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2 New Osteoporosis Drugs in the Works: Biologic Osteoporosis Drugs Denosumab and Odanacatib Show Promise in Clinical Trials
  By Miranda Hitti
WebMD Health News
Reviewed by Louise Chang, MD
Sept. 18, 2008 -- Two experimental osteoporosis drugs are getting attention from bone experts -- and may become the first biologic drugs to treat osteoporosis.
The drugs are called denosumab and odancatib. Results from their latest clinical trials, presented this week in Montreal at the annual meeting of the American Society for Bone and Mineral Research, show that the drugs boosted bone mineral density in postemenopausal women with osteoporosis.
Denosumab and odanacatib are "totally, completely new" ways of approaching osteoporosis, says Susan Bukata, MD, an orthopaedic surgeon and associate professor who directs the University of Rochester's Center for Bone Health.
"This is the new frontier in osteoporosis. This is the step into biologics for osteoporosis treatment," Bukata tells WebMD. She predicts that denosumab or odanacatib probably won't be the first osteoporosis treatments that doctors prescribe for most patients, and she says cost may be a factor in how widely the new drugs get used, if approved by the FDA.
How the New Drugs Work
Denosumab and odanacatib are both biologic drugs that target osteoclasts, which are cells that tear down bone to make way for new bone.
Your bones don't just sit there; they're constantly being remodeled. Osteoclasts are the wrecking crew; other cells, called osteoblasts, are the bone builders.
After you reach peak bone mass at about age 30, the balance between the bone breakdown and bone buildup shifts, favoring bone loss. Age -- and, for women, menopause -- tilts the balance further toward bone loss. In osteoporosis, the bones have become dangerously weak.
"As you age, things slow down," Bukata explains. "Unfortunately, for a lot of people, bone-building capacity slows down a little bit more than their bone-loss capacity."
The basic idea behind the new osteoporosis drugs is to rebalance bone loss and bone building so that those two processes "either stay in balance or, in fact, allow the osteoblasts to catch up a little bit," says Bukata. "By adding these agents, we are able to push things the way a younger person manages bone."
Denosumab's Clinical Trial
Denosumab is a monoclonal antibody given by injection twice a year. It targets a protein called RANK ligand, which osteoclasts need to do their job.
Denosumab has finished its phase lll clinical trials, the last set of trials needed before submitting a drug to the FDA for approval.
In those trials, postmenopausal women with low bone mineral density either got a shot of denosumab every six months or took alendronate (the active ingredient in Fosamax) every week.
A year later, bone mineral density in the lumbar spine and in the hip had improved more for the denosumab group than for the alendronate group.
Bukata notes that because biologic drugs affect the immune system, researchers keep a close eye on infection rates for biologic drugs, but infections weren't more common with denosumab in the trial.
Cancer risk is another thing that researchers would check on, but tumors weren't more common with denosumab than with alendronate, according to a news release from Amgen, the drug company which makes denosumab.
It's also important that denosumab mainly affects the skeleton and not other body systems, says Bukata, who hasn't seen any worrisome data for denosumab.
"I and others fully expect denosumab up in front of the FDA soon," says Bukata, predicting that denosumab will get FDA approval. "Their data has been good, there have been very solid studies, very open reporting all along the way."
Bukata likes the fact that denosumab is given by injection twice a year, and that those injections don't have to be given by a doctor. That should help with compliance, notes Bukata.
Odanacatib's Trial
Odanacatib takes a different biologic tactic. It targets an enzyme called cathepsin K, in order to reduce osteoclast activity.
Odanacatib isn't as far along in the development process as denosumab; odanacatib's phase lll trial is just getting under way. But two-year results from odanacatib's phase llb trial show promise.
"That data definitely made me pay much more attention this drug," says Bukata.
In the trial, postmenopausal women with osteoporosis took an odanacatib pill or a placebo once a week. Patients don't have to take odanacatib with a meal and they don't have to stand or sit after taking it, notes Ron Rogers, a spokesperson for Merck, the drug company that makes odanacatib.
Two years later, women who took a weekly 50-milligram odanacatib pill had significant gains in bone mineral density in their lumbar spine and hip. As expected, the placebo didn't help bone mineral density.
Odanacatib's phase lll trials will test odanacatib for fracture prevention in postmenopausal women with osteoporosis. That trial's results may be four years away, according to Arthur Santora, MD, PhD, Merck's executive director of clinical research.
Bukata says she'll be watching odanacatib's trial with interest.
"Does the bone mass gain continue to hold up in additional years on the medication? If it does, that makes this drug very appealing," says Bukata. "The other thing is, how did the patients tolerate it? What are the side effects that come with it?"
In odanacatib's phase 11b trial, the drug was "generally favorable," report the researchers. Skin rashes, which Merck officials say sidelined another company's cathepsin K inhibitor, didn't stand out in the odanacatib group.
Drugs' Future
Will denosumab and odanacatib catch on, if approved by the FDA? Bukata says that depends on how they stack up against current osteoporosis drugs.
"They have to be as good as what we have, if not better," says Bukata. She's not just talking about effects on bones, but also side effects, patient compliance in taking the drugs, and cost.
For instance, Bukata says that if patients are getting good results from older osteoporosis drugs, they would "have to have a good reason" to switch to a newer type of drug, especially if the new drug is more expensive.
Bukata predicts that most osteoporosis patients would still start treatment with bisphosphonates or other established types of osteoporosis drugs and try newer biologic drugs if other treatments don't work. Patients who can't take current osteoporosis drugs, such as people with poor kidney function, might start out on biologic drugs, Bukata says.
Bukata has no ties to Amgen or Merck. She does lecture on osteoporosis for another drug company, Eli Lilly, on a limited basis.

Pivotal Phase 3 Data Show Denosumab Increased Bone Density at Multiple Skeletal Sites in Early and Later Stage Postmenopausal Women
Overall Incidence of Adverse Events Similar Between Denosumab and Placebo Groups
THOUSAND OAKS, Calif.--(BUSINESS WIRE)--April 2, 2008--Amgen (NASDAQ: AMGN) today announced the publication of results from its 24-month, 332-patient Phase 3 pivotal study in women with early and late stage postmenopausal osteoporosis in the Journal of Clinical Endocrinology and Metabolism.
In this Phase 3 study, twice-yearly subcutaneous injections of denosumab increased bone mineral density (BMD) at all sites measured, including in highly cortical areas of the skeleton. Cortical bone comprises 75 percent of skeletal mass and is a primary determinant of overall strength in vertebral and non-vertebral sites throughout the skeleton.
Denosumab treatment significantly increased lumbar spine BMD compared with placebo at 24 months (6.5 percent vs. -0.6 percent; P less than 0.0001). Denosumab also produced significant increases in BMD at the total hip (3.4 percent vs. -1.1 percent; P less than 0.0001), 1/3 distal radius (wrist) (1.4 percent vs. -2.1 percent; P less than 0.0001), and total body (2.4 percent vs. -1.4 percent; P less than 0.0001). Time since menopause did not influence the BMD response to denosumab.
Denosumab is an investigational fully-human monoclonal antibody in late stage clinical development that specifically targets RANK Ligand, the essential mediator of osteoclasts (the cells that break down bone). RANK Ligand is found in all parts of cortical and trabecular bone.
"The effect of denosumab on wrist BMD - reinforced by the BMD increases at the total body and hip regions - suggests denosumab has a positive effect on highly cortical sites," said Javier San Martin, Global Development Lead for the denosumab osteoporosis program. "It appears that RANK Ligand inhibition results in a pattern of effects on cortical bone that may be beneficial."
The overall incidence of adverse events was similar between the denosumab and placebo groups. The most common adverse events in both treatment groups were arthralgia, nasopharyngitis, and back pain.
Serious adverse events were reported for 18 subjects (11 percent) in the denosumab group and 9 subjects (5.5 percent) in the placebo group (P = 0.074). The higher incidence of serious adverse events in the denosumab group was primarily due to a greater number of subjects who had infections treated as hospital inpatients (8 denosumab, 1 placebo). However, the overall incidence of infections reported as adverse events was balanced between the two groups (60 percent denosumab, 61 percent placebo).
Types of infections in the hospitalized subjects included pneumonia, diverticulitis, appendicitis, sepsis, pyelonephritis, urinary tract infection, and cellulitis in denosumab subjects, and lobar pneumonia in the placebo subject. No opportunistic infections were reported. None of these infections were considered by the site investigators to be related to denosumab treatment. The infections were common for this subject population and responded to standard antibiotic therapy.
Amgen expects the results of its large, pivotal Phase 3 registrational study, which will evaluate denosumab's impact on fracture risk reduction, in women with postmenopausal osteoporosis, in the second half of this year.
Denosumab: Clinical Studies in Bone Loss
Underscoring Amgen's commitment to science, its researchers have created a robust clinical program for denosumab as they explore the bone biology of various diseases associated with the RANK Ligand pathway. In addition to four Phase 3 and two Phase 2 trials in postmenopausal osteoporosis, Amgen has evaluated denosumab's effects on bone erosions in rheumatoid arthritis in a Phase 2 study. In the oncology setting, researchers are evaluating denosumab in four Phase 3 and two Phase 2 studies in advanced cancer patients with, or at risk for, bone metastases. In a Phase 2 study, they evaluated denosumab as a possible treatment for patients with multiple myeloma.
Osteoporosis: Impact and Prevalence
Often referred to as the "silent epidemic," osteoporosis is a global problem that is increasing in significance as the population of the world both increases and ages. The World Health Organization (WHO) has recently identified osteoporosis as a priority health issue along with other major non-communicable diseases.
Although fractures to the vertebrae and hip are the most commonly discussed osteoporotic fractures, they do not account for the majority of fractures. In fact, fractures at skeletal sites such as the wrist, pelvis, humerus, clavicle, femur, and lower leg (tibia/fibula) make up an estimated 59 percent of all osteoporotic fractures in the United States (U.S.)(i).
The economic burden of osteoporosis is comparable to that of other major chronic diseases; for example, in the U.S. the costs associated with osteoporosis-related fractures are equivalent to those of cardiovascular disease and asthma(ii)(iii)(iv). It has been reported that osteoporosis results in more hospital bed-days than stroke, myocardial infarction or breast cancer(v).
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