Merck’s odanacatib has high hurdles to clear

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Encouraging five-year data from a phase IIb trial of Merck & Co’s odanacatib (MK-0822), a novel cathepsin K inhibitor to treat osteoporosis in postmenopausal women, throws the spotlight on the company’s most valuable pipeline candidate - a somewhat surprising statistic given the significant challenges the product still faces.

With sales by 2016 predicted to exceed $500m, odanacatib is already valued at $1.68bn and is set to be Merck’s biggest new product since the launch this year of hepatitis C drug Victrelis. Yet Merck recently revealed that results from a 17,000 patient phase III trial are not due for another 12-18 months, pushing the product’s launch back to 2014, by which time multiple generic bisphosphonates will be on the market and Amgen’s Prolia likely to be more entrenched. Meanwhile question marks remain over the safety of cathepsin K inhibitors. which so far have a somewhat chequered developmental history.

Long-term data

Odanacatib, is an oral, once-weekly pill which can be taken with or without food and has no unique requirements. In contrast, bisphosphonates tend to have strict dosing rules. Fosamax, for example, can also be dosed once-weekly but should be taken soon after waking for the day, must be at least 30 minutes before food or drink, and consumed with plain tap water.

The Merck compound selectively inhibits cathepsin K, a major protease enzyme expressed in osteoclasts that break down existing bone tissue. Inhibiting cathepsin K decreases bone resorption but also importantly does not impair bone formation.

The presentation of encouraging long-term data on odanacatib is important given the FDA’s increasing scrutiny of the adverse effects associated with extended use of bisphosphonates. Just two weeks ago, an FDA advisory committee voted 17 to 6 in favour of updating the labels on bisphosphonates to warn about long-term safety and efficacy issues.

Of the 141 patients in the original two-year phase IIb trial, just 13 women received odanacatib continuously for five years but did show significant increases in bone mineral density in lumbar spine, femoral neck and hip. A pooled analysis showed a marginally greater incidence of adverse and serious adverse events in patients receiving Merck’s drug and two out of 73 women discontinued treatment due to an adverse event, compared with none receiving placebo.

Safety concerns

Importantly, however, there was a lower incidence of skin-related adverse events with odanacatib, and no reference was made of any ‘morphea-like’ skin changes, patches of skin hardening which derailed Novartis’ balicatib, the previous class leader.

Novartis ditched balicatib in 2006 after completing phase II trials. A recently published article in the Journal of the American Academy of Dermatology, which reviewed the incidences of morphea-like skin changes with balicatib, suggested this dermal fibrosis could be a class effect of cathepsin K inhibitors. The authors cite recent evidence that the cathepsin K enzyme, originally thought to only be expressed in osteoclasts, has also been found in lung and dermal fibroblasts and is therefore implicated in the degradation of the extracellular matrix in the lungs and skin. Cathepsin K inhibitors could therefore impair the natural degradation of extracellular matrix proteins.

A number of other clinical stage cathepsin K inhibitor candidates have also fallen by the wayside. Human Genome Sciences and GlaxoSmithKline scrapped development of relacatib in 2009 having completed phase I studies. In July this year Nippon Chemiphar abandoned further development of its phase I candidate, NC-2300, which had been developed since 2005 in collaboration with Velcura Therapeutics.

So far the phase IIb data on odanacatib has not thrown up any serious skin-related events, but the phase III data will provide the ultimate test of the drug’s safety and efficacy.

The 17,000 patient trial started in September 2007, completed enrolment by November 2009, and is an event-driven study assessing the numbers of and time to first vertebral fracture, hip fracture, and non-vertebral fracture, as well as lumbar spine bone mineral density. It appears that clinical events in the placebo-controlled trial have accumulated more slowly than expected and Merck is now expecting to file an NDA in 2013, having previously guided to a regulatory submission in 2012. Clinicaltrials.gov lists June 2013 as the final data collection date required to assess the primary outcome measures.

Meanwhile, results from a much smaller but still important phase III study of odanacatib in 180 post-menopausal women, assessing bone mineral density at lumber spine, neck and hip, should be announced soon given that the trial formally completed in April this year.

Tough market

Generic versions of Merck’s own Fosamax have been on the market since 2008 and by 2014 three more big-selling bisphosphonates, Sanofi and Warner Chilcott’s Actonel, Novartis’ Reclast and Roche’s Boniva will also lose patent protection. Despite increasing safety concerns about these drugs, they are likely to remain widely-used and be even cheaper.

Meanwhile Prolia, an antibody injected subcutaneously once every six months, appears to be gradually gaining the confidence of specialists and the FDA. Yesterday, the regulator approved use of the product to treat cancer-treatment induced bone loss in breast and prostate cancer. After a slow launch, sales are expected to accelerate and should exceed $650m by 2016, according to consensus forecasts from EvaluatePharma.

Indeed, Amgen also recently presented even longer-term phase II extension data with Prolia, showing greater improvements in bone mineral density in lumbar spine and hip, from a larger patient population after eight years of treatment.

While the potential in odanacatib is clear, a number of pretty high hurdles still need to be cleared before Merck can be confident it has another osteoporosis blockbuster in its hands.

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