Shock for Amgen and UCB as side effects undermine romo trial

The drug could face restrictions, if approved at all, analysts say.

Amgen and UCB's romosozumab trounced a comparator drug in a trial in osteoporosis, but there's a big catch: The therapy seems to cause side effects that will delay and could scupper its chances of reaching the market.

First the good news. Romosozumab met all its main clinical endpoints in the ARCH trial, reducing vertebral fractures by 50% compared to alendronate, a widely used bisphosphonate drug for osteoporosis, while also cutting nonvertebral fractures by 19%, Amgen said.

Both reductions were statistically significant and taken together translated to a 27% reduction in the risk of fracture, which is a good result for the new drug—whose proposed trade name is Evenity—against a mainstay of osteoporosis therapy.  Analysts have been carefully tracking romo, pegging it as a potential blockbuster with peak sales potential north of $1 billion a year.

The bad news is that there was an imbalance in the rate of serious cardiovascular side effects between romo and alendronate, seen in 2.5% of patients on Amgen and UCB's drug versus 1.9% with alendronate. That new safety signal was not seen in the earlier phase 3 FRAME trial of the drug, according to the developers, although Leerink analysts suggest there was a trend toward increased cardiovascular adverse events in the earlier trial.

There were some other areas of weakness in the data—for example, hip fractures were only slightly reduced—which echoes the results of phase 2 studies where the drug missed the nonvertebral fracture target, according to the analysts.

Amgen has already conceded that it will no longer be able to get approval for romo this year, as the new data will have to be considered alongside its earlier trials by the FDA, where the drug is in midreview. That means that approval—if coming—would be pushed back to 2018 or beyond. Romo is also under regulatory review in Canada and Japan, and UCB is scheduled to submit a marketing application in Europe in the latter half of this year.

Leerink thinks the FDA is likely to re-review the entire clinical database for the product and re-examine the cardiovascular events and rates in the entire sample, and will "probably place significant restrictions on the product’s use, if it is approved at all."

Evercore ISI's Umer Raffat has a similar take, saying that the "surprising" result means the firm is "taking out all romo sales"—which had been tipped at around $800 million—from its modelling.

"We are working on understanding the observed cardiovascular safety signal and will continue to discuss these results with global regulators and experts in the field," said Iris Loew-Friedrich, UCB's chief medical officer, who suggested that the superior fracture reduction is a big impact.

"When we think that patients who have had a fracture are highly likely to suffer another one, the importance of post-fracture care cannot be emphasized enough," she added.

Nevertheless, the delay will mean Evenity could launch into a very different market than at present, with generics of Eli Lilly's big-selling Forteo (teriparatide), due in 2019, likely to be widely used and with Radius' just-approved Tymlos (abaloparatide) having more time to capitalize on its lead.