Nadolol

作者｜YY 在坐拥“法力无边”的GLP-1药物semaglutide的同时，诺和诺德也居安思危地扩展其商业领域。 去年以13亿美元收购亨利医药（KBP Biosciences）的心/肾脏病控制高血压药物ocedurenone（图1），就代表着诺和诺德将业务扩展到代谢疾病以外的战略思想。 Ocedurenone的原本目标是成为同类最优的控制高血压治疗药物，然而近期风光无限的诺和诺德却在ocedurenone的Ⅲ期临床研究Clarion-CKD中遭遇失败。 图1. Ocedurenone化学结构。   01   诺和诺德罕见临床失败 诺和诺德日前表示，在研究了ocedurenone的临床数据之后，他们决定终止这一项目。这将造成约 57 亿丹麦克朗（8.2 亿美元）的减值损失（impairment loss）。之所以做出这一决定，是因为独立监督委员会认为ocedurenone未能达到 12 周后改变血压的主要目标。 Clarion-CKD 是一项针对 600 多名患者的临床项目，研究ocedurenone对高血压失控和晚期慢性肾病患者的作用。该试验未达到其主要终点，即从基线到第 12 周收缩压的变化。 去年10 月在宣布这项购买交易时，诺和诺德高管曾表示，他们预测ocedurenone将满足心脏病和慢性肾病患者的巨大需求。诺和诺德在做出终止Clarion-CKD研究之后表示，目前他们正在重新评估ocedurenone针对其它适应症的研究计划。   02   晚期慢性肾病和难治性高血压 晚期慢性肾病（CKD） 患者的疾病负担很重，并伴有严重的合并症，最常见的是高血压。控制高血压对于这些患者来说至关重要，可以降低相关的发病率和死亡率，以及降低心肾风险，但由于使用现有药物存在安全问题，治疗选择有限。 较轻的 CKD 可能多年都无法确诊，而治疗则集中在更明显的高血压、糖尿病和其他合并症问题上。对于那些未患晚期 CKD 的难治性高血压患者来说，螺内酯（spironolactone，商品名Aldactone）比 β 受体阻滞剂（β-blockers，例如Acebutolol，Nadolol，Propranolol等）和 α 受体阻滞剂（α-blockers，例如Cardura，Minipress等）能更有效地降低血压。然而，服用螺内酯会给患者带来安全风险。然后就是依普利酮（Eplerenone），每天服用两次，虽然安全，但降压效果比螺内酯弱得多。患者选择非常有限。 高血压领域已经有 15-20 年没有新药了。 醛固酮合酶抑制剂baxdrostat公布的II期数据令人鼓舞，但对象是正常肾脏人群。此外，双重内皮素受体拮抗剂aprocitentan也是一个有力竞争者。它在 3 期 PRECISION 试验中针对难治性高血压患者表现出非常好的降压效果，但有水肿副作用，这是内皮素受体拮抗剂常见的副作用。   03   OcedurenoneⅢ期临床失败 是该领域的一大遗憾 Ocedurenone为一款非甾体类、第三代盐皮质激素受体拮抗剂（MRA）。 醛固酮（aldosterone）激素在高血压过程中扮演着重要的角色，尤其是在肾源性高血压中特别突出。醛固酮是一种由肾上腺皮质分泌的激素，它主要作用于肾脏内的盐皮质激素受体，调节钠钾的代谢来维持体内的电解质平衡。它的主要生理作用包括促进肾小管对钠的重吸收，同时增加钾和氢离子的排泄。在肾小管的集合管和近曲小管，醛固酮促进钠的再吸收，这导致血容量增加，从而使血压升高。醛固酮可以增强肾素-血管紧张素系统（RAAS）的活性。RAAS的激活会导致血管收缩和钠水潴留，进一步提高血压。在高血压患者中，醛固酮的水平通常升高，尤其是在原发性高血压（特别是肾性高血压）和部分难治性高血压患者中。长期高血压导致肾脏血管损伤，进而刺激醛固酮的释放。同时血压升高导致RAAS系统过度活跃，促使醛固酮的合成和释放增加。醛固酮释放不当升高会导致高血压、心血管和肾脏终末器官损伤和衰竭，因此针对这种病理的药物开发主要集中在两个方向：抑制醛固酮合成，以及阻断盐皮质激素受体 (MR)，醛固酮是MR的内源性配体。 常见类固醇类MRA（盐皮质激素受体拮抗剂）可以抑制醛固酮与MR受体的作用，可以降低“醛固酮逃逸”，但其应用受到高钾血症的风险而被限制。另外， 由于现有类固醇MRA药物对糖皮质激素受体和雄激素受体有作用，导致多种内分泌的不良事件，同样限制了此类药物的广泛应用。 以ocedurenone为代表的第三代非甾体类盐皮质激素受体拮抗剂（Non-steroidal mineralocorticoid receptor antagonists，nsMRA）被FDA认定为一种独特的新型抗高血压药物，也成为了治疗CKD和难治性高血压的新希望。Ocedurenone与甾体类MRA截然不同，特点是半衰期长（约为 60 小时），盐皮质激素受体 (MR) 亲和力高，而对糖皮质激素、孕酮和雄激素受体的结合亲和力很小或为零。它不会进入大脑，没有活性代谢物。 非甾体 MRA 药物esaxerenone（图2）已在日本获批用于治疗高血压，但其对晚期 CKD 患者的疗效尚未经过测试。拜耳的nsMRA药物finerenone在2021年获得了FDA的批准，用于降低 2 型糖尿病（T2D）相关慢性肾病（CKD）成人患者持续 eGFR （估算肾小球滤过率）下降、肾衰竭、心血管死亡、非致命性心肌梗死（MI）和心力衰竭住院的风险，成为获得FDA批准的首例nsMRA类药物，可显著减缓慢性肾病进展并降低 2 型糖尿病相关慢性肾病患者的心血管风险。 图2. nsMRA拮抗剂药物esaxerenone和finerenone化学结构。 虽然两款nsMRA被不同的监管机构批准上市，但患有难治性高血压的晚期CKD仍然缺乏有效的治疗方法。Ocedurenone原本肩负着人们攻克这一顽症的希望，而且也收获了令人鼓舞的II期临床数据，但最终的III期临床却没有能够达到设定的血压临床终点，这不得不说是一个相当大的遗憾。 参考资料： [1] Novo Nordisk stops the ocedurenone CLARION-CKD trial and recognises impairment loss. Novo Nordisk Press Release. 26. 06. 2024. [2] Kresge, N. Novo to Buy Experimental Heart Drug for Up to $1.3 Billion. Bloomberg. 16. 10. 2023. [3] FDA Approves Kerendia. Drugs.com. July. 2021. [4] Ocedurenone: A Novel Therapy for Uncontrolled Hypertension in Advanced Chronic Kidney Disease. European Medical Journal. 16. 03. 2023. 共建Biomedical创新生态圈！ 如何加入BiG会员？

Drug Combination’s Unique Mechanism of Action Enables Reactivation of Brain Adrenergic Function, Showing Improvements in Multiple Areas of Cognition SAN CARLOS, Calif. & LISBON, Portugal--(BUSINESS WIRE)-- CuraSen Therapeutics, Inc., a clinical-stage company developing small molecule therapies to treat neurodegenerative disease, announced that it will present additional positive Phase 2a data with its combination adrenergic activator, CST-2032/CST-107, in patients with mild cognitive impairment (MCI) or mild dementia from either Alzheimer’s or Parkinson’s disease. The oral presentation will take place at AD/PD™ 2024: The International Conference on Alzheimer’s and Parkinson’s Diseases and Related Neurological Disorders, being held March 5-9, 2024, in Lisbon, Portugal. CST-2032 is one of CuraSen’s two lead product candidates being tested in patients with Alzheimer’s and Parkinson’s disease. Both CST-2032 and CST-103, the company’s other lead clinical candidate, are oral, brain-permeant, beta2 adrenoceptor (β2-AR) agonists delivered in combination with CST-107 (nadolol, a brain-sparing beta blocker) to inhibit peripheral effects of β2-AR agonism. Both CST-2032 and CST-103 work by enabling reactivation of brain adrenergic function lost early in the neurodegenerative disease process. The updated Phase 2a data with CST-2032/CST-107 showed statistically and clinically important effects across several cognitive domains in patients with Alzheimer’s and Parkinson’s disease, such as memory, attention, executive function, facial recognition and impulse control — areas known to be impacted by adrenergic function. Target effect sizes of 0.2-0.3 or higher, as seen in this study, predict success in larger, longer studies. “These encouraging data build on earlier results presented at October 2023’s CTAD conference, reinforcing that treatment with CST 2032/CST-107 can produce meaningful quality-of-life cognitive improvements for Alzheimer’s and Parkinson’s patients, particularly those with mild cognitive impairment, rapidly and safely,” said Anthony Ford, PhD, chief executive officer of CuraSen. “The robust, collective data set from both CST-2032 and CST-103 demonstrate that this novel mechanism of action for restoring adrenergic function to the brain is a highly compelling strategy to address unmet symptoms of neurodegeneration. We plan to evaluate additional doses and refine optimal patient profiles in our upcoming Phase 2 studies, with the goal to significantly increase cognitive performance and ultimately, halt disease progression.” The randomized, placebo-controlled, double-blinded crossover study evaluated 64 patients with MCI or mild dementia from either Alzheimer’s disease or Parkinson’s diseases: AD with MCI = 30 patients randomized; 25 completed AD with dementia = 6 patients randomized; 5 completed PD with MCI = 22 patients randomized; 21 completed PD with dementia = 6 patients randomized; 4 completed Data highlights included: Digit Symbol Substitution test, which measures complex attention, memory and executive function: AD patients with MCI = 0.36 effect size; p=0.02 on Day 14 Facial Expression Recognition response time to accurately recognize facial expressions, which measures social cognition: AD patients with MCI = 0.66 effect size; p=0.04 on Day 14 for happy expression and 0.91 effect size; p = 0.01 on Day 14 for surprise expression Stop Signal test, which measures impulse control PD patients with MCI = 0.52 effect size; p=0.04 on Day 14 Excellent safety and tolerability pro /> No serious adverse events: no increases in heart rate observed one to four hours after dose The company plans to initiate longer studies with both CST-2032/CST-107 and CST-103/CST-107 in AD and PD patients with MCI later this year, as well as develop fixed-dose combination tablets for each of these drug candidates. Study Objectives and Design The study objectives were to establish safety and tolerability of CST-2032/CST-107, identify optimal dosing, and identify cognitive tests responsive to agonist stimulus within the two-week dosing period. Measures of cognition included the digit symbol substitution test, Cambridge neuropsychological test battery, and the facial expression recognition task. The study took place at multiple sites in the United States and New Zealand. Patients received either daily 3 mg of CST-2032 with 3 mg of nadolol for 14 days, or matching placebo, followed by a wash-out period (≥7-d) before crossing over to the other treatment arm. Blood samples are being analyzed for AD biomarkers, and DNA samples for AD and PD genotyping. Abstract Details Title: “CST-2032, a Novel Beta-2 Adrenoceptor Agonist, Improves Cognition in Patients with Impairment Due to Alzheimer’s or Parkinson’s Disease” Abstract #: PO34 Presenter: Gabriel Vargas, MD, PhD, chief medical officer, CuraSen Therapeutics Session: Translational Drug Discovery and Experimental Models 05 Date: Saturday, March 9, 2024 Time: 17:25-17:40 UTC, session time,16:40 - 18:40 UTC Location: Auditorium VII About CuraSen Therapeutics CuraSen is focused on the development of new treatments for neurodegenerative diseases, including Parkinson’s disease, Alzheimer’s disease and other related orphan conditions. CuraSen’s drugs are designed to activate certain receptor populations in the brain to compensate for critical neuronal and glial functions that have otherwise been lost due to degeneration and represent a unique approach in the field. The company is evaluating CST-103 and CST-2032, both selective β2-AR agonists, in combination with CST-107, a β-AR blocker, in multiple Phase 2 clinical studies. CST-3056, an α1A-AR agonist, is in preclinical development for the treatment of Alzheimer’s disease. For more information, please visit .