Baxdrostat

关注并星标CPHI制药在线 醛固酮是人类肾上腺皮质球状带区域分泌的一种盐皮质激素，通过调节肾脏对钠离子的重吸收，维持水盐平衡。过量的醛固酮不适当地激活盐皮质激素受体，会增加血浆体积，导致血压升高。此外，醛固酮水平过高会造成心肌及血管间质纤维化，导致心室和血管重构，诱发白细胞浸润造成及冠脉和心肌损伤、心律失常。 醛固酮合成酶（AS，由CYP11B2基因编码) 控制醛固酮的合成，几十年来一直是治疗高血压的药理学靶点。但由于产生醛固酮的酶和产生皮质醇的酶有93%是相同的，高选择性醛固酮合成酶的研发一直没有突破性进展。 据不完全统计，目前全球药企已研发出几款醛固酮合成酶抑制剂（详见下表），这几款药物主要被开发用于治疗难治性高血压以及慢性肾脏病，其中三款已进入3期临床。 具体品种上，BI 690517是一种新型强效的醛固酮合成酶抑制剂，其设计具有高选择性，可潜在减缓慢性肾病（CKD）患者的肾损害进展并减少心血管事件。 已公布的BI 690517治疗CKD的2期临床试验结果显示：无论是否联合SGLT2抑制剂，BI 690517均可降低蛋白尿，且安全性良好。此外，无论是否联合恩格列净治疗，BI 690517均可显著降低血浆醛固酮水平。 具体数据为：14周时，在恩格列净为背景治疗基础上，10 mg BI 690517治疗组经安慰剂校正后首次晨尿的尿白蛋白/肌酐比值（UACRFMV）中位值降幅度高达 -39.5%，其中高达70%患者实现UACRFMV降幅≥30%；而在未联合恩格列净治疗组中，BI 690517最高可使51%患者实现UACRFMV降幅≥30%。 Baxdrostat是一种小分子高选择性醛固酮合酶抑制剂，能够高选择性抑制醛固酮合成酶，而不会阻断盐皮质激素受体，被开发用于治疗难治性高血压、原发性醛固酮增多症（Spark-PA）以及慢性肾病（CKD）合并高血压。 临床前和1期研究表明，与皮质醇合成酶相比，Baxdrostat对醛固酮合成酶具有非常高的选择性（100:1），多个剂量水平的baxdrostat可降低血浆醛固酮水平，但不降低皮质醇水平。而且，Baxdrostat安全性、耐受性良好，半衰期支持每日一次给药。 已公布的Baxdrostat治疗难治性高血压的2期临床研究BrigHTN结果显示：Baxdrostat可剂量依赖性的降低难治性高血压患者的血压和血醛固酮水平。 值得一提的是，Baxdrostat由CinCor Pharma开发，2023年1月阿斯利康斥资18亿美元收购CinCor Pharma将Baxdrostat纳入囊中。阿斯利康积极探索Baxdrostat联合SGLT2抑制剂达格列净（dapagliflozin）的治疗潜力，目前该组合疗法用于延缓CKD合并高血压成人患者肾功能下降的3期临床试验已经启动。 Lorundrostat（MLS-101）一种高选择性、强效醛固酮合酶抑制剂，2020年Mineralys Therapeutics从Mitsubishi Tanabe获得该药的授权。 已公布的Lorundrostat治疗难治性高血压的2期临床研究Target-HTN结果显示：每天口服一次loundrostat可使难治性高血压患者的血压显著降低。 具体数据为：在意向性治疗群体中，12.5 mg、50 mg和100mg治疗组患者经安慰剂调整的收缩压下降水平分别为1.4 mmHg（未达统计显著水平）、9.7 mmHg（p=0.010）和7.9 mmHg（p=0.037）。而且，肥胖患者服用lorundrostat后血压下降幅度更大：对于BMI≥30 kg/m2的高血压患者，与安慰剂相比，50 mg和100mg lorundrostat治疗组患者的收缩压分别降低16.7 mmHg (p=0.002)和12.3 mmHg (p=0.030)。在亚群分析中，当患者同时使用噻嗪类利尿剂作为背景治疗时，loundrostat疗效更为显著，12.5 mg、50 mg和100mg治疗组经安慰剂调整的收缩压下降水平分别为5.3 mmHg（未达统计显著水平）、13.2 mmHg（p=0.010）和11.4 mmHg（p=0.028）。此外，loundrostat也可降低患者的舒张压、24小时动态血压、夜间收缩压等。 JX09是新一代高选择性醛固酮合成酶抑制剂，临床前研究结果显示其能高效抑制醛固酮合成酶，并极少与机体内的同源酶发生作用，降低该抑制剂对皮质醇路径的影响。 2023年2月，箕星药业通过收购PhaseBio获得PB6440的全球权益。2024年2月，该药在澳大利亚开展的1期临床试验首例受试者成功给药。 总结 整体来看，在研醛固酮合成酶抑制剂并不多，但同靶点间药物间竞争激烈，三款处于3期临床，目前无法预测谁将率先出线。此外，醛固酮合成酶抑制剂除被开发作为单药疗法，还有望联合SGLT2抑制剂、噻嗪类利尿剂等药物治疗慢性肾脏病、难治性高血压等。 【企业推荐】 【智药研习社直播预告】 来源：CPHI制药在线 声明：本文仅代表作者观点，并不代表制药在线立场。本网站内容仅出于传递更多信息之目的。如需转载，请务必注明文章来源和作者。 投稿邮箱：Kelly.Xiao@imsinoexpo.com ▼更多制药资讯，请关注CPHI制药在线▼ 点击阅读原文，进入智药研习社~

Financing brings total funds raised to $176M to advance diverse portfolio of high-impact medicines and expand efforts to additional high unmet needs Current portfolio of CinCos include two clinical-stage obesity therapeutics, two Phase 2 gastrointestinal programs and several pre-clinical programs CINCINNATI--(BUSINESS WIRE)-- CinRx Pharma, a hub-and-spoke biotech accelerating high-impact medicines, today announced the closing of a $73 million financing, bringing the total funds raised to $176 million. Participants in the round include prior investors comprised of industry insiders and high-net-worth individuals. To date, CinRx has launched five companies (“CinCos”) focused primarily on cardiovascular, metabolic and gastrointestinal conditions. In addition to its company creation function, CinRx has forged several CINergy partnerships with existing companies. CinRx plans to use the funds to advance development of its existing portfolio programs and assets to expand in key areas of high unmet medical need. “Our early financings totaling $103 million supported the construction and progression of our seven-company portfolio. Notably, this included the formation, advancement and exit of CinCor Pharma ahead of its $1.8 billion acquisition, underscoring the success of our incredibly effective team and validation of our efficient business model,” said Dr. Jon Isaacsohn, Founder and Chief Executive Officer at CinRx Pharma. “With this infusion of capital, we will continue rapid advancement of existing programs and replicate our proven asset selection process to identify and accelerate more promising new programs with high potential to impact patients’ quality of life.” CinRx’s portfolio of CinCos are managed by a lean team of scientific, technical and drug development experts with decades of experience treating patients and supporting thousands of clinical development programs. Each CinCo was created through a rigorous asset selection process to identify novel therapies with the potential to address significant unmet medical needs and meaningfully reduce disease burden for patients. CinCor Pharma was created to advance baxdrostat (CIN-107), a highly selective, oral small molecule inhibitor of aldosterone synthase for the treatment of hypertension and other cardiorenal conditions from a license agreement with Roche in 2019. CinRx led the clinical design and execution of baxdrostat, and was responsible for CinCor’s successful Series A and Series B financings to fund its early development through its $194 million IPO in 2022. In early 2023, CinCor was acquired by AstraZeneca in a deal worth $1.3 billion upfront and an additional $500 million in biobucks. CinFina Pharma is developing a pipeline of four therapies, in-licensed from Janssen Pharmaceuticals, aimed at providing safe, tolerable and durable options for treating obesity. In March 2024, CinFina announced the dosing of the first patients in a Phase 1 trial of CIN-110, a PYY analog. Upcoming milestones include initiation of a Phase 2 study evaluating CIN-109, a novel GDF-15 molecule focusing on body composition and lean body mass preservation, with and without semaglutide. Additional preclinical development is ongoing to support Investigational New Drug (IND) application submissions for CIN-209 and CIN-210, which are both dual-agonists utilizing GLP-1 therapy in combination with the aforementioned mechanisms of action. CinDome Pharma is developing deudomperidone (CIN-102) as a potential safe, chronic treatment for gastroparesis. Deudomperidone is a novel formulation of a well-known dopamine D2/D3 agonist, domperidone. In May 2023, CinDome presented encouraging QT study data at the 2023 Digestive Disease Week (DDW) Conference. CinDome recently raised $40 million in a Series B financing from Perceptive Advisors and CinRx, and is actively enrolling the Phase 2 envision3D study for adults with diabetic gastroparesis, expected to read out in 2025. CinPhloro Pharma is progressing CIN-103, a small molecule for the long-term management of irritable bowel syndrome with diarrhea (IBS-D). CIN-103 is a pulsatile-release formulation of phloroglucinol, an approved therapy in select countries outside of the U.S., modified for sustained exposure and less frequent dosing. In February 2024, CinPhloro dosed the first patients in the Phase 2 enviva study to evaluate the safety, efficacy and tolerability of CIN-103 for IBS-D. CinPhloro is actively enrolling the enviva study, which is expected to complete in 2025. About CinRx Pharma: CinRx Pharma is a biotech company advancing a diverse portfolio of high-impact medicines through clinical development with a unique hub-and-spoke business model. CinRx’s approach combines financing with the efficient progression of therapeutic candidates within its portfolio, each managed by CinRx’s central infrastructure and operating team. Current CinCos address areas of high unmet medical need including metabolic, gastrointestinal and oncology. Differentiated by an asset selection process agnostic to therapeutic area, a strategic CRO partnership, and insights from thousands of development programs, CinRx identifies, funds and accelerates promising drugs with the potential to have the highest impact on patients’ quality of life. CinRx Pharma is headquartered in Cincinnati, Ohio. For more information, please visit or follow the company on X and LinkedIn.