Spironolactone

导读 作为心力衰竭（心衰）的常见并发症，高钾血症不仅影响患者预后，还会干扰肾素-血管紧张素系统抑制剂（RASi）、醛固酮受体拮抗剂（MRA）等药物的合理使用。如何预防和管理高钾血症、如何平衡心衰用药及高钾血症成为心衰临床管理的难题。 11月16日-18日，2024年美国心脏协会科学年会（2024 AHA）在芝加哥盛大召开。全球心血管领域专家学者汇聚一堂，线上线下联动，共同探讨心血管疾病最新研究成果与未来治疗方向。会上，围绕心衰患者高钾血症管理的多项研究陆续披露，现撷取最新资讯以飨读者。 心衰合并高钾血症优化管理前沿进展 MRA是心衰的基石治疗药物之一，被指南推荐用于射血分数降低的心衰（HFrEF）患者1。不同的MRA药物在心衰患者临床结局和高钾血症等安全性结局等方面是否存在差异呢？一项meta分析2对比了螺内酯与依普利酮在心衰合并高钾血症人群中的疗效和安全性，结果显示，相比螺内酯，依普利酮显著改善左心室射血分数，减少左心室收缩末期容积、舒张末期容积，降低全因死亡率。在男性患者中，依普利酮可减少心血管死亡或住院率，以及高钾血症和女性乳房发育不良事件，但无统计学差异，仍需相关临床研究进一步探讨和验证。 图1：依普利酮改善左心室射血分数更具优势 ARTS研究3证实非奈利酮对HFrEF患者血钾水平升高的影响显著小于螺内酯（P < 0.0001-0.0107），而ARTS-HF研究4则证实了非奈利酮在HFrEF患者中的具有与依普利酮类似的高钾血症风险，有4.3%和0.5%的患者血钾水平≥5.6 mmol/或>6.0 mmol/L，FINEARTS-HF研究5比较了非奈利酮与安慰剂在HFmrEF/HFpEF患者中的疗效和安全性，2024 AHA公布的一项研究分析了FINEARTS-HF中非奈利酮对血钾的影响，结果显示，与安慰剂相比，非奈利酮治疗1个月时对血钾的影响为+0.19（0.17-0.21）mmol/l，这一差异在试验期间持续存在，但不增加与高钾血症相关的住院风险，且两组均未出现高钾血症相关死亡。 图2：非奈利酮轻微增加HFmrEF/HFpEF患者血钾水平 MRA等指南指导的药物治疗（GDMT）带来了高钾血症挑战，低钠高钾饮食摄入也增加了高钾血症风险6，导致临床难以缩短指南与实践的差距。2024 AHA大会上，一项针对HFrEF合并高钾血症人群的单中心研究7比较了“Snak-Chat”跨学科干预方案（营养师远程监测优化MRA剂量）与标准护理方案的有效性。1年随访结果显示，与标准护理相比，“Snak-Chat”组达到MRA剂量优化的患者比例显著增加，左心室射血分数显著改善，心衰住院率显著降低，且未出现高钾血症或死亡事件的差异，提示营养师参与的跨学科优化MRA方案具有改善患者预后的优势。 图3：“Snak-Chat”干预方案优化MRA剂量，降低心衰住院率 心衰临床管理仍需破解高钾困局 慢性高钾血症患者往往存在导致血钾升高的基础疾病，如慢性肾脏病、长期服用RAASi类药物的疾病等1。一项队列研究8分析了心衰患者中肾功能障碍、使用GDMT与高钾血症发生率之间的关联，结果显示，心衰患者的高钾血症患病率随肾功能下降而增加，研究认为高钾血症不应作为启动或滴定GDMT的障碍，提出应进一步探索在心衰合并肾功能恶化的情况下提高GDMT利用率同时减少高钾血症的发生。 图4：心衰患者的高钾血症患病率随肾功能而增加 一项纳入超过400万例心衰住院患者的回顾性研究9分析了合并高钾血症心衰患者的预后，结果显示，合并高钾血症的心衰患者将面临更高的室颤和心脏骤停风险，平均住院时间更长、首次入院死亡率更高，多变量分析显示高钾血症是住院死亡的独立危险因素（调整后OR 1.9[1.8-2]，p<0.001）。研究提出应进一步探索新型钾结合剂是否可以改善患者结局。 既往EMPHASIS-HF10、BIOSTAT-CHF11等研究表明，高钾血症可导致心衰患者减量或停用RAASi药物，增加心血管风险，这可能是高钾血症导致不良预后的重要原因。2024 AHA大会公布的研究再次强调了GDMT的基石地位及管理高钾血症的重要性，而本次AHA大会也为临床解决心衰患者高钾血症管理问题带来破局方案。 快速、长期可行：优化心衰高钾管理新趋势 高钾血症风险令医生难以在HFrEF患者中充分使用MRA方案，钾离子结合剂是解决此类棘手问题、确保GDMT落实的可行办法。2024 AHA年会Late Breaking口头演讲重磅披露了REALIZE-K研究12结果，该研究是一项针对HFrEF合并高钾血症普遍/高风险患者的前瞻性、双盲、安慰剂对照试验，也是首个顺利完成的评估环硅酸锆钠（SZC）在此类人群中能否实现快速、长期持续优化MRA的RCT研究。 该研究共纳入366例患者，在开放标签导入（open-label run-in）期间，患者接受了螺内酯滴定（目标：50 mg/天），期间出现高钾血症的患者启动环硅酸锆钠（SZC）治疗。在SZC和螺内酯≥25 mg/天的治疗背景下维持正常血钾（血K+ 3.5-5.0 mEq/L）水平的患者被随机分为继续SZC组或安慰剂组。 研究主要终点为最佳治疗反应百分比（定义为随访1-6个月以来血钾正常、每天接受螺内酯≥25 mg且无高钾血症急诊就诊事件）。关键次要终点包括1）接受任何剂量螺内酯治疗、无高钾血症急诊就诊事件、血钾正常的患者百分比；2）每天接受螺内酯≥25 mg的患者百分比；3）首次高钾血症发作的时间（sK+>5.0 mEq/L）；4）因高钾血症首次减量或停用螺内酯的时间；5）6个月时的KCCQ-CSS。整体安全性终点为不良事件和严重不良事件、生命体征、体检和实验室检查。 在主要终点方面，与安慰剂组相比，SZC组的最佳治疗反应百分比更高（OR 4.45[95%CI 2.89-6.86]，P<0.001；估计%：71% vs. 36%），且在每次随机分组后随访中始终占有优势。排除随机分组时接受15 g剂量SZC（或安慰剂）患者或使用更保守的K+阈值来定义高钾血症（K+≥5.5 mEq/L而不是>5.0 mEq/L）时，SZC带来的最佳治疗反应百分比仍然更高（OR 4.82[95CI 3.03-7.08]，P＜0.001；OR 5.37[95CI 2.97-9.70]，P＜0.001）。 图5：SZC组的最佳治疗反应百分比更高 图6：每次随访中SZC组的最佳治疗反应百分比均更高 图7：调整变量后SZC组的最佳治疗反应百分比仍旧更高 在5个次要关键终点方面，与安慰剂相比，SZC改善了前4个：接受任何剂量螺内酯治疗、无高钾血症急诊就诊事件、血钾正常的患者比例（OR 4.58 [2.78-7.55]，P<0.001；估计%：58% vs. 23%）；螺内酯≥25 mg/天患者比例（OR 4.33 [2.50-7.52]，P<0.001；估计%：81% vs. 50%）；首次高钾血症发作的时间（HR 0.51[0.37-0.71]，P<0.001）；因高钾血症而首次减少/停止螺内酯剂量的时间（HR 0.37[0.17-0.73]，P=0.006）。 图8：次要关键终点对比 在整体安全性终点方面，SZC组与安慰剂组相比不良事件和严重不良事件风险类似。 REALIZE-K研究证实，在HFrEF合并高钾血症患者中，SZC能够在治疗1-6个月期间快速优化螺内酯剂量的情况下，显著增加正常钾血水平患者的百分比，并降低了高钾血症抢救事件和减量/停用螺内酯的风险，这种使用新型钾离子结合剂的策略，为平衡心衰患者MRA方案的临床获益与血钾升高风险带来全新解决办法。 2024 AHA也公布了回顾分析研究GALVANIZE Outcome13的结果，该研究显示，在接受RAASi治疗的患者中，长期使用SZC较短期使用SZC的高钾血症相关住院或急诊就诊率降低44%，高钾血症相关住院率降低41%，高钾血症相关急诊就诊率降低52%（p均<0.01）。这意味着长期SZC方案是一种改善患者结局、减轻患者负担、节约公共卫生资源的优选方案。 图9：长期SZC方案降低高钾血症相关住院/急诊就诊率 高钾血症作为心衰治疗中的一大挑战，限制了MRA等基石药物的应用，增加了患者心血管事件和死亡风险。通过合理使用MRA方案、营养师参与的个体化治疗策略，可有效降低高钾血症风险，确保患者能够接受指南推荐的最佳治疗方案，从而改善其长期预后。REALIZE-K研究的结果为临床寻找既能快速优化MRA方案，又能减少高钾血症风险和患者负担的管理手段提供了线索和参考。 参考资料： 1.《中华内科杂志》编辑委员会,et al.中华内科杂志, 2022,61(9) : 981-999. 2.Eplerenone: The New Standard in Heart Failure Management-Insights Into Improved Ejection Fraction and Reduced Mortality Compared to Spironolactone: A Systematic Review And Meta Analysis.2024 AHA.Presentation Number: Mo2153. 3.PittB,KoberL,PonikowskiP,etal.Eur HeartJ,2013,34(31):2453-2463. 4.SatoN,Ajioka M,etal.CircJ,2016,80(5):1113-1122. 5.Finerenone and Risk of Hyperkalemia in Patients with Heart failure with Mildly Reduced or Preserved Ejection Fraction 6.中国医师协会心血管内科医师分会心力衰竭学组,et al.中华医学杂志, 2021,101(42) : 3451-3458. 7.Breaking the Cycle: 'Snak-Chat' Intervention Transforms Heart Failure Management with MRA Optimization.2024 AHA.Presentation Number: MDP232. 8.Prevalence of Kidney Dysfunction and Hyperkalemia in a Specialized Heart Failure Clinic.2024 AHA.Presentation Number: MDP1213 9.Hyperkalemia In Patients With Heart Failure Correlates to Worse Inpatient Outcomes.2024 AHA.Presentation Number: Su1077 10.EschalierR, et al. J Am Coll Cardiol, 2013, 62(17):1585-1593. 11.BeusekampJC, et al. Eur J Heart Fail, 2018, 20(5):923-930. 12.Sodium Zirconium Cyclosilicate and MRA Optimization in Heart Failure With Reduced Ejection Fraction and Hyperkalemia: Main Results From REALIZE-K Randomized Controlled Trial 13.Hyperkalemia-Related Hospitalization Associated with Short-Term vs. Long-Term Outpatient SZC Therapy Among RAASi Users: The GALVANIZE Outcome study.2024 AHA.Presentation Number: MDP992 本材料由阿斯利康提供，旨在满足您的医学信息需求，仅供医疗卫生专业人士参考，不用于推广目的。 审批编号：CN-147868；有效期至：2025-2-20 END 医脉通是专业的在线医生平台，“感知世界医学脉搏，助力中国临床决策”是平台的使命。医脉通旗下拥有「临床指南」「用药参考」「医学文献王」「医知源」「e研通」「e脉播」等系列产品，全面满足医学工作者临床决策、获取新知及提升科研效率等方面的需求。

Fast Track Designation is designed to expedite FDA review of important new drugs to treat serious conditions and fill an unmet medical need. Fast Track Designation for LP-184 (STAR-001) recognizes Glioblastoma (GBM) as a serious condition impacting more than 13,000 U.S. adults each year and approximately 300,000 globally. A phase 1b/2a clinical trial for recurrent GBM is targeted to start in late 2024/early 2025. LP-184, which will be developed as STAR-001 for CNS and other neuro-oncology indications by Starlight Therapeutics , a wholly owned subsidiary of Lantern Pharma, has the potential to be the first new drug for treating GBM in more than 20 years. DALLAS--(BUSINESS WIRE)--Lantern Pharma Inc. (NASDAQ: LTRN), an artificial intelligence (AI) company dedicated to developing cancer therapies and transforming the cost, pace, and timeline of oncology drug discovery and development, today announced that the FDA has granted Fast Track Designation for investigational drug candidate, LP-184, for treatment of Glioblastoma. LP-184 is currently in a Phase 1A clinical trial designed to evaluate the safety and tolerability of the synthetically lethal investigational drug candidate in a broad range of solid tumors, including Glioblastoma (GBM) . LP-184 was optimized and advanced in part with Lantern’s AI platform, RADR®, to aid in the validation of mechanisms that could be exploited in the clinical setting to eradicate challenging cancers, and uncover insights in targeted patient populations. RADR® is Lantern’s AI platform for cancer therapy discovery, development and rescue with over 100 billion data points and aiding in the development of both Lantern’s portfolio and development initiatives with Lantern’s collaborators. About GBM and the need for improved and novel therapies. Glioblastoma (GBM) affects nearly 13,000 patients annually in the US and approximately 300,000 globally, with a mortality rate of 94%. Current standard of care therapies result in a life expectancy in GBM patients of less than 15 months. A major limitation to development of new drugs in the treatment of GBM is the need for potential drugs to have the ability to cross the blood brain barrier (BBB) as well as the ability to counteract the inherent and adaptive resistance of GBM cancer cells to temozolomide, the current standard of care in GBM. This resistance is largely derived from the expression of the DNA repair enzyme MGMT 1 . LP-184 activity is agnostic to MGMT expression, meaning it does not depend on the under or over-expression of MGMT in GBM and has shown in-vivo, preclinical activity in both types of GBM models. No new drugs for GBM have been approved in over two decades. Lantern Pharma is advancing LP-184, a molecule which demonstrates synthetic lethality when combined with agents that cause DNA damage repair deficiency. 2 Additionally, LP-184 has shown that it causes double-stranded breaks in the DNA of recurrent GBM (rGBM) cancer cells in multiple in-vivo models and is currently being advanced in early clinical stage studies. “Receiving FDA Fast Track Designation for Lantern Pharma’s LP-184 in GBM reinforces our belief that this drug-candidate can help in the critical need to find effective treatment options for patients with GBM and further supports the potential of LP-184 to address the challenges in aggressive CNS cancers, where patients have a critical need for novel and life extending therapies” said Panna Sharma, President and CEO of Lantern Pharma. Current status of LP-184 & STAR-001 in clinical trials & development LP-184 is currently being studied in a phase 1A clinical trial to evaluate the safety, tolerability and maximum tolerated dose (MTD) of the potential therapy in a wide range of tumors, including GBM. The full study design can be viewed here (clinicaltrials.gov) . Once the MTD has been established, Lantern has plans to advance the drug-candidate LP-184 as STAR-001 through its wholly owned subsidiary, Starlight Therapeutics, in GBM and other CNS and brain cancers. Lantern also anticipates further using RADR® to determine potential additional suitability for LP-184 in combination with other approved agents for the control of cancer progression in multiple other patient subgroups. Lantern has provided information on the development of LP-184 in GBM and has also discussed its plan to advance STAR-001 (LP-184 for CNS cancers) in multiple publicly available webinars, including on: June 26, 2024 — STAR-001 in Multiple Brain and CNS Cancers with Dr. Marc Chamberlain, and July 31, 2024 — Born from AI, Lighting The Way in CNS Cancer Treatment with Mr. Panna Sharma. The proposed goals for the development of Phase 1b/2a clinical studies are targeting a rGBM specific trial to begin in late 2024 or early 2025. This trial is being planned to assess LP-184 in a Phase 1b/2a study as mono-therapy and in combination with spironolactone in rGBM to assess safety, pharmacokinetics and preliminary efficacy. Concurrently, Lantern will conduct a retrospective correlative analysis of multiple key markers of DNA damage as exploratory endpoints. EGFR expression or mutation status, MGMT status and expression of DNA damage repair pathway are also planned to be studied as potential response predictors to help inform and guide future late-stage trials and to stratify enrollment. About the FDA Fast Track process The FDA’s Fast Track process is designed to facilitate development and expedite the review of therapies intended to treat serious conditions and address unmet medical needs to potentially bring important new medicines to patients sooner. Companies whose programs are granted Fast Track Designation are eligible for more frequent interactions with the FDA during clinical development. For more information on Fast Track designation, please visit the FDA’s website at . About Lantern Pharma: Lantern Pharma (NASDAQ: LTRN) is an AI company transforming the cost, pace, and timeline of oncology drug discovery and development. Our proprietary AI and machine learning (ML) platform, RADR ® , leverages over 100 billion oncology-focused data points and a library of 200+ advanced ML algorithms to help solve billion-dollar, real-world problems in oncology drug development. By harnessing the power of AI and with input from world-class scientific advisors and collaborators, we have accelerated the development of our growing pipeline of therapies that span multiple cancer indications, including both solid tumors and blood cancers and an antibody-drug conjugate (ADC) program. On average, our newly developed drug programs have been advanced from initial AI insights to first-in-human clinical trials in 2-3 years and at approximately $1.0 - 2.5 million per program. Our lead development programs include a Phase 2 clinical program and multiple Phase 1 clinical trials. We have also established a wholly-owned subsidiary, Starlight Therapeutics, to focus exclusively on the clinical execution of our promising therapies for CNS and brain cancers, many of which have no effective treatment options. Our AI-driven pipeline of innovative product candidates is estimated to have a combined annual market potential of over $15 billion USD and have the potential to provide life-changing therapies to hundreds of thousands of cancer patients across the world. Please find more information at: Website: LinkedIn: X: @lanternpharma Forward-looking Statements: This press release contains forward-looking statements within the meaning of Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended. These forward-looking statements include, among other things, statements relating to: future events or our future financial performance; the potential advantages of our RADR ® platform in identifying drug candidates and patient populations that are likely to respond to a drug candidate; our strategic plans to advance the development of our drug candidates and antibody drug conjugate (ADC) development program; estimates regarding the development timing for our drug candidates and ADC development program; expectations and estimates regarding clinical trial timing and patient enrollment; our research and development efforts of our internal drug discovery programs and the utilization of our RADR ® platform to streamline the drug development process; our intention to leverage artificial intelligence, machine learning and genomic data to streamline and transform the pace, risk and cost of oncology drug discovery and development and to identify patient populations that would likely respond to a drug candidate; estimates regarding patient populations, potential markets and potential market sizes; sales estimates for our drug candidates and our plans to discover and develop drug candidates and to maximize their commercial potential by advancing such drug candidates ourselves or in collaboration with others. Any statements that are not statements of historical fact (including, without limitation, statements that use words such as “anticipate,” “believe,” “contemplate,” “could,” “estimate,” “expect,” “intend,” “seek,” “may,” “might,” “plan,” “potential,” “predict,” “project,” “target,” “model,” “objective,” “aim,” “upcoming,” “should,” “will,” “would,” or the negative of these words or other similar expressions) should be considered forward-looking statements. There are a number of important factors that could cause our actual results to differ materially from those indicated by the forward-looking statements, such as (i) the risk that our research and the research of our collaborators may not be successful, (ii) the risk that observations in preclinical studies and early or preliminary observations in clinical studies do not ensure that later observations, studies and development will be consistent or successful, (iii) the risk that we may not be successful in licensing potential candidates or in completing potential partnerships and collaborations, (iv) the risk that none of our product candidates has received FDA marketing approval, and we may not be able to successfully initiate, conduct, or conclude clinical testing for or obtain marketing approval for our product candidates, (v) the risk that no drug product based on our proprietary RADR ® AI platform has received FDA marketing approval or otherwise been incorporated into a commercial product, and (vi) those other factors set forth in the Risk Factors section in our Annual Report on Form 10-K for the year ended December 31, 2023, filed with the Securities and Exchange Commission on March 18, 2024. You may access our Annual Report on Form 10-K for the year ended December 31, 2023 under the investor SEC filings tab of our website at or on the SEC’s website at . Given these risks and uncertainties, we can give no assurances that our forward-looking statements will prove to be accurate, or that any other results or events projected or contemplated by our forward-looking statements will in fact occur, and we caution investors not to place undue reliance on these statements. All forward-looking statements in this press release represent our judgment as of the date hereof, and, except as otherwise required by law, we disclaim any obligation to update any forward-looking statements to conform the statement to actual results or changes in our expectations. 1 In patients with glioblastoma (GBM) an aggressive and severe type of brain tumor, the cancer medicine temozolomide is more effective in those with a methylation of the gene’s promoter . Overall, MGMT methylation or hyper-methylation is associated with prolonged patient survival in clinical prediction models, while under-methylation or no-methylation can be derived as a result of exposure to temozolomide and cause resistance to temozolomide therapy and therefore no benefit from the use of temozolomide in GBM. 2 Bachchu Lal, Aditya Kulkarni, Joseph McDermott, Rana Rais, Jesse Alt, Ying Wu, Hernando Lopez-Bertoni, Sophie Sall, Umesh Kathad, Jianli Zhou, Barbara S. Slusher, Kishor Bhatia, John Laterra; Preclinical Efficacy of LP-184, a Tumor Site Activated Synthetic Lethal Therapeutic, in Glioblastoma. Clin Cancer Res 15 October 2023; 29 (20): 4209 4218. Contacts Investor Relations mailto: ir@lanternpharma.com ph: (972) 277-1136