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Odanacatib for Postmenopausal Osteoporosis

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Odanacatib for Postmenopausal Osteoporosis Issues in Emerging Health Technologies Odanacatib for Postmenopausal Osteoporosis Issue 119 May 2012 Summary The overall incidence of adverse events of odanacatib during the phase 2 trial and its Odanacatib belongs to a new class of extension studies was generally similar to osteoporosis drugs designed to block placebo, and no dose-related trends were cathepsin K, a lysosomal protease that observed. plays a role in the function of osteoclasts. By inhibiting cathepsin K, odanacatib It is not yet known whether odanacatib reduces bone resorption by osteoclasts. reduces the risk of fracture or has clinical Odanacatib is not currently licensed for advantages over currently available sale in Canada or the United States. therapeutic options. A phase 3 trial is currently assessing the long-term safety Current evidence on the safety and and efficacy of odanacatib compared with efficacy of odanacatib for postmenopausal placebo for the prevention of hip, osteoporosis is limited by the small vertebral, and non-vertebral fractures in number of participants who enrolled in women with postmenopausal osteoporosis one phase 2 trial and its extension studies, who have not previously experienced a hip and the use of surrogate measures of fracture or received pharmacologic efficacy. treatment for osteoporosis prior to trial The phase 2 trial assessed the efficacy of initiation. This study did not use an active odanacatib compared with placebo for the treatment as a comparator or include treatment of postmenopausal women with Canadian study sites. Pending the results, low bone mineral density who had not industry may file a submission in 2013 previously experienced a fragility fracture. with regulatory authorities for the Patients excluded from the trial were approval of odanacatib for the treatment women who had ever used intravenous of postmenopausal osteoporosis. bisphosphonates; received treatment with oral bisphosphonates, estrogen replacement therapy, or raloxifene within Background the previous six months; or received treatment with teriparatide within the Bone loss occurs when the rate of bone resorption by previous 12 months. osteoclasts exceeds the rate of bone formation by osteoblasts during the bone remodelling process.1 Results of the phase 2 trial and its Progressive bone loss leads to the deterioration of extension studies showed progressive bone tissue, low bone mineral density, skeletal increases in bone mineral density at the fragility, and eventually osteoporosis. Individuals lumbar spine, total hip, femoral neck, and with osteoporosis are at an increased risk for fractures trochanter in postmenopausal women who — particularly at the hip, spine (vertebral fractures), were continuously treated with odanacatib and wrist (non-vertebral fractures). for up to five years. A rapid reversal of the Currently available treatments are limited by antiresorptive effect was observed in moderate-to-poor clinical efficacy for the prevention women who discontinued treatment with of fractures (particularly hip and other non-vertebral odanacatib, resulting in a reduction in fractures), adverse effects, patient comorbidities, and bone mineral density at all sites toward poor compliance.2-4 Oral bisphosphonates are the baseline levels. most commonly prescribed treatment for osteoporosis, but compliance is limited by gastrointestinal intolerance, and discontinuation rates Odanacatib for Postmenopausal Osteoporosis of greater than 50% have been reported within 2013 with regulatory authorities for the approval of 12 months of starting treatment.5,6 Furthermore, odanacatib for the treatment of postmenopausal concerns have been raised regarding the safety of osteoporosis. long-term bisphosphonates use.7 Osteonecrosis of the jaw has been observed in patients receiving long-term, high-dose intravenous bisphosphonates Patient Population for cancer.8 Whether the lower-dose bisphosphonate therapy used for osteoporosis increases the risk for Postmenopausal osteoporosis occurs when a fall in osteonecrosis of the jaw over that observed in estrogen levels causes the rate of bone resorption to untreated patients of similar age and frailty has yet increase, resulting in excessive bone loss.1 to be confirmed.9 Other adverse effects, including Osteoporosis affects more than 1.5 million atypical fractures of the femur and esophageal Canadians.18 The prevalence of osteoporosis has been cancer, have been reported in patients receiving estimated to increase from 6% of women aged 50 to long-term bisphosphonate therapy, but there is 59 years, to more than 40% of women aged 80 years currently not enough evidence to establish a and older.18 Fragility fractures represent 80% of all causative link.10 fractures in menopausal women older than 50 years.19 Fractures increase the risk of chronic pain, bone deformity, depression, long-term disability, and The Technology mortality.20,21 Fragility fractures have been associated with extended hospital stays, increased wait times for Odanacatib (Merck & Co., Inc.) belongs to a new orthopedic surgery and long-term care beds, and class of osteoporosis drugs designed to selectively substantial health care costs.20,22 It is estimated that block cathepsin K, an osteoclast lysosomal protease the annual cost of acute care hospitalizations for 11 responsible for the breakdown of bone collagen. fragility fractures in Canada is C$1.2 billion, with the By inhibiting cathepsin K, odanacatib reduces bone annual cost of hip fractures alone being resorption by osteoclasts. Although cathepsin K is C$618.6 million.23 Given the increasing proportion of primarily expressed in osteoclasts, it has also been adults older than 50 years, the annual cost of hip found in other cell types, including synovial fractures alone is projected to increase to fibroblasts, skin fibroblasts, macrophages, dendritic C$2.4 billion by 2041.24 cells, chondrocytes, epithelial cells of various tissues, melanocytes, and tumour cells.12,13 Potential adverse effects of cathepsin K inhibition may be the Current Practice result of “off-target” inhibition of other cathepsins or by inhibition of cathepsin K in cells other than 13 Given that various clinical factors can increase the osteoclasts. risk of fracture independent of a low bone mineral density, Osteoporosis Canada guidelines25 The development of two previous investigational recommend that the initiation of pharmacologic cathepsin K inhibitors, balicatib and relacatib, has treatment for osteoporosis should be based on an been halted. Investigation of balicatib was assessment of the absolute fracture risk using a discontinued when serious dermatological adverse validated fracture prediction tool such as the effects (including scleroderma and morphea-like Canadian Association of Radiologists and skin lesions) and an increased risk of upper Osteoporosis Canada (CAROC) tool26 or the World respiratory tract infections were observed during a 14,15 Health Organization (WHO) Fracture Risk phase 2 clinical trial. Clinical development of Assessment (FRAX) tool.27 Both have been relacatib ceased after the completion of an 16 calibrated to estimate the 10-year risk of a major unpublished phase 1 trial. fragility fracture in Canadians.28-30 Osteoporosis is defined by the presence of a fragility fracture, a bone Regulatory Status mineral density of more than 2.5 standard deviations below peak bone mass in an individual older than 50 years (T-score of less than 2.5) in the absence of a Odanacatib is not currently licensed for sale in fragility fracture, or a high (> 20%) 10-year risk of Canada or the United States. Pending results from a 25 fracture using the CAROC or FRAX tools. phase 3 trial,17 industry may file a submission in Odanacatib for Postmenopausal Osteoporosis Pharmacological therapy is now considered in all patients at high (> 20%) 10-year risk of fracture and The Evidence selected patients at moderate (10% to 20%) 10-year risk of fracture, but not in patients who are One phase 2 trial33 and its extension studies34-37 estimated to be at low (< 10%) 10-year risk of assessing odanacatib for the treatment of fracture.25 Oral bisphosphonates (alendronate and postmenopausal osteoporosis was identified. The risedronate) are the most commonly used first-line results are summarized in Table 1. Two treatment for the prevention of fractures in phase 2 trials38,39 and one phase 3 trial40 evaluating postmenopausal women, in conjunction with the effect of odanacatib on bone mineral density in calcium and vitamin D supplementation, and postmenopausal women have been completed, but lifestyle measures (such as appropriate diet, regular results have not yet been published. A phase 3 trial exercise, and smoking cessation).3,4,25 Other first- investigating the effect of odanacatib on bone mineral line treatment options include an intravenous density in osteoporotic postmenopausal women bisphosphonate (zoledronic acid), a monoclonal previously treated with alendronate has been planned, antibody (denosumab), a bone-forming agent but is not yet open for participant recruitment.41 An (teriparatide), a selective estrogen receptor ongoing phase 3 trial is evaluating the safety and modulator (raloxifene), and estrogen replacement efficacy of odanacatib for the prevention of fractures therapy.25,31 Calcitonin or etidronate are considered in postmenopausal women with osteoporosis.17 second-line alternatives for the prevention of fractures in postmenopausal women who do not A multi-centre, randomized, double-blinded, placebo- tolerate first-line
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