LTBP1

本文研究揭开了与血管疾病相关的平滑肌细胞蛋白质组特征，或有助于识别出潜在的治疗性靶点来加速向临床上的转化。 组成动脉中间层的平滑肌细胞（SMCs）是参与心血管疾病发生的关键细胞类型，心血管疾病是全世界人群死亡率和发病率的主要原因。 近日，一篇发表在国际杂志Arteriosclerosis, Thrombosis, and Vascular Biology上题为“Secreted Protein Profiling of Human Aortic Smooth Muscle Cells Identifies Vascular Disease Associations”的研究报告中，来自弗吉尼亚大学等机构的科学家们通过探索机体中所产生的用来抵御致命威胁的生物胶水，找到了关于中风、心脏病发作和心血管疾病发生的重要答案。 研究者Mete Civelek表示，我们想通过研究更好地理解影响机体心血管疾病风险的因素，比如动脉粥样硬化，动脉粥样硬化的主要特点是脂质斑块在血管中堆积，当这些板块形成时，机体就会在其上面形成纤维帽（fibrous caps）结构，从而防止其松动，从而引发心脏病发作和中风发生。 研究人员认为，机体在这些斑块上所建立的支架可能包含重要的线索，或能改善他们对心血管疾病发病机制的理解，通过采用一种聪明的方案，科学家们就能获取重要的新见解，从而推动挽救人类生命疗法的发展。 文章中，研究人员结合了20年人类遗传学的发现和关于平滑肌细胞（斑块形成的动脉的主要组成部分）的独特资源进行研究，结果发现，我们的遗传组成会影响平滑肌细胞分泌蛋白质的方式，这些蛋白质能为斑块提供力量防止其破碎引发心脏病发作和中风发生。 图片来源：https://www.ahajournals.org/doi/10.1161/ATVBAHA.123.320274 为了在潜在的致死性斑块上构建保护性支架，排列在血管中的平滑肌细胞就能分泌一种称之为“细胞外基质”的物质，其是一种富含蛋白质的纤维胶状材料。研究人员测定了从123名心脏移植供体中收集的平滑肌细胞中的这些蛋白及其相关蛋白质，并通过逆向研究识别出了制造这些蛋白质的基因。 他们这样做的目的就是确定染色体上的20个位置，其中容纳了能影响关键蛋白质产生的基因，研究人员还精准定位了一种自然发生的基因变异，这种变异能让特定个体动脉硬化的风险更高，同时他们还识别出了能促进心血管疾病风险的特殊蛋白类型。临床医生或许就能利用这些新见解来识别出斑块会发生脱落并引发心脏病发作或中风风险的患者。 相关研究结果或能帮助解释为何平滑肌细胞有时有益有时有害，同时也有望促进科学家们寻找治疗动脉粥样硬化和心血管疾病的新型疗法。如今研究人员识别出了名为LTBP1的特殊蛋白，其在斑块稳定性上扮演着重要角色，后期他们还将继续深入研究是否这种蛋白能作为一种有益的治疗性靶点并将这一研究发现转化为对患者的护理。 综上，本文研究揭开了与血管疾病相关的平滑肌细胞蛋白质组特征，或有助于识别出潜在的治疗性靶点来加速向临床上的转化。（生物谷Bioon.com） 参考文献： Rédouane Aherrahrou,Ferheen Baig,Konstantinos Theofilatos, et al. Secreted Protein Profiling of Human Aortic Smooth Muscle Cells Identifies Vascular Disease Associations, Arteriosclerosis, Thrombosis, and Vascular Biology (2024). DOI:10.1161/ATVBAHA.123.320274

Doctors may be able to leverage the new insights to identify patients at greatest risk of having atherosclerotic plaques break free and cause heart attacks or strokes. University of Virginia School of Medicine scientists have found important answers about strokes, heart attacks and cardiovascular diseases by probing the biological glue our bodies create to protect us from those deadly dangers. The researchers, led by Mete Civelek, PhD, wanted to better understand factors that influence our risk for cardiovascular diseases such as atherosclerosis, the hardening of the arteries. Atherosclerosis is characterized by the buildup of fatty plaques in our blood vessels. When these plaques form, our bodies build fibrous caps over them to keep them from breaking loose and causing heart attacks and strokes. Civelek and his team thought that the scaffolding our bodies build over these plaques might contain important clues that could improve our understanding of cardiovascular diseases, the leading cause of death around the world. And by taking a clever approach, the scientists were able to obtain important new insights that could advance the development of lifesaving treatments. "We combined two decades of human genetics findings and a unique resource of smooth muscle cells, an important component of arteries where the plaques develop," said Civelek, of UVA's Center for Public Health Genomics and the Department of Biomedical Engineering. "We discovered that our genetic makeup impacts the ways smooth muscle cells secrete proteins that provide strength to plaques and prevent them from rupturing and causing heart attacks and strokes." Vital Cellular Glue To construct the protective scaffolding over the potentially deadly plaques, smooth muscle cells that line our blood vessels secrete what is known as "extracellular matrix" -- a fibrous, glue-like material rich in proteins. Civelek and his team measured these proteins, and related proteins, in smooth muscle cells collected from 123 heart transplant donors. The scientists were then able to work backward, essentially, to identify genes that made those proteins. Doing this let the scientists identify 20 locations on our chromosomes that house genes that influence the production of the critical proteins. It also let them pinpoint a naturally occurring gene variation that puts certain people at higher risk for hardening of the arteries, as well as identify types of proteins that contribute to our cardiovascular risk. Doctors may be able to leverage the new insights to identify patients at greatest risk of having the plaques break free and cause heart attacks or strokes, the UVA researchers say. The findings also shed important light on why the efforts of the smooth muscle cells sometimes are beneficial and sometimes are harmful. That information will be a great asset to researchers seeking to develop new treatments for atherosclerosis and cardiovascular diseases, Civelek says. "We identified one protein, LTBP1, that we think plays an important role in plaque stability," he said. "We will continue to study if this protein can be a beneficial therapeutic target and hope to translate our findings to patient care soon."

Phase 3 EFZO-FIT™ study of efzofitimod in patients with pulmonary sarcoidosis enrolling in the U.S., Europe and Japan. Phase 2 proof-of-concept study of efzofitimod in patients with SSc-ILD expected to begin in 2023. February 2023 follow-on common stock offering of approximately $52.0 million in gross proceeds. Company to host conference call and webcast today, March 9th, at 5:00 p.m. EST / 2:00 p.m. PST. SAN DIEGO, March 09, 2023 (GLOBE NEWSWIRE) -- aTyr Pharma Inc. (Nasdaq: LIFE) (“aTyr” or the “Company”), a biotherapeutics company engaged in the discovery and development of first-in-class medicines from its proprietary tRNA synthetase platform, today announced fourth quarter and full year 2022 results and provided a corporate update. “2022 was an important year for aTyr as we advanced our lead therapeutic candidate, efzofitimod, to a global pivotal Phase 3 study in patients with pulmonary sarcoidosis, the most prevalent form of interstitial lung disease (ILD),” said Sanjay S. Shukla, M.D., M.S., President and Chief Executive Officer of aTyr. “This study, which is known as EFZO-FIT™, is expected to be the largest interventional study in sarcoidosis to date and is currently enrolling patients at multiple centers in the U.S., Europe and Japan.” “We are also expanding the clinical development program for our novel immunomodulator efzofitimod with plans to initiate a Phase 2 proof-of-concept study in patients with systemic sclerosis (SSc, or scleroderma)-associated ILD (SSc-ILD) this year, which increases the potential market opportunity in these forms of ILD with high unmet medical need. As a result of program prioritization and proceeds from a recent public offering, we project that we will have sufficient cash to fund both of our efzofitimod clinical trials and the company’s operations into 2026. We are very proud of our progress and look forward to the year ahead as we continue our pursuit to develop a new class of medicines.” Fourth Quarter 2022 and Subsequent Period Highlights Continued enrollment in EFZO-FIT™, a global pivotal Phase 3 randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of efzofitimod in patients with pulmonary sarcoidosis. This is a 52-week study consisting of three parallel cohorts randomized equally to either 3.0 mg/kg or 5.0 mg/kg of efzofitimod or placebo dosed intravenously once a month for a total of 12 doses. The study intends to enroll up to 264 subjects with pulmonary sarcoidosis and is currently enrolling at multiple centers in the U.S., Europe and Japan. Kyorin Pharmaceutical Co., Ltd. (Kyorin), aTyr’s partner for the development and commercialization of efzofitimod for ILD in Japan, dosed the first patient in Japan in EFZO-FIT™. This achievement triggered a $10.0 million milestone payment to aTyr in the fourth quarter. Under the collaboration and license agreement with Kyorin, aTyr has received $20.0 million in upfront and milestone payments to date and is eligible to receive up to an additional $155.0 million in the aggregate upon the achievement of certain development, regulatory and sales milestones, as well as tiered royalties on any net sales in Japan. Kyorin has the exclusive rights to develop and commercialize efzofitimod in Japan for all forms of ILD. Announced U.S. Food and Drug Administration (FDA) clearance of an Investigational New Drug (IND) application for a Phase 2 randomized, double-blind, placebo-controlled, proof-of-concept study to evaluate the efficacy, safety and tolerability of efzofitimod in patients with SSc-ILD. This is expected to be a 28-week study with three parallel cohorts randomized 2:2:1 to either 270 mg or 450 mg of efzofitimod or placebo dosed intravenously monthly for a total of 6 doses. It is expected that the study will enroll 25 patients with progressive disease who are currently receiving background mycophenolate therapy at multiple centers in the U.S. The primary objective of the study will be to evaluate the efficacy of multiple doses of intravenous efzofitimod on pulmonary, cutaneous and systemic manifestations in patients with SSc-ILD. The Company plans to initiate this study in 2023. Received European Union (EU) orphan drug designation for efzofitimod for the treatment of sarcoidosis from the European Commission based on the opinion of the European Medicines Agency (EMA) Committee for Orphan Medicinal Products. To qualify for EMA orphan status, a product must, among other things, be intended for the treatment, prevention or diagnosis of a disease that is life-threatening or chronically debilitating for which either no satisfactory method of diagnosis, prevention or treatment exists, or if such method exists, the medicine is of significant benefit to those affected by such condition. EMA orphan drug designation provides certain benefits, including the potential for 10 years of market exclusivity following market authorization, potential reduction in regulatory fees and a centralized EU market authorization process. Announced that the Company will present data on the mechanism of action and an exposure-efficacy analysis for efzofitimod at the upcoming American Thoracic Society (ATS) 2023 International Conference, which is scheduled to take place May 19 – 24 in Washington, DC. Received a Notice of Allowance from the European Patent Office for a patent covering the use of efzofitimod in combination with the anti-fibrotic pirfenidone for the treatment of lung inflammation or fibrosis. Announced latent transforming growth factor beta binding protein 1 (LTBP1) as the target of a domain of aspartyl-tRNA synthetase (DARS). LTBP1 is a key regulator of transforming growth factor beta (TGF-β), a central player in the pathogenesis of fibrotic diseases. The Company expects to present additional findings around the interaction between LTBP1 and this domain of DARS at an upcoming scientific conference. Raised gross proceeds of approximately $52.0 million through the issuance of 23,125,000 shares of common stock in February 2023 from a public offering, which included the partial exercise of the underwriters’ option to purchase additional shares. Year Ended 2022 Financial Highlights and Cash Position Cash & Investment Position: Cash, restricted cash, cash equivalents and investments as of December 31, 2022, were $69.3 million. Subsequent to the end of the year, the Company received a $10.0 million milestone payment in connection with the Kyorin Agreement and generated gross proceeds of approximately $52.0 million from the public offering of common stock. Based on the Company’s current operational plans and existing cash, aTyr believes the Company’s cash runway will extend into 2026. R&D Expenses: Research and development expenses were $42.8 million for the year ended 2022, which consisted of clinical trial costs for the Phase 3 EFZO-FIT™ study, manufacturing costs for the efzofitimod and ATYR2810 programs, and research and development for the efzofitimod and discovery programs. G&A Expenses: General and administrative expenses were $14.0 million for the year ended 2022. Conference Call and Webcast Details aTyr will host a conference call and webcast today at 5:00 p.m. EST / 2:00 p.m. PST to discuss its financial results and provide a corporate update. Interested parties may access the call by registering here in order to obtain a dial in, personalized passcode and webcast information. Links to a live audio webcast and replay may be accessed on the aTyr website Events page at: . An audio replay will be available for at least 90 days following the event. About Efzofitimod aTyr is developing efzofitimod as a potential therapeutic for patients with fibrotic lung disease. Efzofitimod, a fusion protein comprised of the immunomodulatory domain of histidyl-tRNA synthetase fused to the FC region of a human antibody, is a selective modulator of neuropilin-2 that downregulates innate immune responses in inflammatory disease states. aTyr’s lead indication for efzofitimod is pulmonary sarcoidosis, a major form of interstitial lung disease. Clinical proof-of-concept for efzofitimod was recently established in a Phase 1b/2a multiple-ascending dose, placebo-controlled study of efzofitimod in patients with pulmonary sarcoidosis, which demonstrated safety and a consistent dose response and trends of benefit of efzofitimod compared to placebo on key efficacy endpoints, including steroid reduction, lung function, clinical symptoms and inflammatory biomarkers. aTyr is currently conducting EFZO-FIT™, a Phase 3 study of efzofitimod in pulmonary sarcoidosis patients. About aTyr aTyr is a biotherapeutics company engaged in the discovery and development of first-in-class medicines from its proprietary tRNA synthetase platform. aTyr’s research and development efforts are concentrated on a newly discovered area of biology, the extracellular functionality and signaling pathways of tRNA synthetases. aTyr has built a global intellectual property estate directed to a potential pipeline of protein compositions derived from 20 tRNA synthetase genes and their extracellular targets. aTyr’s primary focus is efzofitimod, a clinical-stage product candidate which binds to the neuropilin-2 receptor and is designed to downregulate immune engagement in fibrotic lung disease. For more information, please visit . Forward-Looking Statements This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Forward-looking statements are usually identified by the use of words such as “believes,” “expects,” “intends,” “may,” “plans,” “project,” “will,” “would,” and variations of such words or similar expressions. We intend these forward-looking statements to be covered by such safe harbor provisions for forward-looking statements and are making this statement for purposes of complying with those safe harbor provisions. These forward-looking statements include statements regarding our belief that we will have sufficient cash to fund both of our efzofitimod clinical trials and the company’s operations into 2026; the expected size of, and number of patients to be enrolled in, the EFZO-FIT™ study; our expectations regarding the size of the EFOZ-FIT™ study being the largest interventional study in sarcoidosis to date; the potential therapeutic benefits and applications of efzofitimod and our discovery programs; and timelines and plans with respect to certain development activities and development goals, including our expectation that our Phase 2 proof-of-concept study of efzofitimod in patients with SSc-ILD will begin in 2023. These forward-looking statements also reflect our current views about our plans, intentions, expectations, strategies and prospects, which are based on the information currently available to us and on assumptions we have made. Although we believe that our plans, intentions, expectations, strategies and prospects, as reflected in or suggested by these forward-looking statements, are reasonable, we can give no assurance that the plans, intentions, expectations or strategies will be attained or achieved. All forward-looking statements are based on estimates and assumptions by our management that, although we believe to be reasonable, are inherently uncertain. Furthermore, actual results may differ materially from those described in these forward-looking statements and will be affected by a variety of risks and factors that are beyond our control including, without limitation, our assumptions and expectations underlying our belief that we will have sufficient cash runway into 2026 may not be accurate, the fact that NRP2 and tRNA synthetase biology is not fully understood, uncertainty regarding the COVID-19 pandemic, and geopolitical conflicts, including the risk of delays in our clinical trials, risks associated with the discovery, development and regulation of our product candidates, including the risk that results from clinical trials or other studies may not support further development, the risk that we may cease or delay preclinical or clinical development activities for any of our existing or future product candidates for a variety of reasons, the fact that our collaboration agreements are subject to early termination, and the risk that we may not be able to raise the additional funding required for our business and product development plans, as well as those risks set forth in our Quarterly on Form 10-Q for the quarter ended September 30, 2022 filed with the SEC on November 14, 2022 and in our subsequent SEC filings. Except as required by law, we assume no obligation to update publicly any forward-looking statements, whether as a result of new information, future events or otherwise. ATYR PHARMA INC. Consolidated Statements of Operations (in thousands, except share and per share data) Three Months Ended Years Ended December 31, December 31, 2022 2021 2022 2021 Revenues: License and collaboration agreement revenues $ 10,386 $ — $ 10,386 $ — Total revenues 10,386 — 10,386 — Operating expenses: Research and development $ 14,910 $ 5,955 $ 42,808 $ 23,264 General and administrative 3,426 2,685 13,982 10,751 Total operating expenses 18,336 8,640 56,790 34,015 Loss from operations (7,950 ) (8,640 ) (46,404 ) (34,015 ) Total other income (expense), net 427 79 1,061 238 Consolidated net loss (7,523 ) (8,561 ) (45,343 ) (33,777 ) Net loss attributable to noncontrolling interest in Pangu BioPharma Limited 2 2 5 9 Net loss attributable to aTyr Pharma, Inc. $ (7,521 ) $ (8,559 ) $ (45,338 ) $ (33,768 ) Net loss per share, basic and diluted $ (0.26 ) $ (0.31 ) $ (1.60 ) $ (1.77 ) Shares used in computing net loss per share, basic and diluted 29,116,524 27,791,737 28,419,569 19,080,878 ATYR PHARMA INC. Condensed Consolidated Balance Sheets (in thousands) December 31, December 31, 2022 2021 Cash, cash equivalents, restricted cash and available-for-sale investments $ 69,311 $ 107,911 Other receivables 11,775 435 Property and equipment, net 3,059 543 Operating lease, right-of-use assets 7,250 1,267 Financing lease, right-of-use assets 1,248 — Prepaid expenses and other assets 3,143 5,381 Total assets $ 95,786 $ 115,537 Accounts payable, accrued expenses and other liabilities $ 12,968 $ 5,033 Current portion of operating lease liability 630 980 Current portion of financing lease liability 264 — Long-term operating lease liability, net of current portion 9,633 398 Long-term financing lease liability, net of current portion 1,007 — Total stockholders’ equity 71,284 109,126 Total liabilities and stockholders’ equity $ 95,786 $ 115,537 Contact: Ashlee Dunston Director, Investor Relations and Corporate Communications adunston@atyrpharma.com