Long-awaited Loft data justify sellside’s odanacatib caution

It is hard to believe that just 18 months ago the oral osteoporosis project odanacatib was Merck & Co’s most valuable R&D asset. Since then safety concerns have hit forecasts, while the rise of Keytruda (pembrolizumab) has overshadowed most other things in the group’s pipeline.

Long-awaited disclosure of data from odanacatib’s 16,000-patient Loft study yesterday confirmed the project’s limited relevance. Not only do earlier safety fears seem justified, further analysis of cardiac events will push US filing out by another six months or more.

Ironically it was Loft, a phase III study, that had turned odanacatib from zero to hero two years ago, when an interim analysis showed the project to prevent fractures. As recently as February 2013 sellside consensus saw 2018 odanacatib sales hitting $1.4bn.

However, Merck’s decision to delay filing was taken as a sign that safety issues needed to be quantified (Merck’s odanacatib caution throws Amgen a bone, February 4, 2013). More data were presented in May, at which point Merck said it hoped to submit odanacatib in the second half of this year.

This will now not take place, the company having decided instead to wait until a blinded extension of Loft allows it to re-analyse major cardiovascular adverse events; US filing will now take place next year, Merck says.

Safety imbalance

The problem is obvious if a detailed look is taken at the Loft data presented yesterday at the American Society for Bone and Mineral Research (ASBMR) meeting. Specifically, the pivotal programme threw up an imbalance in incidence of stroke, atrial fibrillation, death, the skin condition morphea, and bone fractures.

The numbers of events in the huge trial are relatively tiny – for instance 271 deaths on odanacatib versus 242 on placebo – and none is statistically significant, but all occurred with greater frequency in the active group. There is some discrepancy between the cerebrovascular events reported by investigators and those assessed by the trial’s adjudication committee.

On the efficacy side Merck confirmed that Loft met all four of its primary endpoints, reducing relative risks of radiographically assessed hip fractures by 54%, and clinical hip, non-vertebral and vertebral fractures by 47%, 23% and 72% respectively. This is in line with the efficacy of bisphosphonates, like Merck’s off-patent Fosamax, which are standard of care in osteoporosis.

Commercially, therefore, odanacatib’s benefit is limited to the convenience of once-weekly oral dosing and the avoidance of osteonecrosis of the jaw; this is the major side effect of bisphosphonates. However, the Merck project’s own safety issues will surely be scrutinised closely by the FDA.

At present consensus forecasts are for 2020 odanacatib sales to reach $668m, EvaluatePharma computes.

Osteonecrosis of the jaw is also the subject of a warning on the label for Amgen’s anti-RANKL MAb Prolia, an agent that had struggled to make headway, but whose sales benefited from the odanacatib delay.

At the ASBMR meeting Amgen highlighted a new analysis of an open-label extension of Prolia’s pivotal study, showing increases in percentages of women reaching non-osteoporotic T-scores at the lumbar spine and hip over eight years of treatment.

Perhaps even more closely watched is Amgen’s follow-on project, romosozumab, which in a phase II trial showed increases in lumbar spine and hip bone mineral density after one year’s treatment. These increases continued over a second year’s treatment, the company said at the ASBMR.

However, it is romosozumab’s phase III programme, including the 7,000-patient Frame study, that is now investors’ key focus for the project, with data readout expected in 2016. One of the results of odanacatib’s protracted delay therefore is that potential US approval is now timed to occur at roughly the same time as romosozumab’s pivotal readout.

But whatever dynamic this sets up, and whatever doubts might enter the regulators’ minds, there is another spanner in the works, namely that this market is dominated by cheap generics. Without a clear safety or efficacy advantage all the novel agents will underwhelm.

To contact the writer of this story email Jacob Plieth in London at [email protected] or follow @JacobEPVantage on Twitter