Investigational therapy denosumab increased bone mineral density with twice-yearly dosing
One year data published in New England Journal of MedicineAmgen (NASDAQ: AMGN), the world's largest biotechnology company, announced today the publication of Phase 2 data demonstrating twice-yearly injections of denosumab (previously referred to as AMG 162), a RANK Ligand inhibitor, significantly increased bone mineral density (BMD) in the total hip, lumbar spine, distal 1/3 radius and total body compared to placebo. The results of this one-year study appeared in the Feb. 23, 2006 issue of the New England Journal of Medicine. Data results also included an open-label FOSAMAX® (alendronate)* arm of the same clinical trial.
Researchers reported that subcutaneous injections of denosumab significantly increased BMD at the total hip from 1.9 to 3.6 percent in women who were administered the therapy twice yearly as compared with a decrease of 0.6 percent in the placebo group (p<0.001) at one year. The open label FOSAMAX® group receiving 70 mg weekly had an increase of 2.1 percent during the same time frame. Results also indicated that denosumab had a rapid onset of action. A significant decrease in serum levels of C-telopeptide, a biomarker of bone resorption, was achieved within 72 hours after dosing.
"These exciting data suggest that denosumab, when administered in twice-yearly injections, may show promise in the treatment of osteoporosis," said Michael McClung, MD, FACP, principal investigator of the denosumab study, Providence Portland Medical Center, and director of the Oregon Osteoporosis Center, Portland, Ore. "Continued research will further our understanding of the potential of denosumab in bone loss management."
Denosumab targets RANK Ligand, a protein that acts as the primary mediator of osteoclast (cells that break down bone) activity. This investigational therapy is the first RANK Ligand inhibitor in late stage development.
Amgen is studying denosumab for its potential in a broad range of conditions associated with bone destruction including osteoporosis, treatment-induced bone loss, bone metastases, multiple myeloma and rheumatoid arthritis. Data recently presented at the American College of Rheumatology 2005 Annual Scientific Meeting show further increase in bone mineral density in postmenopausal women with osteoporosis after two years of treatment.
"These data reinforce the essential role that RANK Ligand inhibition plays in decreasing bone loss," said Willard Dere, MD, senior vice president of global development and chief medical officer, Amgen. "We are committed to expanding our data on denosumab with an extensive Phase 3 clinical program to evaluate the effect of denosumab on preventing fractures in men and women."
In the one-year trial results, researchers also reported twice-yearly subcutaneous injections of denosumab significantly increased lumbar spine BMD from 3.0 to 6.7 percent after 12 months as compared with a decrease of 0.8 percent in the placebo-treated patients (p<0.001). Across all doses and dosing intervals, distal 1/3 radius BMD increased from 0.4 to 1.3 percent as compared with a decrease of 2.0 percent in those taking placebo (p<0.001), and total body BMD increased from 0.6 to 2.8 percent as compared with a decrease of 0.2 percent in the placebo group (p<0.01).
The incidence of adverse events was similar among the denosumab, placebo, and FOSAMAX® groups, with the exception of dyspepsia. Dyspepsia occurred in 7 percent of placebo patients, 6 to 15 percent of denosumab patients and 26 percent of open-label FOSAMAX® patients. The most common adverse events among all groups included upper respiratory infection (common cold), arthralgia (joint pain), nasopharyngitis (sore throat), back pain and headache. No neutralizing antibodies to denosumab were observed.
Denosumab Study Design
This is an ongoing, multi-center dose-ranging trial. Investigators randomized 412 healthy postmenopausal women, average age 63, with low BMD to receive denosumab, placebo or FOSAMAX®. The purpose of the study was to determine the safety and efficacy of denosumab on lumbar spine BMD compared with placebo at 12 months. The doses of denosumab evaluated included 6, 14 or 30 mg every three months or 14, 60, 100 or 210 mg every six months. The researchers administered all doses of denosumab via subcutaneous injection. Patients receiving FOSAMAX® followed the approved indication and oral dosing instructions of 70 mg once weekly.
At entry, the average lumbar spine T score ranged from -2.0 to - 2.2 across dose groups, consistent with a diagnosis of osteopenia (thinning bone). Approximately a quarter of the patients had osteoporosis as defined by a T score equal to or below -2.5 at the lumbar spine.
About RANK Ligand
Bone is constantly formed and removed through a natural process of remodeling. Bone resorption is dependent on RANK Ligand, the protein that acts as the primary mediator of osteoclast formation, function and survival. Osteoclasts are cells responsible for bone removal.
Preclinical models have demonstrated that inhibiting RANK Ligand significantly improves cortical and trabecular bone density, volume and strength. Cortical bone is the protective outer shell around every bone in the body. Trabecular bone is known as spongy bone and is surrounded by the harder cortical layer.
The Need for Bone Loss Treatments
Bone loss represents a significant clinical and economic burden. Osteoporosis is a major public health threat for an estimated 44 million Americans, or 55 percent of the population 50 years of age and older. In the U.S. today, 10 million individuals are estimated to already have the disease and almost 34 million more are estimated to have low bone mass, placing them at increased risk for osteoporosis. Of the 10 million Americans estimated to have osteoporosis, eight million are women and two million are men. In addition, one in two women and one in four men over age 50 will have an osteoporosis-related fracture in their remaining lifetime.
In Europe, recent estimates have stated that approximately 3.8 million people have experienced bone fractures related to osteoporosis.
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*FOSAMAX® is a registered trademark of Merck & Co., Inc.
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