Nancy A. Melville

October 19, 2012

MINNEAPOLIS, Minnesota — The investigational drug odanacatib shows efficacy in boosting bone mineral density (BMD) and improving markers of bone formation and resorption in osteoporotic postmenopausal women previously treated with alendronate, researchers reported here at the American Society for Bone and Mineral Research (ASBMR) 2012 Annual Meeting.

Odanacatib, an oral cathepsin K inhibitor (Merck & Co), has shown potential in previous trials to improve BMD at the spine and hip among postmenopausal women.

A pivotal trial of the drug involving 16,000 postmenopausal women with osteoporosis was halted in July when an interim analysis showed a significant reduction in fracture risk. The data safety monitoring board recommended stopping the trial early so that all patients could be offered the treatment.

Researchers designed the current double-blind, placebo-controlled study to assess odanacatib's effect on BMD and bone remodeling biomarkers.

They randomly assigned 243 postmenopausal women to receive odanacatib, 50 mg once weekly, or placebo for 24 months. All participants received vitamin D3, 5600 IU/wk, and calcium supplementation (to 1200 mg/d).

Participants were at least 60 years of age, had a low BMD T score (–2.5 or less but greater than –3.5) at the total hip, had no history of hip fracture, and had been treated with alendronate for 3 years or more. They were allowed to have been off of alendronate therapy for up to 3 months immediately before enrollment in the study.

Assessments of BMD by dual-energy x-ray absorptiometry at baseline and 6, 12, and 24 months showed that the odanacatib group had significant BMD improvements at 24 months at 3 key hip sites and the lumbar spine, compared with placebo.

Women in the odanacatib group had a 1.73% improvements in the femoral neck from baseline to 24 months and a 1.83% improvement in the trochanter. By contrast, women in the placebo group had a decline of 0.94% and 1.35%, respectively.

Total hip and lumbar spine in the odanacatib group increased by 0.83% and 2.28%, compared with a decrease of 1.87% for total hip and no significant change from baseline at the lumbar spine for the placebo group.

The bone formation biomarkers s-P1NP and s-BSAP increased significantly at 24 months compared with placebo. Meanwhile, the biomarker of bone resorption, u-NTx/Cr, decreased compared with placebo at the same time.

"There was a significant increase in serum P1NP 3 months after initiation of the trial and, at 6 months, there was a diversion between the treatment group and the placebo patients," said lead author Tobias De Villiers, MD, from Mediclinic Panorama, Stellenbosch, South Africa.

"In the end, at 24 months, there was a statistically significant increase in the treatment group, compared to baseline and placebo, suggesting there is more than just an antiresorptive effect occurring."

Adverse events did not significantly differ between the 2 treatment groups. Treatment discontinuations due to adverse events in the treatment group were 9%, compared with 3.3% in the placebo group. The most common clinical adverse events in the odanacatib and placebo groups, respectively, were urinary tract infection (11.5% vs 16.5%), back pain (11.5% vs 9.9%), arthralgia (9.0% vs 9.9%), and fractures (4.9% vs13.2%).

Dr. De Villiers emphasized that the study was not designed to evaluate fractures.

"The study's results suggest that alendronate-experienced patients with low BMD may gain by switching to odanacatib 50 mg once weekly," he concluded. "The treatment has been found to be generally safe and well tolerated, and the drug may offer a viable alternative for patients who are in need of continued therapy and want to obtain benefit beyond that received with alendronate."

Cathespsin K inhibitors also have the potential for treating various other conditions, including metastatic bone disease, osteoarthritis, and rheumatoid arthritis, according to Kong Wah Ng, MD, from the Department of Endocrinology and Diabetes and St Vincent's Institute, at St Vincent's Hospital, Fitzroy, Victoria, Australia. However, the fact that cathepsin K is not expressed solely in osteoclasts needs to be further explored.  

"Very low levels of cathepsin K exist in other adult tissues, including the heart, lungs, skeletal muscle, central nervous system etc., and potential adverse effects resulting from its inhibition may take years of scrutiny before they are recognized," Dr. Ng said.

"For example, it took many years before the uncommon adverse effects of osteonecrosis of the jaw and atypical femur fractures related to chronic use of bisphosphonates were acknowledged", he said.

Dr. Ng added that he was somewhat skeptical about claims that bone formation was preserved. "In data published to date, bone formation was suppressed, but to a much lesser extent than seen with other antiresorptives," he said.

Dr. Ng expressed confidence, however, that the drug will gain an important place in the market for osteoporosis treatment, but the nature of that place is the question.

"I believe that cathepsin K inhibition has a place in the treatment of postmenopausal osteoporosis," he said. "It is part of a new generation of 'designer' drugs where the function of osteoclast is disrupted by targeting an enzyme that plays a vital role in bone resorption."

"That it is able to do so without killing the osteoclast or curtailing its formation is a point of difference between odanacatib and other antiresorptives currently in use, such as the bisphosphonates and denosumab," he said.

"Odanacatib does offer some advantages over the oral agents, but whether it can match the convenience and efficacy of parenteral therapy, such as denosumab and zoledronic acid, remains to be seen."

Dr. De Villiers' is on the speaker's bureau for Merck Sharp & Dohme Corp., a subsidiary of Merck & Co. Dr. Ng has disclosed no relevant financial relationships.

American Society for Bone and Mineral Research (ASBMR) 2012 Annual Meeting. Abstract 1027. Presented October 13, 2012.

Comments

3090D553-9492-4563-8681-AD288FA52ACE

processing....