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In patients with Cushing’s syndrome maintained on Recorlev, a lower baseline mUFC was associated with higher cortisol normalization rate. Lower mUFC at baseline was also associated with lower maintenance dose requirements and lower rates of potentially clinically important liver-related adverse events and liver test abnormalities. The SONICS study previously showed that Recorlev treatment was effective at normalizing cortisol across the spectrum of Cushing’s syndrome severity. CHICAGO--(BUSINESS WIRE)-- Xeris Biopharma Holdings, Inc. (Nasdaq: XERS), a growth-oriented biopharmaceutical company committed to improving patients’ lives by developing and commercializing innovative products across a range of therapies, today announced it presented a post-hoc analysis from its previously published SONICS study on the effects of levoketoconazole (Recorlev®) in adults with Cushing’s syndrome at ENDO 2024 in Boston, June 1-4, 2024. “The results of this analysis suggest that patients with Cushing’s syndrome/disease with lower mUFC(s) normalize at a higher rate than those with more severe disease and may require lower doses of Recorlev and experience lower rates of liver-related adverse events. This exploratory analysis brings further perspective to the importance of individualizing and tailoring medical management,” said James Meyer, PharmD, Xeris’ Senior Director, Publications and Medical Communications. Title: Effects of Levoketoconazole on 24-hour Mean UFC (mUFC) in the SONICS Study: Relation to Baseline mUFC in Adults with Cushing’s Syndrome: A Post-hoc Analysis (SAT-085) This post-hoc exploration included all enrolled patients in SONICS who were treated and had a post-baseline mUFC, aiming to further elucidate relationships between baseline biochemical disease severity, drug dose, and intermediate-term mUFC response. For the current analyses, 92 patients treated with levoketoconazole and with baseline mUFC measurement (modified ITT) were stratified into 3 baseline mUFC subgroups: Group 1 (≤ 2.5x upper limit of normal (ULN)); Group 2 (>2.5x to ≤ 5x ULN); or Group 3 (>5x ULN) and analyzed in respect to mUFC response, average daily dose, and adverse events following 6 months of maintenance therapy. Groups 1 and 2 were similar in baseline characteristics; whereas Group 3 differed with younger age, fewer female participants, more recently diagnosed, and more frequently on prior therapy. Group 2 (Baseline mUFC 267.9 nmol/D) had the highest apparent mUFC response rate (12/33 [36.4%]), 95% CI 0.20, 0.54) as compared with Group 1 (Baseline mUFC 498.7 nmol/D) (12/38 [31.6%], 95% CI 0.16, 0.47) or Group 3 (Baseline mUFC 1672.8 nmol/D) (5/21 [23.8%]; 95% CI 0.01, 0.55); Group 3 having a notably lower response. Daily doses of levoketoconazole were related to baseline mUFC. Thus, Group 3 used a nominally higher average daily dose (631 mg and 741 mg) during maintenance therapy and at the last dose in the 6-month maintenance phase (regardless of completion status) than Group 1 (475 mg and 545 mg) or Group 2 (548 mg and 611 mg). Group 3 had more liver-related AEs of special interest than Group 1 or 2 (14% vs 7.9% or 3.0%) and more AEs leading to discontinuation (24% vs 12% or 16%). Group 3 had a higher incidence of liver test (ALT, AST, GGT) abnormalities compared to Group 1 and Group 2. This post hoc analysis demonstrated: Normalization of mUFC with levoketoconazole in Cushing’s syndrome patients maintained on levoketoconazole in the SONICS study for up to 6 months appeared to vary inversely with baseline mUFC. Lower mUFC at baseline was also associated with lower maintenance dose requirements and lower rates of potentially clinically important liver-related AEs and liver test abnormalities. Whether observed baseline characteristic differences between the highest tertile of baseline mUFC and the 2 lower tertiles were simply coincidental to or confounders or mediators of the described relationships with mUFC remains to be explored. About Cushing’s Syndrome Endogenous Cushing’s syndrome is a rare, serious, and potentially fatal endocrine disease caused by chronic elevated cortisol exposure–often the result of a benign tumor of the pituitary gland. This benign tumor tells the body to overproduce high levels of cortisol for a sustained period of time, which often results in characteristic physical signs and symptoms that are distressing to patients. The disease is most common among adults between the ages of 30–50, and it affects women three times more often than men. Women with Cushing's syndrome may experience a variety of health issues including menstrual problems, difficulty becoming pregnant, excess male hormones (androgens), primarily testosterone, which can cause hirsutism (growth of coarse body hair in a male pattern), oily skin, and acne.3 Additionally, the multisystem complications of the disease are potentially life threatening. These include metabolic changes such as high blood sugar or diabetes, high blood pressure, high cholesterol, fragility of various tissues including blood vessels, skin, muscle, and bone, and psychological disturbances such as depression, anxiety, and insomnia.3 Untreated, the five-year survival rate is only approximately 50%.4 About Recorlev® Recorlev® (levoketoconazole) is a cortisol synthesis inhibitor for the treatment of endogenous hypercortisolemia in adult patients with Cushing’s syndrome for whom surgery is not an option or has not been curative.1 Endogenous Cushing’s syndrome is a rare but serious and potentially lethal endocrine disease caused by chronic elevated cortisol exposure.2 Recorlev is the pure 2S,4R enantiomer of ketoconazole, a steroidogenesis inhibitor.1 Recorlev has demonstrated in two successful Phase 3 studies to significantly reduce mean urine free cortisol.1 The Phase 3 program for Recorlev included SONICS and LOGICS, two multinational studies designed to evaluate the safety and efficacy of Recorlev when used to treat endogenous Cushing’s syndrome. The SONICS study met its primary and secondary endpoints, significantly reducing and normalizing mean urinary free cortisol concentrations without a dose increase.1,2 The LOGICS study, which met its primary endpoint and key secondary endpoint, was a double-blind, placebo-controlled randomized-withdrawal study of Recorlev that was designed to supplement the efficacy and safety information provided by SONICS.1 The ongoing open-label OPTICS study will gather further useful information related to the long-term use of Recorlev. Recorlev was approved by the US FDA in December 2021 and received orphan drug designation from the FDA and the European Medicines Agency for the treatment of endogenous Cushing's syndrome. Indication & Important Safety Information for Recorlev® BOXED WARNING: HEPATOTOXICITY AND QT PROLONGATION HEPATOTOXICITY Cases of hepatotoxicity with fatal outcome or requiring liver transplantation have been reported with oral ketoconazole. Some patients had no obvious risk factors for liver disease. Recorlev is associated with serious hepatotoxicity. Evaluate liver enzymes prior to and during treatment. QT PROLONGATION Recorlev is associated with dose-related QT interval prolongation. QT interval prolongation may result in life-threatening ventricular dysrhythmias such as torsades de pointes. Perform ECG and correct hypokalemia and hypomagnesemia prior to and during treatment. INDICATION Recorlev is a cortisol synthesis inhibitor indicated for the treatment of endogenous hypercortisolemia in adult patients with Cushing’s syndrome for whom surgery is not an option or has not been curative. Limitations of Use Recorlev is not approved for the treatment of fungal infections. CONTRAINDICATIONS Cirrhosis, acute liver disease or poorly controlled chronic liver disease, baseline AST or ALT > 3 times the upper limit of normal, recurrent symptomatic cholelithiasis, a prior history of drug induced liver injury due to ketoconazole or any azole antifungal therapy that required discontinuation of treatment, or extensive metastatic liver disease. Taking drugs that cause QT prolongation associated with ventricular arrythmias, including torsades de pointes. Prolonged QTcF interval > 470 msec at baseline, history of torsades de pointes, ventricular tachycardia, ventricular fibrillation, or prolonged QT syndrome. Known hypersensitivity to levoketoconazole, ketoconazole or any excipient in Recorlev. Taking certain drugs that are sensitive substrates of CYP3A4 or CYP3A4 and P-gp. WARNINGS AND PRECAUTIONS Hepatotoxicity Serious hepatotoxicity has been reported in patients receiving Recorlev, irrespective of the dosages used or the treatment duration. Drug-induced liver injury (peak ALT or AST greater than 3 times upper limit of normal) occurred in patients using Recorlev. Avoid concomitant use of Recorlev with hepatotoxic drugs. Advise patient to avoid excessive alcohol consumption while on treatment with Recorlev. Routinely monitor liver enzymes and bilirubin during treatment. QT Prolongation Use Recorlev with caution in patients with other risk factors for QT prolongation, such as congestive heart failure, bradyarrythmias, and uncorrected electrolyte abnormalities, with more frequent ECG monitoring considered. Routinely monitor ECG and blood potassium and magnesium levels during treatment. Hypocortisolism Recorlev lowers cortisol levels and may lead to hypocortisolism with a potential for life-threatening adrenal insufficiency. Lowering of cortisol levels can cause nausea, vomiting, fatigue, abdominal pain, loss of appetite, and dizziness. Significant lowering of serum cortisol levels may result in adrenal insufficiency that can be manifested by hypotension, abnormal electrolyte levels, and hypoglycemia. Routinely monitor 24-hour urine free cortisol, morning serum or plasma cortisol, and patient’s signs and symptoms for hypocortisolism during treatment. Hypersensitivity Reactions Hypersensitivity to Recorlev has been reported. Anaphylaxis and other hypersensitivity reactions including urticaria have been reported with oral ketoconazole. Risks Related to Decreased Testosterone Recorlev may lower serum testosterone in men and women. Potential clinical manifestations of decreased testosterone concentrations in men may include gynecomastia, impotence and oligospermia. Potential clinical manifestations of decreased testosterone concentrations in women include decreased libido and mood changes. ADVERSE REACTIONS Most common adverse reactions (incidence > 20%) are nausea/vomiting, hypokalemia, hemorrhage/contusion, systemic hypertension, headache, hepatic injury, abnormal uterine bleeding, erythema, fatigue, abdominal pain/dyspepsia, arthritis, upper respiratory infection, myalgia, arrhythmia, back pain, insomnia/sleep disturbances, and peripheral edema. DRUG INTERACTIONS Consult approved product labeling for drugs that are substrates of CYP3A4, P-gp, OCT2, and MATE prior to initiating Recorlev. Sensitive CYP3A4 or CYP3A4 and P-gp Substrates: Concomitant use of Recorlev with these substrates is contraindicated or not recommended. Atorvastatin: Use lowest atorvastatin dose possible and monitor for adverse reactions for dosages exceeding 20 mg daily. Metformin: Monitor glycemia, kidney function, and vitamin B12 and adjust metformin dosage as needed. Strong CYP3A4 Inhibitors or Inducers: Avoid use of these drugs 2 weeks before and during Recorlev treatment. Gastric Acid Modulators: See Full Prescribing Information for recommendations regarding concomitant use with Recorlev. USE IN SPECIFIC POPULATIONS Lactation: Advise not to breastfeed during treatment and for one day after final dose. To report SUSPECTED ADVERSE REACTIONS, contact Xeris Pharmaceuticals, Inc. at 1-877-937-4737 or FDA at 1-800-FDA-1088 or . Please see Full Prescribing Information including Boxed Warning. About Xeris Xeris (Nasdaq: XERS) is a growth-oriented biopharmaceutical company committed to improving patient lives by developing and commercializing innovative products across a range of therapies. Xeris has three commercially available products; Gvoke®, a ready-to-use liquid glucagon for the treatment of severe hypoglycemia, Keveyis®, a proven therapy for primary periodic paralysis, and Recorlev® for the treatment of endogenous Cushing’s syndrome. Xeris also has a robust pipeline of development programs to extend the current marketed products into important new indications and uses and bring new products forward using its proprietary formulation technology platforms, XeriSol™ and XeriJect®, supporting long-term product development and commercial success. Xeris Biopharma Holdings is headquartered in Chicago, IL. For more information, visit , or follow us on X, LinkedIn, or Instagram. Forward-looking Statement Any statements in this press release other than statements of historical fact are forward-looking statements. Forward-looking statements include, but are not limited to, statements about future expectations, plans and prospects for Xeris Biopharma Holdings, Inc. including statements regarding expectations for the release of clinical data, post hoc analyses or results from clinical trials, including the SONICS study, the market and therapeutic potential of its products and product candidates, including the levoketoconazole (Recorlev®), the potential utility of its formulation platforms and other statements containing the words “will,” “would,” “continue,” “expect,” “should,” “anticipate” and similar expressions, constitute forward-looking statements within the meaning of The Private Securities Litigation Reform Act of 1995. These forward-looking statements are based on numerous assumptions and assessments made in light of Xeris’ experience and perception of historical trends, current conditions, business strategies, operating environment, future developments, geopolitical factors, and other factors it believes appropriate. By their nature, forward-looking statements involve known and unknown risks and uncertainties because they relate to events and depend on circumstances that will occur in the future. The various factors that could cause Xeris’ actual results, performance or achievements, industry results and developments to differ materially from those expressed in or implied by such forward-looking statements, include, but are not limited to, its financial position and need for financing, including to fund its product development programs or commercialization efforts, whether its products will achieve and maintain market acceptance in a competitive business environment, its reliance on third-party suppliers, including single-source suppliers, its reliance on third parties to conduct clinical trials, the ability of its product candidates to compete successfully with existing and new drugs, and its and collaborators’ ability to protect its intellectual property and proprietary technology. No assurance can be given that such expectations will be realized and persons reading this communication are, therefore, cautioned not to place undue reliance on these forward-looking statements. Additional risks and information about potential impacts of financial, operational, economic, competitive, regulatory, governmental, technological, and other factors that may affect Xeris can be found in Xeris’ filings, including its most recently filed Annual Report on Form 10-K filed with the Securities and Exchange Commission, the contents of which are not incorporated by reference into, nor do they form part of, this communication. Forward-looking statements in this communication are based on information available to us, as of the date of this communication and, while we believe our assumptions are reasonable, actual results may differ materially. Subject to any obligations under applicable law, we do not undertake any obligation to update any forward-looking statement whether as a result of new information, future developments or otherwise, or to conform any forward-looking statement to actual results, future events, or to changes in expectations. 1. Recorlev [prescribing information]. Chicago, IL: Xeris Pharmaceuticals, Inc.; 2021. 2. Fleseriu M, et al. Lancet Diabetes Endocrinol. 2019;7(11):855-865. 3. Pivonello R et al. Lancet Diabetes Endocrinol. 2016; 4: 611-29. 4. Plotz CM, et al. Am J Med. 1952 November;13(5):597-614. Recorlev®, Xeris Pharmaceuticals®, Xeris CareConnectionTM, Keveyis®, Gvoke®, and Ogluo® are trademarks owned by or licensed to Xeris Pharmaceuticals, Inc. PANTHERx Rare Pharmacy is a service mark of PANTHERx Rare, LLC. All other trademarks referenced herein are the property of their respective owners. All rights reserved. US-PR-22-00001 1/22

作者｜景言 近 30 年来，随着生活水平的提高，我国高脂血症患病率明显增加。自从他汀类药物问世以来，高胆固醇的问题解决大半。依折麦布作为首个胆固醇吸收抑制剂，它的发现可以说实力与运气并存，研发人员在无心插柳之时发现了这项足以改变后世降脂方案的用药。令人深思的是其设计研究的过程中没有任何已知的靶点可供参考，是一种完全基于受体外、脱离受体模型的研究方式，是一种“早于受体的抑制剂”。其所走过的路径提供了开拓思维的借鉴意义，本文通过分享其研发与验证的小故事，希望为新药研发领域带来一些启发。 图1：依折麦布的研发历程概览  01  依折麦布的研发历程一直以来，对于药物研发的基本思路是首先发现某一作用靶点，进而研究其增强或抑制剂，再通过不断优化其有机结构完成某一新药的研发与推广。而依折麦布作为首个胆固醇吸收抑制剂，其上市时间远早于其靶点受体的发现，这一不走寻常路的药物研发成为了医疗制药领域的轶事。20世纪80年代末，医药巨头默沙东公司研发的洛伐他汀横空出世，其强大的治疗效果使其名利双收，从此制药领域引发了降脂药物的研发热潮。 图2: 洛伐他汀在这次热潮中，先灵葆雅公司将注意力放在了ACAT上——其是催化胆固醇重新酯化进而进入人体的关键酶。他们以ACAT抑制剂为起点，设计优化分子结构并进行有机结构的改进和筛选，再通过生物测试验证其降脂效果。然而结果却不尽如人意，实际治疗效果远远达不到预期。但在研究过程中得到的一个产率不到5%的副产物有着意想不到的降脂活性。然而这一产物虽然在体外有着优异的ACAT抑制作用，但是在体试验中，对试验动物的高脂血症治疗效果收效甚微。频繁出现的体内和体外疗效差异使得先灵葆雅公司高层在再三讨论后，决定放弃体外试验，直接在试验动物体内开展在体试验进行药物筛选。但随着研究的进展，高额的科研支出并没有换来满意的结果，最终公司决定终止这一研究，以收集数据、发表文章作为项目的收尾。峰回路转，在实验组撰写论文、收集数据时，补充做了两组新化合物的实验，意外的发现这两个化合物具有很强的在体效果，对血脂的降低作用达到了更高的疗效。在此基础上，研究组进一步探索，最终在仓鼠的胆管中发现了与之类似且活性更高的代谢产物，进而对这种复合物进行化学修饰，并研制成了早期的“依折麦布”。然而以动物实验为基础的在体实验由于缺乏相关的机制基础，不仅缺乏分子层面的支持，而且在人体和仓鼠之间的异质性问题也没有得到解决。但先灵葆雅公司决定放手一搏，跳过机制研究直接进行临床试验。幸运的是依折麦布在临床试验中表现出了优异的疗效，并存在更加宽广的安全窗口。但造化弄人，依折麦布的上市又将是一个极具挑战的问题。辉瑞公司在1996年上市的阿托伐他汀（立普妥）的强大降脂作用为整个医药行业的降脂药物研发拉高了门槛。这对只能降低15%左右胆固醇的依折麦布来说是一条难以逾越的鸿沟。于是依折麦布的研发上市再次被先灵葆雅公司搁置。 图3: 阿托伐他汀（立普妥）由于立普妥现象级的降脂效果，导致新型他汀类降脂药物的优化在其面前就好似蚍蜉撼树，此时“同是天涯沦落人”的默沙东找到先灵葆雅，由默沙东牵头开展了他汀类药物与依折麦布的联合治疗。令人惊喜的是，两者的联合应用显示出了很好的协同效应导致了更强的降脂效果，更为重要的是他汀与依折麦布的联合应用减少了他汀的使用量，一定程度上避免了他汀大量使用导致的肌肉疼痛等症状。而此时，依折麦布的作用机制以及靶点仍属未知。在临床试验期间，两家公司合力攻坚终于弄清楚依折麦布的作用靶点，同时首次发现胃肠道的胆固醇吸收受体NPC1L1。 图4  02  胆固醇的吸收途径体内胆固醇主要来源于两个方面。一方面是内源性的，主要在肝脏中乙酰辅酶A在羟甲基戊二酸单酰辅酶A（HMG-COA）和角鲨烯单加氧酶（SM）限速酶的作用下，经酶促反应从头合成。他汀类药品作用机制为抑制HMG-COA还原酶以减少内源性胆固醇的生成，实现降低胆固醇的作用。另一方面是外源性的，即食物中胆固醇的吸收和由肝脏分泌的胆汁。而饮食来源的胆固醇约占全部胆固醇的50%。进入肠道的食物胆固醇是酯化胆固醇，必须经消化液中胆固醇酯酶的水解，使之变为游离胆固醇后才能被吸收。游离胆固醇通过形成混合乳糜微粒，与小肠刷状缘充分接触并被其表面的NPC1L1介导进入上皮细胞内，在酰基辅酶A胆固醇酰基转移酶（ACAT）的作用下又重新酯化，生成胆固醇酯，最后与载脂蛋白一起组成乳糜微粒经由淋巴管、胸导管进入循环血液。一般认为空肠起始段和部分回肠是胆固醇吸收的主要部位。上述即为胆固醇吸收的主要途径。 图5：胆固醇吸收机制示意图此外，小肠近腔侧除了具有NPC1L1之外还有ABCG5/G8等诸多转运蛋白共同辅助完成胆固醇吸收过程。例如ABCG5/G8将ACAT难以酯化的胆固醇（部分植物来源胆固醇）排出体外。因此，有关NPC1L1和ACAT的探索长久以来都是降脂研究的热点。  03  机制与受体的验证先灵葆雅随后在Science上发表文章阐明NPC1L1受体的存在以及依折麦布对其的抑制作用。 图6在人体中，胆固醇的吸收发生在小肠近端空肠，在那里膳食胆固醇和胆汁胆固醇都可以从肠腔吸收。胆固醇吸收的二级动力学、其甾醇特异性以及依折麦布的抑制作用都表明，这一过程是由一种特定的转运蛋白介导的。然而，这种假定的胆固醇转运体的身份仍然难以捉摸。为了确定参与胆固醇摄取的基因，研究者准备了两个cDNA文库进行测序，一个来自大鼠空肠粘膜，另一个来自激光捕获显微解剖分离的空肠肠细胞。将从这些文库中获得的16500个表达序列标签(est)与所有公开的大鼠est相结合，并将大鼠序列与小鼠和人类数据进行交叉比对进行注释。该序列数据库分析了含有胆固醇转运体中预期特征的所有转录本，即预测跨膜结构域、细胞外信号肽、n链糖基化位点以及已知胆固醇相互作用基序(如胆固醇传感结构域)的序列。从这个分析中只有一个可信的候选基因:NPC1L1的大鼠同源基因。而NPC1L1缺失小鼠对胆固醇吸收抑制剂依折麦布完全不敏感，提示NPC1L1或相关蛋白可能是该药物的分子靶点。 图7：NPC1L1的发现之后，我国著名学者宋保亮院士团队也在Cell子刊上面发表了NPC1L1受体的工作机制。 图8简言之，即细胞膜上的NPC1L1受体通过携带胆固醇，向胞内形成与网格蛋白形成网格蛋白复合体，在微丝和肌动蛋白的牵拉下以胞吞的形式进入细胞内吸收胆固醇，而NPC1L1再次回到细胞膜准备下一次的吸收过程。依折麦布的作用则是抑制NPC1L1的内陷，组织网格蛋白复合体的形成，从而抑制胆固醇的吸收。 图9：NPC1L1吸收胆固醇及依折麦布作用机制  写在最后  作为现代新型降脂药物的代表，依折麦布的研发和上市过程可谓是一波三折，但正因如此使之成为医疗制药行业一段脍炙人口的佳话。依折麦布的成功背后离不开研发人员严谨求实的科学态度和及锋而试不离不弃的坚守，企业高层的放手一搏和超凡魄力也常让人不禁为之暗生敬意，拍手叫绝。谨以此则小故事向诸敢想、敢干、肯坚持、不放弃的科研学者和为人类福祉谋进步的制药企业致敬与学习。Reference1.Scott W. Altmann et al. ,Niemann-Pick C1 Like 1 Protein Is Critical for Intestinal Cholesterol Absorption. Science303,1201-1204(2004).DOI:10.1126/science.10931312.Cannon CP, et al. Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes. N Engl J Med. 2015 Jun 18;372(25):2387-97. doi: 10.1056/NEJMoa14104893.Ge L, Wang J, Qi W, Miao HH, Cao J, Qu YX, Li BL, Song BL. The cholesterol absorption inhibitor ezetimibe acts by blocking the sterol-induced internalization of NPC1L1. Cell Metab. 2008 Jun;7(6):508-19. doi: 10.1016/j.cmet.2008.04.0014.Sudhop T, Lütjohann D, Kodal A, Igel M, Tribble DL, Shah S, Perevozskaya I, von Bergmann K. Inhibition of intestinal cholesterol absorption by ezetimibe in humans. Circulation. 2002 Oct 8;106(15):1943-8. doi:10.1161/01.cir.0000034044.95911.dc5.Scott W. Altmann et al. ,Niemann-Pick C1 Like 1 Protein Is Critical for Intestinal Cholesterol Absorption.Science303,1201-1204(2004).DOI:10.1126/science.1093131声明：发表/转载本文仅仅是出于传播信息的需要，并不意味着代表本公众号观点或证实其内容的真实性。据此内容作出的任何判断，后果自负。若有侵权，告知必删！长按关注本公众号   粉丝群/投稿/授权/广告等请联系公众号助手 觉得本文好看，请点这里↓