Endocrine Society's 97th Annual Meeting and Expo, March 5–8, 2015 - San Diego
FRI-264:
Preclinical and Clinical Development of a Novel Recovery Booster Therapy (NDD) for Hip Fracture in Older Women
Helenius Jan Kloosterboer1, Peter Schot2 and Marjanne Prins2
1KC2, Oss, Netherlands
2OrgaNext Research,
Presentation Number: FRI-264
Date of Presentation: March 6, 2015
Abstract
Abstract:
NDD, a fixed combination of a low dose of nandrolone decanoate (ND) and vitamin D3 (D3), is in development as Recovery Booster therapy for older women with vitamin D deficiency in order to mitigate disuse atrophy and loss of physical function after hip fracture surgery. After surgery the risk of muscle wasting is high and full recovery is hampered due to low muscle mass. The objective of NDD treatment is to reverse the post-operative catabolic state, activate muscle cells, increase muscle mass, improve functional outcome and restore vitamin D3 sufficiency. Studies with human skeletal satellite cells show that nandrolone and 1a,25-dihydroxyvitamin D3 have a synergistic effect on muscle cell proliferation. Receptor studies show that in muscle cells the two compounds increase the expression of their own and each other’s receptor, which may explain the synergistic effect on proliferation of muscle cells. Nandrolone inhibits the proliferation of human prostate LNCaP cells and this effect is enhanced by 1a,25-dihydroxyvitamin D3. In Phase I studies the safety, tolerability and kinetics of NDD were investigated in healthy women (65-79 years of age). Women received subcutaneously an injection of 0.5 ml sesame oil containing 25 mg ND and 14.000 IU D3 in a single dose study and 25 mg ND and 28.000 IU D3 in a multiple dose study (2 injections at day 1 followed by a single weekly injection for 3 weeks). In both studies NDD was safe and well tolerated. Both ND and D3 were released from the depots. Nandrolone shows first order kinetics. Mean serum D3 concentrations did not increase after the first dosing, but did after the 3 subsequent ones. Consequently, the mean AUC0-72h for D3 is higher after the fourth dosing than after the first dosing. Despite the increase in D3 levels, the mean 25(OH)D3 level and mean AUC0-72h hardly changed during treatment. However, mean screening corrected serum 25(OH)D3 levels in subjects with a low screening value (<30 ng/ml) increased, while the screening corrected mean level of 25(OH)D3 in subjects with high screening levels (> 30 ng/ml) showed a decrease. This difference in effect may be explained by homeostatic regulation of D3 metabolites. The long-term effects on 25(OH)D3 levels 90 days after the last injection indicate that 28.000 IU D3 once a week are sufficient to restore 25(OH)D3 to adequate levels. Procollagen type III N-terminal peptide increased significantly (P<0.001) in the multiple dose study with NDD, which is indicative of an early anabolic response of NDD. A pivotal Phase IIb/III in which 3 low doses of nandrolone combined with 28.000 IU D3 will be investigated is in preparation. The duration of this study is 6 months and primary endpoints will be muscle mass, functional activity (gate speed) and 25(OH)D3 levels (>20 ng/ml). All subjects will participate in a physical rehabilitation program. So far, our studies indicate that NDD is a promising treatment for recovery after hip fracture.
Disclosure: HJK: Consultant, Roche Diagnostics, Consultant, PantarheiBio, Scientific Adviser, OrgaNext Research. PS: Employer, OrgaNext Research. MP: Owner, OrgNext Research