麻豆传媒

ATLANTA -- Development of the investigational cathepsin K inhibitor odanacatib for the treatment of osteoporosis has been stopped by study sponsor Merck, after a safety analysis found an increased risk of stroke, researchers reported here.

In the double-blind base phase of the large phase III clinical study known as , which enrolled more than 16,000 postmenopausal women with osteoporosis, there were 240 strokes among patients receiving odanacatib, for a significant 32% greater risk of stroke versus placebo (HR 1.32, 95% CI 1.02-1.70, P=0.03), according to , of Brigham and Women's Hospital in Boston.

And then, in the long-term extension phase of the trial, which enrolled more than 8,000 patients, the total number of strokes was 324, giving a hazard ratio of 1.37 (95% CI 1.10-1.71, P=0.005), which was "very significant," she said at the .

There also was a trend towards an increased risk of atrial fibrillation or flutter, with a hazard ratio of 1.25 (95% CI 0.98-1.60, P=0.07) in the base phase and 1.22 (95% CI 0.99-1.50, P=0.06) during the extension phase. There had been a total of 306 atrial fibrillation or flutter events during the trial.

She and her colleagues also considered whether there were subgroups of patients who were at particular risk. "We did not see any evidence on the basis of age, prior stroke or transient ischemic attack, or other risk factors for stroke such as diabetes, hypertension, or prior myocardial infarction," she said.

"We observed that inhibition of cathepsin K in postmenopausal women appeared to increase the risk of stroke, and also was associated with a trend for an increased risk of atrial fibrillation or flutter. At this time, the mechanistic underpinnings to explain these findings remain unknown, but we believe warrant further investigation," O'Donoghue said.

In contrast, when the study began, "preclinical data had suggested that inhibition of cathepsin K may actually interfere with or hinder atherogenesis and might promote plaque stability," she said.

Beginning in 2007, the LOFT study randomized women whose T-score was -2.5 or lower at the total hip or femoral neck to 50 mg odanacatib per week or placebo. In July 2012, the data monitoring committee recommended that the study be stopped because of robust efficacy for the fracture data and a favorable benefit-risk profile, but also recommended that patients continue on treatment and that safety data collection be continued through 60 months.

Following completion of the base phase of the trial, a preliminary assessment raised concerns about higher rates of some types of cardiovascular events among patients receiving odamacatib, O'Donoghue said.

So the , an academic research organization based at Brigham and Women's Hospital, was asked to adjudicate the cardiovascular events for the LOFT program.

They identified a total of 4,410 cardiovascular events and deaths and 1,100 cerebrovascular events during a mean 34.5 months of follow-up in the base period and an additional 9.7 months in the extension phase.

For the composite endpoint of cardiovascular death, there were 518 events during the base period, for an overall nonsignificant hazard ratio of 1.12 (95% CI 0.95-1.34, P=0.18).

For all-cause mortality, there also was a nonsignificant hazard ratio of 1.13 (P=0.10).

The in the phase III LOFT trial were presented in a separate session at the meeting by , of the Oregon Osteoporosis Center in Portland. A total of 16,071 patients had been randomized, 8,257 had entered the long term extension study, and 6,047 completed it.

The study took place at 388 study sites in 40 countries. "This was a very large study," McClung pointed out.

The mean age at the time of randomization was 73, and 47% had a prior vertebral fracture. Mean BMD T-scores were -2.7 at both the lumbar spine and the femoral neck. Mean follow-up was 44 months.

Over the 5 years of follow-up, there were relative risk reductions of 52% for vertebral fractures, 48% for hip fractures, 26% for nonvertebral fractures, and 67% for clinical vertebral fractures (P<0.001 for all).

In addition, compared with placebo, treatment with odanacatib was associated with increases in BMD of 10.9% (95% CI 10.5-11.2) at the lumbar spine and 10.3% (95% CI 10-10.6) at the total hip (P<0.001 for both).

"Our results showed that odanacatib, over an interval of 5 years, significantly reduced the risk of vertebral, hip, nonvertebral, and clinical fractures. There also were substantial and progressive BMD improvements," he said.

"Despite these very positive efficacy data, 2 weeks ago Merck made the announcement that because of a confirmed risk of stroke noted in the study, further development of odanacatib will not occur," McClung concluded.