MINNEAPOLIS – The investigational antisclerostin antibody AMG 785 produced rapid increases in bone mineral density roughly 50% to 60% higher than standard drugs in postmenopausal women with low bone mineral density in a phase II trial.
At 1 year, the increase in spine bone mineral density (BMD) was 4% with alendronate (Fosamax), 7% with teriparatide (Forteo), and 11.3% with AMG 785 given in a subcutaneous dose of 210 mg/mo.
Patrice Wendling/IMNG Medical Media
Dr. Michael McClung
Increases in BMD followed a similar, but slightly less dramatic pattern, at the total hip (2% vs. 1.5% vs. 4.1%) and femoral neck (1% vs. 1% vs. 3.7%), Dr. Michael McClung reported at the annual meeting of the American Society for Bone and Mineral Research (ASMBR) The differences in BMD at all three sites significantly favored AMG 785 over either active comparator.
AMG 785 is thought to increase bone formation on quiescent surfaces by inhibiting sclerostin, a protein encoded by the SOST gene in osteocytes that downregulates osteoblast-mediated bone formation.
The phase II results are the first longer-term response data presented for an antisclerostin antibody and build on preclinical work, suggesting that these bone-building drugs increase bone formation without the increase in bone resorption seen with some osteoanabolic agents. Data were also presented at the meeting from two phase I studies of Eli Lilly’s antisclerostin antibody, blosozumab.
The drug will be useful for that small proportion of patients who have had substantial bone loss and destruction of the architecture and strength of their bone over time, Dr. McClung said in an interview.
"There are some patients who are truly in need of skeletal reconstruction, and this would be the strategy to do that," he said. "None of our other drugs have that potential.
"The idea of being able to rebuild the skeletal architecture, the skeletal mass, and the skeletal strength back toward, or even to, normal is a really exciting prospect."
The phase II trial randomly assigned 419 postmenopausal women with low bone mineral density to one of five doses of subcutaneous AMG 785 (70 mg monthly, 140 mg monthly, 210 mg monthly, 140 mg every 3 months, or 210 mg every 3 months) or placebo, and one of two open-label active comparators: 70 mg weekly oral alendronate or 20 mcg daily subcutaneous teriparatide.
The women had average lumbar spine, total hip, and femoral neck T scores of –2.3, -1.5, and –1.9, respectively, but did not have severe osteoporosis. Their average age was 67 years.
At 1 year, all doses of AMG 785 significantly increased BMD at the hip, spine, and femoral neck compared with placebo (P less than .005). A clear dose-response relationship was observed, both in terms of the total dose and dosing interval favoring the higher and monthly doses, said Dr. McClung, director of the Oregon Osteoporosis Center in Portland.
Serum bone turnover marker analyses revealed that all doses of AMG 785 increased PINP (procollagen type I N-terminal propeptide) and reduced CTX (C-telopeptide of type I collagen) from baseline by week 1. As expected, researchers observed decreases in both markers with alendronate and increases in both markers with teriparatide.
Although some have characterized antisclerostin antibodies as a game-changer in osteoporosis, Dr. McClung cautioned that the results are just the first step and said the study produced some surprises in that the very dramatic changes in bone makers occurred within a week of beginning therapy, but the effects on stimulating bone formation were transient and the values returned to baseline between 6 and 12 months, despite patients continuing on therapy.
"There’s lots we need to learn about this," he said, noting that the blunting of the bone response has not been observed in animals. "It seems unlikely that we’ll simply identify patients in need of skeletal restoration and add a sclerostin therapy and treat them until they don’t have osteoporosis anymore.
"Likely we’ll use sclerostin therapy for a relatively short time – 6 months, 12 months – followed by probably another drug, like an antiresorptive drug, and then attempt to take advantage of that first burst of anabolic activity again."
Still, it was hard to miss the buzz over this new therapeutic target, with 20 or so sclerostin abstracts at the meeting and the AMG 785 study winning the 2012 ASBMR Most Outstanding Clinical Abstract Award.
Early positive signals from the phase II trial also prompted Amgen to initiate a phase III randomized, alendronate-controlled trial in more than 5,000 postmenopausal women with osteoporosis to determine whether AMG 785 can prevent fractures, the Holy Grail in osteoporosis management.