Novel Small Molecule for Improved Dental Implant Osseointegration

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.