Molecule of the Month
Cinacalcet hydrochloride (AMG-073) is a calcimimetic agent that has proven effective in the treatment of secondary hyperparathyroidism, a common complication of chronic kidney disease. The drug increases the sensitivity of the calcium receptor in the parathyroid gland to extracellular calcium and thereby reduces the levels of parathyroid hormone (PTH). It is currently undergoing phase III trials at Amgen, which is developing the drug under license from NPS Pharmaceuticals. Amgen plans to file an NDA for cinacalcet hydrochloride during the second half of 2003.
Several presentations at the World Congress of Nephrology (June 2003, Berlin) supported the excellent therapeutic activity and long-term efficacy of cinacalcet in patients with secondary hyperparathyroidism. A randomized, double-blind clinical trial that enrolled 33 patients with baseline serum PTH levels of 300 pg/ml and above despite standard treatment established that doses of up to 50 mg/day of cinacalcet for one year reduced the mean serum PTH levels by 23%. In an open-label extension of the same study, all 33 patients received up to 180 mg/day of cinacalcet for two years. After 12 weeks of treatment, patients originally randomized to receive placebo had 43% and 16% reductions in their serum levels of PTH and calcium x phosphorus product, respectively. At the end of the study, patients treated with cinacalcet for three years showed serum PTH levels 30% lower compared to baseline, suggesting that long-term treatment with cinacalcet does not reduce the drug's therapeutic effects. The most common adverse event reported throughout the trials was asymptomatic hypocalcemia.
Four phase II clinical trials included 297 hemodialysis patients with uncontrolled secondary hyperparathyroidism unresponsive to standard therapies and randomized them to receive placebo or cinacalcet at doses of up to 180 mg/day. Cinacalcet dose-dependently reduced the plasma levels of PTH, and these effects were associated with an 8-13% decrease in the levels of calcium x phosphorus product. The percentage of patients who reached a mean PTH level of 250 pg/ml or less was higher with cinacalcet than with placebo in all four trials, and the differences between treatments were significant at drug doses of at least 100 mg/day. Cinacalcet was well tolerated and no significant differences were found in the safety profiles.
Efficacy was also maintained in a single-center clinical trial that evaluated cinacalcet for three years in five patients with secondary hyperparathyroidism, with a 64% reduction in the patients' serum PTH levels compared to baseline. The authors also found reductions in the serum levels of bone-specific alkaline phosphatase, which might indicate a normalization of the bone formation rate. The transient asymptomatic hypocalcemia detected in some patients was easily controlled by increasing the dose of calcium carbonate or vitamin D sterols.
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