New, Long-Term Data for Odanacatib, Merck’s Investigational Cat K Inhibitor, Showed Positive Results in Treating Osteoporosis

Novel, Anti-Resorptive Therapy Showed Treatment Effect Rapidly Stopped After Discontinuation and BMD Continuously Increased With Minimal Inhibition of Bone Formation After Three Years

DENVER - New data from a Phase IIB clinical study of odanacatib, Merck & Co., Inc.’s oral, once-weekly investigational treatment for osteoporosis, showed that when stopping treatment after two years, the increases in lower back (lumbar spine) bone mineral density (BMD) were reversed over the next year, while BMD at the hip (femoral neck) remained above levels observed at the start of the study. Additionally, three years of treatment with odanacatib 50 mg demonstrated increases in BMD at key fracture sites and minimal impact on the formation of new bone as measured by biochemical markers of bone turnover. These new data were presented at the 31st Annual Meeting of the American Society for Bone and Mineral Research (ASBMR).

“The ’rapid off’ effect results showed that the drug’s effect did not persist long after the drug cleared the body,” said Art Santora II, MD, PhD, Executive Director Clinical Research, Merck Research Labs. “Additionally, the continued increases in BMD seen at three years while sparing bone formation adds to the existing scientific evidence for the potential of odanacatib as a novel treatment option for osteoporosis"

Odanacatib is currently in Phase III clinical trials and is being evaluated in a large-scale, global outcomes study to determine its effects on vertebral, hip and non-vertebral fractures. Odanacatib is a cathepsin K inhibitor that selectively inhibits the cathepsin K enzyme. Cathepsin K is known to play a central role in the function of osteoclasts, which are cells that break down existing bone tissue, particularly the protein components of bone. Inhibition of cathepsin K is a novel approach to the treatment of osteoporosis.

Odanacatib study design
A one-year extension study was conducted following the completion of a two-year Phase IIB study in which odanacatib 50 mg was shown to increase BMD and decrease bone resorption in postmenopausal women with low BMD (T-scores equal to or less than -2.0 but equal to or greater than -3.5). Of the 399 women in the two-year study (who had received placebo or odanacatib 3, 10, 25 or 50 mg weekly), 189 women continued into the extension study and were re-randomized to odanacatib 50 mg (n=97) once weekly or placebo (n=92) for an additional year. In addition, all women received open-label supplementation with Vitamin D3, 5600 IU weekly, and those with total calcium intake (dietary plus supplemental) below 1000 mg per day received open-label 500 mg daily calcium supplements. Throughout the study, odanacatib was given with or without food and without the need for the patient to remain in the upright or any other position for a specified period of time.

The extension study’s primary objective was the assessment of the resolution (reversal) of the effect of odanacatib after stopping therapy. This was measured as the percent change in lumbar spine BMD (primary endpoint of the study) at three years compared to baseline among patients who received odanacatib 50 mg in the study’s two-year base period and then switched to placebo for the third-year extension (n=18) versus those who received odanacatib 50 mg for all three years of the study (n=20). Percent change from baseline in BMD measurements at the total hip, femoral neck, trochanter, total body and one-third radius were secondary endpoints. Other secondary endpoints included change from baseline in biochemical markers of bone resorption (s-CTX, u-NTx, u-DPyr), bone formation (s-BSAP, s-P1NP), other markers of osteoclast number (s-TRAP-5b) and cathepsin K activity (s-1CTP).

Of the 189 extension study participants, 169 (89.4 percent) completed three years of treatment, and 20 (10.6 percent) dropped out of the study. Reasons for early discontinuation were similar among odanacatib and placebo groups. All patients who completed the third year of treatment were included in the BMD efficacy analyses; all 189 women were included in the safety analyses.

Study results for effects of discontinuing therapy and BMD measurements
Following discontinuation of odanacatib treatment and the switch to placebo in the extension study, BMD increases with odanacatib 50 mg in the two-year base study were largely reversed at the end of the extension study. BMD decreased at all sites, with values remaining slightly but not significantly above their baseline values, except at the femoral neck where BMD remained significantly above baseline. The rate of bone loss was greater in the initial six-month period following discontinuation of treatment and then leveled off in the second six months.

Continued treatment with odanacatib 50 mg once weekly for three years resulted in a sustained increase in BMD of almost eight percent at the lumbar spine, six percent at the total hip, five percent at the femoral neck of the hip and seven percent at the trochanter of the hip after three years when compared to baseline. There was little change in total body BMD (-0.4 percent) or one-third radius BMD (-0.26) with continued treatment of odanacatib 50 mg for three years.

Study results for effects on biochemical markers of bone formation and resorption
Measures of new bone formation (sBSAP (serum bone specific alkaline phosphatase) and sP1NP (serum N-terminal propeptides of type 1 collagen)) decreased initially in patients continuously treated with odanacatib through all three years of the study. Formation markers reached their lowest point after approximately six months after the base study start, but subsequently rose to levels similar to those in patients treated with placebo for three years. Among patients who discontinued odanacatib treatment in the one-year extension, results showed an initial rise in sBSAP and sP1NP at six months, which was resolved over the next six months by the end of the study.

Among patients continuing odanacatib 50 mg through the third year of study treatment, the bone resorption markers uNTx (urinary N-telopeptides/creatinine ratio) and sCTx (serum C-terminal telopeptides of Type 1 collagen) each remained reduced at three years compared with baseline. Discontinuation of treatment was associated with increases in all markers of bone resorption within one week to levels approximately twice baseline levels but subsequently returned toward baseline in the following 12 months.

Safety results with odanacatib in the extension study
The safety analysis contained two groups: placebo or odanacatib, both of which included patients treated in the first two years with placebo and different doses of odanacatib. The overall incidence of adverse experiences (AEs) for the extension was similar between the odanacatib and placebo groups. The most common clinical AEs regardless of treatment group were back pain, arthralgia (joint pain), extremity pain and nasopharyngitis (common cold). Urinary tract infections occurred more frequently in the odanacatib group compared to the placebo group (10 vs. 1, respectively); none of these events were classified as drug-related by study investigators, none led to discontinuation of study drug and all resolved following antibiotic therapy. Moreover, the incidence did not differ among all treatment groups in the first two years of the study or in the odanacatib 50 mg group for the entire three-year period. The incidence of skin disorders in the extension was slightly higher in the placebo group than the odanacatib group (15 vs. 12, respectively) and discontinuations due to clinical AEs were similar in both groups (four each).

About BMD and osteoporosis
Bone mineral density (BMD) is the amount of mineralized bone tissue in a certain volume of bone. It is measured through a non-invasive test to detect low bone density, which helps diagnose osteoporosis and predict an individual’s fracture risk.

Osteoporosis, a disease in which the density and strength of bone are reduced, affects more than 75 million people in the United States, Europe, South America, Japan and Australia. The underlying mechanism for the development of osteoporosis is an imbalance in the body’s natural processes of bone resorption (breakdown of existing bone at the cellular level) and bone formation (creation of new bone at the cellular level). Excessive bone resorption and inadequate bone formation can cause bones to become more porous and fragile, which in turn increases the risk of fractures. The most commonly recognized fractures associated with osteoporosis are at the hip, spine and wrist. 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 four 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.

About Merck
Merck & Co., Inc. is a global research-driven pharmaceutical company dedicated to putting patients first. Established in 1891, Merck currently discovers, develops, manufactures and markets vaccines and medicines to address unmet medical needs. The Company devotes extensive efforts to increase access to medicines through far-reaching programs that not only donate Merck medicines but help deliver them to the people who need them. Merck also publishes unbiased health information as a not-for-profit service. For more information, visit www.merck.com.

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