Merck's odanacatib increased BMD over 2 years at key fracture sites in Phase IIB study

WHITEHOUSE STATION, N.J., 17 sept 2008– Two-year data from a Phase IIB study of odanacatib (formerly MK-0822), an investigational, selective cathepsin-K inhibitor in development for the treatment of osteoporosis by Merck & Co., Inc., demonstrated dose- dependent increases in bone mineral density (BMD) at the total hip, lumbar spine and femoral neck fracture sites and decreased indices of bone resorption compared to placebo in postmenopausal women with low BMD. The results were reported today at the 30th Annual Meeting of the American Society for Bone and Mineral Research (ASBMR).
"Significant BMD increases were seen in the second year of treatment with odanacatib and these 24-month results confirm the positive increases seen at earlier timepoints," said Dr. Michael McClung, study investigator and director of the Oregon Osteoporosis Center in Portland, Oregon. "These data reinforce the potential of odanacatib as a novel treatment option for osteoporosis."
Odanacatib selectively inhibits the cathepsin K enzyme believed to play a central role in osteoclastic bone resorption, particularly in the degradation of the protein component of bone. Inhibition of cathepsin K is a novel approach to the treatment of osteoporosis that differs from those of currently approved treatments.
About the study
The multi-center, double-blind, randomized, placebo-controlled study evaluated doses of 3, 10, 25 or 50 mg of odanacatib administered orally, once-weekly and without regard to the timing of meals or the patient's physical position in 399 postmenopausal women with low BMD (T-scores equal to or less than -2.0 but equal to or greater than -3.5) for 24 months. Participants were provided with 5600 IU weekly, supplemental vitamin D, and 500 mg daily calcium carbonate was given to women with average daily calcium intakes of less than 1000 mg from all sources. The primary study endpoint was the LS mean change in BMD from baseline at the lumbar spine. Secondary endpoints included the LS mean change from baseline in BMD at the total hip, femoral neck, hip trochanter, and distal forearm, and changes in bone turnover based on biochemical markers.
"Bone mineral density" or BMD is the amount of mineralized bone tissue in a certain volume of bone and is one non-invasive measure used to help determine a patient's fracture risk. Odanacatib increased BMD
In the study, once-weekly treatment with 10, 25 and 50 mg of odanacatib significantly increased BMD at the lumbar spine, total hip and femoral neck at 24 months compared to baseline values. The 50 mg dose (n=58) resulted in LS mean percent increases in BMD of
5.48 percent at the lumbar spine compared to baseline values while treatment with placebo (n=61) resulted in a decrease of 0.19 percent compared to baseline (p=0.001). Similarly, the 50 mg dose resulted in LS mean percent increases in BMD of 3.16 percent at the total hip and 3.84 percent at the femoral neck compared to baseline values while treatment with placebo resulted in decreases of 0.93 percent and 0.85 percent respectively compared to baseline (p=0.001). Treatment with 3 mg odanacatib resulted in decreases in BMD at the lumbar spine, total hip and femoral neck. Changes in bone resorption and bone formation
The study also assessed biochemical markers of bone resorption including sCTx (serum C-terminal telopeptides of Type 1 collagen) and uNTx (urinary N-telopeptides/creatinine ratio). Treatment with 50 mg of odanacatib resulted in decreases from baseline of 51.83 percent in uNTx and 30.57 percent in sCTx (p=0.001). sCTx and uNTx changes for placebo were an increase of 32.77 percent and a decrease of 4.62 percent respectively.
Treatment with the 50 mg dose reduced biochemical markers of new bone formation including s-BSAP (bone specific alkaline phosphatase) and sP1NP (serum N-terminal propeptides of type 1 collagen). s-BSAP was reduced from baseline by 13.26 percent (p=0.002) and sP1NP was reduced by 20.20 percent from baseline (p=0.011). s-BSAP and sP1NP changes for placebo were increases of 3.38 percent and 1.29 percent respectively.
Safety results with odanacatib
The number of patients experiencing a drug-related adverse experience was similar between the 50 mg odanacatib group and placebo (34.6 percent and 39.8 percent respectively). Likewise, the discontinuation rates due to drug-related adverse experiences were similar between the 50 mg odanacatib group and placebo (7.7 percent and 4.8 percent respectively). For the 50 mg odanacatib group, the most common drug-related adverse experiences, as assessed by investigators, were nausea, headache, rash and muscle spasms. There was no dose-dependent increase in the incidence of skin adverse experiences or upper respiratory tract infections observed through 24 months.
Phase III study underway
The effect of odanacatib 50 mg on vertebral, hip and non-vertebral fractures is currently being evaluated in a large, global Phase III study.
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About osteoporosis
Osteoporosis, a disease in which the density and strength of bone are reduced, affects more than 75 million people in the U.S., Europe, South America and Japan. As bones become more porous and fragile, the risk of fracture is greatly increased. The most common fractures associated with osteoporosis occur at the hip, spine and wrist and the risk of having an osteoporosis-related fracture increases with age. One in three women over age 50 will experience an osteoporotic fracture, as will one in five men. According to the International Osteoporosis Foundation (IOF), the worldwide incidence of hip fracture is projected to increase by 240 percent in women and 310 percent in men by 2050.