All of the women studied had received alendronate (Fosamax) for at least 3 years.
Patients could have been off the bisphosphonate for up to 3 months prior to enrollment, but many switched directly over to odanacatib, said study coauthor Dr. Albert Leung, executive director of clinical research at Merck Research Laboratories.
"This drug has the potential to give additional benefits when [patients] have been treated with alendronate for a number of years and the treatment effect has reached a plateau and they may need a different treatment," he said in an interview.
In July 2012, a pivotal 16,731-patient, phase III trial of odanacatib was stopped early after an interim analysis showed a "favorable benefit-risk profile" for fracture risk reduction in postmenopausal women with previously untreated osteoporosis.
"It could be quite a population that may benefit from this drug," Dr. Leung remarked.
The study's data monitoring committee, however, flagged safety concerns in "certain selected areas" for further follow-up. Those safety risks have not been identified as the trial is still closing, but will be monitored along with efficacy in a double-blind, placebo-controlled, extension trial going out to 5 years of treatment, he said.
Merck, which plans to submit regulatory applications for odanacatib in the United States and Europe in the first half of 2013, has high hopes for odanacatib despite competition from generic drugs because of its novel mechanism of action.
Odanacatib inhibits cathepsin K, the primary protease in osteoclasts that breaks down bone collagen during bone resorption. Unlike traditional antiresorptive drugs like bisphosphonates, however, odanacatib does not interfere with the function of the entire osteoclast osteoclast /os·teo·clast/ (os´te-o-klast?)
1. a large multinuclear cell associated with absorption and removal of bone.
2. an instrument used for osteoclasis. or reduce the number of osteoclasts. This characteristic is important, as osteoclasts secrete signaling factors to stimulate osteoblasts, the cells responsible for bone formation. As a result, there is greater bone formation with odanacatib, Dr. Leung explained.
The phase II trial enrolled women at least 60 years of age (mean 71 years) with a BMD T score of -2.5 to more than -3.5 at any hip site without a prior fragility fracture or those with a history of fragility fracture (except hip fracture), and a BMD T score of -1.5 and more than -3.5 at any hip site.
The women were randomly assigned to odanacatib 50 mg once weekly or placebo for 24 months, as well as 5,600 IU of vitamin D3 per week and calcium at dosages up to 1,200 mg/ day. The study was not powered to assess fractures.
At 24 months, the change in BMD at the lumbar spine was significant at 2.28% for odanacatib vs. a loss of 0.30% with placebo (P less than .001).
BMD change was not significant at the distal forearm, with losses of 0.92% vs. 1.14%, respectively.
As expected, urinary collagen type I cross-linked N-telopeptide, a biomarker of bone resorption, increased with placebo, compared with a significant 47% decrease with odanacatib.
The bone formation marker, serum type I procollagen, rose inexplicably with placebo, but this increase was surpassed by a significant gain of 31.2% with odanacatib.
Most unexpected, however, was an increase in the resorption resorption /re·sorp·tion/ (re-sorp´shun)
1. the lysis and assimilation of a substance, as of bone.
2. reabsorption.
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re·sorp·tion
n. marker collagen type I cross-linked C-telopeptide (sCTx) with once-weekly odanacatib.
Dr. Leung said the finding appears to correlate with the bone density changes because sCTx levels remained relatively stable during the first 12 months of treatment before rising in the second year of the study.
Finally, adverse events were similar in both groups. The most common adverse events in the odanacatib and placebo arms were urinary tract infection urinary tract infection (UTI),
n infection in one or more of the structures that make up the urinary system. Occurs more often in women and is most commonly caused by bacteria. (11.5% vs. 16.5%, respectively), back pain (11.5% vs. 9.9%), arthralgia (9% vs. 9.9%), and fractures (4.9% vs. 13.2%).
Treatment discontinuation rates due to adverse events were 9% vs. 3.3%, he said. |
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