Introduction: This reports primary and key secondary endpoints from a phase 2 trial on the efficacy and safety of the human sclerostin antibody AMG 785/CDP7851; the trial was done in postmenopausal woman with low bone mineral density (BMD). Pre-clinical studies showed that bone mass and strength was increased with the administration of antibodies that neutralize sclerostin.
Methods: Postmenopausal women between the ages of 55 and 85 (mean age: 67 years) were enrolled in this phase 2, international, randomized, placebo-controlled study. They had either a lumbar spine, total hip, or femoral neck T-score of ≤ -2.0 and ≥ -3.5. For the first year of the trial, the women were randomized into the following groups:
The percentage change from baseline in the lumbar spine BMD at month 12 was the primary endpoint (AMG compared with placebo).
Results: There were 419 women in the study, and mean lumbar spine, total hip, and femoral neck T-scores were -2.3, -1.5, and -1.9, respectively. At month 12 at each of the 3 sites, all 5 regimens of AMG 785 significantly increased BMD compared to placebo (p< 0.005). AMG 785 210 mg QM showed the largest gains: there were rapid BMD increased in the lumbar spine (11.3%) and at the total hip (4.1%) Increases achieved with ALN and TPTD were significantly less (p < 0.0001).
By week 1, all 5 regimens of AMG 785 increased serum PINP from baseline; they also reduced serum CTX from baseline. With ALN and TPTD, the bone turnover marker changes followed the expected profiles; ALN decreased both markers, while TPTD increased both.
Adverse events were generally balanced between the AMG 785 groups and placebo; however, mild injection site reactions were higher with AMG 785 (4% placebo; 12% AMG 785).
Conclusions: The increases in lumbar spine and hip BMD with AMG 785 were superior to those seen with ALN and TPTD—a testimony to the mechanism of action of AMG 785. It causes a simultaneous stimulation of bone formation and a decrease in bone resorption. AMG 785 was well-tolerated, and these phase 2 trial results support further investigation of AMG 785 as a treatment for postmenopausal osteoporosis.
Commentary by Pauline M. Camacho MD, FACE
This is a very interesting study that looked at the efficacy of a promising new agent for osteoporosis, AMG 785, a monoclonal antibody inhibitor of sclerostin. Sclerostin has anti-anabolic effects, and individuals who have genetic mutations that lead to decreased sclerostin function have very dense bones.
In this study, AMG785 was compared to placebo and two established agents for osteoporosis, alendronate and teriparatide. At one year, the increase in spine bone mineral density was 4% with alendronate, 7% with teriparatide, and 11.3% with AMG 785. All doses of AMG 785 significantly increased BMD at the spine, hip, and femoral neck compared to placebo.
Bone turnover marker changes seen in the AMG 785 group showed an increase in the bone formation marker PINP ( procollagen type I N-terminal propeptide) and decrease seen in the bone resorption marker CTX (C-telopeptide).
With only one approved anabolic agent in the US, this drug will be a welcome addition to the treatment of osteoporosis once approved by the FDA.