Denosumab (A Monoclonal Antibody to Receptor Activator of Nuclear Factor-Kappa B Ligand (RANKL) in Crohn's Disease

1.0 Hypothesis Moderate to severely active Crohn's disease (CD) will respond to treatment with Denosumab, (a monoclonal antibody to Receptor Activator of Nuclear factor-Kappa B ligand (RANKL)

The principal research questions to be addressed:

1. Determine if a single dose of Denosumab can induce a clinical response by 12 weeks in persons with active CD 2. Determine if a single dose of Denosumab can induce a clinical remission by 12 weeks in persons with active CD 3. Determine if a single dose of Denosumab can reduce markers of systemic (C-reactive protein, CRP) and intestinal (fecal calprotectin, FCAL) inflammation in persons with active CD.
2. Background Current treatment paradigms of CD involve a step-up approach, where persons with mild disease are treated with 5-aminosalicylate (5-ASA), budesonide or even no therapy. Persons who fail to respond to these relatively inexpensive and well tolerated medications, will often require more intensive therapies including systemic corticosteroids, immunomodulatory agents such as azathioprine or methotrexate, or biologic agents. While the latter have proven efficacy in the treatment of CD, they are quite costly, and their use may result in significant side effects. Currently, the biologic agents infliximab and adalimumab, which specifically antagonize tumor necrosis factor alpha (TNF) are the ultimate step in the medical management of CD. However, nearly one-third of subjects will not respond to a standard anti-TNF based induction regimen, and response can be lost in about one-half of all subjects who responded to the initial induction over the course of one year. Of those who start an anti-TNF and respond, continuous therapy is recommended, the costs of which may exceed $25000-$40000 per year. Furthermore, the combination of an immunomodulator with an anti-TNF agent enhances clinical response, but may increase the risk of infectious complications, and their use is also associated with hepatosplenic T cell lymphoma, which is rare but almost uniformly fatal. In a population based costing study from Manitoba infliximab patients represented a very small proportion of all inflammatory bowel disease (IBD) patients, yet they accounted for a total of approximately $2 million in drug costs in 2005/06, which represented approximately half of all prescription drug costs for IBD patients in Manitoba. Hence, it would be desirable to have a medication that is as effective at inducing and maintaining remission with an improved side effect profile and with a lower cost of provision.

2.1 What is Denosumab: Denosumab, a fully human monoclonal antibody to RANKL was approved for the treatment of postmenopausal osteoporosis in June 2010. It is administered subcutaneously once every 6 months and is highly effective in reducing the risk of vertebral, non-vertebral, and hip fracture risk. A mixed treatment comparison meta-analysis showed Denosumab to be more effective than strontium ranelate, raloxifene, alendronate, and risedronate in preventing new vertebral fractures. It is an agent that works in men as well as women. According to the 2010 Osteoporosis Canada Clinical Practice Guidelines, Denosumab is a first-line option for the pharmacological management of postmenopausal osteoporosis (PMO). "Owing to its efficacy, safety, and potential to improve adherence rates, Denosumab is considered an appropriate first-line pharmacologic option for PMO management." The registration of Denosumab was the culmination of the discovery and clarification of the internal bone microenvironment regulation of bone remodeling: the osteoblast-produced competitors: RANKL and osteoprotegerin (OPG); and the osteoclast receptor: RANK. Our understanding of the pathophysiology of normal bone homeostasis and the pathogenesis of osteoporosis and its integration with the immune response has been greatly advanced by the discovery of RANKL-RANK ligation on osteoblast and osteoclast precursors. Osteoblasts express RANKL which can bind to osteoclast precursors (RANK) or an osteoblast derived soluble decoy receptor -OPG. The binding of RANK to RANKL induces a signaling and gene expression cascade that results in differentiation and maturation of osteoclasts which can ultimately lead to osteoporosis. OPG blocks this interaction, thereby inhibiting osteoclast formation and hence decreases bone resorption. It has been shown that agents that enhance RANKL production are associated with the development of osteoporosis whereas agents that block RANKL reduce bone mineral loss.

When RANKL is upregulated in the estrogen-deficient state and exceeds the amount of OPG, there is an increase in osteoclastogenesis and bone resorption, and this is the major mechanism for bone mass loss and osteoporotic fractures in the postmenopausal state. The human monoclonal antibody to RANKL (Denosumab) was the first product developed to reduce bone resorption by inhibiting RANKL binding to RANK. Denosumab does not accumulate in bone. Extension of the registration trial ('FREEDOM') 5-year data indicates continued safety and efficacy, and this will be extended to 10 years to generate even longer-term data. The profound but reversible suppression of bone turnover that is seen with Denosumab partly explains the continuous increase in bone mineral density seen through 8 years of the phase II clinical trials. As noted above, Denosumab is effective in both men and women and it is potentially effective in glucocorticoid-induced osteoporosis.