Dibotermin alfa Other names: Divotermine alpha

Dibotermin alfa is an osteoinductive protein that results in the induction of new bone tissue at the site of implantation. Dibotermin alfa binds to receptors on the surface of mesenchymal cells and causes cells to differentiate into cartilage- and bone-forming cells. The differentiated cells form trabecular bone as the matrix is degraded, with vascular invasion evident at the same time. The bone formation process develops from the outside of the implant towards the centre, until the entire dibotermin alfa implant is replaced by trabecular bone.

Placement of dibotermin alfa into trabecular bone resulted in transient resorption of the bone surrounding the implant, followed by replacement with new, more dense bone. Remodeling of the surrounding bone occurs in a manner that is consistent with the biomechanical forces placed on it. The ability of dibotermin alfa implant to support bone remodeling may be responsible for the biological and biomechanical integration of the new bone induced by dibotermin alfa with that of the surrounding bone. Radiographic, biomechanical and histologic evaluation of the induced bone indicates that it functions biologically and biomechanically as native bone. Furthermore, non-clinical studies have indicated that the bone induced by dibotermin alfa, if fractured, can repair itself in a manner indistinguishable from native bone.

Non-clinical studies have suggested that bone formation initiated by dibotermin alfa is a self-limiting process, forming a well-defined volume of bone. This self-limitation is likely due to the loss of dibotermin alfa from the implant site, as well as the presence of BMP inhibitors in the surrounding tissues. In addition, several non-clinical studies indicate that there is a negative feedback mechanism at the molecular level that limits bone induction by BMPs.

Histological evidence from animal studies of lumbar interbody fusion using anterior or posterior surgical approaches showed dibotermin alfa administered with titanium, PEEK or allograft interbody devices was biocompatible and produced consistently high rates of fusion independent of surgical approach or device material with less fibrous tissue evident compared with autograft.

Clinical pharmacology studies demonstrate that the matrix alone is not osteoinductive and is no longer present in biopsies taken as early as 16 weeks post-implantation.

Dibotermin alfa is active at the site of implantation. In two exploratory studies, pre- and post-surgery serum samples were collected from a few long-bone fracture patients. Dibotermin alfa was not detectable in serum.

In animal studies (rats) using implant containing radiolabelled dibotermin alfa, the mean residence time at the site of implantation was 4-8 days. Peak levels of circulating dibotermin alfa (0.1% of the implanted dose) were observed within 6 hours following implantation. When injected intravenously, the terminal half-life of dibotermin alfa was 16 minutes in rats and 6.7 minutes in cynomolgus monkeys. It is concluded, therefore, that at the site of implantation, dibotermin alfa is slowly released from the matrix and rapidly cleared when taken up into the systemic circulation.

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, acute and repeated exposure toxicity and genotoxicity.

In reproductive toxicity studies in rats, where dibotermin alfa was administered intravenously to maximize systemic exposure, increased foetal weight and increased foetal ossification was observed and a treatment-related effect could not be ruled out. The clinical relevance of these effects is unknown.

Anti-dibotermin antibodies have been investigated in pregnant rabbits following hyper-immunisation with dibotermin alfa to experimentally induce anti-dibotermin alfa antibodies. In some foetuses with decreased body weights, there were decreases in ossification of frontal and parietal bones (4 out of 151 foetuses), which is generally considered to be reversible, and antibody related effects could not be ruled out. There were no other alterations in foetal external, visceral, or skeletal morphology.

Dibotermin alfa has demonstrated variable effects on human tumour cell lines in vitro. The available in vivo data on human tumour cell lines do not suggest a potential for promotion of tumour growth or metastasis. As a single use product, dibotermin alfa has not been tested for in vivo carcinogenicity.

Dibotermin alfa has been studied in a canine spinal implantation model. Dibotermin alfa was implanted directly onto the exposed dura following a laminectomy. Although narrowing of the neuroforamen and stenosis was observed, no mineralization of the dura, no spinal cord stenosis, and no neurological deficits subsequent to the application of dibotermin alfa were observed.