Merck & Co. Inc. made more headway on its primary care ambitions with the termination of a large, multicenter Phase III study of osteoporosis drug odanacatib, in light of positive efficacy for fracture prevention with apparently acceptable safety.

Merck needs new candidates to help fill the void that will be left by Singulair (montelukast), which had sales of $5.5 billion in 2011 and goes off patent in August. And while many big pharmas have shifted toward specialty and rare diseases, Merck has maintained a focus in traditional primary care markets Also see "Merck Eyes Primary Care Opportunities Despite Challenges" - Pink Sheet, 29 February, 2012..

Despite the challenges, Merck has been pursuing two large primary care categories saturated by generics – osteoporosis and insomnia – with the intention of filling lingering areas of unmet need Also see "Waiting For Blockbusters: Osteoporosis Market Burdened With Black Box Warnings, Reimbursement Woes, And Spare Pipelines" - Pink Sheet, 2 January, 2012.. Merck’s insomnia therapy suvorexant completed Phase III successfully, in contrast with failures for others in the dual orexin receptor antagonist class, and will be filed in 2012 Also see "Merck On Track To File Novel Sleep Aid Suvorexant In 2012" - Pink Sheet, 6 February, 2012..

Odanacatib inhibits cathepsin K (cat-K), the enzyme responsible for breaking down existing bone tissue. But while the drug reduces resorption, it does not prevent bone formation. However, other drugs in the class have not made it through development – notably Novartis AG’s balicatib, which was dropped due to skin thickening and other side effects. Merck has noted that its candidate is more selective for cat-K Also see "Blocking Cathepsin K: Merck Wins Where Novartis Lost" - Pink Sheet, 17 September, 2008..

At the time of an interim analysis, a data monitoring committee recommended stopping the study of approximately 16,000 women early because odanacatib showed “robust efficacy” with a “favorable benefit-risk profile,” Merck announced after the market close on July 11.

The study tested the once weekly oral drug against placebo. The event-driven trial, which began in 2007 and enrolled across 40 countries, was set to continue until hip fractures were reported in 237 patients. It will take months to wind down the study, the company said.

The data monitoring committee noted that “safety issues remain in certain selected areas” and that it had made recommendations with respect to following up on them, the company said. Merck will be running an extension trial that will allow further evaluation of these safety issues and also additional analysis of the drug’s efficacy.

The data is still being collected and reviewed, and the final analysis will be submitted for presentation and publication in 2013, Merck said. The company plans to file for approval in the U.S., Europe and Japan in the first half of 2013.

A Crowded Landscape

The drug would need to offer important advantages in order to make it in the osteoporosis market, which features many generics, including Merck’s own alendronate (Fosamax), which was a market leader until its patent expiration in 2008, as well as a range of branded options, such as Eli Lilly & Co.’s Forteo (teriparatide) and Warner Chilcott PLC’s Actonel (risedronate).

Before generics became available, osteoporosis drug sales peaked at $8 billion, Bernstein analyst Tim Anderson commented in a July 11 note.

“With a host of approved osteoporosis medicines already available – many of which have gone generic already – it will be critical to see how the fracture data with odanacatib stacks up versus existing therapies,” Anderson wrote.

Merck’s Phase III trial only tested odanacatib against placebo. “For odanacatib to be a major commercial success, it will have to have robust enough fracture data such that on a side-by-side comparison to other products it stands above the competition,” Anderson said.

To gauge commercial potential, greater clarity is also needed on safety, though Anderson noted that early termination of the study suggests that any safety issues are manageable.

Longer-term follow up is needed to ensure problems like thigh bone fracture or osteonecrosis of the jaw don’t crop up, Leerink Swann analyst Seamus Fernandez commented in a July 12 note. Awareness of the potential for damage with long-term use is high in the wake of reports of fracture risk with bisphosphonates Also see "Bisphosphonates Labels Should Discuss Duration Of Use, Advisory Panels Conclude" - Pink Sheet, 9 September, 2011..

Based on what is known, odanacatib appears to have an excellent tolerability profile that would make it the drug of choice in the 20% to 30% of patients who can’t tolerate bisphosphonates, Fernandez wrote. The fact that the trial was stopped early for “robust efficacy” suggests that the drug may have demonstrated the ability to prevent more than 40% of fractures, given that other osteoporosis therapies have reduced fractures by 35% to 40%, he surmised.

Odanacatib Phase III Success Suggests Merck’s Primary Care Gamble Is Paying Off

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