Denosumab Fares Well in Extension Trials

SAN DIEGO – Denosumab produced progressive increases in bone mineral density at key skeletal sites, along with a sustained reduction in biomarkers of bone turnover, through 8 years in a long-term extension of a clinical trial.

These 8-year continuous treatment data are both highly reassuring and clinically relevant, Dr. Michael McClung observed at the annual meeting of the American Society for Bone and Mineral Research.

"Because the effects of denosumab on inhibiting bone remodeling are actually quite quickly reversible upon discontinuing therapy, long-term treatment with denosumab is anticipated to be important. Furthermore, denosumab, like other antiresorptive agents, is not the cure for osteoporosis and so maintaining bone strength with long-term therapy becomes necessary," according to Dr. McClung, founding director of the Oregon Osteoporosis Center, Portland.

Other investigators presented 5-year denosumab (Prolia) safety and efficacy updates from the ongoing extension of the landmark 7,868-patient phase III Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) trial. The original 3-year results of FREEDOM were instrumental in winning marketing approval of the novel RANK ligand inhibitor for the treatment of postmenopausal women with osteoporosis at high risk for fracture. The FREEDOM trial is being extended to 10 years of denosumab therapy in the original treatment arm and 7 years in placebo-treated patients who crossed over to open-label active therapy.

Dr. McClung reported on the 200 postmenopausal women with osteoporosis or low bone mass who completed a 4-year phase 2 study of denosumab by subcutaneous injection of 60 mg once every 6 months and then enrolled in a 4-year extension study.

During the first 4 years on denosumab, the women showed an average 8% gain in bone mineral density at the lumbar spine and a 5% gain at the total hip. By 8 years, these gains had increased to 17% at the lumbar spine compared with baseline and 7% at the total hip. Reductions in the bone turnover markers, serum C-telopeptide of type I collagen, and bone-specific alkaline phosphatase remained stable throughout the 8 years of treatment, he added.

Also at the meeting, Dr. Steven R. Cummings presented an analysis of years 4 and 5 of the extension of the FREEDOM trial in which he concluded that denosumab significantly reduced the estimated risk of new vertebral fractures by 36% and nonvertebral fractures by 51% compared with placebo.

What’s unusual about his analysis is that there is actually no placebo arm in the extension phase of the trial. For purposes of comparison, he employed a novel "virtual twin" simulation method he and his colleagues created and have subsequently validated (Stat. Med. 2010;29:1127-36). The statistical tool uses data from the initial placebo-controlled phase of the trial to project expected outcomes for a cohort of "virtual twins" had they remained on placebo during the study extension.

Based on the virtual twin method, the projected yearly incidence of nonvertebral fractures in years 4 and 5 was 2.6% in the virtual twins on placebo, compared with 1.3% in the real denosumab-treated group. The projected incidence of new vertebral fractures in the extension phase was 2.2% per year in the virtual twins, compared with 1.4% in women on denosumab, according to Dr. Cummings, professor of medicine, epidemiology, and biostatistics at the University of California, San Francisco.

"Long-term treatment with denosumab is anticipated to be important."

He was first author of the landmark core 3-year FREEDOM trial, in which denosumab reduced the risk of new nonvertebral, vertebral, and hip fractures by 20%, 68%, and 40%, respectively, compared with placebo (N. Engl. J. Med. 2009;361:756-65).

Dr. Henry G. Bone presented an updated safety analysis of denosumab through 5 years of the extended FREEDOM trial.

"The bottom line for this report is that through the 4th and 5th years of this program, the long-term extension and crossover data do not indicate any progression of infection or malignancy," said Dr. Bone, head, endocrinology division, St. John Hospital and Medical Center, Detroit.

For example, the denosumab prescribing information cautions that cellulitis and erysipelas occurred more often in the active treatment arm than in placebo-treated controls during the first 3 years of the trial: four cases in year 1 in the denosumab arm, one case in year 2, and eight in year 3, compared with just one case in 3 years of placebo. The trend suggested a potential worsening problem over time with denosumab. But there were only two cases of the serious skin infections in year 4 of denosumab therapy and one in year 5, along with one case during 2 years of therapy in patients crossed over from placebo.

"I think that’s informative about what the long-term trend might be," he commented.

The safety analysis included 2,343 women on the RANK ligand for the full 5 years and 2,207 crossed over to open-label denosumab after 3 years on placebo.

An increased risk of endocarditis is also mentioned in the prescribing information based on three cases that occurred in the first 3 years; however, no further cases have occurred during the extension phase. Moreover, upon closer inspection one of the three cases of endocarditis appears suspect, as it didn’t result in hospitalization or antibiotic therapy.

Malignancy rates have remained similar and stable over time in both study arms, with no evidence of a concentration of cases in any organ system, according to Dr. Bone.

Dr. McClung and Dr. Bone disclosed that they serve as consultants to and are on the speakers bureau of Amgen, which sponsored the clinical trials. Dr. Cummings is also a consultant to the company.

SAN DIEGO – Denosumab produced progressive increases in bone mineral density at key skeletal sites, along with a sustained reduction in biomarkers of bone turnover, through 8 years in a long-term extension of a clinical trial.

These 8-year continuous treatment data are both highly reassuring and clinically relevant, Dr. Michael McClung observed at the annual meeting of the American Society for Bone and Mineral Research.

"Because the effects of denosumab on inhibiting bone remodeling are actually quite quickly reversible upon discontinuing therapy, long-term treatment with denosumab is anticipated to be important. Furthermore, denosumab, like other antiresorptive agents, is not the cure for osteoporosis and so maintaining bone strength with long-term therapy becomes necessary," according to Dr. McClung, founding director of the Oregon Osteoporosis Center, Portland.

Other investigators presented 5-year denosumab (Prolia) safety and efficacy updates from the ongoing extension of the landmark 7,868-patient phase III Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) trial. The original 3-year results of FREEDOM were instrumental in winning marketing approval of the novel RANK ligand inhibitor for the treatment of postmenopausal women with osteoporosis at high risk for fracture. The FREEDOM trial is being extended to 10 years of denosumab therapy in the original treatment arm and 7 years in placebo-treated patients who crossed over to open-label active therapy.

Dr. McClung reported on the 200 postmenopausal women with osteoporosis or low bone mass who completed a 4-year phase 2 study of denosumab by subcutaneous injection of 60 mg once every 6 months and then enrolled in a 4-year extension study.

During the first 4 years on denosumab, the women showed an average 8% gain in bone mineral density at the lumbar spine and a 5% gain at the total hip. By 8 years, these gains had increased to 17% at the lumbar spine compared with baseline and 7% at the total hip. Reductions in the bone turnover markers, serum C-telopeptide of type I collagen, and bone-specific alkaline phosphatase remained stable throughout the 8 years of treatment, he added.

Also at the meeting, Dr. Steven R. Cummings presented an analysis of years 4 and 5 of the extension of the FREEDOM trial in which he concluded that denosumab significantly reduced the estimated risk of new vertebral fractures by 36% and nonvertebral fractures by 51% compared with placebo.

What’s unusual about his analysis is that there is actually no placebo arm in the extension phase of the trial. For purposes of comparison, he employed a novel "virtual twin" simulation method he and his colleagues created and have subsequently validated (Stat. Med. 2010;29:1127-36). The statistical tool uses data from the initial placebo-controlled phase of the trial to project expected outcomes for a cohort of "virtual twins" had they remained on placebo during the study extension.

Based on the virtual twin method, the projected yearly incidence of nonvertebral fractures in years 4 and 5 was 2.6% in the virtual twins on placebo, compared with 1.3% in the real denosumab-treated group. The projected incidence of new vertebral fractures in the extension phase was 2.2% per year in the virtual twins, compared with 1.4% in women on denosumab, according to Dr. Cummings, professor of medicine, epidemiology, and biostatistics at the University of California, San Francisco.

"Long-term treatment with denosumab is anticipated to be important."

He was first author of the landmark core 3-year FREEDOM trial, in which denosumab reduced the risk of new nonvertebral, vertebral, and hip fractures by 20%, 68%, and 40%, respectively, compared with placebo (N. Engl. J. Med. 2009;361:756-65).

Dr. Henry G. Bone presented an updated safety analysis of denosumab through 5 years of the extended FREEDOM trial.

"The bottom line for this report is that through the 4th and 5th years of this program, the long-term extension and crossover data do not indicate any progression of infection or malignancy," said Dr. Bone, head, endocrinology division, St. John Hospital and Medical Center, Detroit.

For example, the denosumab prescribing information cautions that cellulitis and erysipelas occurred more often in the active treatment arm than in placebo-treated controls during the first 3 years of the trial: four cases in year 1 in the denosumab arm, one case in year 2, and eight in year 3, compared with just one case in 3 years of placebo. The trend suggested a potential worsening problem over time with denosumab. But there were only two cases of the serious skin infections in year 4 of denosumab therapy and one in year 5, along with one case during 2 years of therapy in patients crossed over from placebo.

"I think that’s informative about what the long-term trend might be," he commented.

The safety analysis included 2,343 women on the RANK ligand for the full 5 years and 2,207 crossed over to open-label denosumab after 3 years on placebo.

An increased risk of endocarditis is also mentioned in the prescribing information based on three cases that occurred in the first 3 years; however, no further cases have occurred during the extension phase. Moreover, upon closer inspection one of the three cases of endocarditis appears suspect, as it didn’t result in hospitalization or antibiotic therapy.

Malignancy rates have remained similar and stable over time in both study arms, with no evidence of a concentration of cases in any organ system, according to Dr. Bone.

Dr. McClung and Dr. Bone disclosed that they serve as consultants to and are on the speakers bureau of Amgen, which sponsored the clinical trials. Dr. Cummings is also a consultant to the company.

SAN DIEGO – Denosumab produced progressive increases in bone mineral density at key skeletal sites, along with a sustained reduction in biomarkers of bone turnover, through 8 years in a long-term extension of a clinical trial.

These 8-year continuous treatment data are both highly reassuring and clinically relevant, Dr. Michael McClung observed at the annual meeting of the American Society for Bone and Mineral Research.

"Because the effects of denosumab on inhibiting bone remodeling are actually quite quickly reversible upon discontinuing therapy, long-term treatment with denosumab is anticipated to be important. Furthermore, denosumab, like other antiresorptive agents, is not the cure for osteoporosis and so maintaining bone strength with long-term therapy becomes necessary," according to Dr. McClung, founding director of the Oregon Osteoporosis Center, Portland.

Other investigators presented 5-year denosumab (Prolia) safety and efficacy updates from the ongoing extension of the landmark 7,868-patient phase III Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) trial. The original 3-year results of FREEDOM were instrumental in winning marketing approval of the novel RANK ligand inhibitor for the treatment of postmenopausal women with osteoporosis at high risk for fracture. The FREEDOM trial is being extended to 10 years of denosumab therapy in the original treatment arm and 7 years in placebo-treated patients who crossed over to open-label active therapy.

Dr. McClung reported on the 200 postmenopausal women with osteoporosis or low bone mass who completed a 4-year phase 2 study of denosumab by subcutaneous injection of 60 mg once every 6 months and then enrolled in a 4-year extension study.

During the first 4 years on denosumab, the women showed an average 8% gain in bone mineral density at the lumbar spine and a 5% gain at the total hip. By 8 years, these gains had increased to 17% at the lumbar spine compared with baseline and 7% at the total hip. Reductions in the bone turnover markers, serum C-telopeptide of type I collagen, and bone-specific alkaline phosphatase remained stable throughout the 8 years of treatment, he added.

Also at the meeting, Dr. Steven R. Cummings presented an analysis of years 4 and 5 of the extension of the FREEDOM trial in which he concluded that denosumab significantly reduced the estimated risk of new vertebral fractures by 36% and nonvertebral fractures by 51% compared with placebo.

What’s unusual about his analysis is that there is actually no placebo arm in the extension phase of the trial. For purposes of comparison, he employed a novel "virtual twin" simulation method he and his colleagues created and have subsequently validated (Stat. Med. 2010;29:1127-36). The statistical tool uses data from the initial placebo-controlled phase of the trial to project expected outcomes for a cohort of "virtual twins" had they remained on placebo during the study extension.

Based on the virtual twin method, the projected yearly incidence of nonvertebral fractures in years 4 and 5 was 2.6% in the virtual twins on placebo, compared with 1.3% in the real denosumab-treated group. The projected incidence of new vertebral fractures in the extension phase was 2.2% per year in the virtual twins, compared with 1.4% in women on denosumab, according to Dr. Cummings, professor of medicine, epidemiology, and biostatistics at the University of California, San Francisco.

"Long-term treatment with denosumab is anticipated to be important."

He was first author of the landmark core 3-year FREEDOM trial, in which denosumab reduced the risk of new nonvertebral, vertebral, and hip fractures by 20%, 68%, and 40%, respectively, compared with placebo (N. Engl. J. Med. 2009;361:756-65).

Dr. Henry G. Bone presented an updated safety analysis of denosumab through 5 years of the extended FREEDOM trial.

"The bottom line for this report is that through the 4th and 5th years of this program, the long-term extension and crossover data do not indicate any progression of infection or malignancy," said Dr. Bone, head, endocrinology division, St. John Hospital and Medical Center, Detroit.

For example, the denosumab prescribing information cautions that cellulitis and erysipelas occurred more often in the active treatment arm than in placebo-treated controls during the first 3 years of the trial: four cases in year 1 in the denosumab arm, one case in year 2, and eight in year 3, compared with just one case in 3 years of placebo. The trend suggested a potential worsening problem over time with denosumab. But there were only two cases of the serious skin infections in year 4 of denosumab therapy and one in year 5, along with one case during 2 years of therapy in patients crossed over from placebo.

"I think that’s informative about what the long-term trend might be," he commented.

The safety analysis included 2,343 women on the RANK ligand for the full 5 years and 2,207 crossed over to open-label denosumab after 3 years on placebo.

An increased risk of endocarditis is also mentioned in the prescribing information based on three cases that occurred in the first 3 years; however, no further cases have occurred during the extension phase. Moreover, upon closer inspection one of the three cases of endocarditis appears suspect, as it didn’t result in hospitalization or antibiotic therapy.

Malignancy rates have remained similar and stable over time in both study arms, with no evidence of a concentration of cases in any organ system, according to Dr. Bone.

Dr. McClung and Dr. Bone disclosed that they serve as consultants to and are on the speakers bureau of Amgen, which sponsored the clinical trials. Dr. Cummings is also a consultant to the company.