Simvastatin

引言 系统性红斑狼疮（systemic lupus erythematosus，SLE）等自身免疫性疾病严重威胁人类健康，目前仍然缺乏有效的根治性手段，寻找控制疾病发生发展的免疫学机制是研发新型有效疾病防治手段的关键。树突状细胞（dendritic cells，DC）是机体功能最为强大的抗原提呈细胞，鉴定不同的树突状细胞亚群在疾病发生发展中的致病作用及代谢调控机制是免疫学研究的前沿热点。DC在抗原或炎症刺激下能从外周组织迁移至引流淋巴结，进而控制适应性免疫应答。迁移性DC的功能活化如何影响自身免疫性疾病发生发展，该过程又如何受到细胞代谢的调控仍不清楚。 2024年10月18日，海军军医大学免疫所暨免疫与炎症全国重点实验室刘娟教授团队针对“树突状细胞迁移的代谢调控与自身免疫”这一核心科学问题，在Nature Metabolism杂志在线发表了题为Farnesyl pyrophosphate potentiates dendritic cell migration in autoimmunity through mitochondrial remodelling的研究论文。该研究首次报道了甲羟戊酸代谢中间产物法尼基焦磷酸能够通过重塑线粒体结构和代谢促进迁移性树突状细胞的存活，从而加剧系统性红斑狼疮的机体炎症反应。这项工作不仅揭示了树突状细胞迁移及功能的新型代谢调控机制，也解析了自身免疫性疾病的新型发病机制，为开发新型的疾病干预手段开辟了新的方向。 这项工作中，研究人员通过分析人类scRNA-seq数据，并结合转录组学、代谢组学、透射电子显微镜等手段研究了狼疮病人及小鼠中迁移性DC的转录和代谢特征。同时通过构建树突状细胞条件性的Hmgcr（羟甲基戊二酰辅酶A还原酶）基因缺陷小鼠来研究胆固醇代谢对DC功能及自身免疫病的调控作用。结果表明，迁移性DC在狼疮病人皮肤组织中明显富集，而甲羟戊酸途径的中间体法尼基焦磷酸（Farnesyl Pyrophosphate，FPP）在狼疮来源的迁移性DC中明显积累。Hmgcr/FPP通路能够协调蛋白质香叶基香叶基化和线粒体重塑来促进迁移性DC的存活和生发中心反应。分子机制层面，FPP介导的RhoA蛋白香叶基香叶基化能够促进RhoA-MFN相互作用，进而诱发线粒体融合和三羧酸循环，进而促进迁移性DC的线粒体呼吸及内质网稳定性。辛伐他汀作为一种甲羟戊酸途径的化学抑制剂，可恢复迁移性DC的线粒体紊乱，抑制狼疮小鼠过度的DC迁移及存活，进而改善SLE小鼠的炎症损伤。 模式图：法尼基焦磷酸通过重塑线粒体结构和代谢促进DC迁移和自身免疫（Credit: Nature Metabolism） 总之，该研究通过整合多组学数据和免疫学功能研究，首次证明了胆固醇代谢中间体FPP的积累通过重塑线粒体结构与代谢促进迁移性DC的存活，从而加剧病理性自身免疫和炎症反应。该研究不仅解析了在系统性红斑狼疮等自身免疫病中驱动DC异常迁移的新型代谢机制，也为深入认识自身免疫性疾病的免疫学原理、并研发新型的细胞和代谢靶向策略提供了全新的思路。 参考文献 https://www.nature.com/articles/s42255-024-01149-x 责编|探索君 排版|探索君 来源|BioArt End 往期精选 围观 一文读透细胞死亡(Cell Death) | 24年Cell重磅综述（长文收藏版） 热文 Cell | 是什么决定了细胞的大小？ 热文 Nature | 2024年值得关注的七项技术 热文 Nature | 自身免疫性疾病能被治愈吗？科学家们终于看到了希望 热文 CRISPR技术进化史 | 24年Cell综述

Vadadustat clinical data on display for nephrologist and healthcare providers in advance of U.S. market availability expected in January 2025 CAMBRIDGE, Mass., Oct. 15, 2024 /PRNewswire/ -- Akebia Therapeutics®, Inc. (Nasdaq: AKBA), a biopharmaceutical company with the purpose to better the lives of people impacted by kidney disease, today announced that it will present data at the American Society of Nephrology Kidney Week 2024 (ASN Kidney Week), which will take place in San Diego, CA from October 24-27. Akebia-supported posters will be presented at ASN Kidney Week on Thursday, October 24 from 10:00 AM – 12:00 PM PDT. Abstracts are available here. ASN Kidney Week attendees can also visit Akebia at Booth #2202 in the Exhibit Hall. Of note, six posters present clinical data on vadadustat, Akebia's oral hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitor, including post-marketing surveillance of use in Japan where vadadustat is approved for use in dialysis and non-dialysis dependent patients. In March 2024, Vafseo® (vadadustat) was approved by the U.S. Food and Drug Administration for the treatment of anemia due to chronic kidney disease (CKD) in adults who have been receiving dialysis for at least three months. In parallel with its ongoing commercial launch of Vafseo and expected product U.S. market availability in January 2025, Akebia continues to engage with the nephrology community by sharing important data to further scientific exchange and dialogue about Vafseo and anemia of CKD. All Akebia-supported posters to be presented at ASN Kidney Week 2024: Real-World Evidence of Vadadustat in Patients with Anemia and CKD: Interim Results from Postmarketing Surveillance (VIOLET survey) in Japan - Poster #: TH-PO899 Framework to Assess the Benefits and Risks of Treatments and Dosing Regimens for CKD Anemia - Poster #: TH-PO900 On-Treatment Analyses of Cardiovascular Safety in the Vadadustat Phase 3 Program - Poster #: TH-PO901 Major Adverse Cardiovascular Events (MACE) in Patients Randomized to Vadadustat vs Darbepoetin Alfa During the 3 Months After Dialysis Initiation - Poster #: TH-PO902 Safety and Efficacy of Vadadustat in Erythropoiesis-Stimulating Agent-Naïve Patients New to Dialysis Who Have CKD-Related Anemia - Poster #: TH-PO907 Long Term Safety of Vadadustat for Treatment of Anemia-Related to CKD in Phase 3 Trials - Poster #: TH-PO908 Ferric Citrate for the Prevention of Renal Failure in Adults with Advanced CKD: The FRONTIER Trial - Poster #: TH-PO1187 About Akebia Therapeutics Akebia Therapeutics, Inc. is a fully integrated biopharmaceutical company with the purpose to better the lives of people impacted by kidney disease. Akebia was founded in 2007 and is headquartered in Cambridge, Massachusetts. For more information, please visit our website at , which does not form a part of this release. About Vafseo® (vadadustat) tablets Vafseo® (vadadustat) tablets is a once-daily oral hypoxia-inducible factor prolyl hydroxylase inhibitor that activates the physiologic response to hypoxia to stimulate endogenous production of erythropoietin, increasing hemoglobin and red blood cell production to manage anemia. Vafseo is approved for use in 37 countries. INDICATION VAFSEO is indicated for the treatment of anemia due to chronic kidney disease (CKD) in adults who have been receiving dialysis for at least three months. Limitations of Use VAFSEO has not been shown to improve quality of life, fatigue, or patient well-being. VAFSEO is not indicated for use: As a substitute for red blood cell transfusions in patients who require immediate correction of anemia. In patients with anemia due to CKD not on dialysis. IMPORTANT SAFETY INFORMATION about VAFSEO (vadadustat) tablets CONTRAINDICATIONS Known hypersensitivity to VAFSEO or any of its components Uncontrolled hypertension WARNINGS AND PRECAUTIONS Increased Risk of Death, Myocardial Infarction (MI), Stroke, Venous Thromboembolism, and Thrombosis of Vascular Access A rise in hemoglobin (Hb) levels greater than 1 g/dL over 2 weeks can increase these risks. Avoid in patients with a history of MI, cerebrovascular event, or acute coronary syndrome within the 3 months prior to starting VAFSEO. Targeting a Hb level of greater than 11 g/dL is expected to further increase the risk of death and arterial and venous thrombotic events. Use the lowest effective dose to reduce the need for red blood cell (RBC) transfusions. Adhere to dosing and Hb monitoring recommendations to avoid excessive erythropoiesis. Hepatotoxicity Hepatocellular injury attributed to VAFSEO was reported in less than 1% of patients, including one severe case with jaundice. Elevated serum ALT, AST, and bilirubin levels were observed in 1.8%, 1.8%, and 0.3% of CKD patients treated with VAFSEO, respectively. Measure ALT, AST, and bilirubin before treatment and monthly for the first 6 months, then as clinically indicated. Discontinue VAFSEO if ALT or AST is persistently elevated or accompanied by elevated bilirubin. Not recommended in patients with cirrhosis or active, acute liver disease. Hypertension Worsening of hypertension was reported in 14% of VAFSEO and 17% of darbepoetin alfa patients. Serious worsening of hypertension was reported in 2.7% of VAFSEO and 3% of darbepoetin alfa patients. Cases of hypertensive crisis, including hypertensive encephalopathy and seizures, have also been reported in patients receiving VAFSEO. Monitor blood pressure. Adjust anti-hypertensive therapy as needed. Seizures Seizures occurred in 1.6% of VAFSEO and 1.6% of darbepoetin alfa patients. Monitor for new-onset seizures, premonitory symptoms, or change in seizure frequency. Gastrointestinal (GI) Erosion Gastric or esophageal erosions occurred in 6.4% of VAFSEO and 5.3% of darbepoetin alfa patients. Serious GI erosions, including GI bleeding and the need for RBC transfusions, were reported in 3.4% of VAFSEO and 3.3% of darbepoetin alfa patients. Consider this risk in patients at increased risk of GI erosion. Advise patients about signs of erosions and GI bleeding and urge them to seek prompt medical care if present. Serious Adverse Reactions in Patients with Anemia Due to CKD and Not on Dialysis The safety of VAFSEO has not been established for the treatment of anemia due to CKD in adults not on dialysis and its use is not recommended in this setting. In large clinical trials in adults with anemia of CKD who were not on dialysis, an increased risk of mortality, stroke, MI, serious acute kidney injury, serious hepatic injury, and serious GI erosions was observed in patients treated with VAFSEO compared to darbepoetin alfa. Malignancy VAFSEO has not been studied and is not recommended in patients with active malignancies. Malignancies were observed in 2.2% of VAFSEO and 3.0% of darbepoetin alfa patients. No evidence of increased carcinogenicity was observed in animal studies. ADVERSE REACTIONS The most common adverse reactions (occurring at ≥ 10%) were hypertension and diarrhea. DRUG INTERACTIONS Iron supplements and iron-containing phosphate binders: Administer VAFSEO at least 1 hour before products containing iron. Non-iron-containing phosphate binders: Administer VAFSEO at least 1 hour before or 2 hours after non-iron-containing phosphate binders. BCRP substrates: Monitor for signs of substrate adverse reactions and consider dose reduction. Statins: Monitor for statin-related adverse reactions. Limit the daily dose of simvastatin to 20 mg and rosuvastatin to 5 mg. USE IN SPECIFIC POPULATIONS Pregnancy: May cause fetal harm. Lactation: Breastfeeding not recommended until two days after the final dose. Hepatic Impairment : Not recommended in patients with cirrhosis or active, acute liver disease. Please note that this information is not comprehensive. Please click here for the Full Prescribing Information, including BOXED WARNING and Medication Guide. Forward-Looking Statements Statements in this press release regarding Akebia Therapeutics, Inc.'s ("Akebia's") strategy, plans, prospects, expectations, beliefs, intentions and goals are forward-looking statements within the meaning of the U.S. Private Securities Litigation Reform Act of 1995, as amended, and include, but are not limited to, statements regarding: Akebia's expectations as to the timing of the market availability of Vafseo; and Akebia's plans with respect to its ongoing commercial launch of Vafseo, including that Akebia's continued engagement with the nephrology community by sharing important data will further scientific exchange and dialogue about Vafseo and anemia of CKD. The terms "intend," "believe," "plan," "goal," "potential," "anticipate, "estimate," "expect," "future," "will," "continue," derivatives of these words, and similar references are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. Actual results, performance or experience may differ materially from those expressed or implied by any forward-looking statement as a result of various risks, uncertainties and other factors, including, but not limited to, risks associated with: whether Vafseo will be commercially available when expected; the potential demand and market potential and acceptance of, as well as coverage and reimbursement related to, Auryxia® and Vafseo, including estimates regarding the potential market opportunity; the competitive landscape for Auryxia and Vafseo, including potential generic entrants; the ability of Akebia to attract and retain qualified personnel; Akebia's ability to implement cost avoidance measures and reduce operating expenses; decisions made by health authorities, such as the FDA, with respect to regulatory filings; the potential therapeutic benefits, safety profile, and effectiveness of Vafseo; the results of preclinical and clinical research; the direct or indirect impact of the COVID-19 pandemic on the markets and communities in which Akebia and its partners, collaborators, vendors and customers operate; manufacturing, supply chain and quality matters and any recalls, write-downs, impairments or other related consequences or potential consequences; and early termination of any of Akebia's collaborations. Other risks and uncertainties include those identified under the heading "Risk Factors" in Akebia's Quarterly Report on Form 10-Q for the quarter ended June 30, 2024, and other filings that Akebia may make with the U.S. Securities and Exchange Commission in the future. These forward-looking statements (except as otherwise noted) speak only as of the date of this press release, and, except as required by law, Akebia does not undertake, and specifically disclaims, any obligation to update any forward-looking statements contained in this press release. Akebia Therapeutics® and Vafseo® are registered trademarks of Akebia Therapeutics, Inc. and its affiliates. Akebia Therapeutics Contact Mercedes Carrasco [email protected] SOURCE Akebia Therapeutics, Inc. WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED