Evaluation of the efficacy, safety and pharmacokinetic profile of oral recombinant human parathyroid hormone [rhPTH(1–31)NH2 ] in postmenopausal women with osteoporosis

• Published in: Bone (New York, N.Y.) N.Y.), 2013-03, Vol.53 (1), p.160-166
• Main Authors: Henriksen, K, Andersen, J.R, Riis, B.J, Mehta, N, Tavakkol, R, Alexandersen, P, Byrjalsen, I, Valter, I, Nedergaard, B.S, Teglbjærg, C.S, Stern, W, Sturmer, A, Mitta, S, Nino, A.J, Fitzpatrick, L.A, Christiansen, C, Karsdal, M.A
• Format: Article
• Language: English
• Subjects: Administration, Oral; Aged; Aged, 80 and over; Anabolic; Biological and medical sciences; Bone Density; Diseases of the osteoarticular system; Double-Blind Method; Enzyme-Linked Immunosorbent Assay; Female; Fundamental and applied biological sciences. Psychology; Humans; Medical sciences; Middle Aged; Orthopedics; Osteoporosis; Osteoporosis, Postmenopausal - drug therapy; Osteoporosis, Postmenopausal - physiopathology; Osteoporosis. Osteomalacia. Paget disease; Parathyroid Hormone - adverse effects; Parathyroid Hormone - pharmacokinetics; Parathyroid Hormone - therapeutic use; Peptide Fragments - adverse effects; Peptide Fragments - pharmacokinetics; Peptide Fragments - therapeutic use; Recombinant Proteins - adverse effects; Recombinant Proteins - pharmacokinetics; Recombinant Proteins - therapeutic use; rhPTH(1–31)NH2; Teriparatide; Vertebrates: anatomy and physiology, studies on body, several organs or systems
• ISSN: 8756-3282; 1873-2763
• DOI: 10.1016/j.bone.2012.11.045

Abstract Context Treatment of osteoporosis with subcutaneous (SC) injections of rhPTH(1–34) or rhPTH(1–84) is associated with significant improvements in BMD and reductions in osteoporotic fractures. However, subcutaneous injections can be associated with discomfort and thus deteriorating compliance. Objective The UGL-OR1001 trial aimed to establish the efficacy and safety parameters of a novel oral tablet formulation of rhPTH(1–31)NH2 and matching placebo tablets and open-label teriparatide positive control in postmenopausal women with osteoporosis. Design 24 weeks of randomized, double-blind treatment with once daily doses of 5 mg oral treatment or corresponding placebo, or open-label subcutaneous teriparatide. Patients or other participants Women diagnosed with postmenopausal osteoporosis as detected by lumbar spine DXA, with an exclusion of those with prior treatment with bone active agents. Intervention(s) Orally formulated recombinant human PTH(1–31)NH2 and placebo, or open-label subcutaneous teriparatide as a positive control. Main outcome measure(s) The primary endpoint was to characterize the percent change from baseline in bone mineral density (BMD) at L1–L4 axial lumbar spine after 24 weeks in the rhPTH(1–31)NH2 arm. Secondary and exploratory endpoints included safety and tolerability of the oral formulation, measurement of biochemical markers of bone turnover, and evaluation of the PK profile at first and last dose. The study was registered at ClinicalTrials.gov with the identifier: NCT01321723. Results The oral tablet formulation of rhPTH(1–31)NH2 resulted in similar PK profiles at both timepoints with mean Cmax values similar to subcutaneous administration. In the rhPTH(1–31)NH2 arm, a 2.2% increase in lumbar spine BMD was observed compared to baseline ( p < 0.001), while no change was observed in the placebo arm. Open-label teriparatide resulted in a 5.1% increase in LS BMD ( p < 0.001). In the oral PTH study arm, the bone formation marker osteocalcin was increased by 32%, 21% and 23% at Weeks 4, 12 and 24, respectively. There was no significant increase in the level of the bone resorption marker CTx-1. Conclusions In summary, these data demonstrate that enteric-coated oral tablet formulation technology consistently generated robust levels of exposure of rhPTH(1–31)NH2 leading to induction of bone formation without inducing bone resorption resulting in significantly increased levels of LS BMD. Few adverse events were observed, recommending t