Scientists from the U.S. Food and Drug Administration raised concerns about the cardiovascular risks of Amgen Inc.'s experimental osteoporosis medicine romosozumab, saying those issues cannot be ignored.
Amgen and its partner UCB SA are seeking to market the medicine in the U.S. under the brand name Evenity to treat osteoporosis, a skeletal disease characterized by low bone mass and structural deterioration of bone tissue, leading to bone fragility and increased risk of fractures of the hip, spine and wrist.
The injectable drug is a monoclonal antibody that binds and inhibits sclerostin, a protein thought to interfere with bone formation. The medicine is intended to reduce fractures.
If approved in the U.S., romosozumab would be the first in the class of sclerostin inhibitors. Regulators in Japan cleared the drug for that market last week — the product's first approval.
Amgen and UCB have provided substantial evidence of the effectiveness to support one year of romosozumab therapy to treat osteoporosis in postmenopausal women, the FDA said.
But the agency is convening a Jan. 16 meeting to hear from its Bone, Reproductive and Urologic Drugs Advisory Committee on how to handle the cardiovascular concerns with romosozumab.
The application has already run into trouble at the FDA, which initially rejected it in 2017 after the results of a trial, known as Study 142, or ARCH, showed a higher incidence of positively adjudicated serious adverse cardiovascular events. The FDA told the companies they needed to evaluate the newly emerged cardiovascular findings.
Amgen and UCB resubmitted the romosozumab application in July 2018, although with a narrower indication.
More limited population
The FDA, however, suggested in its briefing documents ahead of the Jan. 16 meeting that it may be necessary to further limit who gets romosozumab.
Amgen and UCB initially proposed marketing romosozumab for treating osteoporosis in postmenopausal women. But in their resubmission to the FDA, the companies narrowed the use to those at high risk of fracture.
The drugmakers also agreed to include a black-box warning — the FDA's highest risk alert — in romosozumab's labeling cautioning patients and prescribers about the potential cardiovascular risks.
Amgen's and UCB's original submission to the FDA included data from a comprehensive phase 1 and phase 2 program and a phase 3 placebo-controlled trial, known as FRAME, or Study 337, which showed no imbalance of cardiovascular events.
One main difference between the trials was the control group: ARCH included the drug alendronate as the control, whereas FRAME was a placebo-controlled fracture trial. Alendronate is a bisphosphonate sold under the brand name Fosamax by Merck & Co. Inc.
"This raises the question of whether alendronate may confer a cardioprotective effect in the first year of therapy," FDA drug reviewers said. "While it may be biologically plausible that alendronate and other bisphosphonates could have a cardioprotective effect, their very high specificity to bone and osteoclasts would not suggest that such a benefit occurs."
The scientists noted that to date, studies evaluating that question have yielded mixed results, leaving unsolved whether the cardiovascular safety outcomes seen in the ARCH and FRAME trials could be generalized to the U.S. population.
More data needed
The osteoporosis population generally is postmenopausal women, who are typically older patients already at an increased risk of cardiovascular disease.
So the FDA wants its advisory committee to provide input on whether additional cardiovascular safety data are needed to better define a potential off-target cardiovascular effect of romosozumab.
If those data are needed, the FDA wants to know whether the companies should provide it before or after approval. The agency also wants to know if the indicated population for romosozumab should be further narrowed to one at low cardiovascular and cerebrovascular risk and how to define such a group of patients.
In addition, regulators want advice from the committee on whether romosozumab should be contraindicated in patients at high risk of cardiovascular or cerebrovascular disease and how to identify that population.