Odanacatib Adds Bone in Alendronate-Pretreated Osteoporosis

MINNEAPOLIS – Odanacatib added bone density in postmenopausal women with osteoporosis previously treated with alendronate, according to results from a study presented at the annual meeting of the American Society for Bone and Mineral Research.

In a phase II trial involving 243 patients, the investigational oral cathepsin K inhibitor began to distinguish itself from placebo at 12 months. At 2 years, the change from baseline in femoral neck bone mineral density (BMD) was significantly increased by 1.73%, compared with a loss of 0.94% for placebo (P less than .001).

Merck Research Laboratories

BMD changes in the treatment group at 2 years were also significantly different from placebo at the trochanter (1.83% vs. –1.35%) and for the total hip (0.83% vs. –1.87%, both P less than .001).

All of the women studied had received alendronate (Fosamax) for at least 3 years. Patients could have been off the bisphosphonate for up to 3 months prior to enrollment, but many switched directly over to odanacatib, said study coauthor Dr. Albert Leung, executive director of clinical research at Merck Research Laboratories.

"This drug has the potential to give additional benefits when [patients] have been treated with alendronate for a number of years and the treatment effect has reached a plateau and they may need a different treatment," he said in an interview.

In July 2012, a pivotal 16,731-patient, phase III trial of odanacatib was stopped early after an interim analysis showed a "favorable benefit-risk profile" for fracture risk reduction in postmenopausal women with previously untreated osteoporosis.

"It could be quite a population that may benefit from this drug," Dr. Leung remarked.

The study’s data monitoring committee, however, flagged safety concerns in "certain selected areas" for further follow-up. Those safety risks have not been identified as the trial is still closing, but will be monitored along with efficacy in a double-blind, placebo-controlled, extension trial going out to 5 years of treatment, he said.

Merck, which plans to submit regulatory applications for odanacatib in the United States and Europe in the first half of 2013, has high hopes for odanacatib despite competition from generic drugs because of its novel mechanism of action.

Odanacatib inhibits cathepsin K, the primary protease in osteoclasts that breaks down bone collagen during bone resorption. Unlike traditional antiresorptive drugs like bisphosphonates, however, odanacatib does not interfere with the function of the entire osteoclast or reduce the number of osteoclasts. This characteristic is important, as osteoclasts secrete signaling factors to stimulate osteoblasts, the cells responsible for bone formation. As a result, there is greater bone formation with odanacatib, Dr. Leung explained.

The phase II trial enrolled women at least 60 years of age (mean 71 years) with a BMD T score of –2.5 to more than –3.5 at any hip site without a prior fragility fracture or those with a history of fragility fracture (except hip fracture), and a BMD T score of –1.5 and more than –3.5 at any hip site. The women were randomly assigned to odanacatib 50 mg once weekly or placebo for 24 months, as well as 5,600 IU of vitamin D₃ per week and calcium at dosages up to 1,200 mg/day. The study was not powered to assess fractures.

At 24 months, the change in BMD at the lumbar spine was significant at 2.28% for odanacatib vs. a loss of 0.30% with placebo (P less than .001).

BMD change was not significant at the distal forearm, with losses of 0.92% vs. 1.14%, respectively.

As expected, urinary collagen type I cross-linked N-telopeptide, a biomarker of bone resorption, increased with placebo, compared with a significant 47% decrease with odanacatib.

The bone formation marker, serum type I procollagen, rose inexplicably with placebo, but this increase was surpassed by a significant gain of 31.2% with odanacatib.

Most unexpected, however, was an increase in the resorption marker collagen type I cross-linked C-telopeptide (sCTx) with once-weekly odanacatib. Dr. Leung said the finding appears to correlate with the bone density changes because sCTx levels remained relatively stable during the first 12 months of treatment before rising in the second year of the study.

Finally, adverse events were similar in both groups. The most common adverse events in the odanacatib and placebo arms were urinary tract infection (11.5% vs. 16.5%, respectively), back pain (11.5% vs. 9.9%), arthralgia (9% vs. 9.9%), and fractures (4.9% vs. 13.2%). Treatment discontinuation rates due to adverse events were 9% vs. 3.3%, he said.

Dr. Leung and several of his coauthors are employees of Merck, the trial sponsor.

MINNEAPOLIS – Odanacatib added bone density in postmenopausal women with osteoporosis previously treated with alendronate, according to results from a study presented at the annual meeting of the American Society for Bone and Mineral Research.

In a phase II trial involving 243 patients, the investigational oral cathepsin K inhibitor began to distinguish itself from placebo at 12 months. At 2 years, the change from baseline in femoral neck bone mineral density (BMD) was significantly increased by 1.73%, compared with a loss of 0.94% for placebo (P less than .001).

Merck Research Laboratories

BMD changes in the treatment group at 2 years were also significantly different from placebo at the trochanter (1.83% vs. –1.35%) and for the total hip (0.83% vs. –1.87%, both P less than .001).

All of the women studied had received alendronate (Fosamax) for at least 3 years. Patients could have been off the bisphosphonate for up to 3 months prior to enrollment, but many switched directly over to odanacatib, said study coauthor Dr. Albert Leung, executive director of clinical research at Merck Research Laboratories.

"This drug has the potential to give additional benefits when [patients] have been treated with alendronate for a number of years and the treatment effect has reached a plateau and they may need a different treatment," he said in an interview.

In July 2012, a pivotal 16,731-patient, phase III trial of odanacatib was stopped early after an interim analysis showed a "favorable benefit-risk profile" for fracture risk reduction in postmenopausal women with previously untreated osteoporosis.

"It could be quite a population that may benefit from this drug," Dr. Leung remarked.

The study’s data monitoring committee, however, flagged safety concerns in "certain selected areas" for further follow-up. Those safety risks have not been identified as the trial is still closing, but will be monitored along with efficacy in a double-blind, placebo-controlled, extension trial going out to 5 years of treatment, he said.

Merck, which plans to submit regulatory applications for odanacatib in the United States and Europe in the first half of 2013, has high hopes for odanacatib despite competition from generic drugs because of its novel mechanism of action.

Odanacatib inhibits cathepsin K, the primary protease in osteoclasts that breaks down bone collagen during bone resorption. Unlike traditional antiresorptive drugs like bisphosphonates, however, odanacatib does not interfere with the function of the entire osteoclast or reduce the number of osteoclasts. This characteristic is important, as osteoclasts secrete signaling factors to stimulate osteoblasts, the cells responsible for bone formation. As a result, there is greater bone formation with odanacatib, Dr. Leung explained.

The phase II trial enrolled women at least 60 years of age (mean 71 years) with a BMD T score of –2.5 to more than –3.5 at any hip site without a prior fragility fracture or those with a history of fragility fracture (except hip fracture), and a BMD T score of –1.5 and more than –3.5 at any hip site. The women were randomly assigned to odanacatib 50 mg once weekly or placebo for 24 months, as well as 5,600 IU of vitamin D₃ per week and calcium at dosages up to 1,200 mg/day. The study was not powered to assess fractures.

At 24 months, the change in BMD at the lumbar spine was significant at 2.28% for odanacatib vs. a loss of 0.30% with placebo (P less than .001).

BMD change was not significant at the distal forearm, with losses of 0.92% vs. 1.14%, respectively.

As expected, urinary collagen type I cross-linked N-telopeptide, a biomarker of bone resorption, increased with placebo, compared with a significant 47% decrease with odanacatib.

The bone formation marker, serum type I procollagen, rose inexplicably with placebo, but this increase was surpassed by a significant gain of 31.2% with odanacatib.

Most unexpected, however, was an increase in the resorption marker collagen type I cross-linked C-telopeptide (sCTx) with once-weekly odanacatib. Dr. Leung said the finding appears to correlate with the bone density changes because sCTx levels remained relatively stable during the first 12 months of treatment before rising in the second year of the study.

Finally, adverse events were similar in both groups. The most common adverse events in the odanacatib and placebo arms were urinary tract infection (11.5% vs. 16.5%, respectively), back pain (11.5% vs. 9.9%), arthralgia (9% vs. 9.9%), and fractures (4.9% vs. 13.2%). Treatment discontinuation rates due to adverse events were 9% vs. 3.3%, he said.

Dr. Leung and several of his coauthors are employees of Merck, the trial sponsor.

MINNEAPOLIS – Odanacatib added bone density in postmenopausal women with osteoporosis previously treated with alendronate, according to results from a study presented at the annual meeting of the American Society for Bone and Mineral Research.

In a phase II trial involving 243 patients, the investigational oral cathepsin K inhibitor began to distinguish itself from placebo at 12 months. At 2 years, the change from baseline in femoral neck bone mineral density (BMD) was significantly increased by 1.73%, compared with a loss of 0.94% for placebo (P less than .001).

Merck Research Laboratories

BMD changes in the treatment group at 2 years were also significantly different from placebo at the trochanter (1.83% vs. –1.35%) and for the total hip (0.83% vs. –1.87%, both P less than .001).

All of the women studied had received alendronate (Fosamax) for at least 3 years. Patients could have been off the bisphosphonate for up to 3 months prior to enrollment, but many switched directly over to odanacatib, said study coauthor Dr. Albert Leung, executive director of clinical research at Merck Research Laboratories.

"This drug has the potential to give additional benefits when [patients] have been treated with alendronate for a number of years and the treatment effect has reached a plateau and they may need a different treatment," he said in an interview.

In July 2012, a pivotal 16,731-patient, phase III trial of odanacatib was stopped early after an interim analysis showed a "favorable benefit-risk profile" for fracture risk reduction in postmenopausal women with previously untreated osteoporosis.

"It could be quite a population that may benefit from this drug," Dr. Leung remarked.

The study’s data monitoring committee, however, flagged safety concerns in "certain selected areas" for further follow-up. Those safety risks have not been identified as the trial is still closing, but will be monitored along with efficacy in a double-blind, placebo-controlled, extension trial going out to 5 years of treatment, he said.

Merck, which plans to submit regulatory applications for odanacatib in the United States and Europe in the first half of 2013, has high hopes for odanacatib despite competition from generic drugs because of its novel mechanism of action.

Odanacatib inhibits cathepsin K, the primary protease in osteoclasts that breaks down bone collagen during bone resorption. Unlike traditional antiresorptive drugs like bisphosphonates, however, odanacatib does not interfere with the function of the entire osteoclast or reduce the number of osteoclasts. This characteristic is important, as osteoclasts secrete signaling factors to stimulate osteoblasts, the cells responsible for bone formation. As a result, there is greater bone formation with odanacatib, Dr. Leung explained.

The phase II trial enrolled women at least 60 years of age (mean 71 years) with a BMD T score of –2.5 to more than –3.5 at any hip site without a prior fragility fracture or those with a history of fragility fracture (except hip fracture), and a BMD T score of –1.5 and more than –3.5 at any hip site. The women were randomly assigned to odanacatib 50 mg once weekly or placebo for 24 months, as well as 5,600 IU of vitamin D₃ per week and calcium at dosages up to 1,200 mg/day. The study was not powered to assess fractures.

At 24 months, the change in BMD at the lumbar spine was significant at 2.28% for odanacatib vs. a loss of 0.30% with placebo (P less than .001).

BMD change was not significant at the distal forearm, with losses of 0.92% vs. 1.14%, respectively.

As expected, urinary collagen type I cross-linked N-telopeptide, a biomarker of bone resorption, increased with placebo, compared with a significant 47% decrease with odanacatib.

The bone formation marker, serum type I procollagen, rose inexplicably with placebo, but this increase was surpassed by a significant gain of 31.2% with odanacatib.

Most unexpected, however, was an increase in the resorption marker collagen type I cross-linked C-telopeptide (sCTx) with once-weekly odanacatib. Dr. Leung said the finding appears to correlate with the bone density changes because sCTx levels remained relatively stable during the first 12 months of treatment before rising in the second year of the study.

Finally, adverse events were similar in both groups. The most common adverse events in the odanacatib and placebo arms were urinary tract infection (11.5% vs. 16.5%, respectively), back pain (11.5% vs. 9.9%), arthralgia (9% vs. 9.9%), and fractures (4.9% vs. 13.2%). Treatment discontinuation rates due to adverse events were 9% vs. 3.3%, he said.

Dr. Leung and several of his coauthors are employees of Merck, the trial sponsor.