Merck's Osteoporosis Candidate Reduces Fracture Risk, But Safety Issues Remain

Results from a pivotal Phase 3 trial on Merck’s experimental once-weekly oral treatment for osteoporosis have demonstrated that the cathepsin K inhibitor, odanacatib, significantly reduced the risk of 3 types of osteoporotic fractures in postmenopausal women compared to placebo.

In the Long-Term Odanacatib Fracture Trial (LOFT) study presented at the American Society for Bone and Mineral Research Annual Meeting in Houston, 16,713 women aged 65 years or older who were diagnosed with osteoporosis and had been postmenopausal for 5 years or more were randomized to receive odanacatib 50 mg/week (n=8357) or placebo (n=8356), in addition to vitamin D 5600 IU/week and calcium up to 1200 mg/day, as required.

Compared to the placebo patients, those who received odanacatib experienced a 47% relative risk reduction of hip fractures, a 23% relative risk reduction of non-vertebral fractures, and a 72% relative risk reduction of vertebral fractures, Merck reported. Additionally, odanacatib treatment “led to progressive increases over 5 years in bone mineral density at the lumbar spine and total hip,” the company said in a press release.

In light of that data, Merck now plans to submit a New Drug Application to the FDA for odanacatib next year.

“Despite the important and serious consequences of fractures related to osteoporosis and our ability to identify patients who would benefit from therapy, many patients with osteoporosis are not being treated,” noted Michael McClung, MD, founding director of the Oregon Osteoporosis Center in Portland, in the press release. “There is a need for additional treatment options. The effects of odanacatib on fracture risk from the LOFT study are very encouraging.”

During the study, however, 12 patients in the odanacatib group developed adjudicated morphea-like skin lesions that resolved or improved following discontinuation of the drug. Additionally, adjudicated atrial fibrillation was reported in 92 patients in the odanacatib group, compared to 80 patients in the placebo group, and 109 patients in the odanacatib group experienced stroke, compared to 86 patients in the placebo group.

In response to those risks, Merck said it would continue to “collect data from the blinded extension study and is planning additional analyses of data from the trial, including an independent re-adjudication of major adverse cardiovascular events, in support of regulatory submissions.”

Nevertheless, Keith Kaufman, vice president of clinical research on diabetes and endocrinology at Merck, stated that the company “believes the currently available data support a favorable benefit/risk profile for odanacatib.”