title: Evaluation of the efficacy, safety and pharmacokinetic profile of oral recombinant human parathyroid hormone [rhPTH(1-31)NH(2)] in postmenopausal women with osteoporosis.
abstract: BACKGROUND
  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)NH(2) and matching placebo tablets and open-label teriparatide positive control in postmenopausal women with osteoporosis.
  
  
  METHODS
  24 weeks of randomized, double-blind treatment with once daily doses of 5mg oral treatment or corresponding placebo, or open-label subcutaneous teriparatide.
  
  
  METHODS
  Women diagnosed with postmenopausal osteoporosis as detected by lumbar spine DXA, with an exclusion of those with prior treatment with bone active agents.
  
  
  METHODS
  Orally formulated recombinant human PTH(1-31)NH(2) and placebo, or open-label subcutaneous teriparatide as a positive control.
  
  
  METHODS
  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)NH(2) 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)NH(2) resulted in similar PK profiles at both timepoints with mean C(max) values similar to subcutaneous administration. In the rhPTH(1-31)NH(2) 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)NH(2) leading to induction of bone formation without inducing bone resorption resulting in significantly increased levels of LS BMD. Few adverse events were observed, recommending this orally delivered drug candidate for further development.
authors.affiliation: Nordic Bioscience A/S, Bone Biology, Herlev, Denmark. kh@nordicbioscience.com
authors.forename: K
authors.initials: K
authors.lastname: Henriksen
authors.forename: J R
authors.initials: JR
authors.lastname: Andersen
authors.forename: B J
authors.initials: BJ
authors.lastname: Riis
authors.forename: N
authors.initials: N
authors.lastname: Mehta
authors.forename: R
authors.initials: R
authors.lastname: Tavakkol
authors.forename: P
authors.initials: P
authors.lastname: Alexandersen
authors.forename: I
authors.initials: I
authors.lastname: Byrjalsen
authors.forename: I
authors.initials: I
authors.lastname: Valter
authors.forename: B S
authors.initials: BS
authors.lastname: Nedergaard
authors.forename: C S
authors.initials: CS
authors.lastname: Teglbjaerg
authors.forename: W
authors.initials: W
authors.lastname: Stern
authors.forename: A
authors.initials: A
authors.lastname: Sturmer
authors.forename: S
authors.initials: S
authors.lastname: Mitta
authors.forename: A J
authors.initials: AJ
authors.lastname: Nino
authors.forename: L A
authors.initials: LA
authors.lastname: Fitzpatrick
authors.forename: C
authors.initials: C
authors.lastname: Christiansen
authors.forename: M A
authors.initials: MA
authors.lastname: Karsdal
mesh_terms: D000284:Administration, Oral; D000368:Aged; D000369:Aged, 80 and over; D015519:Bone Density; D004311:Double-Blind Method; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D008875:Middle Aged; D015663:Osteoporosis, Postmenopausal / Q000188:drug therapy* / Q000503:physiopathology; D010281:Parathyroid Hormone / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D010446:Peptide Fragments / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011994:Recombinant Proteins / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use
chemical_list: D010281:Parathyroid Hormone; D010446:Peptide Fragments; D011994:Recombinant Proteins; C102836:parathyroid hormone (1-31)amide, human