Javier San Martin

Denosumab for Prevention of Fractures in Postmenopausal Women with Osteoporosis

BACKGROUND Denosumab is a fully human monoclonal antibody to the receptor activator of nuclear factor-kappaB ligand (RANKL) that blocks its binding to RANK, inhibiting the development and activity of osteoclasts, decreasing bone resorption, and increasing bone density. Given its unique actions, denosumab may be useful in the treatment of osteoporosis. METHODS We enrolled 7868 women between the ages of 60 and 90 years who had a bone mineral density T score of less than -2.5 but not less than -4.0 at the lumbar spine or total hip. Subjects were randomly assigned to receive either 60 mg of denosumab or placebo subcutaneously every 6 months for 36 months. The primary end point was new vertebral fracture. Secondary end points included nonvertebral and hip fractures. RESULTS As compared with placebo, denosumab reduced the risk of new radiographic vertebral fracture, with a cumulative incidence of 2.3% in the denosumab group, versus 7.2% in the placebo group (risk ratio, 0.32; 95% confidence interval [CI], 0.26 to 0.41; P<0.001)--a relative decrease of 68%. Denosumab reduced the risk of hip fracture, with a cumulative incidence of 0.7% in the denosumab group, versus 1.2% in the placebo group (hazard ratio, 0.60; 95% CI, 0.37 to 0.97; P=0.04)--a relative decrease of 40%. Denosumab also reduced the risk of nonvertebral fracture, with a cumulative incidence of 6.5% in the denosumab group, versus 8.0% in the placebo group (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01)--a relative decrease of 20%. There was no increase in the risk of cancer, infection, cardiovascular disease, delayed fracture healing, or hypocalcemia, and there were no cases of osteonecrosis of the jaw and no adverse reactions to the injection of denosumab. CONCLUSIONS Denosumab given subcutaneously twice yearly for 36 months was associated with a reduction in the risk of vertebral, nonvertebral, and hip fractures in women with osteoporosis. (ClinicalTrials.gov number, NCT00089791.)

Comparison of the Effect of Denosumab and Alendronate on BMD and Biochemical Markers of Bone Turnover in Postmenopausal Women With Low Bone Mass : A Randomized, Blinded, Phase 3 Trial

Denosumab is a fully human monoclonal antibody that inhibits bone resorption by neutralizing RANKL, a key mediator of osteoclast formation, function, and survival. This phase 3, multicenter, double‐blind study compared the efficacy and safety of denosumab with alendronate in postmenopausal women with low bone mass. One thousand one hundred eighty‐nine postmenopausal women with a T‐score ≤ −2.0 at the lumbar spine or total hip were randomized 1:1 to receive subcutaneous denosumab injections (60 mg every 6 mo [Q6M]) plus oral placebo weekly (n = 594) or oral alendronate weekly (70 mg) plus subcutaneous placebo injections Q6M (n = 595). Changes in BMD were assessed at the total hip, femoral neck, trochanter, lumbar spine, and one‐third radius at 6 and 12 mo and in bone turnover markers at months 1, 3, 6, 9, and 12. Safety was evaluated by monitoring adverse events and laboratory values. At the total hip, denosumab significantly increased BMD compared with alendronate at month 12 (3.5% versus 2.6%; p < 0.0001). Furthermore, significantly greater increases in BMD were observed with denosumab treatment at all measured skeletal sites (12‐mo treatment difference: 0.6%, femoral neck; 1.0%, trochanter; 1.1%, lumbar spine; 0.6%, one‐third radius; p ≤ 0.0002 all sites). Denosumab treatment led to significantly greater reduction of bone turnover markers compared with alendronate therapy. Adverse events and laboratory values were similar for denosumab‐ and alendronate‐treated subjects. Denosumab showed significantly larger gains in BMD and greater reduction in bone turnover markers compared with alendronate. The overall safety profile was similar for both treatments.

Effect of denosumab on bone density and turnover in postmenopausal women with low bone mass after long-term continued, discontinued, and restarting of therapy: a randomized blinded phase 2 clinical trial.

INTRODUCTION Denosumab is a fully human monoclonal antibody that inhibits receptor activator of nuclear factor-kappa B ligand (RANKL), an essential mediator of osteoclast formation, function, and survival that has been shown to decrease bone turnover and increase bone mineral density (BMD) in treated patients. We assessed the long-term efficacy and safety of denosumab, and the effects of discontinuing and restarting denosumab treatment in postmenopausal women with low bone mass. METHODS Postmenopausal women with a lumbar spine T-score of -1.8 to -4.0 or proximal femur T-score of -1.8 to -3.5 were randomized to denosumab every 3 months (Q3M; 6, 14, or 30 mg) or every 6 months (Q6M; 14, 60, 100, or 210 mg); placebo; or open-label oral alendronate weekly. After 24 months, patients receiving denosumab either continued treatment at 60 mg Q6M for an additional 24 months, discontinued therapy, or discontinued treatment for 12 months then re-initiated denosumab (60 mg Q6M) for 12 months. The placebo cohort was maintained. Alendronate-treated patients discontinued alendronate and were followed. Changes in BMD and bone turnover markers (BTM) as well as safety outcomes were evaluated. RESULTS Overall, 262/412 (64%) patients completed 48 months of study. Continuous, long-term denosumab treatment increased BMD at the lumbar spine (9.4% to 11.8%) and total hip (4.0% to 6.1%). BTM were consistently suppressed over 48 months. Discontinuation of denosumab was associated with a BMD decrease of 6.6% at the lumbar spine and 5.3% at the total hip within the first 12 months of treatment discontinuation. Retreatment with denosumab increased lumbar spine BMD by 9.0% from original baseline values. Levels of BTM increased upon discontinuation and decreased with retreatment. Adverse event rates were similar among treatment groups. CONCLUSIONS In postmenopausal women with low BMD, long-term denosumab treatment led to gains in BMD and reduction of BTM throughout the course of the study. The effects on bone turnover were fully reversible with discontinuation and restored with subsequent retreatment.

Effects of denosumab on bone mineral density and bone turnover in postmenopausal women.

CONTEXT Denosumab is an investigational fully human monoclonal antibody against receptor activator of nuclear factor-kappaB ligand, a mediator of osteoclastogenesis and osteoclast survival. OBJECTIVE This study evaluated the ability of denosumab to increase bone mineral density (BMD) and decrease bone turnover markers (BTMs) in early and later postmenopausal women with low BMD. DESIGN AND SETTING This 2-yr randomized, double-blind, placebo-controlled study was conducted in North America. PARTICIPANTS Subjects included 332 postmenopausal women with lumbar spine BMD T-scores between -1.0 and -2.5. INTERVENTIONS SUBJECTS were randomly assigned to receive denosumab sc, 60 mg every 6 months, or placebo. Randomization was stratified by time since onset of menopause (< or =5 yr or > 5 yr). MAIN OUTCOME MEASURES The primary end point was the percent change in lumbar spine BMD by dual-energy x-ray absorptiometry at 24 months. Additional end points were percent change in volumetric BMD of the distal radius by quantitative computed tomography; percent change in BMD by dual-energy x-ray absorptiometry for the total hip, one-third radius, and total body; hip structural analysis; percent change in BTMs; and safety. RESULTS Denosumab significantly increased lumbar spine BMD, compared with placebo at 24 months (6.5 vs. -0.6%; P<0.0001) with similar results for both strata. Denosumab also produced significant increases in BMD at the total hip, one-third radius, and total body (P < 0.0001 vs. placebo); increased distal radius volumetric BMD (P < 0.01); improved hip structural analysis parameters; and significantly suppressed serum C-telopeptide, tartrate-resistant acid phosphatase-5b, and intact N-terminal propeptide of type 1 procollagen. The overall incidence of adverse events was similar between both study groups. CONCLUSIONS Twice-yearly denosumab increased BMD and decreased BTMs in early and later postmenopausal women.

Effects of denosumab on bone mineral density and bone turnover in postmenopausal women transitioning from alendronate therapy

Patients treated with bisphosphonates for osteoporosis may discontinue or require a switch to other therapies. Denosumab binds to RANKL and is a potent inhibitor of bone resorption that has been shown to increase bone mineral density (BMD) and decrease fracture risk in postmenopausal women with osteoporosis. This was a multicenter, international, randomized, double‐blind, double‐dummy study in 504 postmenopausal women ≥ 55 years of age with a BMD T‐score of −2.0 or less and −4.0 or more who had been receiving alendronate therapy for at least 6 months. Subjects received open‐label branded alendronate 70 mg once weekly for 1 month and then were randomly assigned to either continued weekly alendronate therapy or subcutaneous denosumab 60 mg every 6 months and were followed for 12 months. Changes in BMD and biochemical markers of bone turnover were evaluated. In subjects transitioning to denosumab, total hip BMD increased by 1.90% at month 12 compared with a 1.05% increase in subjects continuing on alendronate (p < .0001). Significantly greater BMD gains with denosumab compared with alendronate also were achieved at 12 months at the lumbar spine, femoral neck, and 1/3 radius (all p < .0125). Median serum CTX levels remained near baseline in the alendronate group and were significantly decreased versus alendronate (p < .0001) at all time points with denosumab. Adverse events and serious adverse events were balanced between groups. No clinical hypocalcemic adverse events were reported. Transition to denosumab produced greater increases in BMD at all measured skeletal sites and a greater reduction in bone turnover than did continued alendronate with a similar safety profile in both groups. Copyright

Effects of Denosumab Treatment and Discontinuation on Bone Mineral Density and Bone Turnover Markers in Postmenopausal Women with Low Bone Mass

CONTEXT Denosumab treatment for 24 months increased bone mineral density (BMD) and reduced bone turnover markers (BTM) in postmenopausal women. OBJECTIVE The aim was to determine the effects of prior denosumab or placebo injections on BMD, BTM, and safety over 24 months after treatment discontinuation. DESIGN We conducted an off-treatment extension of a phase 3, randomized, double-blind, parallel-group study. PARTICIPANTS A total of 256 postmenopausal women with a mean age of 59 yr and a mean lumbar spine T-score of -1.61 at randomization participated in the study. INTERVENTIONS Participants received placebo or 60 mg denosumab every 6 months for 24 months, followed by 24 months off treatment. MAIN OUTCOME MEASURES We measured the percentage changes in BMD and BTM, and evaluated safety. RESULTS Of the 256 participants enrolled in the posttreatment phase, 87% completed the study. During 24 months of denosumab treatment, BMD increased (lumbar spine, 6.4%; total hip, 3.6%; 1/3 radius, 1.4%), and BTM decreased (serum C-terminal telopeptide of type 1 collagen, 63%; and N-terminal propeptide of type 1 procollagen, 47%), compared with placebo. After discontinuation, BMD declined, but the previously treated denosumab group maintained higher BMD than the previously treated placebo group at these sites (P ≤ 0.05). Final BMD at month 48 strongly correlated with month 0 BMD. After denosumab discontinuation, BTM increased above baseline within 3 months (serum C-terminal telopeptide of type 1 collagen) or 6 months (N-terminal propeptide of type 1 procollagen) and returned to baseline by month 48. Adverse event rates during the off-treatment phase were similar between groups. CONCLUSIONS In postmenopausal women with low BMD, the effects of 60 mg denosumab treatment for 24 months on BMD and BTM are reversible upon discontinuation, reflecting its biological mechanism of action. Residual BMD measurements remained above those of the group previously treated with placebo.

Effects of denosumab on bone histomorphometry: the FREEDOM and STAND studies.

Denosumab, a human monoclonal antibody against RANKL, reversibly inhibits osteoclast‐mediated bone resorption and has been developed for use in osteoporosis. Its effects on bone histomorphometry have not been described previously. Iliac crest bone biopsies were collected at 24 and/or 36 months from osteoporotic postmenopausal women in the FREEDOM study (45 women receiving placebo and 47 denosumab) and at 12 months from postmenopausal women previously treated with alendronate in the STAND study (21 continuing alendronate and 15 changed to denosumab at trial entry). Qualitative histologic evaluation of biopsies was unremarkable. In the FREEDOM study, median eroded surface was reduced by more than 80% and osteoclasts were absent from more than 50% of biopsies in the denosumab group. Double labeling in trabecular bone was observed in 94% of placebo bones and in 19% of those treated with denosumab. Median bone‐formation rate was reduced by 97%. Among denosumab‐treated subjects, those with double labels and those with absent labels had similar levels of biochemical markers of bone turnover. In the STAND trial, indices of bone turnover tended to be lower in the denosumab group than in the alendronate group. Double labeling in trabecular bone was seen in 20% of the denosumab biopsies and in 90% of the alendronate samples. Denosumab markedly reduces bone turnover and also reduces fracture numbers. Longer follow‐up is necessary to determine how long such low turnover is safe.

Effect of denosumab on bone mineral density and biochemical markers of bone turnover: Six-year results of a phase 2 clinical trial

CONTEXT This is a study extension to evaluate the efficacy and safety of long-term treatment with denosumab in postmenopausal women with low bone mass. OBJECTIVE Our objective was to describe changes in bone mineral density (BMD) and bone turnover markers as well as safety with 6 yr of denosumab treatment. DESIGN We conducted an ongoing 4-yr, open-label, single-arm, extension study of a dose-ranging phase 2 trial. This paper reports a 2-yr interim analysis representing up to 6 yr of continuous denosumab treatment. SETTING This multicenter study was conducted at 23 U.S. centers. PATIENTS Of the 262 subjects who completed the parent study, 200 enrolled in the study extension and 178 (89%) completed the first 2 yr. INTERVENTION All subjects received denosumab 60 mg sc every 6 months. MAIN OUTCOME MEASURES We evaluated BMD at the lumbar spine, total hip, femoral neck, and one third radius; biochemical markers of bone turnover; and safety, reported as adverse events. RESULTS Over a period of 6 yr, continuous treatment with denosumab resulted in progressive gains in BMD in postmenopausal women with low bone mass. Reduction in bone resorption was sustained over the course of continuous treatment. Independent of past treatment and discontinuation period, subjects demonstrated responsiveness to denosumab therapy as measured by BMD and bone turnover markers. The safety profile of denosumab did not change over time. CONCLUSIONS In this study, denosumab was well tolerated and effective through 6 yr of continuous treatment in postmenopausal women with low bone mass.

Burosumab Therapy in Children with X-Linked Hypophosphatemia

BACKGROUND X‐linked hypophosphatemia is characterized by increased secretion of fibroblast growth factor 23 (FGF‐23), which leads to hypophosphatemia and consequently rickets, osteomalacia, and skeletal deformities. We investigated burosumab, a monoclonal antibody that targets FGF‐23, in patients with X‐linked hypophosphatemia. METHODS In an open‐label, phase 2 trial, we randomly assigned 52 children with X‐linked hypophosphatemia, in a 1:1 ratio, to receive subcutaneous burosumab either every 2 weeks or every 4 weeks; the dose was adjusted to achieve a serum phosphorus level at the low end of the normal range. The primary end point was the change from baseline to weeks 40 and 64 in the Thacher rickets severity total score (ranging from 0 to 10, with higher scores indicating greater disease severity). In addition, the Radiographic Global Impression of Change was used to evaluate rachitic changes from baseline to week 40 and to week 64. Additional end points were changes in pharmacodynamic markers, linear growth, physical ability, and patient‐reported outcomes and the incidence of adverse events. RESULTS The mean Thacher rickets severity total score decreased from 1.9 at baseline to 0.8 at week 40 with every‐2‐week dosing and from 1.7 at baseline to 1.1 at week 40 with every‐4‐week dosing (P<0.001 for both comparisons); these improvements persisted at week 64. The mean serum phosphorus level increased after the first dose in both groups, and more than half the patients in both groups had levels within the normal range (3.2 to 6.1 mg per deciliter [1.0 to 2.0 mmol per liter]) by week 6. Stable serum phosphorus levels were maintained through week 64 with every‐2‐week dosing. Renal tubular phosphate reabsorption increased from baseline in both groups, with an overall mean increase of 0.98 mg per deciliter (0.32 mmol per liter). The mean dose of burosumab at week 40 was 0.98 mg per kilogram of body weight with every‐2‐week dosing and 1.50 mg per kilogram with every‐4‐week dosing. Across both groups, the mean serum alkaline phosphatase level decreased from 459 U per liter at baseline to 369 U per liter at week 64. The mean standing‐height z score increased in both groups, with greater improvement seen at all time points with every‐2‐week dosing (an increase from baseline of 0.19 at week 64) than with every‐4‐week dosing (an increase from baseline of 0.12 at week 64). Physical ability improved and pain decreased. Nearly all the adverse events were mild or moderate in severity. CONCLUSIONS In children with X‐linked hypophosphatemia, treatment with burosumab improved renal tubular phosphate reabsorption, serum phosphorus levels, linear growth, and physical function and reduced pain and the severity of rickets. (Funded by Ultragenyx Pharmaceutical and Kyowa Hakko Kirin; ClinicalTrials.gov number, NCT02163577; EudraCT number, 2014‐000406‐35).

The Tactics of Modern-Day Regulatory Trials

Fractures are an important public health problem affecting patients of all ages. Although most fractures heal quickly, some heal poorly and some do not heal at all. To achieve an optimal healing outcome, the standard of care for most fractures consists of reduction followed by immobilization, with a myriad of options regarding the approach to fracture-healing. Currently, biopharmaceutical companies are sponsoring research with regard to products that aim to enhance or accelerate fracture-healing; however, as there are no approved and marketed systemic therapies for fracture-healing, the development and commercialization process for such products will require close collaboration between industry, academia, and regulators to determine how to bring these products to market in the most efficient manner. The following manuscript provides a brief overview of the regulatory process in the United States for systemic therapies in fracture-healing and discusses key issues that may arise in connection with the regulatory approval of these novel investigational treatments.