Nancy A. Melville

October 16, 2012

October 16, 2012 (Minneapolis, Minnesota) — The human sclerostin antibody CDP7851/AMG 785, newly named romosozumab, shows efficacy in rapidly increasing bone mineral density (BMD) at the lumbar spine and hip in postmenopausal women with low BMD, according to research presented here at the American Society for Bone and Mineral Research (ASBMR) 2012 Annual Meeting.

Previous animal and phase 1 studies have shown that the antibody binds to and inhibits the protein sclerostin, which is secreted by bone cells and inhibits bone formation.

"The neutralization of sclerostin resulted in increased bone mass reconstruction of skeleton architecture and improved bone strength," said lead author Michael R. McClung, MD, director of the Oregon Osteoporosis Center, in Portland.

In the phase 2 study on the drug, Dr. McClung and his colleagues randomly assigned 419 postmenopausal women aged 55 to 85 years to 1 of 9 treatment groups.

Participants in 4 of the groups received once-monthly subcutaneous injections of romosozumab, 70 mg, 140 mg, or 210 mg or placebo.

Participants in 3 groups received injections of 140 mg, 210 mg, or placebo once every 3 months. There were 2 open-label active comparator groups, with 1 group receiving 70 mg of oral alendronate weekly and the other receiving 20 μg of subcutaneous teriparatide daily.  

All the women, who had lumbar spine, total hip, or femoral neck T scores of –2.0 or less and –3.5 or greater, were treated for 12 months. The study's primary endpoint was the percentage change from baseline in lumbar spine BMD in the romosozumab group at month 12 compared with placebo.

At the end of the 12-month treatment period, all the women in the romosozumab group showed significant increases in lumbar spine, total hip, and femoral neck T scores compared with placebo (P < .005).

The greatest improvements were seen in the group receiving romosozumab, 210 mg monthly, which had rapid increases in lumbar spine BMD of up to 11.3% at the lumbar spine and 4.1% at the total hip. The increases were significantly greater than improvements observed with alendronate and teriparatide (P < .0001).

In all the romosozumab dose groups, increases in serum procollagen I N-terminal peptide (PINP), a serum marker of bone formation, and reductions in serum carboxy-terminal collagen crosslinks, a marker of bone resorption, from baseline were observed very rapidly, by week 1.

PINP levels returned to baseline after 12 months of therapy, however, while the decreased CTX or bone resorption levels persisted.

Dr. McClung said the reasons for the return of the bone formation marker to baseline were not well understood.

"This is the very first observation of that," he said. "We aren't able to explain the change yet. But, it is clear that bones are very smart and it's hard to trick them for very long without inducing this kind of counteractive response."

Adverse events did not significantly differ between the romosozumab and placebo groups, with the exception of mild injection site reactions, which the authors described as "generally mild" (4% placebo, 12% romosozumab).

"Romosozumab led to rapid, progressive and marked increases in bone mineral density at important skeletal sites, with lumbar spine and hip bone mineral density improvements up to 12 months that were superior to those observed with alendronate and teriparatide," Dr. McClung said.

"These data support the idea that inhibiting sclerostin might have therapeutic benefit and provides a platform for future studies evaluating its effectiveness as a treatment for osteoporosis."

Phase 3 Trial Evaluating Fracture Rates

A multicenter, international phase 3 clinical trial program including more than 5000 postmenopausal women with osteoporosis has been launched by Amgen and UCB to evaluate romosozumab for the treatment of postmenopausal osteoporosis.

The primary endpoint of the new trials will be the incidence of new vertebral fractures at 12 months, with initial results expected by the end of 2015.

The discovery of sclerostin's role in bone formation has generated much interest, and many are watching to see how the drug fares in trials, said Murray J. Favus, MD, director of the Bone Program at the University of Chicago, Illinois.

"There is a lot of buzz and anticipation about [romosozumab]," he said. "Usually, the most potent agents increase bone density more than the less potent agents, so we shall see what the fracture data show."

"In the meantime, the drug is on track to be well received from what we know."

Dr. McClung has ' received research grants and consulting fees and serves on the speaker' bureaus for Amgen and Merck. Dr. Favus has disclosed no relevant financial relationships.

American Society for Bone and Mineral Research (ASBMR) 2012 Annual Meeting. Abstract 1025. Presented October 13, 2012.

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