Source: European Medicines Agency (EU) Revision Year: 2016 Publisher: Olympus Biotech International Limited, 40 Upper Mount Street, Dublin 2, Ireland Tel +353 87 9278653, medicalinfo@olympusbiotech.com
Pharmacotherapeutic group: Drugs for treatment of bone diseases, bone morphogenetic proteins
ATC code: M05BC02
Osigraft is an osteoinductive and osteoconductive medicinal product.
Eptotermin alfa, the active substance, initiates bone formation through the induction of cellular differentiation in mesenchymal cells, which are recruited to the implant site from bone marrow, periosteum and muscle. Once bound at the cell surface, the active substance induces a cascade of cellular events leading to the formation of chondroblasts and osteoblasts, which play a key role in the bone formation process. The collagen matrix is insoluble and consists of particles with a size range of 75-425µm. This provides an appropriate bioresorbable scaffold for the anchorage dependent cell proliferation and differentiation processes induced by the active substance. The cellular events induced by the active substance take place within the collagen matrix. The matrix is also osteoconductive and it allows bone in-growth into the defect area from the surrounding healthy bone.
The new bone formed is mechanically and radiographically comparable to normal bone. The new bone remodels naturally, cortices are formed and marrow elements are generated. However, use of Osigraft does not guarantee repair; additional surgery may be required.
The Tibial Nonunion pivotal trial compared Osigraft with autograft, with a primary efficacy endpoint at 9 months post-treatment. Clinical outcomes of pain and weight-bearing were comparable to the autograft (81% success in the Osigraft group, 77% success in the autograft group). The radiographic healing results of the Osigraft treatment group were slightly inferior compared to the autograft control group (68% and 79% respectively).
There are no data on the pharmacokinetics of the active substance in man. However, results from Osigraft implantation studies in animals demonstrate that the active substance eptotermin alfa is largely unavailable systemically.
Single dose and repeat dose studies in a range of animal models (rats, dogs and primates) were performed. The results of these showed no unanticipated or systemic effects of toxicity during the observation period and after administration.
In a 2 year subcutaneous implantation study in rats, heterotopic bone formation was observed, as expected. Sarcoma was associated with the long-term presence of the heterotopic bone. This effect, termed solid state carcinogenicity, frequently has been observed in rats where solid materials (plastics or metals) were implanted subcutaneously.
Heterotopic ossification commonly occurs in humans following accidental or surgical trauma. Heterotopic ossification may also occur following use (see section 4.8). However, there is evidence to suggest that heterotopic ossification is not linked to sarcoma in humans.
The effect of anti-OP-1 antibodies on the bone healing process was studied in dogs following two long bone defects treated with repeat implantations. The results of radiological and histological examinations in this non-clinical study showed bone healing with the initial and repeat exposure in the same animal. Antibodies to OP-1 and bovine bone collagen type 1 were found after both exposures; the antibody peak concentration was higher after the second implantation. The antibody levels declined towards baseline during the follow-up period.
Controlled studies of the effects of exposure to eptotermin alfa on pre and postnatal development were performed in rabbit models. Eptotermin alfa in Freund’s adjuvant was first administered subcutaneously with booster doses given after 14 and 28 days. Blood and milk samples were collected at regular intervals and analysed using a solid phase enzyme-linked immunoassay (ELISA) test. Detectable levels of IgG and IgM antibodies to eptotermin alfa developed and were found in the serum of all exposed adult animals. Antibodies to eptotermin alfa were found in sera from pooled foetal and umbilical cord blood at levels that correlated to that of the maternal blood. Antibodies were detectable in adults and offspring during the gestation and lactation periods. Significantly high titers of IgG class anti-OP-1 antibodies were detected in milk throughout the whole post-natal phase study until the lactation day 28 (see section 4.6).
A statistically significant increase in foetal malformations (misaligned sternabrae) was seen in litters of the OP-1 immunized group. In another study a difference in body weight gain was seen in the immunized adult females between lactation days 14 to 21 when compared to the control animals. The weight of the offspring in the treated group was noted to be less than that of the control group during the observation period. The clinical implications of these observations for human use of the finished product remain uncertain (see section 4.6).
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