Romosozumab in ARCH: Good Fracture Reduction, but CV Effects a Worry

Nancy A Melville

September 13, 2017

DENVER — Final results of the phase 3 Active-Controlled Fracture Study in Postmenopausal Women With Osteoporosis at High Risk (ARCH) study show encouraging benefits of the anabolic drug romosozumab (Amgen) followed by alendronate in reducing the risk of vertebral and clinical fracture and rapidly improving bone-mineral density (BMD) in high risk patients with osteoporosis.

"We found that bone-forming therapy with romosozumab for 12 months followed by alendronate resulted in reduction of new vertebral fracture at 24 months and of clinical, nonvertebral, and hip fracture at primary analysis," said first author Kenneth G Saag, MD, a professor of medicine in the division of clinical immunology and rheumatology in the University of Alabama at Birmingham department of medicine, in presenting the findings here at the American Society of Bone and Mineral Research (ASBMR) 2017 Annual Meeting; they were simultaneously published in the New England Journal of Medicine.

Many are very excited about the potent effects of this agent, but unexplained cardiovascular side effects have left the drug in regulatory limbo and sparked speculation on the variety of possible causes.

In an editorial accompanying the paper, Clifford J Rosen, MD, Tufts University Medical School, Boston, Massachusetts, writes: "In sum, ARCH revealed that romosozumab has great potential as a short-term anabolic treatment for osteoporosis."

"However, until the cardiovascular and endocrine effects of this antibody are clarified, romosozumab will remain more a part of our expectations than our armamentarium."

FDA Examining ARCH Results, Has Requested More Data

The double-blind, multicenter ARCH study involved 4094 women with a mean age of 74, osteoporosis, and a previous fracture, placing them at high risk for another fracture.

The women were randomized 1:1 to treatment with either 210-mg romosozumab subcutaneous injections given monthly or 70 mg of the oral bisphosphonate alendronate weekly for 12 months, followed by open-label treatment with alendronate 70 mg weekly for another 12 months in both groups.

In terms of one of the primary end points — cumulative incidence of new vertebral fractures at 24 months — there were 127 new vertebral fractures (6.2%) in the romosozumab group compared with 243 among those in the alendronate group (11.9%), representing a 48% relative risk reduction with romosozumab (P < .001).

For the second primary end point of cumulative incidence of clinical fractures at the time of the primary analysis (after clinical fractures had been confirmed in > 330 patients), which occurred at a median time on the study of 33 months, there was a 27% relative risk reduction in the romosozumab group (< .001), and there was a notably lower, yet still statistically significant, 19% relative risk reduction for nonvertebral fractures (= .04).

Meanwhile, improvements in BMD from baseline were significantly higher in the romosozumab group at months 12 and 24 in all three measures of lumbar spine, total hip, and femoral neck (all P < .001 after adjustments).

In terms of overall adverse events, two patients in the romosozumab group and four in the alendronate group developed atypical femoral fractures and one patient in each group developed osteonecrosis of the jaw.

Serious cardiovascular events, though uncommon, were higher in the romosozumab group at 12 months (2.5%) compared with the alendronate group (1.9%).

Cardiac ischemic events, such as heart attack, in addition to cerebrovascular events, such as stroke, were each reported in 0.8% of the romosozumab group and 0.3% of the alendronate group.

Importantly, the cardiovascular events were not observed in the pivotal phase 3 FRAME study of romosozumab, published in 2016 (N Engl J Med. 2016; 375:1532-1543).

That study involved 7180 postmenopausal women and showed a 73% reduction in vertebral fractures compared with placebo. Reductions in nonvertebral fractures were not statistically significant.

'"The imbalance in cardiovascular serious events was not previously observed in the larger, placebo-controlled fracture trial [FRAME], and further evaluation is under way," Dr Saag said.

In response to the serious cardiovascular adverse events observed in the ARCH trial, the US Food and Drug Administration (FDA) rejected the romosozumab new drug application (NDA) in July, as reported by Medscape Medical News; the agency has requested more data from the ARCH study in addition to the BRIDGE trial, which is evaluating romosozumab in men with osteoporosis.

Causes of Cardiovascular Effects Were Mulled, Are Unclear

Romosozumab is a monoclonal antibody that boosts bone formation by targeting sclerostin, which inhibits bone formation, and that mechanism has been a focus of speculation with regard to the causes of the cardiovascular effects seen in the ARCH study, Dr Saag explained.

Some of the specific theories of how romosozumab's inhibition of sclerostin could be linked to cardiovascular effects include the fact that sclerostin "may function as a negative regulator of vascular calcification and inhibition and could [therefore] promote vascular calcification," Dr Saag explained. However, "studies evaluating possible association have shown conflicting results," he added.

Furthermore, some basic-science studies of toxicology results in animals have shown no evidence of vascular mineralization, and vascular calcification has not been reported in patients with sclerosteosis or van Buchem's disease, although Dr Saag admitted the association has not been specifically examined.

Other explanations for the emergence of the findings only in the ARCH study include that the previous FRAME trial involved a somewhat younger population with less advanced osteoporosis.

In addition, the FRAME trial was placebo-controlled, while the ARCH study used an active comparator of alendronate.

Another theory that has been discussed is that alendronate, which was not used in the FRAME study, has in fact been associated with a reduction in risk of cardiovascular disease in some studies, hence theoretically explaining lower rates of events compared with romosozumab.

The effect with alendronate was not observed in two meta-analyses, however. But Dr Saag noted that these meta-analyses included randomized clinical trials that did not adjudicate cardiovascular end points.

"The bottom line is it's not entirely clear what to make of [the cardiovascular events] yet and additional investigation is under way," he said.

"Regrettably, there is not a particular risk factor we can see and it is not possible at this time to identify who the patients at risk may be."

Hopes for Romosozumab Remain High

By most accounts, romosozumab is a highly anticipated addition in the field of new anabolic drugs to join the recently approved drug abaloparatide (Tymlos, Radius Health) in providing unprecedented reductions in fracture risk.

"None of the currently available agents allow you to reduce fractures to the magnitude that these new [anabolic] drugs do," ASBMR president-elect Bart L Clarke, MD, an endocrinologist and associate professor of medicine at the Mayo Clinic in Rochester, Minnesota, told Medscape Medical News.

"The risk reductions we're seeing with these are in the range of 75% or better, whereas everything else we have is about 50% to 70%, and with bisphosphonates, the reduction is in the range of 50% to 60%, so you're potentially adding about another 20% reduction in fractures," he said.

"For a treatment for osteoporosis, these drugs are significant and represent a big advance, we think."

In the question-and-answer session following Dr Saag's presentation, one audience member expressed being more impressed by the benefits than the observed risks of romosozumab.

"These are frail patients at a very high fracture risk, so it's nice to see the benefits," he said. "And I have to say I'm underwhelmed by the cardiovascular events — it's a slight numerical difference out of hundreds of adverse events that were analyzed, and I frankly don't think there's much to it."

However, in his editorial, Dr Rosen was forthright: "The cardiovascular signal for romosozumab is particularly troubling."

"Although it may be surprising that a bone-specific drug has off-target cardiovascular effects, this finding is very consistent with our recent understanding of the skeleton as an endocrine tissue that modulates whole-body homeostasis by secreting peptides such as sclerostin, fibroblast growth factor 23 (FGF-23), and osteocalcin," he writes.

Other bone-targeting therapies, including estrogen and odanacatib, have also been linked to cardiovascular events, Dr Rosen noted.

Until more is known about the risks, the optimism about romosozumab should remain cautious, he concluded.

American Society of Bone and Mineral Research 2017 Annual Meeting. September 11, 2017, Denver, Colorado. Abstract LB-1162.

The study was supported by Amgen, Astellas Pharma, and UCB Pharma. Dr Saag is a consultant for Amgen and Merck. Disclosures for the coauthors are listed on the journal website. Dr Clarke has served on an advisory board for Radius Health regarding abaloparatide and a data safety monitoring board for Amgen pertaining to the drug denosumab but is not an investigator or consultant regarding romosozumab. Dr Rosen is an associate editor with the New England Journal of Medicine.

N Engl J Med. Published online September 11, 2017. Article, Editorial

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