Eplerenone

October 1, 2024 – Santhera Pharmaceuticals (SIX: SANN) announces the positive outcome of the LIONHEART study, confirming vamorolone’s distinctive action also as a mineralocorticoid receptor antagonist, setting it apart from other corticosteroids. The LIONHEART study, an open-label randomized, placebo- and eplerenone-controlled study involving 30 healthy adult male subjects, met its primary endpoint. It demonstrated a statistically significant increase in the urinary sodium/potassium ratio in the vamorolone arm compared to placebo (p<0.0001) following a fludrocortisone challenge. This increased ratio in urine provides clinical evidence for vamorolone’s unique mode of action also as a mineralocorticoid receptor antagonist (MRA) in humans. Combined with its known properties as a dissociative glucocorticoid receptor agonist, these findings further differentiate vamorolone’s pharmacological profile, distinguishing it from other corticosteroids. Cardiac complications such as cardiomyopathy are a leading cause of morbidity and mortality in boys with Duchenne muscular dystrophy (DMD). While treatment with corticosteroids (and ACE inhibitors) has demonstrated a delay in the onset of cardiomyopathy, the addition of MRAs including eplerenone to standard of care has also shown an improvement in left ventricular systolic dysfunction, the benefit of which increases with earlier initiation [1-3]. “Mineralocorticoid receptor antagonists are strongly recommended but late when cardiac function is already reduced and tend to be used in the presence of myocardial fibrosis as detected in magnetic resonance imaging,” explained Prof Karim Wahbi, PhD, MD, Cardiologist at the APHP Hospital Cochin, Paris, France. “What is intriguing about this mechanistic study is whether there is a synergistic benefit of the anti-inflammatory and MRA effects of vamorolone on the evolution of cardiac disease in children who started treatment early or if vamorolone could be of benefit to those who are already experiencing cardiac symptoms and wish to remain on a corticosteroid” “The LIONHEART study is an important milestone to establish the proof of concept for a cardioprotective potential of vamorolone,” stated Shabir Hasham, MD, Chief Medical Officer of Santhera. “We continue to collect data from patients who have been on vamorolone for up to seven years allowing us to better characterize long-term outcomes including any beneficial impact on cardiac complications in DMD.” AGAMREE is a novel drug with a mode of action based on binding to the same receptor as glucocorticoids but modifying its downstream activity. Moreover, it is not a substrate for the 11-β-hydroxysteroid dehydrogenase (11β-HSD) enzymes that may be responsible for local drug amplification and corticosteroid-associated toxicity in local tissues [4-7]. This mechanism has shown the potential to ‘dissociate’ efficacy from steroid safety concerns and therefore AGAMREE is positioned as a dissociative anti-inflammatory drug and an alternative to existing corticosteroids, the current standard of care in children and adolescent patients with DMD [4-7]. In the pivotal VISION-DMD study, AGAMREE met the primary endpoint Time to Stand (TTSTAND) velocity versus placebo (p=0.002) at 24 weeks of treatment and showed a good safety and tolerability profile [4]. The most commonly reported side effects were cushingoid features, vomiting, weight increase and irritability. Side effects were generally of mild to moderate severity. Currently available data show that AGAMREE, unlike corticosteroids, has been shown to be a dual mineralocorticoid antagonist and a dissociative glucocorticoid agonist based on animal experiments [7]. It has no restriction of growth [8] and no negative effects on bone metabolism as demonstrated by normal bone formation and bone resorption serum markers [9]. AGAMREE (vamorolone), an orphan medicinal product, is approved for use in the United States (Prescribing Information), the European Union (Summary of Product Characteristics) and the United Kingdom for the treatment of DMD. The LIONHEART study (SNT-I-VAM-026) is an open label randomized, 3-arm, parallel-group, placebo and eplerenone controlled study to evaluate the mineralocorticoid receptor antagonism (MRA) effect of vamorolone in 30 healthy adult male subjects after challenge with fludrocortisone, a known mineralocorticoid receptor agonist. The primary endpoint was defined as the ratio of sodium to potassium (Na/K) and the corresponding logarithm of the ratio (log10(10*Na/K) in urine at different time-points. Further analysis of the data is ongoing and will be presented at medical conferences. References: [1] Birnkrant et al. (2018) Lancet Neurol. 2018 Apr;17(4):347-361. doi: 10.1016/S1474-4422(18)30025-5. [2] Raman et a. (2015) Lancet Neurol 14: 153–161 doi:10.1016/s1474-4422(14)70318-7 [3] Raman et al. (2017) Orphanet J Rare Dis 12: 39. doi:10.1186/s13023-017-0590-8 [4] Dang UJ et al. (2024) Neurology 2024;102:e208112. doi.org/10.1212/WNL.0000000000208112. Link. [5] Guglieri M et al (2022). JAMA Neurol. 2022;79(10):1005-1014. doi:10.1001/jamaneurol.2022.2480. Link. [6] Liu X et al (2020). Proc Natl Acad Sci USA 117:24285-24293 [7] Heier CR et al (2019). Life Science Alliance DOI: 10.26508 [8] Ward et al., WMS 2022, FP.27 - Poster 71. Link. [9] Hasham et al., MDA 2022 Poster presentation. Link. Duchenne muscular dystrophy (DMD) is a rare inherited X-chromosome-linked disease, which almost exclusively affects males. DMD is characterized by inflammation which is present at birth or shortly thereafter. Inflammation leads to fibrosis of muscle and is clinically manifested by progressive muscle degeneration and weakness. Major milestones in the disease are the loss of ambulation, the loss of self-feeding, the start of assisted ventilation, and the development of cardiomyopathy. DMD reduces life expectancy to before the fourth decade due to respiratory and/or cardiac failure. Corticosteroids are the current standard of care for the treatment of DMD. Santhera Pharmaceuticals (SIX: SANN) is a Swiss specialty pharmaceutical company focused on the development and commercialization of innovative medicines for rare neuromuscular diseases with high unmet medical need. The Company has an exclusive license from ReveraGen for all indications worldwide to AGAMREE® (vamorolone), a dissociative steroid with novel mode of action, which was investigated in a pivotal study in patients with Duchenne muscular dystrophy (DMD) as an alternative to standard corticosteroids. AGAMREE for the treatment of DMD is approved in the U.S. by the Food and Drug Administration (FDA), in the EU by the European Medicines Agency (EMA), and in the UK by the Medicines and Healthcare products Regulatory Agency (MHRA). Santhera has out-licensed rights to AGAMREE for North America to Catalyst Pharmaceuticals and for China to Sperogenix Therapeutics. For further information, please visit www.santhera.com. The content above comes from the network. if any infringement, please contact us to modify.

2024年9月1日，拜耳在2024 年欧洲心脏学会大会（ESC）上，公布了非奈利酮（finerenone）在III 期FINE-HEART研究的汇总分析，以及FINEARTS-HF试验最新数据；显示finerenone 可显著降低全因死亡、心血管和肾脏结局，其研究结果同时发表在《自然医学》上。 关于FINE-HEART FINE-HEART是一项试验汇总性的患者水平分析，纳入FINEARTS-HF、FIDELIO和FIGARO三项研究；该分析旨在探索 finerenone (商品名：Kerendia/Firialta) 对约 19,000 名患有心力衰竭 (HF) 和/或慢性肾病 (CKD) 和 2 型糖尿病 (T2D)患者心血管和肾脏结局的影响，包括合并症负担较重的患者——这是 HF 患者和左心室射血分数 (LVEF) ≥40% 的主要特征。 其中，FIDELIO-DKD 和FIGARO-DKD 试验共随机选择了 48 个国家的约13,000 名患有白蛋白尿 (UACR≥30mg/g) 的CKD 和 T2D 患者。FINEARTS-HF 纳入了来自 37 个国家的约 6,000 名有症状性 HF 且 LVEF ≥40%、利钠肽升高和有结构性心脏病证据的患者；结果显示： 在主要终点上， 与安慰剂组相比，使用 finerenone 治疗的患者心血管 (CV) 死亡在数值上较低，但几乎未达到统计学意义（相对风险降低 11%，HR 0.89 [95% CI, 0.78-1.01; p=0.076]）。 对包括心血管死亡和未确定死亡在内的主要终点的预定敏感性分析中，使用finerenone 的相对风险降低了 12%（HR 0.88 [95% CI, 0.79-0.98; p=0.025]）。 6 个亚组中，finerenone对心血管（CV）死亡的影响基本一致。 与安慰剂相比，finerenone 显着降低了全因死亡以及心血管和肾脏结果。 在次要终点上， Finerenone 将全因死亡率降低了 9%（HR 0.91 [95% CI，0.84-0.99；p=0.027]）； 使用 finerenone 后，首次出现肾衰竭的时间、eGFR 较基线持续下降≥50%（≥4 周）或肾死亡的综合肾脏终点降低了 20%（HR 0.80 [95% CI, 0.72-0.90; p<0.001]），HF 住院发生率降低了 17%（HR 0.83 [95% CI, 0.75-0.92; p<0.001]）。 关于Finerenone Finerenone（BAY948862）是一种研究性非甾体选择性盐皮质激素受体拮抗剂，它能够阻断盐皮质激素受体（MR）的过度激活。MR 的过度激活可能导致纤维化和炎症，而纤维化和炎症是导致肾脏永久性结构损伤的因素之一。2021 年7月，美国FDA 已批准 finerenone 上市，用于在伴有慢性肾病的2 型糖尿病患者中，降低肾衰竭风险、延缓估算肾小球滤过率的下降速度，降低心血管死亡，非致死性心肌梗塞，以及因为心力衰竭住院的风险。 FINEARTS-HF：是一项随机、双盲、安慰剂对照、多中心、事件驱动的Ⅲ期临床研究，适用于诊断为症状性心力衰竭（纽约心脏协会 II-IV 级）且在过去 12 个月内以任何方式测量左心室射血分数 (LVEF) ≥40% 的患者，以及在随机分组前至少接受 30 天利尿剂治疗的患者；根据2024 ESC披露的最新数据，在32 个月的持续时间内，finerenone 显着降低了心血管死亡和总HF事件（定义为 HF 住院或紧急 HF 就诊）综合主要终点的风险，降低了 16%（相对风险降低，比率 (RR) 0.84 [95% CI，0.74-0.95；p=0,0072]）。根据8月份披露的数据，其中大约一半的HF患者LVEF轻度降低或保留。 Finerenone 是首个在 III 期研究中证明对这种常见心力衰竭患者具有明确心血管益处的 MR 拮抗剂。基于上述积极结果，公司计划与美国FDA 讨论递交监管申请，扩展finerenone的适应症。 FIGARO-DKD：2021 年8 月，拜耳宣布 finerenone 在伴有慢性肾病的2 型糖尿病患者中进行的3 期临床试验FIGARO-DKD 中达到主要终点。与此前的3 期临床试验不同，FIGARO-DKD 的主要患者患有症状较轻的1-2 级CKD。在这项研究中，在已经接受最大耐受剂量血管紧张素转换酶抑制剂（ACEi）或血管紧张素受体阻滞剂（ARB）的情况下，使用finerenone 将伴有CKD 的2型糖尿病患者首次出现心血管死亡或非致死心血管事件的风险降低了13%。 FIDELIO-DKD：FIDELIO-DKD研究是一项随机、双盲、安慰剂对照、平行组、多中心、事件驱动的Ⅲ期临床研究，将T2DM合并CKD患者（中国患者372例）按1∶1随机接受finerenone或安慰剂，每天1次口服。根据在2020年美国肾脏病年会肾脏周上重磅公布的数据，结果显示：相比安慰剂，finerenone显著降低主要肾脏事件复合终点风险达18% （HR=0.82，95%CI 0.73~0.93，P=0.001），显著降低主要心血管事件复合终点风险达14%（HR=0.86，95%CI 0.75~0.99，P=0.03）。采用finerenone治疗4个月后，尿白蛋白/肌酐比值相比基线降低达31%，并持续维持较低水平，显著降低次要肾脏事件复合终点（HR=0.76；95%CI 0.65~0.90）。 此外，finerenone用于更广泛心衰和慢性肾病患者的多项研究也正在进行中，包括MOONRAKER项目和FIND-CKD研究等。MOONRAKER项目包括FINEARTS-HF研究、REDEFINE-HF研究、CONFIRMATION-HF研究和FINALITY-HF研究等4项研究，纳入超过15000例患者，是迄今为止规模最大的心衰研究项目之一，旨在评估非奈利酮用于广泛心衰患者[包括HFrEF、HFmrEF、HFpEF和心衰住院患者(不考虑左心室射血分数)]的疗效和安全性。FIND-CKD研究为一项多中心、随机、双盲、安慰剂对照的III期临床研究，将纳入包括中国在内的19个国家270个中心的非糖尿病CKD患者，研究目的在于探索在指南推荐疗法基础上加用finerenone治疗非糖尿病慢性肾病的疗效和安全性。 关于盐皮质激素受体拮抗剂 盐皮质激素是一类由肾上腺皮质球状带细胞分泌的类固醇激素，其中，醛固酮是最常见的一种。醛固酮的分泌受到多种因素的调控，主要包括肾素-血管紧张素-醛固酮系统(RAAS)调节，以及促肾上腺皮质激素、Na+、K+水平等多种因素的影响。当小管液中Na+浓度降低、血压下降或肾血流量减少时，这些因素会刺激肾素释放入血，激活血管紧张素Ⅱ，血管紧张素Ⅱ会刺激醛固酮的合成和分泌。醛固酮通过增强Na+-K+交换及提高膜对Na+的通透性等途径，促进肾小管对Na+的重吸收，同时伴随水的重吸收增加，维持水盐代谢平衡。但是醛固酮过量释放会引起代谢紊乱，包括低血钾、钠水潴留等，同时还促使炎症因子生成，导致靶器官炎症和纤维化。另外，过量的醛固酮会过度活化MR并介导靶器官的病理损害。 醛固酮与MR结合发挥作用。MR广泛分布于多处组织，参与局部物质代谢以及病理损伤的调控，在肾脏及心血管系统中表达最为显著。MR过度激活促进了活性氧的产生，还引发了促炎转录因子如激活蛋白-1和核因子κB等的激活，诱发炎症反应。此外，MR过度激活还参与促纤维化分子的表达，其中包括转化生长因子-β1和纤溶酶原激活物抑制物-1等，这些因子共同促进组织纤维化的发生。除了引发炎症和纤维化反应外，MR的过度激活还能激活免疫系统，导致白细胞浸润等。 在肾脏中，MR过度激活会促进氧化应激、炎症和纤维化的进一步加剧，诱导足细胞损伤，收缩肾小球血管等，导致肾功能逐渐下降，最终进入ESRD。在心脏中，醛固酮介导的MR过度活化也能诱发类似的炎症、纤维化及氧化应激反应，最终导致心力衰竭、恶性心律失常和心肌梗死等不良结局。 因此，盐皮质激素受体拮抗剂（MRA）作为利尿剂调节水、电解质平衡，可用于治疗原发性醛固酮增多症、高血压、心力衰竭（HF）和慢性肾脏病（CKD）等。目前，临床上最常用的MRA 是螺内醋，属于甾体类化合物，由于它对MR 的选择性低，在肾脏中分布的浓度是心脏的6 倍，因此服用后高钾血症的发生率高。依普利酮为第二代MRA，也是甾体类结构，但对MR 的选择性高，抗醛固酮活性较螺内酯强，副作用也低。第三代MRA以非奈利酮为代表，具有非甾体类结构，对MR 的选择性高，在心脏和肾脏平衡分布，不易产生高钾血症。 MRA药物的最新研究进展 关于糖尿病肾病 糖尿病肾病是糖尿病最重要的并发症之一，是引起慢性肾病和终末期肾病（ESRD）的主要原因。约1/3的糖尿病患者会发展为糖尿病肾病，若合并出现大量蛋白尿，大约5年会进展至终末期肾病。根据2021年IDF数据，2021年，全球约5.37亿成年人（年龄20-79周岁）患有糖尿病，占成年人总人口的1/10，预计2045年将增长至7.83亿，占比12.2%。 根据Kenneth Research报告，2018年全球糖尿病肾病治疗药物市场规模为27亿美元，到2024年GAGR将保持在5.9%达到38亿美元，如下图所示（单位：十亿美元）。 参考资料 1、符灵智,许剑峰,马彦卓,等.盐皮质激素受体拮抗剂的研究进展[J].国际心血管病杂志,2024,51(02):69-73. 2、闻悦伽,周小春,王俭勤.盐皮质激素受体拮抗剂在糖尿病肾病治疗中的应用进展[J].生命的化学,2023,43(12):1914-1921.DOI:10.13488/j.smhx.20230673. 3、心关注 药渡媒体商务合作 媒体公关 | 新闻&会议发稿 张经理：18600036371（微信同号） 点击下方“药渡“，关注更多精彩内容 免责声明 “药渡”公众号所转载该篇文章来源于其他公众号平台，主要目的在于分享行业相关知识，传递当前最新资讯。图片、文章版权均属于原作者所有，如有侵权，请及时告知，我们会在24小时内删除相关信息。 微信公众号的推送规则又双叒叕改啦，如果您不点个“在看”或者没设为"星标"，我们可能就消散在茫茫文海之中~点这里，千万不要错过药渡的最新消息哦！👇👇👇