Development of Novel Melanocortin-4 Receptor Peptide Agonists for the Treatment ofMC4R Haploinsufficiency

黑皮质素肽治疗setmelanotide（ImcivreeTM）在治疗罕见的 肥胖综合征、POMC和瘦素受体缺乏。然而，这种药物对大多数人来说是无效的。 一种常见的综合征性肥胖症，即黑皮质素-4受体（MC 4 R）缺乏症（MC 4 R单倍不足）， 患病率大于1/1000人。此外，该药物在治疗饮食性肥胖中无效。在 除了Imcivree没有解决综合征患者未满足的医疗需求之外， Imcivree是四种黑皮质素受体的泛激动剂， 通过激活真皮和滤泡黑素细胞上的黑皮质素-1受体（MC 1 R）来治疗色素沉着过度。 最后，Imcivree的配方并不理想，需要每天皮下给药。在我们的第一阶段 应用，我们建议开发黑皮质素-3受体拮抗剂作为MC 4 R的肽治疗剂 这是因为MC 3R是MC 4 R神经元的负调节因子。然而，在 在开发这些分子的过程中，我们有了惊人的发现。基于 广泛的构效关系（SAR）的工作开始在第一阶段，我们还确定了四个新的 MC 4 R激动剂家族。在经验证的肥胖小鼠模型中表征选择的肽， 在MC 4 R缺陷（MC 4 R +/-小鼠）中，我们发现了这些MC 4 R激动剂肽的两个家族， Imcivree在MC 4 R单倍不足以及饮食性肥胖中具有显著的减肥功效。 最近的工作提供了这些肽的修饰版本，其也降低了MC 1 R功效。 最后，我们已经表明，黑皮质素肽可以配制在可注射的PLGA微球， 一种新的远程加载技术，产生稳定释放肽超过30天， 优化治疗窗、提高患者依从性和降低成本的潜力。在这 II期申请，我们建议1）完成MC 4 R激动剂肽的化学开发， MC 4 R缺乏症的治疗，2）完成多达三种肽开发的GLP前安全性研究 MC 4 R缺陷的候选者，和3）制定和表征药物动力学、功效和 这些肽在我们人MC 4 R缺陷小鼠模型中的副作用概况。这个产品 II期STTR提案将是治疗MC 4 R的一种或多种治疗候选药物 单倍不足，以及这些治疗剂商业化的途径。

The melanocortin peptide therapeutic setmelanotide, (ImcivreeTM), is highly effective in the treatment of the rare obesity syndromes, POMC and leptin receptor deficiency. However, the drug is ineffective for the most common syndromic obesity, melanocortin-4 receptor (MC4R) deficiency (MC4R haploinsufficiency), found at a prevalence greater than 1/1000 individuals. Further, the drug is ineffective in the treatment of dietary obesity. In addition to the fact that Imcivree does not address the unmet medical needs in patients with syndromic obesity due to MC4R deficiency, Imcivree is a pan-agonist of four melanocortin receptors and causes hyperpigmentation by activating the melanocortin-1 receptor (MC1R) on dermal and follicular melanocytes. Lastly, the formulation of Imcivree is not ideal, requiring daily subcutaneous administration. In our Phase I application, we proposed to develop melanocortin-3 receptor antagonists as peptide therapeutics for MC4R deficiency, since the MC3R is a negative regulator of MC4R neurons. However, in the course of developing these molecules, currently still in progress, we made a striking discovery. Based on the extensive structure-activity relationship (SAR) work initiated in Phase 1, we also identified four novel families of MC4R agonists. Characterizing select peptides in a validated obese mouse model of human MC4R deficiency (MC4R+/- mice), we discovered two families of these MC4R agonist peptides that, unlike Imcivree, have significant weight loss efficacy in MC4R haploinsufficiency, as well as in dietary obesity. More recent work provides modified versions of these peptides that have reduced MC1R efficacy as well. Finally, we have shown that melanocortin peptides can be formulated in injectable PLGA microspheres by a new remote-loading technique, yielding steady release of peptide for more than 30 days offering the potential for optimizing the therapeutic window, improving patient compliance, and reducing cost. In this phase II application, we propose to 1) complete the chemical development of MC4R agonist peptides for the treatment of MC4R deficiency, 2) complete pre-GLP safety studies for up to three peptide development candidates for MC4R deficiency, and 3) formulate and characterize the pharmacokinetics, efficacy, and side effect profile of these peptides in our mouse model of human MC4R deficiency. The product of this Phase II STTR proposal will be one or more therapeutic candidates for the treatment of MC4R haploinsufficiency, and a pathway to commercialization of these therapeutics.