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Dibotermin alfa | CAS No: 246539-15-1 | GMP-certified suppliers
A medication that supports bone healing and spinal fusion in adults with acute tibial fractures and degenerative disc disease unresponsive to non-operative treatment.
Therapeutic categories
Primary indications
- Indicated for the treatment of acute tibia fractures in adults, as an adjunct to standard care using open fracture reduction and intramedullary unreamed nail fixation
- Indicated for single-level lumbar interbody spine fusion as a substitute for autogenous bone graft in adults with degenerative disc disease who have had at least 6 months of non-operative treatment for this condition
Product Snapshot
- Dibotermin alfa is an intracavitary implant formulation
- It is used as an adjunct in the treatment of acute tibia fractures and for single-level lumbar interbody spine fusion in adults
- The product is approved and available in the EU market, with investigational status in other regions
Clinical Overview
Pharmacologically, dibotermin alfa is a potent osteoinductive agent belonging to the transforming growth factor-β (TGF-β) superfamily. It promotes bone and cartilage formation by inducing differentiation of mesenchymal progenitor cells into osteoblasts. This anabolic activity is critical for accelerating bone repair and regeneration at the site of implantation.
The mechanism of action involves binding of rhBMP-2 to a heteromeric receptor complex consisting of type I and type II serine/threonine kinase receptors present on mesenchymal cells. Upon ligand binding, type II receptors phosphorylate and activate type I receptors, which then trigger intracellular Smad signaling pathways (Smad1, Smad5, Smad8, and Smad4). These Smads translocate to the nucleus, modulating gene expression to enhance osteogenesis and cartilage formation. Additionally, rhBMP-2 influences osteoblast function by regulating biomarkers such as alkaline phosphatase and modulating parathyroid hormone-dependent signaling.
Clinical data demonstrate that dibotermin alfa implanted with appropriate carriers can accelerate fracture healing rates, reduce secondary surgical interventions, and lower postoperative infection incidence. Radiographic and histological assessments confirm that newly formed bone replicates native bone structure and function.
Key ADME parameters are not conventionally applied due to its local implantation and protein nature, but the recombinant protein undergoes local enzymatic degradation without systemic exposure consistent with other biologics injected or implanted in bone.
Safety considerations include potential inflammatory reactions, ectopic bone formation, and concerns over immunogenicity or antibody development with repeated administration, warranting appropriate clinical monitoring. The product is commercialized under notable brand names such as Infuse (FDA-approved) and Inductos (EMA-approved).
For API sourcing, ensuring recombinant protein integrity, high purity, glycosylation pattern consistency, and absence of contaminants is critical. Suppliers should provide well-characterized batches compliant with regulatory guidelines and supported by robust analytical and manufacturing controls due to the complexity of producing biologically active rhBMP-2.
Identification & chemistry
| Generic name | Dibotermin alfa |
|---|---|
| Molecule type | Biotech |
| CAS | 246539-15-1 |
| UNII | T472P45MG6 |
| DrugBank ID | DB11639 |
Pharmacology
| Summary | Dibotermin alfa functions as a recombinant human bone morphogenetic protein-2 (rhBMP-2) that binds to bone morphogenetic protein receptors type-1 and type-2 on mesenchymal cells, activating Smad-dependent intracellular signaling pathways. This activation induces differentiation of mesenchymal cells into osteoblasts and chondrocytes, promoting bone and cartilage formation. The pharmacodynamic effects include anabolic stimulation of osteoblastic biomarkers and modulation of matrix remodeling enzymes, resulting in the formation of new bone with functional and structural properties comparable to native tissue. |
|---|---|
| Mechanism of action | In the same pathway shared by endogenous BMPs, recombinant human BMP-2 (rhBMP-2) binds and initiates intracellular signal cascade through an oligomeric transmembrane receptor complex formed by type I and II serine/threonine kinase receptor proteins . These BMP receptors are expressed on the surface of mesenchymal cells and upon binding of BMP-2 to the BMP receptor type II, type II receptor phosphorylates and activates type I receptor. Type I receptor may also undergo autophosphorylation. Activated BMP type I receptor then phosphorylates intracellular effector proteins, the receptor-regulated Smads (R-Smads) . Smad1, Smad 5 and Smad 8 associate with the Co-Smad, Smad4 and once activated via complex formation, they translocate to the nucleus where they associate with other transcription factors and bind promoters of target genes to control their expression . This ultimately results in bone formation at the site of implantation. Dibotermin alfa causes mesenchymal cells to differentiate into cartilage- and bone-forming cells. Implantation of dibotermin alfa in trabecular bone results in transient resorption of the bone surrounding the implant, followed by replacement of degraded matrix by newly differentiated cells . In human bone cells isolated from adult mandibulae, recombinant human BMP-2 (rhBMP-2) was shown to stimulate the activity of early biomarkers of osteoblast differentiation, including alkaline phosphatase and parathyroid hormone (PTH)-dependent 3', 5'-cyclic adenosine monophosphate accumulation . At concentrations of 500 ng/mL, rhBMP-2 also enhanced the mRNA expression level of PTH/PTH related-peptide receptor in human bone cells . There was evidence that rhBMP-2 inhibits 1,25-dihydroxyvitamin D3-induced osteocalcin synthesis at both the mRNA and protein level. rhBMP-2 also significantly suppressed MMP-1 production and MMP-1 mRNA expression at concentrations exceeding 500 ng/mL . |
| Pharmacodynamics | Dibotermin alfa promotes bone and cartilage formation through anabolic effects in human osteoblastic cells . Radiographic, biomechanical and histologic evaluation of the induced bone at the site of implantation supports that induced bone from dibotermin alfa therapy is capable of biological and biochemical function as native bone and repair abilities . |
Targets
| Target | Organism | Actions |
|---|---|---|
| Bone morphogenetic protein receptor type-2 | Humans | ligand |
| Bone morphogenetic protein receptor type-1A | Humans | ligand |
ADME / PK
| Absorption | Dibotermin alfa is active at the site of implantation with no detection in the serum. In rat studies with 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 . |
|---|---|
| Half-life | When injected intravenously, the terminal half-life of dibotermin alfa was 16 minutes in rats and 6.7 minutes in cynomolgus monkeys . |
| Route of elimination | As recombinant human bone morphogenetic protein-2 (BMP-2), dibotermin alfa is expected to undergo nonspecific protein degradation pathway shared by endogenous BMP-2. |
| Clearance | At the site of implantation, dibotermin alfa is expected to be slowly released from the matrix and rapidly cleared when taken up into the systemic circulation . |
Formulation & handling
- Dibotermin alfa is a biologic administered via intracavitary implant, requiring specialized handling to maintain stability.
- Formulation must consider the peptide nature to prevent degradation and ensure potency in the implant matrix.
- Storage conditions should minimize exposure to adverse environmental factors to preserve bioactivity before use.
Regulatory status
| Lifecycle | The API's primary patents have expired in the EU, allowing for generic entry and increased competition; the product is currently in a mature phase with established market presence. |
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| Markets | EU |
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Supply Chain
| Supply chain summary | Dibotermin alfa is primarily supplied by originator companies with branded products available in the EU market under the name Inductos. The presence of branded products mainly in the EU suggests a focused regional market. Patent expiry patterns indicate the potential for existing or upcoming generic competition in this region. |
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Safety
| Toxicity | Supportive treatment is recommended in case of overdose. Use of Inductos in patients undergoing cervical spine surgery in amounts lower than or similar to those for lumbar interbody fusion has been associated with reports of localised oedema severe enough to result in airway compromise . There is no evidence of significant hazards on humans based on non-clinical data of acute and repeated exposure toxicity and genotoxicity studies . In reproductive toxicity studies in rats, intravenous administration of dibotermin alfa was associated with increased fetal weight and increased fetal ossification. The clinical relevance of this effect is unknown . In human tumour cell lines in vitro, dibotermin alfa did not display any potential for promotion of tumour growth or metastasis . Studies investigating the carcinogenicity of dibotermin alfa have not been conducted. |
|---|
- Supportive treatment is advised in case of overdose
- Use in cervical spine surgery at doses comparable to lumbar fusion may cause localized edema leading to airway compromise
- Non-clinical studies show no significant acute or repeated dose toxicity or genotoxicity
Dibotermin alfa is a type of Hormonal Agents
Hormonal agents are a prominent category of pharmaceutical active pharmaceutical ingredients (APIs) widely used in the medical field. These substances play a crucial role in regulating and modulating hormonal functions within the body. Hormonal agents are designed to mimic or manipulate the effects of naturally occurring hormones, allowing healthcare professionals to treat various endocrine disorders and hormonal imbalances.
Hormonal agents are commonly employed in the treatment of conditions such as hypothyroidism, hyperthyroidism, diabetes, and hormonal cancers. These APIs work by interacting with specific hormone receptors, either by stimulating or inhibiting their activity, to restore the balance of hormones in the body. They can be administered orally, intravenously, or through other routes depending on the specific medication and patient needs.
Pharmaceutical companies employ rigorous manufacturing processes and quality control measures to ensure the purity, potency, and safety of hormonal agent APIs. These APIs are synthesized using chemical or biotechnological methods, often starting from natural hormone sources or through recombinant DNA technology. Stringent regulatory guidelines are in place to guarantee the efficacy and safety of hormonal agent APIs, ensuring that patients receive high-quality medications.
As the demand for hormone-related therapies continues to grow, ongoing research and development efforts focus on enhancing the effectiveness and reducing the side effects of hormonal agent APIs. This includes the exploration of novel delivery systems, advanced formulations, and targeted drug delivery methods. By continuously advancing our understanding and capabilities in hormonal agents, the medical community can improve patient outcomes and quality of life for individuals with hormonal disorders.
Dibotermin alfa API manufacturers & distributors
Compare qualified Dibotermin alfa API suppliers worldwide. We currently have 1 companies offering Dibotermin alfa API, with manufacturing taking place in 1 different countries. Use the table below to review supplier type, countries of origin, certifications, product portfolio and GMP audit availability.
| Supplier | Type | Country | Product origin | Certifications | Portfolio |
|---|---|---|---|---|---|
| Creative BioMart | Producer | United States | United States | CoA | 1 products |
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