UPDATED: Safety concerns cloud odanacatib PhIII as Merck steps back from FDA filing

Before the cancer program for pembrolizumab (Keytruda) elbowed its way to the front of the line for Merck's ($MRK) pipeline, the osteoporosis drug odanacatib had been in the front row of late-stage prospects. But a growing buzz about potential safety issues raised a cloud of doubt about the therapy, which is likely to linger now that the pharma giant has released Phase III results and laid out plans for a delayed FDA filing.

While building bone mineral density in patients, investigators pointed to data demonstrating a significant reduction in fractures. There was a 54% relative risk reduction of new and worsening morphometric (radiographically assessed) vertebral fractures; a 47% relative risk reduction of clinical hip fractures; a 23% relative risk reduction of clinical nonvertebral fractures and a 72% relative risk reduction of clinical vertebral fractures.

But there was also evidence of a troubling side effect profile that could well damage Merck's prospects. There was a slight increase in the risk of atrial fibrillation as well as more strokes in the odanacatib crowd. A total of 109 patients (1.4%) had a stroke in the drug arm, compared to 89 (1.1%) in the placebo arm. Cardiovascular side effects are going to attract careful regulatory attention. More morphea-like skin lesions and atypical femoral shaft fractures were also reported for 5 patients in the odanacatib group with none in the placebo group. And Merck--which had been expected to file before the end of this year---says it will now delay its FDA submission until next year after it gathers more data.

Mark Schoenebaum, an analyst at ISI who follows Merck closely, says the fracture data Merck reported is in line with the standard of care. But even while there was no statistically significant worsening in cardiovascular events, the placebo arm's ability to do better on atrial fibrillation, stroke, MACE events and deaths would mark this drug for careful scrutiny at the FDA. And even if it is approved with this data, sales could be restricted, as detailing the drug would be made more difficult. Schoenebaum put potential sales at $300 million, well below the bar for success for a company like Merck.

Merck, though, is maintaining its optimistic outlook on this drug.

"Merck believes the currently available data support a favorable benefit/risk profile for odanacatib," said Dr. Keith Kaufman, vice president of clinical research, diabetes and endocrinology for Merck.

Michael McClung

"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. There is a need for additional treatment options. The effects of odanacatib on fracture risk from the LOFT study are very encouraging," said Michael McClung, founding director of the Oregon Osteoporosis Center.

Initially Merck had been reluctant to discuss the safety profile for odanacatib when CEO Ken Frazier announced a big delay in the development and regulatory plans for the therapy. A fresh change in the schedule along with hard numbers on stroke will likely only raise fresh questions about the market prospects for this drug, once tapped as a much-needed blockbuster for Merck. But with pembrolizumab gaining a recent breakthrough approval and a closely watched hep C program in late-stage development, Merck doesn't need this one as badly as it once did.

Odanacatib works by inhibiting cathepsin K, an enzyme that plays a key role in bone resorption. Merck investigators detailed the data in Houston on Monday at the annual meeting of the American Society for Bone and Mineral Research.

- here's the release

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