FDA staff braved the snow and the federal shutdown to post their review of Amgen’s once-rejected osteoporosis drug on Monday, underscoring that the efficacy of the drug in postmenopausal women had been established, and suggesting that the CV signal observed in two trials may not be a significant worry.
The review comes days after Amgen and partner UCB secured Japanese approval for the drug, romosozumab, and precedes a meeting of independent experts on Wednesday who will make their recommendation on the approvability of the drug in the United States. Romosozumab — which is to be sold under the brand name Evenity — functions predominantly as a bone anabolic agent that stimulates bone growth.
The monoclonal antibody was tested in three late-stage studies: the 7,180-patient FRAME study in postmenopausal women with osteoporosis, which tested the drug against a placebo; the 4,093-patient ARCH study in postmenopausal women in osteoporosis, which tested the drug against an osteoporosis drug originally made by Merck called alendronate; and the 245-patient BRIDGE study in men with osteoporosis, which tested the drug against a placebo.
All three pivotal studies showed the drug was effective, but the ARCH and BRIDGE trial demonstrated a signal of cardiovascular-related serious adverse events, which led to the FDA issuing a complete response letter to the companies, after they had applied for approval in postmenopausal women with osteoporosis. Taking into account the CV signal and feedback from the FDA about the paucity of anabolic agents, the duo re-submitted an application to market drug last year, but for a narrower patient population: postmenopausal women with osteoporosis who carry a high risk of fracture. They also proposed a boxed warning as well as a precaution for cardiovascular risk on the drug’s label, if approved. Meanwhile, the drug is under review in Europe.
Globally, 1 in 3 women over age 50 will experience osteoporotic fractures, according to the International Osteoporosis Foundation.
In its review, FDA staff agreed that the effectiveness of romosozumab for the treatment of postmenopausal osteoporosis had been established, but questioned whether the CV signal seen in ARCH and BRIDGE were generalizable to the US population, given that enrolled patients from the US only accounted for 1.8% of the ARCH study, and 1.4% of the BRIDGE study. In their suggested questions for independent panel, the agency’s reviewers did not stress the CV issue.
“The docs read mostly benign and discussion/voting questions are not as critical on CV risk, supporting a favorable panel vote on Wed (1/16) and an eventual approval later in H1:19,” Jefferies analysts wrote in a note, adding that Lilly’s osteoporosis drug Forteo carries a black box warning highlighting the risk of cancer and still rakes in about $2 billion.
The drug “represents a modest $500 million worldwide upside opportunity not widely accounted by consensus, and the drug has shown strong efficacy (beating Fosamax by 48-50%) along with an acceptable safety profile. The prior safety signal seen in the smaller of two key Phase III studies (ARCH vs FRAME) seems more spurious than concerning to us,” they noted.
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