preserved Ejection Fraction (Group 2 PH-HFpEF). The event will focus on Tectonic’s lead program, TX45, an investigational Fc-relaxin fusion protein with optimized pharmacokinetics and biophysical properties that activates the RXFP1 receptor, the GPCR target of the hormone relaxin. TX45 is being evaluated in patients with Group 2 PH-HFpEF in an ongoing Phase 1b hemodynamic proof-of-concept study and a Phase 2 clinical proof-of-concept study. A live question and answer session will follow the formal presentations. About the Key Opinion Leaders: Professor John R. Teerlink, MD, FACC, FAHA, FESC, FHFA, FHFSA, FRCP (London)Professor Teerlink is Professor of Medicine at the University of California San Francisco (UCSF). After graduating from Swarthmore College with a Religion major, he received an MD from Harvard Medical School and completed his Internal Medicine residency and Cardiovascular Medicine fellowship at UCSF, as well as post-doctoral fellowships in Cardiovascular pharmacology (Hoffman-LaRoche; Basel, Switzerland), echocardiography (UCSF) and heart failure (UCSF-affiliated hospital). He is actively involved in the design and execution of many heart failure clinical trials, serving on endpoint, data monitoring, steering and executive committees for numerous international studies investigating a variety of new pharmacologic therapies, as well as stem cell and gene therapies, diagnostic modalities and other devices. He was the lead clinical investigator for the serelaxin development program, serving as Principal Investigator for Pre-RELAX-AHF, RELAX-AHF, RELAX-AHF-2 and RELAX-Repeat, and as a steering committee member for RELAX-AHF-Asia. Dr. Teerlink has served on the US FDA Cardiovascular and Renal Drug Advisory Committee, as well as on other FDA drug, device, diagnostics, and vaccine panels and serves as a consultant on pre-clinical and clinical development programs in multiple areas of cardiology, as well as in non-cardiovascular indications. Dr. Teerlink was a founding physician member of the American Association of Heart Failure Nurses and is a Past President of the Heart Failure Society of America. He was an Associate Editor for the Journal of Cardiac Failure, Guest Editor-in-Chief and Associate Editor for JACC: Heart Failure, and is a clinical scholar presenting many lectures and over 300 publications, including a chapter on Acute Heart Failure in Braunwald’s Heart Disease textbook. He was profiled in The Lancet as an internationally recognized leader in heart failure. Raymond L. Benza, MD, FACC, FAHA, FACPDr. Benza is a Professor and System Director of Pulmonary Hypertension at the Icahn School of Medicine at Mount Sinai, Mount Sinai Fuster Heart Hospital. He is a fellow of the American College of Physicians, the American Heart Association Council on Clinical Cardiology, the American College of Chest Physicians and the American College of Cardiology. He is a diplomat of the American Board of Internal Medicine with certification in the subspecialties of cardiovascular diseases and advanced heart failure and transplantation. Dr. Benza currently holds administrative positions in the Pulmonary Vascular Research Institute and the International Society of Heart and Lung Transplantation and is the former treasurer of that society. He served on President Barak Obama’s Advisory Committee on Organ Transplantation (ACOT) in the Health Resources and Services Administration for 4 years and was knighted in 2015 by his Royal Highness Vittorio Emanuele of Italy for his philanthropic work in patients with pulmonary arterial hypertension and was admitted to the Association of University Cardiologists. He sits on multiple journal editorial committees and is the Steering Committee Chair for several industry trials in PAH. His primary clinical interests are the evaluation and treatment of advanced congestive heart failure, cardiac transplantation, and pulmonary arterial hypertension (PAH). He participates in major clinical studies of new therapies for the treatment of heart failure, mechanical support, and pulmonary hypertension. Dr. Benza is a funded investigator for the National Institutes of Health and the American Heart Association for his work in pulmonary arterial hypertension focusing on risk stratification, pharmacogenomics and new device therapies for this disease state. About TX45, a long-acting Fc-relaxin fusion proteinTX45 is an investigational Fc-relaxin fusion protein with optimized pharmacokinetics and biophysical properties that activates the RXFP1 receptor, the G-protein coupled receptor target of the hormone relaxin. Relaxin is an endogenous protein, expressed at low levels in both men and women that is a pulmonary and systemic vasodilator with lusitropic, anti-fibrotic and anti-inflammatory activity. In normal human physiology, relaxin is upregulated during pregnancy where it exerts vasodilative effects, reduces systemic and pulmonary vascular resistance and increases cardiac output to accommodate the increased demand for oxygen and nutrients from the developing fetus. Relaxin also exerts anti-fibrotic effects on pelvic ligaments to facilitate delivery of the baby. About Group 2 Pulmonary Hypertension in HFpEFThe World Health Organization has defined five groups of pulmonary hypertension (“PH”). Tectonic is focused on the Group 2 subtype, a condition that develops due to left-sided heart disease, specifically pulmonary hypertension secondary to left heart failure with preserved ejection fraction (“PH-HFpEF”). In patients with PH-HFpEF, chronic heart failure leads to increased blood pressure in the pulmonary arteries, exerting severe strain on the right side of the heart, which adapts poorly to the increased pressure. This increased pulmonary pressure gradually causes worsening exercise capacity, shortness of breath and right-sided heart failure which can lead to death. Although several Group 1 PH (Pulmonary Arterial Hypertension, PAH) medications have been explored in Group 2 PH, to date, no medications have been approved for its treatment. About TectonicTectonic is a biotechnology company focused on the discovery and development of therapeutic proteins and antibodies that modulate the activity of G-protein coupled receptors (“GPCRs”). Leveraging its proprietary technology platform called GEODe™ (GPCRs Engineered for Optimal Discovery), Tectonic is focused on developing biologic medicines that overcome the existing challenges of GPCR-targeted drug discovery and harness the human body to modify the course of disease. Tectonic focuses on areas of significant unmet medical need, often where therapeutic options are poor or nonexistent, as these are areas where new medicines have the potential to improve patient quality of life. Tectonic is headquartered in Watertown, Massachusetts. For more information, please visit www.tectonictx.com and follow on LinkedIn. Forward-Looking StatementsThis press release contains “forward-looking statements” within the meaning of the “safe harbor” provisions of the Private Securities Litigation Reform Act of 1995. All statements in this press release other than statements of historical facts are “forward-looking statements. These statements may be identified by words such as “aims,” “anticipates,” “believes,” “could,” “estimates,” “expects,” “forecasts,” “goal,” “intends,” “may,” “plans,” “possible,” “potential,” “seeks,” “will” and variations of these words or similar expressions that are intended to identify forward-looking statements, although not all forward-looking statements contain these words. Forward-looking statements in this press release include statements regarding: the design, objectives, initiation, timing, progress and results of clinical trials of Tectonic’s product candidates, including the ongoing Phase 1b and Phase 2 clinical trials for TX45 in Group 2 PH-HFpEF; and the potential properties and benefits of TX45. These forward-looking statements are based on Tectonic’s expectations and assumptions as of the date of this press release. Each of these forward-looking statements involves risks and uncertainties that could cause Tectonic’s clinical development programs, future results or performance to differ materially from those expressed or implied by the forward-looking statements. Many factors may cause differences between current expectations and actual results, including: the potential that success in preclinical testing and earlier clinical trials does not ensure that later clinical trials will generate the same results or otherwise provide adequate data to demonstrate the efficacy and safety of a product candidate; the impacts of macroeconomic conditions, including the conflict in Ukraine and the conflict in the Middle East, heightened inflation and uncertain credit and financial markets, on Tectonic’s business, clinical trials and financial position; unexpected safety or efficacy data observed during preclinical studies or clinical trials; clinical trial site activation or enrollment rates that are lower than expected; Tectonic’s ability to realize the benefits of its collaborations and license agreements; changes in expected or existing competition; changes in the regulatory environment; the uncertainties and timing of the regulatory approval process; and unexpected litigation or other disputes. Other factors that may cause Tectonic’s actual results to differ from those expressed or implied in the forward-looking statements in this press release are identified under the heading “Risk Factors” in Tectonic’s quarterly report on Form 10-Q filed with the SEC on November 12, 2024, and in other filings that Tectonic makes and will make with the SEC in the future. Tectonic expressly disclaims any obligation to update any forward-looking statements contained herein, whether as a result of any new information, future events, changed circumstances or otherwise, except as otherwise required by law. For more information, please visit www.tectonictx.com and follow on LinkedIn. Source: Tectonic Therapeutic

关注并星标CPHI制药在线 前 言 2024年11月29日，中国国家药监局药品审评中心（CDE）官网公示，阿斯利康（AstraZeneca）申报的1类新药AZD5462片获得临床试验默示许可，拟开发用于治疗心力衰竭。这是AZD5462片首次在中国获批进入临床阶段，标志着阿斯利康在心力衰竭治疗领域迈出了重要一步。AZD5462片是一款RXFP1激动剂小分子药物，目前在国际范围内正处于2期临床研究阶段。 新药研究历程 AZD5462片的研究历程可以追溯到2013年，当时美国国立卫生研究院（NIH）对35万多个化合物进行了高通量筛选，发现了化合物ML290。阿斯利康在此基础上，经过近十年的优化，最终开发出了AZD5462。这一研发过程充满了挑战与创新，涉及多个关键步骤和复杂的化学改造。 首先，阿斯利康的研究团队对ML290进行了结构改造，以提高其对RXFP1受体的选择性和活性。在这一过程中，他们尝试了多种化学修饰，包括替换关键片段、引入羧酸基团等，以改善药物的溶解度和LogD值。经过多次迭代，他们成功得到了AZ7976，这是一个具有高活性但代谢不稳定、难溶的hRXFP1激动剂。 为了进一步优化AZ7976的性质，研究团队继续对其进行改造，最终确定了临床候选药物AZD5462。这一改造的关键在于去除了SF5取代基，并将右侧的苯环改成脂肪片段，从而进一步减小了LogD值，提高了药物的代谢稳定性和溶解度。这些改造使得AZD5462在保留高活性的同时，具备了更好的成药性。 在AZD5462的研发过程中，阿斯利康的研究团队还对其进行了全面的药效学和药代动力学研究。他们发现，AZD5462能够激活RXFP1受体，通过增强内皮介导的血管舒张机制、促进心血管系统中的心脏保护和抗纤维化作用，对心脏和血管产生有益作用。这一发现为AZD5462在治疗心力衰竭方面的应用提供了坚实的理论基础。 RXFP1激动剂小分子药物作用机制 AZD5462片作为RXFP1激动剂，其作用机制主要通过激活RXFP1受体来实现。RXFP1是一种松弛素受体，在心脏、肾脏和血管等器官和组织中广泛表达。松弛素是一种内源性异二聚胰岛素样肽，在心血管系统中具有有益的生理作用，并且具有较好的安全性。AZD5462片通过模拟松弛素的作用，激活RXFP1受体，从而增强内皮介导的血管舒张机制，促进心血管系统中的心脏保护和抗纤维化作用。 在竞品分析方面，目前市场上针对RXFP1受体的药物并不多。其中，诺华开发的重组天然激素类似物Serelaxin是一款已上市的药物，但其在心衰3期临床中因未达到一级终点而失败，最终只能在俄罗斯上市。此外，Serelaxin的半衰期只有10分钟，需要静脉注射，这在一定程度上限制了其临床应用。另一款值得关注的竞品是礼来研发的LY3540378注射液（Volenrelaxin），这是一款长效合成松弛素类似物，同样作为RXFP1激动剂发挥作用，被开发用于治疗慢性心力衰竭。目前，LY3540378正处于II期临床试验阶段，其疗效和安全性尚需进一步验证。 与Serelaxin和LY3540378相比，AZD5462片具有显著的优势。首先，AZD5462片是一款小分子药物，具有更好的口服吸收和生物利用度，能够提供更稳定的药物浓度和更长的半衰期。其次，AZD5462片在临床前研究中表现出良好的安全性和耐受性，没有观察到明显的毒性反应。 新药临床数据 AZD5462片的临床数据为其在治疗心力衰竭方面的应用提供了有力的支持。在临床前研究中，AZD5462片激活了与松弛素H2高度相似的一系列下游通路，并在食蟹猴心力衰竭模型中表现出显著的治疗效果。 具体而言，在食蟹猴心力衰竭模型中，AZD5462片治疗8周后，在第9周、第13周和第17周观察到包括左室射血分数（LVEF）在内的功能性心脏参数的显著改善，而心率或平均动脉血压没有变化。这一结果表明，AZD5462片能够显著改善心力衰竭患者的心脏功能，且对血压和心率等生理指标没有不良影响。 此外，AZD5462片在大鼠和食蟹猴中均表现出良好的耐受性，并已成功完成健康志愿者的I期安全性研究。这些研究结果表明，AZD5462片在人体内同样具有良好的安全性和耐受性，为其进一步的临床应用提供了可靠的基础。 值得注意的是，阿斯利康正在开展AZD5462片的一项2b期临床研究，评估该产品对慢性心力衰竭（HF）患者心功能的影响。该研究拟在国际范围内入组360名受试者，计划于2025年11月完成。这一研究的开展将进一步验证AZD5462片在治疗心力衰竭方面的疗效和安全性，为其未来的上市和临床应用提供有力的支持。 市场价值 AZD5462片作为阿斯利康研发的一款创新药物，在治疗心力衰竭方面具有显著的市场价值。心力衰竭是一种严重的心血管疾病，全球范围内患者数量庞大，且缺乏有效的治疗手段。AZD5462片的研发成功，为心力衰竭患者提供了新的治疗选择，有望显著改善患者的生活质量和预后。从市场规模来看，心力衰竭药物市场具有巨大的潜力。随着人口老龄化和心血管疾病发病率的增加，心力衰竭患者数量将持续增长，对治疗药物的需求也将不断增加。AZD5462片作为一款具有创新性和疗效显著的药物，有望在未来占据一定的市场份额。 此外，AZD5462片的研发成功也体现了阿斯利康在心血管药物研发领域的深厚实力。阿斯利康作为全球知名的制药企业，拥有丰富的研发经验和强大的研发实力。AZD5462片的成功研发，不仅为阿斯利康带来了新的增长点，也为其在心血管药物研发领域树立了良好的品牌形象。 结 语 阿斯利康创新药物AZD5462片获批中国临床，为心力衰竭治疗领域带来了新的希望和突破。这款药物的研发成功，不仅体现了阿斯利康在心血管药物研发领域的深厚实力，也为患者提供了新的治疗选择。未来，随着临床研究的不断深入和临床数据的不断积累，AZD5462片有望成为心力衰竭治疗领域的重要药物之一，为全球患者带来更好的治疗效果和生活质量。 参考文献 1.中国国家药监局药品审评中心(CDE)网站 2.Granberg KL, et al. (2024) Discovery of Clinical Candidate AZD5462, a Selective Oral Allosteric RXFP1 Agonist for Treatment of Heart Failure. J Med Chem. doi: 10.1021/acs.jmedchem.3c02184. END 【智药研习社近期直播预告】 来源：CPHI制药在线 声明：本文仅代表作者观点，并不代表制药在线立场。本网站内容仅出于传递更多信息之目的。如需转载，请务必注明文章来源和作者。 投稿邮箱：Kelly.Xiao@imsinoexpo.com ▼更多制药资讯，请关注CPHI制药在线▼ 点击阅读原文，进入智药研习社~