Nocturia

Allschwil, Switzerland – September 17, 2024 Idorsia Ltd (SIX: IDIA) today announced that new data and analyses of daridorexant, Idorsia’s dual orexin receptor antagonist for the treatment of adults with chronic insomnia, will be presented at Sleep Europe 2024 – the 27th Congress of the European Sleep Research Society (ESRS), taking place in Seville, Spain, September 24–27, 2024. The following posters will be presented: Lederer K, et al. Efficacy and safety of daridorexant in patients with chronic insomnia disorder and comorbid nocturia [P5021], Wednesday, Sep 25, 12:15 – 13:15 and 16:00 – 17:45.McCall WV, et al. Dose-response of daridorexant in insomnia disorder: a meta-analysis of Phase 2 and 3 studies [P298], Wednesday, Sep 25, 12:15 – 13:15 and 16:00 – 17:45.Dauvilliers Y, et al. Effect of daridorexant on wakefulness throughout the night and morning sleepiness in patients with insomnia disorder [P1213], Friday, Sep 27, 10:45 – 13:30.Boof M-L, et al. Repeated dosing of 50 mg daridorexant in patients with severe obstructive sleep apnea: Effect on sleep-disordered breathing and sleep [P1200], Friday, Sep 27, 10:45 – 13:30.Muehlan C, et al. Nighttime Safety of Daridorexant: Response to Noise Stimuli, and effects on Postural Stability, Walking and Memory [P1197], Friday, Sep 27, 10:45 – 13:30.Kaufmann P, et al. Excretion of the Dual Orexin Receptor Antagonist Daridorexant into Breast Milk of Healthy Lactating Women [P1196], Friday, Sep 27, 10:45 – 13:30.Di Marco T, et al. Effect of daridorexant on sleep micro-architecture in adult patients with insomnia disorder – A post-hoc analysis of two pooled Phase 3 studies [P1198], Friday, Sep 27, 10:45 – 13:30.Lettieri CJ, et al. Effect of Daridorexant on Patients with Comorbid Insomnia Disorder and Untreated Mild Obstructive Sleep Apnea: A Post-hoc Analysis of a Phase 3 Study [P1201], Friday, Sep 27, 10:45 – 13:30. The abstracts can be found on the congress website. In addition, Idorsia is supporting a satellite symposium entitled "Overactive wake-signaling and the management of insomnia disorder" on Thursday, September 26, from 12:15-13:15 CEST in Room “Paris 2”. The symposium will be hosted by Diego Garcia-Borreguero (Spain), Yves Dauvilliers (France), Laura Palagini (Italy), and Christina Lang (Germany), and will explore the latest standard of care for patients with chronic insomnia. Notes to the editor About daridorexantDaridorexant is a dual orexin receptor antagonist (DORA) which blocks the binding of the wake-promoting orexin neuropeptides. Rather than inducing sleep through broad inhibition of brain activity, daridorexant selectively blocks the activation of orexin receptors. Consequently, daridorexant reduces overactive wake signaling, allowing sleep to occur and working throughout the night without altering the proportion of sleep stages. Daridorexant is commercially available as QUVIVIQ in the US, Germany, Italy, Switzerland, Spain, the UK, Canada, Austria, and France, and is approved throughout the EU and in Hong Kong. About IdorsiaIdorsia Ltd is reaching out for more – We have more ideas, we see more opportunities and we want to help more patients. In order to achieve this, we will develop Idorsia into a leading biopharmaceutical company, with a strong scientific core. Headquartered near Basel, Switzerland – a European biotech-hub – Idorsia is specialized in the discovery, development and commercialization of small molecules to transform the horizon of therapeutic options. Idorsia has a 25-year heritage of drug discovery, a broad portfolio of innovative drugs in the pipeline, an experienced team of professionals covering all disciplines from bench to bedside, and commercial operations in Europe and North America – the ideal constellation for bringing innovative medicines to patients. Idorsia was listed on the SIX Swiss Exchange (ticker symbol: IDIA) in June 2017 and has over 750 highly qualified specialists dedicated to realizing our ambitious targets. For further information, please contactAndrew C. WeissSenior Vice President, Head of Investor Relations & Corporate CommunicationsIdorsia Pharmaceuticals Ltd, Hegenheimermattweg 91, CH-4123 Allschwil+41 58 844 10 10investor.relations@idorsia.commedia.relations@idorsia.com www.idorsia.com The above information contains certain "forward-looking statements", relating to the company's business, which can be identified by the use of forward-looking terminology such as "estimates", "believes", "expects", "may", "are expected to", "will", "will continue", "should", "would be", "seeks", "pending" or "anticipates" or similar expressions, or by discussions of strategy, plans or intentions. Such statements include descriptions of the company's investment and research and development programs and anticipated expenditures in connection therewith, descriptions of new products expected to be introduced by the company and anticipated customer demand for such products and products in the company's existing portfolio. Such statements reflect the current views of the company with respect to future events and are subject to certain risks, uncertainties and assumptions. Many factors could cause the actual results, performance or achievements of the company to be materially different from any future results, performances or achievements that may be expressed or implied by such forward-looking statements. Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual results may vary materially from those described herein as anticipated, believed, estimated or expected. Attachment Press Release PDF

STAMFORD, Conn.--(BUSINESS WIRE)-- Imbrium Therapeutics L.P. (“Imbrium”), a subsidiary of Purdue Pharma L.P. (“Purdue”), achieved last patient last visit in its Phase 1b study of the investigational drug sunobinop as a potential treatment for overactive bladder syndrome (OAB)*. Sunobinop is an investigational, novel and potential first-in-class oral compound discovered by Imbrium Therapeutics and that is currently in clinical development. Sunobinop is designed to bind to and activate the nociceptin/orphanin-FQ peptide receptor (NOP), a protein that is widely expressed in the central and peripheral nervous system1 and involved in a range of biological functions, including bladder function.2,3 Fifty-one female patients suffering from OAB were enrolled in this multicenter, randomized, double-blind, placebo-controlled crossover study. The study was designed to test the effects of sunobinop at bedtime on key disease symptoms, such as urinary urgency, frequency, incontinence, and nocturia in subjects with OAB compared to placebo. OAB is a life-long urologic disorder that reduces patients’ quality of life. The condition affects 14% of men and women in the U.S.4 "Millions of patients with overactive bladder are in need of additional treatment options for the disruptive, distressing symptoms. This study will help us learn more about sunobinop’s potential to be a new treatment option,” said Dr. Julie Ducharme, Vice President and Chief Scientific Officer. “We look forward to reviewing and analyzing the results later this year.” “We are pleased to achieve last patient last visit in the sunobinop Phase 1b study,” said Craig Landau, MD, President and CEO of Purdue. “Our continued progress in this work demonstrates our ongoing commitment to innovation through research and development.” In addition to OAB, Imbrium is also evaluating sunobinop as a potential treatment for interstitial cystitis/bladder pain syndrome (IC/BPS) and separately for alcohol use disorder. *This release discusses investigational uses of an agent in development and is not intended to convey conclusions about efficacy or safety. There is no guarantee that sunobinop will successfully complete development or gain FDA approval. About Imbrium Therapeutics L.P. Imbrium is a clinical-stage biopharmaceutical company dedicated to advancing medical science through the development of important new therapeutics. We are pursuing treatments for genitourinary disorders, disorders of the central nervous system, oncology chemotherapeutics, and non-opioid approaches to the management of pain. As a subsidiary of Purdue Pharma L.P., Imbrium strives to develop new medicines that serve the unmet needs of patients, physicians, and health systems worldwide. We have built a robust and diversified pipeline of investigational drug candidates, and we seek to actively collaborate with industry and academic partners to identify and advance future impactful medicines. For more information, please visit . References 1. Zaveri, N. The nociceptin opioid receptor (NOP) as a therapeutic target: Progress in translation from preclinical research to clinical utility. J Med Chem. 2016; 59(15): 7011-7028. 2. Lambert, D. The nociception/orphanin FQ receptor: a target with broad therapeutic potential. Nat. Rev. 2008 Aug;7(8):694-710. 3. Lazzeri, M., Calò, G., Spinelli, M., et al. Daily intravesical instillation of 1 mg nociceptin/orphanin FQ for the control of neurogenic detrusor overactivity: a multicenter, placebo controlled, randomized exploratory study. J Urol. 2006 Nov;176(5):2098-102. 4. Reynolds, W., Fowke, J., & Dmochowski, R. The burden of overactive bladder on US public health. Current Bladder Dysfunct Rep. 2016 Mar;11(1):8-13. MR-08567

来源：药渡撰文：哥哈骎     编辑：安非他命长期以来，多肽药物开发最重要的目标被定为最高亲和力、受体选择性和抗酶降解稳定性。然而在满足生物活性的基础上，多肽药物的递送方式逐渐成为了行业的研究热点，尤其是口服活性肽已经成为了追求的新目标。生产口服活性肽需要双重优化过程：1) 优化亲和力和选择性；2) 优化口服有效性。为了合理设计口服活性肽，必须依次满足这两个条件。多肽的化学改性对于实现口服制剂的开发影响重大，这篇文章重点介绍了已经上市或处在临床阶段的口服多肽制剂，希望透过这些成功的经验，指导人们应该从什么角度进行多肽的化学修饰，以同时满足多肽潜在药物的生物活性和口服生物利用度。Cyclosporine A (CsA, 环孢素A)真菌代谢物环孢素A (CsA) 由Sandoz在上世纪60年代末发现。CsA是一个包含7个N-甲基化氨基酸残基的十一元环肽。CsA由占绝对优势的疏水性氨基酸组成，它作为一种口服免疫抑制剂，以Neoral®的商品名称得到批准上市。除了用于移植时免疫抑制外，Neoral®还可用于治疗牛皮癣、严重异位性皮肤炎（severe atopic dermatitis）、坏疽性脓皮病（pyoderma gangrenosum）、慢性自体免疫荨麻疹（chronic autoimmune urticaria）、类风湿性关节炎和其他的相关疾病，但通常只用于比较严重的疾病。在美国常做成眼用乳剂治疗干眼症。由于其高度的疏水性，CsA在纯溶液配方中口服生物利用度差，非常不稳定，这是由于其水溶性差，以及肠上皮细胞的代谢导致的。CsA实现口服递送的机制非常特别，除了环肽结构本身带来的天然优势之外，Me-Leu9和Me-Leu10两个相邻残基之间的酰胺键的构象在其中发挥了微妙但关键的作用（图1）[1]。这个结构特殊的肽骨架酰胺键的cis/trans构象平衡，在很大程度上取决于多肽分子所处环境的极性。在极性溶剂中，或者与受体亲环蛋白（cyclophilin）结合的情况下，trans构象占主导地位。但在非极性溶剂，或者晶体形态下，采取主导的则换成了cis构象。图1. CsA化学结构（红色酰胺键为Me-Leu9-Me-Leu10主链肽键）Kofron等人在他们的研究中发现，cis/trans相互转化动力学（能量壁垒为19 kcal/mol）与CsA和亲环蛋白的结合息息相关[2]。而CsA-亲环蛋白复合物的形成，反过来又对钙调神经磷酸酶产生影响。后者是一种Ca2+/钙调蛋白依赖性蛋白磷酸酶，它是T淋巴细胞中的关键信号酶。由于CsA中这个酰胺键的cis/trans平衡取决于环境的亲水性，研究者因此提出假说，CsA会介导由cis到trans构象的转化，前者利于口服吸收，而后者利于与受体的结合。而这恰好满足了上述口服多肽药物的两个关键条件。CsA在其当前的口服制剂中（Sandimmune Neoral®）以脂质基础配方（这是由于CsA“过高”的亲脂性决定的），具有独特的微乳液给药方式，可实现60%生物利用度并具有相对较低的可变性[3]。CsA这种天然产物机制的复杂性是独一无二的，已成为研究多肽口服制剂生物利用度的主要模型。然而，微妙的构象转化很难复制在其它的合成多肽类似物中，从这个角度上看，CsA仍然像个曲高和寡的孤例，尽管令人高山仰止，但却很难复制它的高生物利用度机制。值得注意的是，2022年10月得到FDA批准上市的Voclosporin (商品名Lupkynis)是CsA的类似物，也是一款口服多肽，是用作治疗狼疮性肾炎的免疫抑制剂。拥有长达30小时的终末半衰期，人的口服生物利用度约为8%[4]。Voclosporin的化学结构实在与它的前辈cyclosporin太相似了，它只是用一个乙烯基替换了CsA 1位氨基酸残基侧链的甲基（图2中红色结构），而其它结构则完全相同。图2. Voclosporin化学结构三-N-甲基化Veber-Hirschmann肽图3. 三-N-甲基化Veber-Hirschmann肽化学结构Veber-Hirschmann肽c(PFwKTF)，是一种环化的生长抑素，对sst2和sst5生长抑素受体有选择性，其三N-甲基化类似物，三-N-甲基化Veber-Hirschmann肽（图3）表现出了更高的生物利用度，可有效穿过Caco-2细胞单层。三-N-甲基化Veber-Hirschmann肽对血浆中的降解具有一定抵抗性，并且实现了10%的大鼠绝对口服生物利用度[5]。显然，这三处溶剂化的酰胺键的N-甲基化增加了多肽的亲脂性。该多肽主链形成了两处βII’和βVI-转角二级结构，以及一个以cis-构象为主导的肽键。而这三处修饰依然保持了未甲基化的，具有生物活性Veber-Hirschmann肽的空间构型[6]。去氨加压素Ferring Pharmaceuticals的去氨加压素Desmopressin是激素肽加压素vasopressin的肽类似物（图4），它比加压素更能抵抗酶降解。其产品DDAVP®以口服剂的形式得到批准上市，用于尿崩症（diabetes insipindus）的治疗。Nocdurna®（仍然是desmopressin）又以舌下片剂的剂型获得批准，用于夜尿症的治疗。不良反应鲜有报道，甚至已经对儿童进行了夜间遗尿治疗。图4. Desmopressin化学结构从化学结构来看，去氨加压素是一种由二硫键连接的亲水性环状肽，具有广泛的氢键潜力。口服的去氨加压素通过细胞旁转运机制被吸收到血流中，口服生物利用度差（0.08-1%）[7]。尽管如此，去氨加压素较高的靶标亲和力实现了低剂量的给药[8]。由于去氨加压素的强大药效和较高的亲水性，去氨加压素和a-鹅膏菌素给人们这样的启发：如果多肽药物的活性和选择性足够高，在稳定性的保障下，即便很低的口服生物利用度，也有可能成为口服制剂的选择。ZYOG1图5. ZYOG1化学结构ZYOG1（图5）是一种可口服的线性肽，含有多个非天然氨基酸和三个Cα-甲基化氨基酸。ZYOG1类似于其他GLP-1激动剂，例如艾塞那肽，是一种源自exendin-4的化合物，并被开发用于治疗糖尿病。N端Val被嵌合到这些线性多肽前体中，以改善它们的生物利用度。尽管ZYOG1的口服生物利用度相对较低，但据称ZYOG1具有与皮下注射的艾塞那肽相当的良好口服功效（尚未公布绝对值）。ZYOG1目前处于临床试验阶段，需要进一步开发以提高其生物利用度，并最终证明这种线性肽是否可以作为口服GLP-1激动剂用于治疗糖尿病。Griselimycin衍生物图6. Griselimycin衍生物化学结构链霉菌衍生的griselimycin衍生物，通过抑制DNA聚合酶对结核分枝杆菌产生高度活性，由此可以充当抗菌剂的角色。通过掺入非天然亲脂性氨基酸残基，进一步提高了其depsipeptide母肽(F = 48%) 实现非常高的口服生物利用度。环己基取代Pro的griselimycin衍生物（R=Cychexyl, 图6），显示出了F=89%的高口服生物利用度，以及提高的生物活性。与其他口服活性肽相比，三种griselimycin衍生物（图6）都具有极高的生物利用度。整体亲脂性的增加，导致了更高的结合亲和力和更高的生物利用度（griselimycin衍生物是由全疏水性氨基酸组成的环肽）。Cyclo(N-Me-D-Ala-Arg(Hoc)2-Gly-Asp(OMe)-Ala-N-MeAla)和Cyclo(N-Me-D-Val-Arg(Hoc)2-Gly-Asp(OMe)-Ala-N-MeAla)图7. Cyclo(N-Me-D-Ala-Arg(Hoc)2-Gly-Asp(OMe)-Ala-N-MeAla) （左）和 Cyclo(N-Me-D-Val-Arg(Hoc)2-Gly-Asp(OMe)-Ala-N-MeAla) （右）化学结构常见的口服多肽似乎比较钟情于六元环肽[9]，这种特征激发了人们把六元直线肽环化的热情。最简单直接的是全Ala环六肽，尽管这样的多肽毫无生物活性，但它却为六元环肽的空间结构研究提供了骨架，可以进行比如N-甲基化的化学修饰，以探索这些化学修饰可能对多肽空间结构带来的影响，以进一步探求这些结构变化带给多肽分子生物学的新特征。在多肽生物活性领域享有盛誉的RGD三肽结构（被多种integrin受体识别）在这种大背景下，被整合到各种六元环肽中，以实现包括消化道通透性提升在内的一系列目标。但亲水性氨基酸的存在削弱了多肽分子的肠道通透性，因此研究人员采用了所谓的LPCM（lipophilic prodrug charge masking，亲脂性前药电荷掩蔽）策略，以对应高极性给这些RGD环肽带来的不利影响[10]。LPC使得原本低细胞旁吸收的亲水性母肽（clog P= -3.3），摇身变成了通过跨细胞途径进入血液循环的多肽前药（clog p=6.6），因此实现了Cyclo(N-Me-D-Val-Arg(Hoc)2-Gly-Asp(OMe)-Ala-N-MeAla) 肽（图7）44%的口服生物利用度[11]。Cyclo(N-Me-D-Ala-Arg(Hoc)2-Gly-Asp(OMe)-Ala-N-MeAla) （图7）在经过口服给药后，被血清酯酶切割成其生物活性形式，成为了integrin αvβ3高活性和高选择性的配体。这个生物活性配体可以增强 VEGF介导的血管新生，因此可以结合化学疗法治疗癌症[12]。MyR-c(MyD 4-4)图8. MyR-c(MyD 4-4)化学结构环肽c(MyD 4-4) （图8）对于细胞质衔接蛋白MyD88的抑制作用，被开发于自身免疫性疾病的治疗[13]。据报道c(MyD 4-4)多肽会破坏MyD88的二聚化和阻断人和小鼠巨噬细胞TLR2和TLR4的刺激。为了克服c(MyD 4-4)低口服生物利用度的缺陷(F=0.84±0.25%)，研究人员在一个仲胺结构上偶合了肉豆蔻酰基（MyR），衍生出了MyR-c(MyD 4-4)多肽[14]。改性后的多肽拥有大幅度提高的口服生物利用度（F = 47.6±16.2%），同时增强了抑制剂的生物活性。研究人员将亲水性的多肽c(MyD 4-4)在改性后口服生物利用度的大幅提高，归功于亲脂性的豆蔻酰基团的引入改变了多肽的空间结构，从而破坏了带正电的精氨酸与带负电的天门冬氨酸之间的盐桥。MyR-c(MyD 4-4)的口服活性，得到了EAE的体内疗效支持，这是一个多发性硬化症的小鼠模型[14]。Endomorphin-1（内啡肽-1）类似物图9. 内啡肽-1类似物化学结构线性阿片肽内啡肽-1由四个天然氨基酸组成，显然容易产生快速酶促降解，生物利用度差，持续时间短。口服给药途径在这些数据面前，看起来有些天方夜谭。然而糖基化令内啡肽-1的生物利用度大大提高，为口服递送打开了一扇大门[15]。经过乳糖和琥珀酸手臂修饰的内啡肽-1类似物（图9），收获了膜通透性700倍的增长和长达2小时的作用时间。但葡萄糖琥珀酸单元显著降低了配体多肽结合μ-阿片受体 (MOR) 的亲和力，尽管在MOR的结合亲和力和激动剂活性等表现上，endomorphin-1类似物受到修饰后呈现出不利影响，但它仍然显示出纳摩尔级的结合亲和力，相对于生物利用度上的优势，生物活性方面的表现已经足够令人满意。它在经过大鼠口服后产生剂量依赖性的疼痛缓解。这个例子表明，在某些情况下糖基化有助于提高多肽的生物利用度，同时保留可以接受的受体结合亲和力。糖基的选择与糖基化的修饰位点，对于多肽口服制剂的开发影响明显。司美格鲁肽图10. Semaglutide化学结构脂化修饰为多肽口服制剂打开了一扇广阔的大门。诺和诺德的2型糖尿病口服多肽制剂Semaglutide（Rybelsus®）的成功 (2019年被FDA批准上市) ，极大激发了从业者开发口服多肽制剂的热情，而它的成功经验之一正是对GLP-1类似物进行脂肪修饰（图10）。Semaglutide在口服给药后，能够保持很长的半衰期（约153-160小时，而注射后为 168小时）。但口服递送的方式显著降低了它的生物利用度，因此需要更高的每日剂量。未来用于多肽口服药的脂化试剂，可能会寻求比semegluitde (18碳) 更短的脂肪酸（例如12碳），这可能会增加生物利用度。编者按：人工智能正在推动药物设计与开发的革新，特别是在小分子药物的领域。通过高效的虚拟筛选、分子设计和优化，AI能够在更短的时间内生成和评估大量的药物候选分子，加速整个药物发现过程，在缩短药物设计周期、提高药物研发效率方面展现出巨大潜力。AI的应用不仅限于小分子药物，还包括生物制剂和药物再利用等领域。未来，随着技术的不断发展和数据的积累，AI有望在药物发现领域取得更多突破，为人类健康事业作出更大贡献。参考资料（可上下滑动）：[1] M. A. Navia, P. R. Chaturvedi, Drug Discovery Today. 1996, 1, 179 –189.[2] J. L. Kofron,P. Kuzmic,V.Kishore,G.Gemmecker, S. W. Fesik,D. H. Rich, J. Am. Chem. Soc. 1992, 114, 2670 –2675.[3] D. E. Yocum, S. e al, Rheumatology, 2000, 39, 156 –164.[4] Center for drug evaluation and research. Multi-disciplinary Review and Evaluation: NDA 213716LUPKINYS (voclosporin). Reference ID: 4735350.[5] E. Biron, et al. Angew. Chem. Int. Ed. 2008, 47, 2595 –2599.[6] H. Kessler, et al. J. Am. Chem. Soc. 1983, 105, 6944–6952.[7] (a) A. Rembratt, et al. Eur. J. Clin. Pharmacol. 2004, 60, 397–402; (b) A. Fjellestad-Paulsen, et al. Clin. Endocrinol. 1993, 38, 177 –182; (c) H. Vilhardt,et al . Pharmacol. 1986, 17, 481–483.[8] “Designing Orally Bioavailable Peptide and Peptoid Macro-cycles”: D. A. Price, A. M. Mathiowetz, S. Liras,in Practical Medicinal Chemistry with Macrocycles (Eds.: E. Marsault, M. L. Peterson), Wiley, Hoboken, NewJersey, 2017.[9] D. S. Nielsen, et al. Chem. Rev. 2017, 117, 8094–8128.[10] M. Weinmüller, et al. Angew. Chem. Int. Ed. 2017, 56, 16405-16409.[11] A. Elgart, et al.Chem. Phys. Lipids. 2012, 165, 438–453.[12] P.-P.Wong, et al. Curr. Biol. 2016, 26, R1161–R1166.  [13] S. Dishon, et al. Sci. Rep. 2018, 8, 9476.  [14] S. Dishon, et al. 2018, unpublished results.[15] D. Muthu, et al. Drug Delivery. 2005, 2, 59–73.*声明：本文仅是介绍医药疾病领域研究进展或简述研究概况或分享医药相关讯息，并非也不会进行治疗或诊断方案推荐，也不对相关投资构成任何建议。内容如有疏漏，欢迎沟通指出！点击下方“药渡“，关注更多精彩内容瞄准靶蛋白降解：中国在PROTAC药物战略布局中的新动向药品再注册新规出台：严监管时代来临，助力医药产业高质量发展辉瑞DMD基因疗法：希望与挑战并存点击蓝字 关注我们