Albert Leung

Odanacatib in the treatment of postmenopausal women with low bone mineral density: five years of continued therapy in a phase 2 study.

Odanacatib (ODN) is a selective inhibitor of the collagenase cathepsin K that is highly expressed by osteoclasts. In this 2‐year, phase 2, dose‐ranging trial, postmenopausal women with bone mineral density (BMD) T‐scores −2.0 to −3.5 at spine or hip were randomized to weekly placebo or ODN 3, 10, 25, or 50 mg plus vitamin D3 and calcium. Prespecified trial‐extensions continued through 5 years. In year 3, all women were re‐randomized to ODN 50 mg or placebo. For years 4 and 5, women who received placebo or ODN 3 mg in years 1 and 2 and placebo in year 3 received ODN 50 mg; others continued year 3 treatments. Endpoints included lumbar spine (primary), hip, 1/3 radius, and total body BMD; markers of bone metabolism; and safety. Women in the year 4 to 5 extension receiving placebo (n = 41) or ODN 50 mg (n = 100) had similar baseline characteristics. For women who received ODN (10–50 mg) for 5 years, spine and hip BMD increased over time. With ODN 50 mg continually for 5 years (n = 13), mean lumbar spine BMD percent change from baseline (95% confidence interval [CI]) was 11.9% (7.2% to 16.5%) versus −0.4% (−3.1% to 2.3%) for women who were switched from ODN 50 mg to placebo after 2 years (n = 14). In pooled results of women receiving continuous ODN (10–50 mg, n = 26–29), year 5 geometric mean percent changes from baseline in bone resorption markers cross‐linked N‐telopeptide of type I collagen (NTX)/creatinine and cross‐linked C‐telopeptide (CTX) were approximately −55%, but near baseline for bone formation markers bone‐specific alkaline phosphatase (BSAP) and amino‐terminal propeptide of type I procollagen (P1NP). In women switched from ODN 10 to 50 mg to placebo after 2 years (n = 25), bone turnover markers were near baseline. In summary, women receiving combinations of ODN (10–50 mg) for 5 years had gains in spine and hip BMD and showed larger reductions in bone resorption than bone formation markers. Discontinuation of ODN resulted in reversal of treatment effects. Treatment with ODN for up to 5 years was generally well‐tolerated.

Efficacy and Tolerability Profile of Etoricoxib in Patients with Osteoarthritis: A Randomized, Double-blind, Placebo and Active- comparator Controlled 12-Week Efficacy Trial

Summary Objective: To evaluate the efficacy of 12 weeks of treatment with etoricoxib, a selective COX-2 inhibitor, in patients with osteoarthritis (OA) of the knee or hip. Methods: In the 12-week placebo- and active comparator-controlled period of a randomized, double-blind study, eligible patients were treated with etoricoxib 60 mg once daily (n = 224), naproxen 500 mg twice daily (n = 221), or placebo (n = 56). Western Ontario McMasters Osteoarthritis Index (WOMAC) pain and physical function subscales and patients global assessment of disease status were primary end points. Key secondary and other end points were patients and investigators global assessment of response to therapy, WOMAC stiffness subscale, investigators global assessment of disease status, rescue paracetamol use, proportion of patients discontinuing due to lack of efficacy, and study joint tenderness. Results: Etoricoxib 60 mg demonstrated efficacy significantly superior to placebo (p ≤ 0.005) and comparable to naproxen 500mg twice daily as assessed by the primary efficacy end points. Secondary and other end points confirmed these results. Treatment effects were evident by day 2, maximal by week 2, and sustained over the entire 12 weeks. Etoricoxib was well tolerated for 12 weeks. Conclusions: Etoricoxib showed rapid and durable treatment effects in patients with OA of the knee or hip. Etoricoxib was generally well tolerated.

The upper GI safety and tolerability of oral alendronate at a dose of 70 milligrams once weekly: a placebo-controlled endoscopy study

OBJECTIVE:Alendronate (10 mg daily) has been shown in long term clinical trials to be an effective treatment for postmenopausal osteoporosis. A weekly dosing regimen of alendronate is preferred by both patients and physicians, as it has the potential to provide greater convenience and enhance compliance. In a 1-yr clinical trial, alendronate (70 mg once weekly) was equally efficacious and at least as well tolerated as the 10-mg daily dose in the treatment of postmenopausal osteoporosis, despite the higher unit dosage required. We conducted a randomized, double blind, placebo- and active-controlled endoscopy study to confirm the results of this clinical trial. We hypothesized that mean endoscopic gastric erosion scores would be similar in subjects receiving alendronate (70 mg once weekly) and those receiving a placebo.METHODS:Two hundred seventy-seven subjects (90 men and 187 women) were randomized to one of three treatment groups: 1) alendronate (70 mg once weekly) for 10 wk (N = 126), 2) placebo (once weekly) for 10 wk (N = 126), or 3) placebo (once weekly) for 10 wk followed by aspirin (650 mg q.i.d.) for the last week as the positive control (N = 25). Esophagogastroduodenoscopy was performed 5 to 7 days after the last dose of alendronate or matching placebo.RESULTS:The mean gastric erosion scores (Lanza scale) were similar in subjects given alendronate (70 mg once weekly) and those given a placebo (0.32 vs 0.35, respectively; 95% CI for difference =− 0.22–0.16, p = 0.75), whereas scores in both groups were significantly lower than in those given aspirin (3.09; p < 0.001). Endoscopic gastroduodenal ulcers occurred in no alendronate (0%), two placebo (1.7%), and five aspirin (23.8%) subjects. The mean erosion scores in the esophagus and duodenum of alendronate and placebo subjects were also similar. The incidences of upper GI symptoms were similar in the alendronate and placebo subjects and did not suggest a relationship with endoscopic lesions.CONCLUSIONS:Alendronate (70 mg once weekly) was not associated with any increase in endoscopic lesions in the upper GI tract relative to a placebo.

Effects of odanacatib on BMD and safety in the treatment of osteoporosis in postmenopausal women previously treated with alendronate: a randomized placebo-controlled trial.

CONTEXT Odanacatib (ODN) is a selective cathepsin K inhibitor being developed to treat osteoporosis. OBJECTIVE The effects of ODN were evaluated on bone mineral density (BMD), biochemical markers of bone turnover, and safety in patients previously treated with alendronate. DESIGN This was a randomized, double-blind, placebo-controlled, 24-month study. SETTING The study was conducted at private or institutional practices. PARTICIPANTS Postmenopausal women (n = 243) ≥ 60 years of age with low BMD at the total hip, femoral neck, or trochanter (T-score ≤-2.5 but >-3.5 without prior fracture or ≤-1.5 but >-3.5 with prior fracture) on alendronate for ≥ 3 years. INTERVENTION The intervention included ODN 50 mg or placebo weekly. MAIN OUTCOME MEASURES The primary end point was percentage change from baseline of femoral neck BMD at month 24. BMD was assessed by dual-energy x-ray absorptiometry at baseline and 6, 12, and 24 months. Biochemical markers of bone turnover (serum C-telopeptides of type 1 collagen, urinary N-telopeptides of type 1 collagen, serum bone specific alkaline phosphatase, and serum N-terminal propeptide of type 1 collagen) were measured at baseline and 3, 6, 12, 18, and 24 months. RESULTS In the ODN group, BMD changes from baseline at the femoral neck, trochanter, total hip, and lumbar spine at 24 months (1.7%, 1.8%, 0.8%, and 2.3%, respectively) were significantly different from the placebo group. ODN significantly decreased urinary N-telopeptides of type 1 collagen to creatinine ratio and significantly increased serum N-terminal propeptide of type 1 collagen compared with placebo. Serum C-telopeptides of type 1 collagen was unexpectedly increased with ODN treatment. The safety profile appeared similar between groups. CONCLUSIONS ODN provided incremental BMD gains in osteoporotic women after alendronate treatment.

A Phase 2, Randomized, Placebo-Controlled, Dose-Ranging Study of the Calcium-Sensing Receptor Antagonist MK-5442 in the Treatment of Postmenopausal Women With Osteoporosis

CONTEXT MK-5442 is an orally bioavailable calcium-sensing receptor antagonist that is hypothesized to stimulate bone formation by stimulating endogenous secretion of a pulse of PTH. Earlier clinical and preclinical studies demonstrated increased bone mineral density (BMD) after treatment. OBJECTIVE Our objective was to identify a dose of MK-5442 that produces osteoanabolic effects without excessive hypercalcemia. DESIGN AND SETTING This was a randomized, double-blind, placebo-controlled, parallel-group trial of private or institutional practice. PARTICIPANTS AND INTERVENTION In total, 383 postmenopausal women with osteoporosis were administered daily oral MK-5442 (2.5, 5, 7.5, 10, or 15 mg) or placebo. MAIN OUTCOME MEASURES Serum PTH and calcium, bone turnover markers, areal BMD, and safety were evaluated. RESULTS A dose-dependent transient increase in PTH occurred after an MK-5442 dose and lasted more than 3.5 hours. Compared with placebo, significant increases in bone formation markers (serum procollagen 1 N-terminal peptide and bone-specific alkaline phosphatase) were observed by 6 months, whereas bone resorption markers (serum C-telopeptide of type 1 collagen, urine N-telopeptides of type 1 collagen) initially decreased but were also significantly increased by 6 months. Despite the biochemical marker changes suggestive of an anabolic response, there were no statistically significant differences between any dose of MK-5442 and placebo in percent change from baseline at month 6 in any of the BMD endpoints. The frequency of hypercalcemia (trough serum calcium ≥ 10.8 mg/dL) was greater with higher MK-5442 doses. CONCLUSION In postmenopausal women with low bone mass, treatment with MK-5442 resulted in transient pulses of PTH. Bone formation markers increased quickly and bone resorption markers decreased temporarily, suggestive of an anabolic window. However, there were no increases in BMD versus placebo.

OP0247 Effects of Odanacatib on BMD and Safety in the Treatment of Osteoporosis in Postmenopausal Women Previously Treated with Alendronate– a Randomized Placebo-Controlled Trial

Background Odanacatib (ODN) is an orally-active cathepsin K inhibitor being developed for the treatment of postmenopausal osteoporosis. Objectives This study evaluated the effects of ODN 50mg once weekly on BMD, bone turnover markers and safety in patients previously treated with alendronate (ALN). Methods This was a randomized, double-blind, placebo-controlled, 24-month study. The primary endpoint was % change from baseline at month 24 of femoral neck (FN) BMD. Postmenopausal women (n=243) ≥60 years of age with low BMD T-score at the total hip, FN or trochanter but no history of hip fracture and who have taken ALN for ≥3years were randomized to receive ODN or placebo. Patients received vitamin D3 and calcium supplementation. BMD was assessed by DXA at baseline, 6, 12 and 24 months. Biochemical markers of bone turnover (sCTx, uNTx, sBSAP and sP1NP) were measured at baseline and 3, 6, 12, 18 and 24 months. Results In the ODN group, BMD changes from baseline at 24 months were significantly increased from placebo at the femoral neck, trochanter, total hip and lumbar spine (1.7%, 1.8%, 0.8%, and 2.3%, respectively). In the placebo group, BMD at the femoral neck, trochanter and total hip declined significantly from baseline by month 24 (-0.9%, -1.4%, and -1.9% respectively). ODN significantly decreased bone resorption marker, u-NTx/Cr, and significantly increased bone formation markers, s-P1NP and s-BSAP, vs. placebo. The increase observed for the bone resorption marker s-CTx with ODN treatment was unexpected. Adverse events were comparable between the 2 treatments arms. The overall safety profile appeared similar between ODN and placebo. Image/graph Conclusions In this study ODN provided incremental BMD gains in osteoporotic women following ALN treatment. Biomarker results suggest that ODN decreases bone resorption while preserving bone formation. Disclosure of Interest S. Palacios Grant/research support from: Merck Sharp & Dohme Corp., S. Bonnick Grant/research support from: Merck Sharp & Dohme Corp., T. De Villiers Speakers bureau: Merck Sharp & Dohme Corp., R. Chapurlat Grant/research support from: Merck Sharp & Dohme Corp., Consultant for: Merck Sharp & Dohme Corp., A. Odio: None Declared, B. Scott Employee of: Merck Sharp & Dohme Corp., C. Le Bailly De Tilleghem Employee of: Merck Sharp & Dohme Corp., C. DaSilva Employee of: Merck Sharp & Dohme Corp., A. Leung Employee of: Merck Sharp & Dohme Corp., D. Gurner Employee of: Merck Sharp & Dohme Corp.

Oral alendronate 70 mg once weekly is not associated with endoscopic upper GI mucosal lesions compared to placebo

Purpose: Animal studies suggest that gastrointestinal safety and tolerability of weekly oral dosing of bisphosphonates will be as well as, if not better tolerated than daily dosing, despite the higher unit dosage required with weekly dosing. In a clinical trial, ALN 70 mg once weekly was equally efficacious and as well tolerated as the 10-mg daily dose in the treatment of postmenopausal osteoporosis (T Schnitzer, Aging Clin Exp Res 2000). We therefore hypothesized that, in humans, mean endoscopic gastric erosion scores would be similar in subjects receiving ALN 70 mg once weekly and those receiving placebo.