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Positive Phase III Data Reported for Osteoporosis Drug Odanacatib
Positive findings have been reported from a pivotal phase III fracture outcomes study of odanacatib (Merck), an investigational once-weekly cathepsin K inhibitor, in postmenopausal women with osteoporosis.
In the Long-Term Odanacatib Fracture Trial (LOFT), odanacatib reduced the risk of osteoporotic hip, spine, and nonvertebral fractures compared with placebo. The results were presented September 15 at the annual meeting of the American Society for Bone and Mineral Research, held in Houston, Texas.
LOFT was a randomized, double-blind, placebo-controlled, event-driven trial, which also included a preplanned, blinded, placebo-controlled extension study. The trial enrolled 16,713 women aged 65 years or older who had been postmenopausal for 5 years or more. The patients were randomly assigned to receive odanacatib 50 mg/week (n = 8,357) or placebo (n = 8,356). All of the patients received vitamin D (5,600 IU/week) and calcium (up to 1,200 mg/day), if required. Safety and efficacy analyses were conducted in 16,071 patients in 40 countries.
Odanacatib significantly reduced the risk of three types of osteoporotic fractures compared with placebo in the primary efficacy analysis, and also reduced the risk of the secondary endpoint of clinical vertebral fractures. Specifically, compared with patients receiving placebo, patients who received odanacatib had a:
- 54% relative risk reduction of new and worsening morphometric (radiographically assessed) vertebral fractures (P
- 47% relative risk reduction in clinical hip fractures (P
- 23% relative risk reduction in clinical nonvertebral fractures (P
- 72% relative risk reduction in clinical vertebral fractures (P
In addition, treatment with odanacatib led to progressive increases over 5 years in bone mineral density (BMD) at the lumbar spine and total hip. Compared with placebo, the change in BMD from baseline at 5 years with odanacatib was 11.2% (P P
The rates of adverse events in the LOFT trial were generally balanced between patients receiving odanacatib or placebo. Events of morphea-like skin lesions and atypical femoral fractures occurred more often in the odanacatib group than in the placebo group. Major adverse cardiovascular events were generally balanced between the two treatments. There were numerically more adjudicated stroke events with odanacatib than with placebo.
In osteoporosis, bone loss occurs because of an imbalance in bone remodeling (i.e., the rate of bone resorption exceeds that of bone formation). Osteoclasts (cells that resorb bone) secrete signaling factors to stimulate osteoblasts (cells that form bone). Odanacatib selectively inhibits cathepsin K, the primary enzyme in osteoclasts that digests proteins during bone resorption. Progressive increases in BMD have been demonstrated with odanacatib.
Source: Merck; September 15, 2014.