Amgen Inc. (Nasdaq: AMGN) has announced the publication of results from two pivotal Phase 3 studies investigating the safety and effectiveness of denosumab at reducing fracture risk in more than 7,800 women with postmenopausal osteoporosis and in more than 1,400 men with non-metastatic prostate cancer undergoing androgen deprivation therapy (ADT) leading to bone loss. In both studies, published today in The New England Journal of Medicine (NEJM), patients receiving twice-yearly denosumab experienced significant increases in bone mineral density (BMD) compared to placebo, associated with more than 60 percent reduction in vertebral fracture in both patient populations.(1,2) These data were previously reported by Amgen at medical congresses.
"The discovery of the RANK Ligand pathway represents a significant advance in the understanding of bone biology," said Roland Baron, Ph.D., D.D.S., professor and chair of department of Oral Medicine, Infection, and Immunity at the Harvard School of Dental Medicine. "These results demonstrate that targeting the RANK Ligand pathway with denosumab could represent a promising new approach in two different disease settings characterized by bone loss."
FREEDOM Osteoporosis Study Results: Significant Fracture Reduction Seen Across the Skeleton in Postmenopausal Women with Osteoporosis
Results from the FREEDOM (Fracture REduction Evaluation of Denosumab in Osteoporosis every six Months) study, showed that women receiving a subcutaneous shot of denosumab twice-yearly experienced a 68 percent reduction in the risk of suffering a vertebral (spine) fracture compared to those receiving placebo as well as a 40 percent reduction in the risk of suffering a hip fracture and a 20 percent reduction in the risk of suffering a nonvertebral fracture. Over the three years of this multi-center, randomized, double-blind, placebo-controlled study, women treated with denosumab experienced significant increases in BMD (8.8 percent at the lumbar spine and 6.4 percent at the total hip).(1)
"These results suggest that denosumab offers a new approach to prevention of fractures in women with postmenopausal osteoporosis," said Steven Cummings M.D., lead investigator, study author, and director of the San Francisco Coordinating Center of the California Pacific Medical Center Research Institute. "It reduces the risk of all major types of fractures and, because it is given as an injection twice a year, it also has the potential to help compliance to treatment."
Fracture is one of the most common health events suffered by postmenopausal women with osteoporosis.(3) Globally, one woman in three over 50 years of age will experience a fracture in her lifetime.(3) A woman who has broken a bone as a result of osteoporosis has more than an eight- out-of-ten chance of breaking another bone.(4) Half of women who break a hip, a life changing event, will permanently need assistance to walk.(5)
The overall incidence and type of side effects with denosumab were similar to placebo in the FREEDOM study. Rates of adverse events (AEs) were similar in both groups (93 percent). Rates of serious AEs were 25.8 percent for denosumab and 25.1 percent for placebo. The most common AEs across both treatment arms were arthralgia, back pain, hypertension and nasopharyngitis. There were no reported cases of osteonecrosis of the jaw among patients taking denosumab. Serious adverse events of skin infections, predominantly cellulitis, were reported more commonly in the denosumab group (0.4 percent vs. <0.1 percent). Mild, transient decreases in serum calcium were observed that had no apparent clinical significance.(1)
HALT Study Results: First Published Study to Demonstrate Fracture Prevention in Men with Non-Metastatic Prostate Cancer Undergoing ADT
Results from the HALT (Hormone AbLation Therapy) study in 1,468 men undergoing ADT for non-metastatic prostate cancer show that patients treated with denosumab experienced a 62 percent reduction in the risk of suffering a new vertebral fracture with denosumab compared to placebo at 36 months, with significant reduction observed as early as month-12.(2) Bone loss and increased fracture risk are serious and under-recognized consequences of ADT(6,7) and currently there are no approved therapies for these patients.
In this multi-center, randomized, double-blind, placebo-controlled study, men receiving 60 mg denosumab administered subcutaneously experienced a 6.7 percent increase in BMD at the lumbar spine compared to those receiving placebo (primary endpoint) at 24 months. Increases in BMD at the lumbar spine were observed as early as one month after starting treatment with denosumab and continued to increase throughout the study. In addition, denosumab produced significant increases in BMD at non-vertebral sites (total hip 4.8 percent, femoral neck 3.9 percent, and distal 1/3 radius 5.5 percent), compared to placebo.(2)
"Bone loss and fractures are an important but often unrecognized problem for prostate cancer survivors. Bone loss is an early adverse effect and even short-term androgen deprivation therapy negatively impacts skeletal health. Prevention of bone loss and fractures has been a key unmet medical need for men with prostate cancer," said Matthew Smith, M.D., Ph.D., study author, associate professor of medicine and the director of Genitourinary Medical Oncology at Massachusetts General Hospital Cancer Center. "In this large international study, denosumab markedly increased bone mineral density and decreased the risk of fractures in many men receiving androgen deprivation therapy for prostate cancer. The efficacy of denosumab was apparent as early as one month and was sustained for three years."
In the HALT trial, the overall incidence and type of side effects with denosumab were similar to placebo. Rates of AEs were similar in both groups (87 percent). Rates of serious AEs were 35 percent for denosumab and 31 percent for placebo. The most common AEs across both treatment arms were arthralgia, back pain, constipation, pain in extremity, and hypertension. There were no reported cases of osteonecrosis of the jaw among patients treated with denosumab. More patients receiving denosumab developed cataracts, though none were considered treatment-related. One patient in the denosumab arm developed hypocalcemia, versus none in the placebo arm. New primary malignancies were reported in 5 percent of patients in each group. Serious AEs of infections were reported in 6 percent of denosumab-treated patients and in 5 percent of placebo-treated patients.(2)
"Amgen scientists in the 1990s were the first to identify the RANK Ligand pathway, a pivotal physiologic mechanism that controls bone remodeling," said Roger Perlmutter, M.D., Ph.D., executive vice president of Research and Development at Amgen. "Today's publications in the New England Journal of Medicine underscore the significance of this finding, and highlight Amgen's focus on using innovative research to address grievous illness."
About Denosumab
Denosumab is the first fully human monoclonal antibody in late stage clinical development that specifically targets RANK Ligand, an essential regulator of osteoclasts (the cells that break down bone). Denosumab is being investigated for its potential to inhibit all stages of osteoclast activity through a targeted mechanism. Denosumab is being studied in a range of bone loss conditions including postmenopausal osteoporosis and bone loss in patients undergoing hormone ablation for prostate and breast cancer.
In February 2009, the U.S. Food and Drug Administration (FDA) accepted the Biologics License Application (BLA), submitted by Amgen for denosumab for the treatment and prevention of osteoporosis in postmenopausal women and cancer treatment-induced bone loss in women and men receiving hormone therapy for either breast cancer or prostate cancer based on these studies and a parallel trial in women with breast cancer. The FDA has provisionally approved the trade name Prolia(TM) in these proposed indications, for which denosumab is administered twice yearly subcutaneously at a 60mg dose. The trade name is only for these indications and may not apply for other indications of denosumab.
Amgen has also submitted marketing applications for use of denosumab in the European Union, Canada, Switzerland, and Australia.
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.
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.(8,9,10) It has been reported that osteoporosis results in more hospital bed-days than stroke, myocardial infarction or breast cancer.(11)
Bone Loss Due to Hormone Ablation Therapy
Worldwide, prostate cancer and breast cancer are two of the most frequent types of cancer affecting men and women, respectively.(12) In the U.S., prostate cancer is the most common cancer in men and breast cancer is the most common cancer in women. It is common for prostate cancer and breast cancer patients to receive hormone ablation therapies that can lead to a decrease in bone mass and increased risk of fractures. Currently there are no approved therapies for bone loss in patients undergoing hormone ablation for either prostate or breast cancer.
About Amgen
Amgen discovers, develops, manufactures and delivers innovative human therapeutics. A biotechnology pioneer since 1980, Amgen was one of the first companies to realize the new science's promise by bringing safe and effective medicines from lab, to manufacturing plant, to patient. Amgen therapeutics have changed the practice of medicine, helping millions of people around the world in the fight against cancer, kidney disease, rheumatoid arthritis, and other serious illnesses. With a deep and broad pipeline of potential new medicines, Amgen remains committed to advancing science to dramatically improve people's lives. To learn more about our pioneering science and our vital medicines, visit www.amgen.com.
1. Cummings SR, et al. Twice Yearly Denosumab, a Monoclonal Antibody to RANK-ligand, for Prevention of Fractures in Postmenopausal Women with Osteoporosis. N Engl J Med, 2009 Aug. 20; published online at www.nejm.org on Aug. 11, 2009.
2. Smith MR, et al. Denosumab for the Prevention of Bone Loss and Fractures in Men Receiving Androgen Deprivation Therapy in Non-Metastatic Prostate Cancer. N Engl J Med, 2009 Aug. 20; published online at www.nejm.org on Aug. 11, 2009.
3. Melton LJ, et al. (1992) Perspective. How Many Women Have Osteoporosis? J Bone Miner Res, 1992;7:1005
4. Kanis JA, et al. A Meta-Analysis of Previous Fracture and Subsequent Fracture Risk. Bone, 2004;35:375.
5. Magaziner J, et al. Predictors of Functional Recovery One Year Following Hospital Discharge for Hip Fracture: A Prospective Study. J Gerontol, 1990;45:M101.
6. Higano 2008; Higano 2004; Conde 2003; Smith 2001; Pfeilschifter 2000.
7. Oefelein MG, Ricchiuti V, Conrad W, Resnick MI. Skeletal fractures negatively correlate with overall survival in men with prostate cancer. J Urol. 2002;168:1005-1007.
8. Burge R, et al. J Bone Miner Res. 2007; 22:465-475
9. "Osteoporosis Fast Facts." Washington (DC): National Osteoporosis Foundation. Accessed on February 24, 2009 at http://www.nof.org/osteoporosis/stats.html.
10. "Economic Cost of Cardiovascular Diseases." Dallas (TX): American Heart Association. Accessed on February 24, 2009 at http://www.americanheart.org/statistics/10econom.html.
11. Lippuner K, et al. "Incidence and direct medical costs of hospitalisations due to osteoporotic fractures in switzerland." Osteoporosis International.1997;7:414-25.
12. WHO. Media Center. Fact sheet No. 297. February 2009 at http://www.who.int/mediacentre/factsheets/fs297/en/index.html