Source: European Medicines Agency (EU) Revision Year: 2018 Publisher: Medtronic BioPharma B.V., Earl Bakkenstraat 10, 6422 PJ Heerlen, The Netherlands, tel +31 (0) 45 566 8000, fax +31 (0) 45 566 8012
Pharmacotherapeutic group: Drugs for treatment of bone diseases, Bone Morphogenetic Proteins
ATC code: M05BC01
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 InductOs implant is replaced by trabecular bone.
Placement of InductOs 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 InductOs to support bone remodeling may be responsible for the biological and biomechanical integration of the new bone induced by InductOs 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 InductOs, if fractured, can repair itself in a manner indistinguishable from native bone.
Non-clinical studies have suggested that bone formation initiated by InductOs 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.
The efficacy and safety of InductOs were demonstrated in a randomised, controlled, multicenter, non-inferiority study of 279 patients aged 19–78 years undergoing an open anterior lumbar interbody fusion procedure. Patients had received at least six months of non-operative treatment prior to treatment with InductOs for anterior lumbar spine fusion. Patients were randomised to receive a titanium interbody fusion device filled with either InductOs or autogenous bone graft taken from the iliac crest.
At 24 months post-operation, InductOs was demonstrated to be statistically non-inferior to autogenous bone graft with a success rate for radiologically determined fusion of 94.4% for InductOs versus 88.9% for autogenous bone graft (95% two-sided CI of the difference: -1.53, 12.46). For pain and disability (Oswestry score), the success rate was 72.9% in the group using InductOs versus 72.5% in the group using autogenous bone graft (95% two-sided CI of the difference: -11.2, 12.0).
A post-hoc meta-analysis of 6 controlled clinical trials with data from patients treated with InductOs or autogenous bone graft administered using CE-marked interbody fusion devices or allograft bone spacers and various surgical approaches showed that, at 24 months post-surgery, InductOs was associated with a higher fusion success rate (95%, 241 out of 255 patients) compared with autogenous bone graft (85%, 177 out of 209 patients), with an odds ratio of 3.26 (95% CI: 1.172, 9.075; P=0.024). The estimated absolute difference in fusion success rate between InductOs and autogenous bone graft was 11.7% (95% CI: 0.8%, 22.5%; P=0.035).
In a pooled safety data analysis of 8 clinical trials at 24 months post-surgery, the frequency of patients with pseudarthrosis was approximately 2-fold lower following treatment with InductOs (4.8%, 22 out of 456 patients) compared with autogenous bone graft (12.7%, 31 out of 244 patients).
The efficacy of InductOs was demonstrated in a multinational, randomized, controlled, single-blind study of 450 patients (age range 18 to 87 years; 81% male) with open tibial shaft fractures requiring surgical management. Patients received (in a 1:1:1 ratio) standard care (control group) consisting of intramedullary (IM) nail fixation and routine soft-tissue management, standard care plus InductOs 0.75 mg/ml, or standard care plus InductOs 1.5 mg/ml. Patients were followed for 12 months after soft-tissue closure.
In the acute tibia fracture pivotal trial, InductOs increased the probability of fracture healing; patients treated with InductOs 1.5 mg/ml had a 44% reduced risk for treatment failure (secondary intervention to promote fracture healing) compared with patients in the standard-care group (RR = 0.56; 95% CI = 0.40 to 0.78). These results were independently corroborated by a radiology panel blinded to treatment. The number of secondary and subsequent interventions was significantly reduced for the InductOs patients, particularly with regard to more invasive interventions, such as bone graft and exchange nailing (P=0.0326).
The proportion of patients healed after treatment with InductOs 1.5 mg/ml was significantly higher at all visits from 10 weeks to 12 months post-operative, suggesting accelerated fracture healing.
InductOs 1.5 mg/ml was significantly effective (compared to standard care) in patients both with or without a history of smoking.
Severity of fractures: Treatment with InductOs 1.5 mg/ml was significantly effective in all fracture classes, including severe Gustilo IIIB fractures (52% reduced risk of secondary interventions as compared to standard-care patients).
The proportion of patients with healed soft-tissue wounds was significantly higher at the 6-week post-treatment visit in the InductOs 1.5 mg/ml group compared with the standard-care group (83% versus 65%; P=0.0010). The proportion of patients with hardware failure (locking screws bent or broken) was significantly lower in the InductOs 1.5 mg/ml group as compared to standard-care group (11% versus 22%; P=0.0174).
InductOs 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 InductOs 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, InductOs has not been tested for in vivo carcinogenicity (see also section 4.3).
InductOs has been studied in a canine spinal implantation model. InductOs 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 InductOs were observed.
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