It has been previously reported that prolonged treatment with rhPTH(134) or rhPTH(184) in rats is associated with the development of bone neoplasms including osteosarcomas. However, to date there has been no evidence of an increased osteosarcoma risk of in patients treated with rhPTH(134) or rhPTH(184), or in diseases associated with chronic PTH elevation. Abaloparatide (ABL) is a novel analog of PTHrP(134) currently being developed as a treatment for osteoporosis. In completed clinical studies, earlier and greater BMD gains were seen with ABL compared to rhPTH(134). This study was conducted to evaluate the potential for ABL to induce osteosarcomas in rats following long-term treatment. Six-week-old F344 rats (60/sex per dose) were treated with 0, 10, 25, or 50 μg/kg ABL or 30 μg/kg hPTH(134) daily for 2 years. Human PTH(134) was included as a positive control, at a dose known to result in osteosarcomas in rats. Hyperostosis, increased bone radiopacity and BMD were noted in rats treated with ABL at ≥10 μg/kg or hPTH(134), consistent with expected pharmacodynamics. Osteosarcomas were observed in both ABL and hPTH(134) treated rats. Comparison of these findings for ABL and hPTH(134), at similar exposure multiples to the human therapeutic dose (25 μg/kg ABL and 30 μg/kg hPTH), showed comparable incidence of osteosarcomas. In female rats, there was one primary osteosarcoma in vehicle controls, 11, 22 and 37 with ABL at 10, 25 and 50 μg/kg respectively, and 24 with hPTH(134). There were no metastatic osteosarcomas observed in vehicle controls, two, three and 16 with ABL 10, 25 and 50 μg/kg respectively, and nine with hPTH(134). In conclusion, close to whole life treatment with ABL in rats resulted in the dose and time dependent formation of osteosarcomas, with a comparable incidence to hPTH(134) at similar exposure. These results suggest no increased risk of osteosarcoma would be expected in patients treated with ABL compared to rhPTH(134).
17 May 2014 - 20 May 2014