Merck’s bone drug shows promise in 24 month trial

Drug company Merck said its investigational drug odanacatib (formerly MK-0822) for the treatment of osteoporosis in postmenopausal women showed promise after 24 months in a Phase IIB trial where compared to placebo it significantly increased bone mineral density (BMD).

The findings were announced on Tuesday 16th September at the 30th Annual Meeting of the American Society for Bone and Mineral Research (ASBMR) in Montreal, Quebec, Canada.

Bone is not a dead tissue, it is very much alive and its strength and resilience, which is due in part to the amount of bone mineral present, relies on the balance between two processes, bone formation and bone resorption. These processes are controlled by osteoblasts to form bone, and osteoclasts to resorb bone which degrades BMD.

Bone mineral density or BMD is the amount of mineralized bone tissue in a certain volume of bone and is one of the non-invasive ways of estimating a person’s risk of bone fracture. Osteoporosis is a disease that reduces the density and strength of bone.

The risk of fracture goes up because the bones become more porous and fragile and lose their elasticity and resilience. The most common breakages occur at the hip, spine and wrist, and fracture risk goes up with age.

Odanacatib is a selective cathepsin-K inhibitor that reduces the effect of the enzyme cathepsin-K, thought to play a key role in bone resorption and the degradation of bone proteins in particular. This is a new approach to the treatment of osteoporosis, which currently depends on bisphosphonates such as ibandronate (e.g. Boniva) and zoledronic acid (e.g. Zometa) to inhibit the action of osteoclasts.

Odanacatib showed a dose-dependent increase in BMD at the "total hip, lumbar spine and femoral neck fracture sites and decreased indices of bone resorption compared to placebo in postmenopausal women with low BMD," said Merck in a press release.

Study investigator and director of the Oregon Osteoporosis Center in Portland, Oregon, Dr Michael McClung, told the ASBMR meeting:

"Significant BMD increases were seen in the second year of treatment with odanacatib and these 24-month results confirm the positive increases seen at earlier timepoints."

"These data reinforce the potential of odanacatib as a novel treatment option for osteoporosis," he added.

The Phase IIB trial was a multi-centre, double-blind, randomized, placebo-controlled study involving 399 postmenopausal women with low BMD. Low BMD was defined as T-scores equal to or less than -2.0 but equal to or greater than -3.5. A T-score is the number of standard deviations away from the mean compared to a healthy person of the same age and sex.

The trial evaluated doses of 3, 10, 25 or 50 mg given orally, once a week for 24 months, "without regard to the timing of meals or the patient’s physical position", said Merck.

The participants were also given weekly doses of vitamin D (5600 IU) and for those with an average daily intake below 1,000 mg; they were also given 500 mg daily supplements of calcium carbonate.

The primary end point of the study was the mean change in BMD (using least squares) from baseline at the lumbar spine. Secondary endpoints included changes at the total hip, femoral neck, hip trochanter (part of the thigh bone at the hip joint), and distal forearm (the part that is furthest from the body), and changes in bone turnover based on biochemical markers.

After 24 months, the results showed that:

• Once-weekly treatment with 10, 25 and 50 mg of odanacatib significantly increased BMD at the lumbar spine, total hip and femoral neck compared to baseline.
• The 50 mg dose (58 patients) resulted in LS (least squares) mean per cent increases in BMD of 5.48 per cent at the lumbar spine compared to baseline.
• Treatment with placebo (61 patients) showed a decrease of 0.19 per cent compared to baseline (p<0.001).
• Similarly, the 50 mg dose resulted in LS mean per cent increases in BMD of 3.16 per cent at the total hip and 3.84 per cent at the femoral neck compared to baseline.
• Treatment with placebo resulted in decreases of 0.93 per cent at the total hip and 0.85 per cent at the femoral neck compared to baseline (p<0.001).
• Treatment with 3 mg odanacatib showed BMD decreases at the lumbar spine, total hip and femoral neck.
• For secondary endpoints, treatment with 50 mg of odanacatib resulted in biochemical marker decreases from baseline of 51.83 per cent in uNTx and 30.57 per cent in sCTx (p< 0.001).
• For placebo, changes in sCTx and uNTx were an increase of 32.77 per cent and a decrease of 4.62 per cent respectively.
• Treatment with 50 mg of odanacatib also led to reduced biochemical markers of new bone formation including s-BSAP (bone specific alkaline phosphatase) and sP1NP (serum N-terminal propeptides of type 1 collagen).
• For placebo, changes in biochemical markers of new bone formation were increases of 3.38 per cent for s-BSAP and 1.29 per cent for sP1NP.
• For safety results, the number of participants in the 50 mg dose group who experienced a drug related adverse event was similar to the number in the placebo group (34.6 and 39.8 per cent respectively).
• Discontinuation rates due to drug-related adverse events were also similar between the two groups (7.7 per cent for the 50 mg dose group and 4.8 per cent for the placebo group).
• The most common drug related adverse event in the 50 mg dose group were: nausea, headache, rash and muscle spasms. The investigators said there were "no dose-dependent increase in the incidence of skin adverse experiences or upper respiratory tract infections observed through 24 months".
  sCTx stands for serum C-terminal telopeptides of Type 1 collagen, and uNTx stands for urinary N-telopeptides/creatinine ratio.

Merck said that the Phase III is already under way and is investigating the effect of the 50 mg dose of odanacatib on vertebral, hip and non-vertebral fractures.

Osteoporosis affects more than 75 million people in the US, Europe, South America and Japan. 1 in 3 women over the age of 50 and 1 in 5 men have bone fractures due to osteoporosis, and according to figures from the International Osteoporosis Foundation (IOF), the worldwide rate of hip fracture is likely to rise 240 per cent in women and 310 per cent in men by 2050.

(Source: 30th Annual Meeting of the American Society for Bone and Mineral Research: Merck: September 2008)