New data from a Phase IIB clinical study of Odanacatib, oral, once-weekly investigational treatment for osteoporosis, showed that when stopping treatment after two years, the increases in lumbar spine bone mineral density ( BMD ) were reversed over the next year, while BMD at the femoral neck remained above levels observed at the start of the study. Additionally, three years of treatment with Odanacatib 50 mg demonstrated increases in bone mineral density at key fracture sites and minimal impact on the formation of new bone as measured by biochemical markers of bone turnover.

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.

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 bone mineral density 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 of the effect of Odanacatib after stopping therapy. This was measured as the percent change in lumbar spine bone mineral density ( 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.

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 bone mineral density 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.

Measures of new bone formation [ sBSAP ( serum bone specific alkaline phosphatise ) 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.

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 for the extension was similar between the Odanacatib and placebo groups. The most common clinical side effects regardless of treatment group were back pain, arthralgia, extremity pain and nasopharyngitis. 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 adverse experiences were similar in both groups.

Source: 31st Annual Meeting of the American Society for Bone and Mineral Research ( ASBMR ), 2009

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