New Drug - Odanacatib - For the Treatment of Osteoporosis
At one time, bisphosphonates were the gold standard for osteoporosis treatment, but these medications come with a lot of restrictions and gastrointestinal and esophageal issues that some people just can’t handle due to the damage they can cause. In addition to these side effects are the more serious ones like renal damage and failure, atypical femur fractures, atrial fibrillation and osteonecrosis of the jaw. These more serious effects are considered rare, but it does happen to some taking these medications, so finding alternate ways to treat bone loss is very important especially in the form of a new type of drug that works on different pathways connected to bone physiology.
These medications have a poor permeability while in the stomach making it difficult for our bodies to absorb the full amount of the active ingredients that is necessary to slow bone resorption. Because these medications have to be taken on an empty stomach with water only, plus you have to wait to eat and stay upright for 30-60 minutes—depending on which dosage you are taking—approximately 60% of patients stop taking the treatment within a year, so their bone mineral density doesn’t have a chance to improve. This is not the only treatment for osteoporosis, but they all have a degree of limitation causing poor compliance that result in more bone loss.
Forteo® is a daily injection that is very expensive, and some insurance companies don’t cover it or it comes with high insurance copay for the patient. Prolia is another option but some can’t take it if they are taking immunosuppressant’s that are used to treat rheumatoid arthritis, lupus, Crohn’s, multiple sclerosis and psoriasis.
Due to the limitations and side effects of these drugs, new treatment medications are on the horizon. Limitations and side effects aren’t the only problems we see, so we need new treatments that work more proficiently while eliminating as many side effects as possible. Of course no drug is side effect free, but one that is nearing market approval is odanacatib, by Merck.
Odanacatib is a new type of bone loss treatment since it is a cathepsin K inhibitor, that works entirely differently than the bisphosphonates, Forteo®, Evista®, Prolia®, hormone replacement therapy and calcitonin which comes in nasal spray and injection. Cathepsin K is the primary enzyme, that resorbs bone, within osteoclasts—the cells that breakdown bone. Odanacatib selectively inhibits this resorbing enzyme during the remodeling phase resulting in increased bone mineral density. When bone resorbing cells are limited in their action, it gives the bone formation cells—osteoblasts—the chance to do more work, and the result is an increase in formation of bone.
Merck studied odanacatib for many years and has successfully completed a recent Phase III fracture outcome study. This new therapy, if approved by the Food and Drug Administration (FDA), will be given orally in a once weekly dose of 50 milligrams. There aren’t any postural or food restrictions with this medication, as there are with the oral bisphosphonates, so patient compliance should be improved.
In the Long-Term Odanacatib Fracture Trial (LOFT) the following fracture risk reductions were documented among the participants. In LOFT, odanacatib significantly reduced the risk of three types of osteoporotic fractures compared to placebo in the primary efficacy analysis, and also reduced the risk of the secondary endpoint of clinical vertebral fractures. Specifically, compared to patients receiving placebo, patients who received odanacatib had a:
- 54% relative risk reduction of new and worsening morphometric (radiographically-assessed) vertebral fractures (p<0.001),
- 47% relative risk reduction of clinical hip fractures (p<0.001),
- 23% relative risk reduction of clinical non-vertebral fractures (p<0.001), and
- 72% relative risk reduction of clinical vertebral fractures (p<0.001).
The following side effects were compared between the placebo group and the drug group. In some cases the placebo arm had similar numbers of side effects as those taking the drug. There were also other side effects seen in the odanacatib group that were significantly higher in incidence than the placebo arm of the study. See this chart for comparison of the two groups within the LOFT study.
Skin Lesions (12 patients) 0.1% incidence
Skin Lesions (3 patients) < 0.1% incidence
Atypical Femoral Fracture (5) 0.1%
Atypical Femoral Fracture ( 0 patients)
Atrial Fibrillation (92) 1.1%
Atrial Fibrillation (80) 1.0%
Strokes (109) 1.4%
Strokes (86) 1.1%
Cerebrovascular events (305) 3.8%
Cerebrovascular events (290) 3.6%
The LOFT study enrolled 16,713 women age of 65 or older diagnosed with osteoporosis, the participants needed to be 5 years or more post-menopausal. In addition to the 50 mg of odanacatib they also took 5600 IUs of vitamin D a week and 1,200 mgs of calcium per day.
Merck plans on filing a New Drug Application with the FDA sometime in 2015. If this application is approved, Merck can proceed to the next step towards marketing of this drug for the treatment of osteoporosis.
Merck News. (9-15-14). Merck Announces Data from Pivotal Phase 3 Fracture Outcomes Study for Odanacatib, an Investigational Oral, Once-Weekly Treatment for Osteoporosis. Retrieved: 10-5-14 http://www.mercknewsroom.com/news-release/research-and-development-news/merck-announces-data-pivotal-phase-3-fracture-outcomes-st