New molecular entities on the horizon for the treatment of osteoporosis face a tough row to hoe in their quest for approval from the Food & Drug Administration. That was the subject of a presentation at the 2006 Annual Meeting of the American College of Clinical Pharmacy (ACCP), held in October in St. Louis.
The FDA requires that new agents seeking approval for osteoporosis undergo a minimum three-year study with vertebral fracture reduction as the pri- mary endpoint, explained Sheryl F. Vondracek, Pharm.D., FCCP, BCPS, associate professor at the University of Colorado Health Sciences Center.
"These are very large, long, and costly studies, and enrollment for trials is harder now that three therapies for osteoporosis are already approved. It's difficult for companies to find treatment-naïve patients." On average, 9,000 patients are required for a hip study and between 900 and 7,000 for other fracture studies, Vondracek told the audience.
A once-yearly IV bisphosphonate that looks promising is zoledronic acid, for which an FDA submission is planned by the end of this year. The HORIZON Pivotal Fracture Trial, which evaluated the drug in 7,736 women aged 65 to 89 years, showed a 60% decrease in vertebral fractures at year one, 71% by year two, and 70% at year three. Hip fractures were reduced by 40% at year three.
"These results are comparable to agents we already have. Patients and pro-viders, however, may prefer once-yearly IV administration over every three months," said Vondracek. Other benefits include modest cost and a favorable safety profile. So far, the risk of renal failure and osteonecrosis of the jaw seems to be negligible. "It will play a good role in patients who are noncompliant and have nonadherence issues, and it will definitely have its niche in the market." Other ongoing studies with zoledronic acid include a prevention study, a male osteoporosis trial, and a comparative study with daily oral risedronate.
Also in the works are the second-generation selective estrogen receptor modulators (SERMs) that work by selectively binding to estrogen receptors. Lasofoxifene (Oporia), from Pfizer and Ligand Pharmaceuticals, was rejected by the FDA when an NDA was filed for the prevention of osteoporosis, however. Data from a phase III treatment trial (PEARL) are expected by the end of this year, and NDA refiling is expected sometime in 2007.
"I don't really feel that the SERMs are going to play a big role in therapy," said Vondracek. "They're not expected to be big players." Two other SERMs in development include bazedoxifene (Ligand/ Wyeth) and arzoxifene (Eli Lilly). An NDA for osteoporosis prevention was filed for bazedoxifene in June 2006, but an NDA submission is not expected for the latter drug until 2009.
A different type of therapy that may offer an alternative to IV bisphosphonates with subcutaneous dosing every six months is denosumab, a fully human monoclonal antibody currently in phase III trials. The biologic works by specifically binding to the receptor activator of nuclear factor kappa B ligand (RANKL), blocking its ability to bind with its receptor RANK on osteoclasts, and preventing their differentiation and activation.
"The phase III trial for denosu-mab will be performed outside our country because the U.S. sites no longer accept true placebo-controlled trials for osteoporosis," Vondracek explained. Most are not truly placebo-controlled, because patients still take vitamin D and calcium or some other form of treatment. There is current debate as to whether placebo-controlled trials are ethical.
Potential concerns with denosumab include the development of neutralizing antibodies and an increased risk of infection. The cost will also most likely be high. The current phase III trial is a three-year fracture study in postmenopausal women with osteoporosis that began enrollment in 2004. Anticipated filing of an NDA is expected in 2009.