leptin

iStock/ synthetick After psychological side effects doomed the first generation of cannabinoid receptor 1–targeting drugs for weight loss, Novo Nordisk, Corbus Pharmaceuticals and Skye Bioscience are betting that a new mechanism of action will improve the safety profile. Nearly 20 years after the FDA’s rejection of what would have been the first approved drug in the class, a new generation of CB1 receptor inhibitors is undergoing early- and mid-stage clinical trials for the treatment of obesity. Novo Nordisk, Corbus Pharmaceuticals and Skye Bioscience are all hoping the improved safety profiles of their therapies will lead to a new method of treating the disease. “What’s interesting about this is it’s a comeback story for a class that was entirely abandoned,” said Corbus CEO Yuval Cohen. “In 2006, it was viewed as an exciting class of drugs—and then it had a catastrophic setback at FDA.” Rimonabant, the first-in-class cannabinoid receptor 1 (CB1) receptor antagonist from Sanofi, which was approved in Europe for weight loss, worked to suppress appetite by blocking endocannabinoid receptors in the brain. While rimonabant successfully helped patients lose weight, it greatly increased instances of depression, anxiety and suicidality in patients. In the CRESCENDO study , four rimonabant-treated patients committed suicide. The FDA deemed the drug unapprovable in 2006, and European regulators withdrew it from the market in 2008. “After the rejection, none of the other [pharma companies] tried to file [with the FDA],” Cohen told BioSpace . “There was such a stigma around it that it was considered an untouchable mechanism of action.” A New Approach Now, Novo, Corbus and Skye are hoping to bring a version to the market that is safer and just as effective as the early class by avoiding the CB1 receptors in the brain. Instead, these compounds will work on peripheral receptors throughout the body, which will also allow for higher dosing, Cohen said. “There’s a lot of evidence out there of this particular target being found in the peripheral tissues, especially in adipose tissues and important organs like the liver, muscles and even the GI tract,” said Skye CEO Punit Dhillon. Peripherally restricted CB1-targeting drugs, such as Skye’s nimacimab, Corbus’s CRB-913 and Novo’s monlunabant , do not cross the blood-brain barrier, therefore reducing the chance of neuropsychiatric effects such as depression. “The idea was to keep the bits that are working but avoid some of the risks involved with the first class, which was too much of it went into the brain,” Cohen said. In Phase Ib studies of nimacimab, patients reported no serious adverse events. “We’ve been really successful in terms of having zero incidents of any neuropsychiatric [effects] or depression or any concerns in our Phase I data,” Dhillon told BioSpace . However, last month, Phase IIa results from monlunabant revealed “mild to moderate neuropsychiatric side effects,” such as anxiety, irritability and sleep disturbances. No serious adverse events were reported in relation to the neuropsychiatric side effects, according to Novo. Patients treated with the drug saw an average of 15 lbs of weight loss after 16 weeks of treatment, compared to just 1.5 lbs for the placebo group. ‘Amazing Little Engines’ CB1 receptors are a type of G-protein coupled receptor—what Cohen describes as “amazing little engines” that activate appetite in all living things and push them to find food. Activation of the receptors promotes food intake, fat storage and energy storage in the body. One type of CB1-targeting drug is an inverse agonist, which “puts this process in reverse and hits the gas pedal,” Cohen explained. “So suddenly, rather than being obsessed with food-seeking, we are no longer hungry and obsessed with food.” With appetite suppressed, fat in the body is converted to energy and weight loss can occur. But instead of acting on CB1 receptors in the brain, the new class of inhibitors bind to peripheral receptors throughout the body thanks to a smaller molecule. This metabolic rewiring can reintroduce insulin sensitivity, glucose tolerance and other healthy lipid profiles that are compromised in patients with obesity, Dhillon said. Cannabinoid pathways are also integral to signaling the presence of a hormone called leptin, which tells the brain how much fat is stored in the body. “It is possible to get that response peripherally. If you can sensitize the body to the effects of leptin, it’s possible to be able to more easily release fat from fat cells,” Louis Aronne, Sanford I. Weill professor of metabolic research at Weill-Cornell Medical College and director of the Center for Weight Management and Metabolic Clinical Research, told BioSpace . One hypothesis is that fat gets locked in fat cells, and it is difficult in obesity to get it out, Aronne noted. “If you could take fat out of fat cells and have it floating around in the bloodstream instead of locked away in the fat cells, your brain would be able to sense the fatty acids as nutrition floating around and would use that as a trigger to suppress your appetite,” he explained. “That’s one way peripherally acting drugs could have central mechanisms.” CB1/GLP-1 Combinations Weight loss medications are one of biopharma’s hottest current trends. GLP-1 drugs, such as Novo’s Wegovy and Eli Lilly’s Zepbound, exploded onto the market to regulate blood sugar and restrict caloric intake by curbing appetite and making patients feel full longer. While CB1-targeting drugs can be used on their own, they also could be paired with GLP-1s. In fact, Skye is combining nimacimab and Wegovy in a Phase II study . Forty patients will be randomized to either a treatment group that will receive nimacimab injection or a placebo in conjunction with Wegovy. “We feel there is a strong argument that [CB1 inhibitors] can be combined with GLP-1s really well,” Dhillon said. “If GLP-1s are doing a good job [with caloric restriction], and CB1s are doing a good job in re-establishing metabolic pathways, then we’re getting it from both sides and hopefully achieving a better body composition over time.” Meanwhile, Corbus’ CRB-913 was used in conjunction with GLP-1 medications Wegovy, Zepbound and liraglutide in preclinical testing . Mice with diet-induced obesity showed decreased body weight when given CRB-913. These effects were enhanced when GLP-1 drugs were added, including statistically significant reductions in body fat, liver triglycerides, liver fat deposits, insulin resistance and leptinemia. “What we have shown preclinically is if you combine CB1-targeting drugs with incretin-targeting drugs, you can add on to the different effects and lead to more weight loss,” Cohen noted. “What this ends up being in clinical usage remains to be seen. But there are important populations where modifying with CB1 makes a lot of sense.” These populations include those who cannot or do not want to use GLP-1 drugs, those who need a higher degree of weight loss with combined mechanisms of action, and those who have reached their goal weight on GLP-1 drugs and want to switch to a drug to help maintain that weight loss, he said. Combining a CB1-targeting drug with a GLP-1 medicine could also mean the patient would take a smaller dose of the GLP-1—which could lead to fewer gastrointestinal side effects and a greater chance of adherence to the medication regimen, Aronne said. “One of the things that may happen with GLP-1s is we may use too much of it in an effort to get someone’s weight down,” he continued. “If you had a mechanism that gave additive weight loss, but it didn’t have nausea or vomiting or any of the GI side effects, that might be a brilliant way to help.” Time Will Tell Aronne sees the field of obesity treatment going in a similar direction to treatment for hypertension or other indications where medication is started early before the condition gets out of hand. “Eventually, instead of having to treat people with BMIs of 40 and above, we’re going treat people as soon as they get to obesity,” Aronne said. “[That way], you never get to a BMI of 30, 40 or 50, where the damage accrues.” Whether CB1 inhibitors are part of that treatment process remains to be seen. Early data are promising, but the answers will come from the trials of nimacimab, monlunabant and CRB-913. “I think the class is at a potentially important fork in the road,” Cohen said. “If the data are good, that could really just provide a complete change in the mindset around this mechanism.”

来源：药渡 撰文：哥哈骎     编辑：维他命 众所周知，大多数多肽分子无法穿越血脑屏障，这是因为血脑屏障是一种高度选择性的生物屏障，由特殊类型的血管内皮细胞组成，这些细胞形成了一种严格控制的屏障，保护大脑免受外部物质的影响。多肽分子因为其自身的特性，决定了其中大多数个体无法有效穿越血脑屏障： #多肽分子 影响穿越血脑屏障的特性 01 多肽分子的大小 血脑屏障对分子的大小有选择性，通常只允许小分子通过。多肽分子通常较大，其体量超过了血脑屏障的孔隙大小限制，因此难以穿越。 02 结构 多肽分子通常由氨基酸组成，它们的分子结构不利于穿越血脑屏障。相比之下，小分子药物通常具有更小、更简单的分子结构，更容易通过血脑屏障。 03 电荷 许多多肽分子带有电荷，这会增加它们与血脑屏障内皮细胞之间的相互作用，使其更难穿越。 1 什么样的分子 可以穿越血脑屏障？ 血脑屏障是一种高度选择性的屏障，通常只允许一些特定类型的分子通过： 1 小分子药物  小分子药物通常具有相对较小的尺寸和简单的化学结构，这使它们更容易穿越血脑屏障。 2 非极性分子  极性低的分子更容易通过血脑屏障，因为它们可以在脂质双层中更容易地溶解。 3 特定的载体蛋白  有一些专门的载体蛋白负责将特定的物质运输穿越血脑屏障，例如，葡萄糖转运蛋白（GLUT1）负责将葡萄糖运输到脑细胞中。 4 气体  氧气和二氧化碳等小分子气体可以自由地穿越血脑屏障，以满足大脑对氧气的需求。 需要注意的是，即使一种分子具备上述特性，也不一定能够轻松穿越血脑屏障，因为屏障具有高度的选择性，只允许一些特定的分子通过。此外，大多数药物都需要经过专门的药物研发和设计，以确保它们足够小、脂溶性足够高，能够通过血脑屏障，有效地治疗中枢神经系统疾病。 2 血脑屏障并不拒绝所有多肽 尽管大多数多肽不能穿越血脑屏障，但研究人员正在寻找方法来克服这个限制，以便将多肽用于治疗中枢神经系统疾病。这些方法包括改变多肽的分子结构，使用脑靶向技术，或者将多肽与载体结合，以增加其在血脑屏障上的穿透性。Banks最新发表在Peptides上的综述文章对于可穿越血脑屏障的多肽进行了论述。 多肽科学在上世纪70年代实现了大爆发。早期多肽科学的发现之一是外周给药的多肽可以影响大脑功能。这使得美国科学家Kastin和荷兰科学家De Wied提出，多肽可以穿过血脑屏障的主张。Kastin是第一个提出肽可以穿过血脑屏障的人，并于1975 年找到了三肽黑素细胞刺激激素（MSH，melanocyte-stimulating hormone，由脑下垂体前叶分泌的激素，对于调节皮肤色素的合成和分布具有重要作用。MSH对于刺激黑素细胞产生黑色素，以及调节食欲等生理过程也具有影响）穿越血脑屏障的证据。MSH释放抑制因子-1（MIF-1）是一种下丘脑三肽，控制MSH的垂体分泌。Kastin发现外周给药的MIF-1具有垂体外作用（这种作用不是通过垂体分泌MSH介导的）。这些作用包括减弱药物或电惊厥休克引起的遗忘症、药物引起的体温过低、帕金森病治疗效果的调节以及抗抑郁活性。Kastin还证明了外周注射3H-MIF-1后，大脑中存在放射性。 但人们已知，在某种情况下，外周物质在不穿越血脑屏障的情况下，同样能够影响大脑。例如，胰岛素能够改变色氨酸穿越血脑屏障的行为，反过来又会影响到大脑中serotonin（血清素）的合成。确定多肽作用位点可能非常困难，例如无法确定是在大脑内介导还是由外周组织介导的。但如果有适当的激动剂或拮抗剂存在时，有时可以确定作用位点。比如，外周给药的脑啡肽类似物对脑电图1-4Hz δ波段的影响可被纳曲酮（naltrexone）阻断，但不会被甲基纳曲酮（methylnaltrexone）阻断。由于纳曲酮可以穿过血脑屏障，但甲基纳曲酮不能，这表明外周施用的脑啡肽类似物的作用位点位于血脑屏障后的大脑部位。这是一种通过拮抗效果，间接证明多肽可以穿越血脑屏障直接作用于大脑的手段。 除了以上的拮抗作用外，给药方式导致的药效区别，也可以间接证明多肽分子可以穿越血脑屏障。比如，已知二环肽“Cyclo [His-Pro]” 通过作用于大脑，来逆转乙醇诱导的麻醉。如果通过ICV（Intracerebroventricular，颅内脑室内）给药“Cyclo [His-Pro]”，其产生的效力比通过静脉注射强约200倍。Cyclo [His-Pro]对于酶解非常稳定，静脉注射后可以缓慢进入大脑。因此，外周给药Cyclo [His-Pro]逆转乙醇麻醉的能力，可能取决于这种穿过血脑屏障的能力。 穿越血脑屏障的多肽，还包括以下一些例子： 1 Angiopep-2 Angiopep-2是一种多肽，具有通过血脑屏障的特殊能力。它可以与特定的受体（LRP1）相互作用，从而穿越血脑屏障，用于传递药物或治疗中枢神经系统疾病。 2 Tat 多肽 Tat（Trans-Activator of Transcription）多肽是源自人类免疫缺陷病毒（HIV）的一部分，具有一定的血脑屏障穿越能力。研究人员已经利用Tat 多肽来开发用于传递药物或治疗神经系统疾病的方法。 3 Leptin Leptin是一种由脂肪细胞分泌的多肽激素，它对于食欲和体重控制非常重要。尽管leptin本身不能轻松穿越血脑屏障，但在某些情况下，它可以通过特定的受体介导通道进入中枢神经系统。 4 胰岛素 胰岛素可被视作一种多肽激素，用于调节血糖水平。它可以通过与脑内的胰岛素受体相互作用，穿越血脑屏障，以维持大脑对葡萄糖的需求。 5 胰淀素 胰淀素（Amylin）是由胰岛细胞分泌的多肽，与胰岛素一起调节血糖。它也可以穿越血脑屏障，并在中枢神经系统中发挥作用。 从商业化的角度来看，可穿越血脑屏障的上市多肽药物包括： 1 Leuprorelin Leuprorelin是一种GnRH激动剂多肽药物，用于治疗多种与性激素有关的疾病，如前列腺癌和子宫内膜异位症。它可以通过穿越血脑屏障，影响垂体释放促性腺激素，从而影响性激素水平。 2 Oxytocin 催产素（Oxytocin）是一种多肽激素，对于社交行为和情感调节具有重要作用。它可以穿越血脑屏障，影响中枢神经系统，有助于产生情感联系。 3 Insulin 胰岛素是一种多肽激素，用于调节血糖水平。它可以穿越血脑屏障，以维持大脑对葡萄糖的需求，并影响食欲和代谢。 4 GLP-1类似物 GLP-1是一类多肽激素，用于治疗2型糖尿病和肥胖症。某些GLP-1类似物能够穿越血脑屏障，改善食欲和体重控制，同时也可能对神经保护有益。 5 Somatostatin Analogues 生长抑素（somatostatin）类似物是一类多肽药物，用于治疗神经内分泌肿瘤和其他内分泌疾病。它们可以通过穿越血脑屏障，抑制生长激素的分泌，用于治疗垂体瘤等疾病。 3 多肽分子何以 以庞大身躯通过血脑屏障？ 在研究δ睡眠诱导肽 (DSIP，Delta Sleep-Inducing Peptide，是九肽激素。在大脑中产生，具有影响睡眠模式和生理节律的作用）是否可以穿过血脑屏障的过程中，研究者发现，在外周注射DSIP的条件下，它可以诱导睡眠。通过先进的放射免疫测定法（radioimmunoassay）分析，研究者证明了DSIP确实完整地穿过了血脑屏障。 在回答DSIP以何种机理穿越被大多数多肽分子视作“天堑”的血脑屏障的过程中，研究者通过对比DSIP和其类似物发现，这些个体虽然在分子量上可比拟，但进入中枢神经系统的能力却判若云泥。在分子尺寸相近的情况下，表现出如此巨大的转运速度差异，说明分子不是通过“leakage passage”的途径穿越血脑屏障的。相反，脂溶性是进入大脑速率的关键指标：许多肽能够凭借其高亲脂性穿过血脑屏障。 从这个角度来看，Lipinski 5规则预测多肽口服药物方面似乎偏差较大。Lipinski当年在审查了2245个口服小分子的溶解度和渗透性数据（92%分子量小于600 Da）后归纳出了Lipinski 5规则。其中一项发现是，分子量小于500 Da的分子比大于500 Da 的分子，能更好地穿过血脑屏障。但许多人将此误解为穿越血脑屏障的绝对门槛，尽管Lipinski在原始论文和后续论文中警告称，Lipinski 5规则不适用于某些类别的分子，例如抗寄生虫药物。迄今为止，通过非饱和机制 (unsaturated mechanism，药物通过主动转运或特殊的受体介导通道进入大脑组织，而不是依靠被动的扩散机制） 穿过血脑屏障的最大物质是CINC-1（一种细胞因子，参与炎症和免疫反应的调节），其分子量为7.8 kDa 。 在2糖尿病和肥胖症领域正火的肠促胰素受体激动剂，也可能为多肽穿越血脑屏障提供了证据。尽管主攻方向是糖尿病和肥胖症，但人们对这些GLP-1、GIP多肽改变β淀粉样蛋白水平、阿尔茨海默病胰岛素抵抗等领域也产生了浓厚的兴趣，因此，它们穿越血脑屏障的能力也成为了重点研究的对象。脂溶性并不能很好地预测这些多肽穿过血脑屏障的难易程度，但绝对电荷却是一个有用的指标。这些多肽分子似乎主要通过吸附转胞吞作用（adsorptive transcytosis，药物与细胞膜上的特定受体或配体结合，然后与细胞膜内的囊泡或内涵体融合，从而使分子或药物进入细胞内部）进入大脑。 Kastin研究的Tyr-MIF-1（MIF-1的类似物）的运输是单向的，从大脑到血液方向。负责运转Tyr-MIF-1的转运蛋白被称作Peptide Transport System-1（PTS-1），它是一种蛋白质转运系统，用于运输小肽进入细胞内。这个系统在细菌和其他生物体中都有发现。PTS-1是一种专门用于小肽的主动转运系统，通常包括一组蛋白质组成，包括膜蛋白和质粒蛋白。这个系统的作用是将外部环境中的小肽从细胞外部引导到细胞内部，以供细胞进行营养摄取或其他代谢过程。 转运蛋白与受体一样，对其配体具有很强的特异性。PTS-1转运蛋白对于N 末端酪氨酸的小肽（4-5个氨基酸）结合性较强。PTS-1对Tyr-MIF-1和Met-脑啡肽具有较高的亲和力，但对Leu-脑啡肽的亲和力较弱。PTS-1不转运苯丙氨酸-MIF-1 ，苯丙氨酸-MIF-1和Tyr-MIF-1之间的唯一区别是苯丙氨酸和酪氨酸（4-羟基的区别），但被PTS-1运转的能力却天差地别。即便是D-Tyr-MIF-1也无法被PTS-1转运，说明了N-酪氨酸构象的重要性。 衰老会改变血脑屏障的转运蛋白，包括PTS-1。昼夜节律、亮氨酸、血清素、铝、酒精依赖、压力和围产期吗啡等因素，也会改变血脑屏障对某些肽的通透性。 值得注意的是，一些多肽在脑内给药与外周给药时具有相反的作用。例如，外周注射的胰岛素可增强进食、降低血糖水平、升高血液胰岛素水平，而颅内脑室内给药的胰岛素则倾向于抑制进食、增加血液葡萄糖水平、降低血液胰岛素水平。再比如，中枢系统给药的生长抑素会增加生长激素的释放，而外周施用的生长抑素则减少生长激素的释放。又比如，当降钙素进入中枢神经系统时，葡萄糖刺激的胰岛素释放会增强，但当降钙素外周给药时，葡萄糖刺激的胰岛素释放会受到抑制。以上的南辕北辙的现象使科学家猜测，在某些情况下，中枢神经系统中的肽可以充当其自身的反调节剂甚至拮抗剂。 4 开发穿越血脑屏障 多肽药物的意义 上述研究发现已经充分说明，许多多肽具有穿越血脑屏障的能力。尽管参加系统循环的多肽可以通过多种机制影响大脑功能，但其中许多机制都涉及血脑屏障。多肽药物及其类似物通过多种机制交叉作用，包括跨膜扩散（取决于脂溶性）、饱和机制、吸收转胞吞作用，实现穿越血脑屏障的过程。一旦进入中枢神经系统，多肽可以增强它们在外周发挥的作用，但也可能发挥完全不同的作用。能够穿越血脑屏障的多肽，就像拥有了一本可以免签多国的护照，在多肽生物学功能方面能够发挥普通多肽无法企及的重要作用，可以体现在以下几个方面： 1 治疗中枢神经系统疾病  许多神经系统疾病，如脑肿瘤、帕金森病、阿尔茨海默病等，需要通过药物治疗。开发能够穿越血脑屏障的多肽药物，可以将多肽运输到中枢系统，使多肽分子能够有效地到达病灶，从而提高治疗的效果。 2 减少副作用  由于血脑屏障的存在，一些药物可能需要在体内使用高剂量，以确保足够的药物到达大脑。这可能导致非中枢神经系统的副作用。通过使用能够穿越血脑屏障的多肽药物，可以减少需要用于治疗的药物剂量，从而减轻潜在的副作用。 3 提高药物的靶向性  开发能够穿越血脑屏障的多肽药物，可以实现对中枢神经系统的更精确靶向。这有助于减少药物在非目标组织的分布，从而提高治疗的特异性。 4 开发新的治疗方法  血脑屏障限制了许多潜在治疗方法的应用，包括基因治疗和RNA干扰疗法。通过开发能够穿越血脑屏障的多肽药物，可以扩展新的治疗方法的应用范围。 5 改善药物递送  在某些情况下，需要将药物直接传递到大脑内部的特定区域，例如，治疗特定类型的癫痫。穿越血脑屏障的多肽药物可以帮助实现更精确的药物递送。 参考资料： 1. Banks, W. A. Viktor Mutt lecture: Peptides can cross the blood-brain barrier. Peptides. 2023. 169. 171079. 2. Banks, W. A. Peptides and the blood–brain barrier. Peptides. 2015. 72, 16–19. 3. Sanchez-Navarro, M. et al. Peptide Shuttles for Blood–Brain Barrier Drug Delivery. Pharmaceutics. 2022. 14, 1874. 专栏作者 哥哈骎 南开大学本科、硕士，德国比勒菲尔德大学博士。多肽化学、多肽API GMP生产专家、欧洲制药公司首席科学家； 拥有Lean Six Sigma黑带认证； 著有专著《Side Reactions in Peptide Synthesis》。 *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！ 「度伐利尤单抗」两连胜，阿斯利康重磅免疫疗法再添新筹码 Science：攻克“不可成药”靶点，揭秘如何降解KRAS蛋白 35年来首款！FDA批准BMS新型精神分裂症药物，5款新药紧随其后……

The news also resulted in a modest increase in Soleno’s stock price; it was up by 6.3% when markets closed on 27 August. Credit: eamesBot / Shutterstock. The US Food and Drug Administration (FDA) is set to decide on whether to approve Soleno Therapeutics ’ lead therapy, diazoxide choline (DCCR), for treating hyperphagia associated with Prader-Willi syndrome, a rare genetic disorder. The regulatory agency has accepted the new drug application (NDA) for DCCR and has granted it priority review status . The priority status allows for various privileges including a faster approval process of six months, compared to the usual ten months. The FDA has also set a Prescription Drug User Fee Act (PDUFA) target action date of 27 December 2024. The agency has also announced its intention to hold an advisory committee (AdComm) meeting to “discuss the application for DCCR”. An AdComm is convened upon request of the FDA to review and evaluate the safety and efficacy data of a therapy. While the AdComm recommendations can affect a therapy’s FDA approval,  its recommendations are non-binding, and the final decision is made by the FDA. The news also resulted in a modest increase in Soleno’s stock price; it was up by 6.3% when markets closed on 27 August after the news was released compared to the previous day. The company’s market cap currently stands at $1.9bn. See Also: Catalent gets grant for activated formylglycine-generating enzymes for protein production Novo Nordisk’s Wegovy sales weaken as Eli Lilly’s Zepbound exerts pressure DCCR is an extended-release tablet containing a crystalline salt formulation of diazoxide, an activator of the adenosine triphosphate (ATP)-sensitive potassium (KATP) channel. These channels are present in a variety of cells including pancreatic β cells, and adipocytes. The regulation of these cells can help manage hyperphagia, an excessive desire to eat, which is a hallmark of Prader-Willi syndrome. Soleno’s NDA is supported by data from five studies; a Phase I trial in healthy volunteers, three Phase II trials, and a Phase III trial. The placebo-controlled open-label Phase III DESTINY PWS study (NCT03440814) enrolled 125 participants with Prader-Willi syndrome aged four years or younger. After a year of follow-up, the trial met its primary endpoint by demonstrating significant improvements in the Hyperphagia Questionnaire for Clinical Trials (HQ-CT) score. Greater improvements in HQ-CT scores were seen in patients with more severe baseline hyperphagia, with an HQ-CT score of over 22. Patients on DCCR also observed reductions in leptin, insulin, and insulin resistance, along with an increase in adiponectin. Soleno is also evaluating DCCR as a treatment for paediatric patients with genetic obesities, including SH2B1 deficiency obesity, obesity associated with PCSK1 mutation (rs6232 variant), and SIM1 deficiency obesity. The open-label Phase II trial (NCT05532020) is expected to enrol approximately 30 patients aged five years or younger suffering from either of the three genetic obesity disorders.