The novel oral osteoporosis drug odanacatib significantly reduced fractures in postmenopausal women but was also associated with a significantly higher risk for stroke, according to data from a 5-year extension of a large phase III clinical trial.

Based on an independent analysis and verification of the risk for stroke, the drug’s sponsor, Merck, has withdrawn odanacatib from review by the Food and Drug Administration. “We are disappointed that the overall benefit-risk profile for odanacatib does not support filing or further development,” Roger M. Perlmutter, MD, president of Merck Research Laboratories, said in a statement.

Treatment with odanacatib for up to 5 years reduced the risk of hip, vertebral, and nonvertebral fractures, Michael R. McClung, MD, an endocrinologist and founding director of the Oregon Osteoporosis Center in Portland, reported at the annual meeting of the North American Menopause Society in Orlando, Fla.

Compared with placebo, odanacatib resulted in relative risk reductions of 52% for vertebral fracture, 48% for hip fracture, 26% for nonvertebral fracture, and 67% for clinical vertebral fracture (all values, P less than .001). Lumbar spine bone density increased by a mean of 10.9%, as did total hip bone density by a mean of 10.3%, in the odanacatib group (for both, P less than .001), according to results presented at the meeting.

The Long-Term Odanacatib Fracture Trial (LOFT) was a randomized, double-blind placebo-controlled study that investigated the efficacy and safety of odanacatib, a cathepsin K inhibitor, as a treatment for osteoporosis and for fracture prevention in postmenopausal women. Odanacatib was taken as an oral, once-weekly 50-mg pill.

During the base period of the study, 16,071 postmenopausal women aged 65 and older were enrolled, and 12,290 completed the study. Women had to have total hip or femoral neck bone mineral density T scores less than or equal to –2.5, or a radiographically confirmed vertebral fracture and total hip or femoral neck T scores less than or equal to –1.5. Participants were demographically well matched between study arms; 6,092 odanacatib patients and 6,198 on placebo completed the base period of the study.

The original phase III study was stopped early because of robust efficacy data (Osteoporos Int. 2015 Feb;26[2]:699-712). Participants were eligible to continue in a preplanned 5-year double-blind, placebo-controlled extension period of the LOFT study; 3,432 odanacatib and 2,615 placebo participants completed the full 5 years.

An early, but statistically nonsignificant, signal for increased stroke and atrial fibrillation and flutter was seen at the end of the study’s base period. The trend continued and appeared to be amplified during the 5-year, double-blind, placebo-controlled extension period of the LOFT study.

Merck requested outside analysis of the safety data by the TIMI (Thrombolysis in Myocardial Infarction) Study Group, an independent cardiovascular research group based at the Brigham and Women’s Hospital, Boston. Michelle O’Donoghue, MD, was the principal investigator for the analysis. .

In an interview, Dr. O’Donoghue said that the TIMI study group was brought in by Merck for a “second perspective,” to add rigor to an examination of events that had not been anticipated in the base period of the LOFT study. This was an important step, said Dr. O’Donoghue, because LOFT was not a dedicated cardiovascular safety trial.

The prespecified primary endpoints for TIMI’s safety analysis included new-onset atrial flutter or atrial fibrillation, as well as a composite endpoint of major adverse cardiovascular events (MACE), defined as myocardial infarction, stroke, or cardiovascular death.

Examination of the composite MACE endpoint showed a numeric, but not statistically significant, difference between the odanacatib and placebo arms of the extension study. However, in a preplanned subanalysis, when the 324 stroke events were isolated, a hazard ratio (HR) for stroke of 1.37 for odanacatib emerged (95% confidence interval [CI], 1.10-1.71; P = .005).

Atrial fibrillation and atrial flutter were more common in the odanacatib group, but the difference was not significant (HR, 1.22; 95% CI, 0.99-1.50; P = .06). Dr. O’Donoghue said that the individuals with supraventricular arrhythmias were not the same individuals who had strokes, although the strokes were almost entirely ischemic, rather than hemorrhagic, events.

Dr. O’Donoghue, a cardiovascular medicine specialist at Brigham and Women’s Hospital, noted in her presentation that “preclinical data suggested that inhibition of cathepsin K may reduce atherosclerosis progression and promote plaque stability.”

Odanacatib is a cathepsin K inhibitor, one of a member of a class of proteases. Cathepsin K targets kinins that are involved in bone resorption, but it is expressed in other tissues as well, and it may target other classes of kinins. However, exactly how odanacatib may have contributed to strokes in the study population remains a mystery.

“The mechanistic underpinnings to explain these findings is unknown and warrants investigation,” Dr. O’Donoghue said. “It’s a little bit more unsatisfying when you’re not able to provide a cause. … I share the disappointment of the endocrinologists in the community who were very hopeful for the cathepsin K class to be the next breakthrough in the management of osteoporosis.”

Dr. McClung reported financial relationships with Merck and several other pharmaceutical companies. Dr. O’Donoghue reported receiving grant support from several pharmaceutical companies. The LOFT trial and the TIMI study group analysis were sponsored by Merck.

koakes@frontlinemedcom.com

On Twitter @karioakes

Odanacatib reduced fractures but upped stroke risk