Novel Small Molecule for Improved Dental Implant Osseointegration

用于改善牙种植体骨整合的新型小分子

• 批准号: 10257506
• 负责人: MARIA INES MORANO
• 金额: $ 79.38万
• 依托单位: CAYMAN CHEMICAL COMPANY, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-16 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10257506
• 关键词: 3-Dimensional; Acceleration; Address; Agonist; Alveolar ridge; Anabolic Agents; Biological; Biomechanics; Bone Density; Bone Regeneration; Calvaria; Caymans; Cells; Chemicals; Clinical; Clinical Research; Collagen; Defect; Dental; Dental Implants; Dentists; Development; Devices; Dose; EP4 receptor; Edentulous Mouth; Evaluation; Failure; Formulation; Fracture; Funding; Goals; Grant; Hydrogels; Implant; In Vitro; Injury; Jaw; Lead; Legal patent; Mechanics; Medicine; Metabolic; Methods; Modeling; Modification; Oral; Oryctolagus cuniculus; Osseointegration; Osteogenesis; Osteoporosis; Patients; Periodontal Diseases; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Porifera; Process; Property; Rattus; Reporting; Safety; Series; Sum; Surface; Survival Rate; System; Testing; Titanium; Tooth structure; bone; bone strength; design; edentulism; efficacy study; efficacy testing; first-in-human; flexibility; improved; in vivo; meetings; novel; novel therapeutics; older patient; osteogenic; programs; recombinant human bone morphogenetic protein-2; reconstruction; regeneration potential; repaired; response; safety study; sex; small molecule; standard of care; three-dimensional modeling

PROJECT SUMMARY/ABSTRACT Oral implants are widely accepted in dental medicine as a reconstructive treatment option for replacement of missing teeth because of congenital tooth agenesis, periodontal diseases, or injury. Although the survival rate of dental implants over a 10-year observation has been reported to be higher than 90% in totally edentulous jaws, dental implants do fail in some patients due to a variety of bone density problems such as osteoporosis. Thus, a major clinical challenge for dental implant therapy is improving and accelerating the mechanical anchorage of the titanium implants into the jawbone to facilitate earlier functional loading. While various modifications of implant surfaces have helped osseointegration of implants, a bone anabolic agent would increase the predictability of a positive response for many of the bone density problems seen especially in older patients with partial or complete edentulism. Cayman Chemical Company, Inc. had discovered and patented a series of EP4 receptor agonists designed, synthesized, and screened for target potency and selectivity, cell activity, and metabolic and physicochemical properties amenable to the rapid systemic clearance desirable for local administration. The lead compound of the series, KMN-159, was tested during Phase I of the project and demonstrated its in vitro osteogenic differentiation capacity as well as its in vivo bone regeneration potential in rat critical defect models of non-union fracture and calvarial repair. Moreover, we demonstrated that KMN-159 does not induce ectopic bone formation in contrast to the standard of care rhBMP-2. During Phase II of the project we will evaluate the effects of KMN-159-collagen hydrogel combination as an accelerant of dental implant osseointegration in 2D and 3D in vitro systems (Aim 1a) and in vivo in a rat experimental alveolar ridge bone defect model (Aim1b). The most efficacious formulation dose of KMN-159 will be employed in Aim 2 to demonstrate improved biomechanical strength of the implant. Finally, a Demo Batch of KMN-159 prepared under GMP conditions and formulated in Helistat absorbable collagen sponges will be used to test efficacy and safety in a GLP rabbit implant model accepted by the FDA. All the in vivo studies were designed to consider sex as a biological variable. In sum, Cayman’s goal is to offer dentists a novel, effective, safe, economical, and easy-to- use small molecule drug (KMN-159)-device combination that will increase the rate of dental implant osseointegration as well as the strength of the bone-implant interface. This stable, prepackaged, ready-to-use, flexible and easily-fitted osseointegration accelerant would augment the bone’s natural repair process and could thus facilitate earlier implant loading and decrease the number of implant failures as compared to those receiving implants alone.

项目概要/摘要 口腔种植体作为替代牙周组织的重建治疗选择在牙科医学中被广泛接受。 由于先天性牙齿发育不全、牙周疾病或损伤而导致的牙齿缺失，虽然存活率较低。 据报道，经过 10 年的观察，全口无牙颌的种植牙率高于 90%， 由于骨质疏松症等各种骨密度问题，某些患者的种植牙确实会失败。 牙种植治疗的主要临床挑战是​​改善和加速牙种植体的机械锚固 将钛植入物植入颌骨以促进早期功能加载，同时进行各种修改。 种植体表面有助于种植体的骨整合，骨合成代谢剂会增加 对许多骨密度问题的积极反应的可预测性，特别是在老年患者中 开曼化学公司发现了一系列 EP4 并获得了专利。 设计、合成和筛选受体激动剂的靶标效力和选择性、细胞活性和 代谢和理化特性适合局部快速全身清除 该系列的先导化合物 KMN-159 在项目第一阶段进行了测试， 其体外成骨分化能力以及体内骨再生潜力 此外，我们还证明了 KMN-159。 与 rhBMP-2 的治疗标准相比，在第二阶段不会诱导异位骨形成。 该项目我们将评估 KMN-159-胶原水凝胶组合作为牙种植体促进剂的效果 2D 和 3D 体外系统（目标 1a）和大鼠实验牙槽嵴骨体内的骨整合 缺陷模型 (Aim1b) 将在目标 2 中采用最有效的 KMN-159 配方剂量。 最后，KMN-159 的演示批次得到了改善。 GMP 条件和 Helistat 可吸收胶原蛋白海绵配制将用于测试功效和安全性 在 FDA 接受的 GLP 兔子植入模型中，所有体内研究都将性别视为一种因素。 总之，开曼的目标是为牙医提供一种新颖、有效、安全、经济且易于使用的方法。 使用小分子药物（KMN-159）-器械组合可提高种植牙率 这种稳定、预包装、即用型的产品具有良好的骨整合能力以及骨-种植体界面的强度。 灵活且易于安装的骨整合促进剂将增强骨骼的自然修复过程，并且可以 与接受治疗的患者相比，因此有利于更早的种植体装载并减少种植体失败的次数 单独植入。