Amgen has released pooled data from two pivotal phase III, global, randomized, placebo-controlled trials evaluating AMG 416, a novel calcimimetic, for the treatment of secondary hyperparathyroidism (SHPT) in patients with chronic kidney disease (CKD) receiving hemodialysis. Both studies met the primary endpoint, demonstrating that a greater proportion of patients in the AMG 416 groups achieved a greater than 30% reduction in parathyroid hormone (PTH) during the efficacy assessment phase compared with placebo.

"Secondary hyperparathyroidism is a complex and challenging condition that can be difficult to manage, as it may require patients to take demanding drug regimens multiple times a day," said John Cunningham, lead author of the studies, professor of nephrology at the University College London Medical School and consultant physician at The Royal Free Hospital, London. "Providing patients with CKD on hemodialysis with a calcimimetic that can be administered intravenously on the same schedule as dialysis has the potential to fulfill an unmet need in this patient population."

AMG 416 is a novel calcimimetic agent in clinical development for the treatment of SHPT in patients with CKD who are receiving hemodialysis. In the registrational programs, AMG 416 is administered intravenously at the end of dialysis. AMG 416 acts by binding to and activating the calcium-sensing receptor on the parathyroid gland, thereby causing decreases in PTH. Sustained elevations in PTH are known to lead to significant clinical consequences for patients with CKD.

In the two phase III placebo-controlled studies, an aggregate of 1,023 patients with moderate-to-severe SHPT (PTH greater than 400pg/mL) on hemodialysis were randomized to receive intravenous AMG 416 or placebo three times a week. The primary endpoint of both studies was the proportion of patients achieving greater than 30% reduction in PTH during the efficacy assessment phase, defined as weeks 20 through 27. Secondary endpoints included the proportion of patients with PTH less than or equal to 300pg/mL, and percent reductions in PTH, albumin adjusted calcium (cCa), phosphate (P) and cCa x P. In the AMG 416 group, 74.7% of patients achieved a greater than 30% reduction from baseline in PTH compared with 8.9% in the placebo arm.

Furthermore, a statistically significant proportion of patients (51.5%) randomized to receive AMG 416 achieved PTH less than or equal to 300pg/mL, compared with 5.9% in the placebo-controlled group, despite similar baseline mean PTH values of 724pg/mL and 716pg/mL, respectively. Significant reductions in phosphate as well as fibroblast growth factor 23 (FGF23) were also observed, with two-thirds of AMG 416-treated patients experiencing a greater than 30% reduction in FGF23 concentrations compared with 30% of placebo-treated patients.

Reductions in serum calcium were observed and symptomatic hypocalcemia occurred more frequently in patients treated with AMG 416 compared to placebo (7% v. 0.2%, respectively). Additional adverse events included muscle spasms and gastrointestinal symptoms (e.g. nausea and vomiting), and they were reported more frequently with AMG 416 compared with placebo. Rates of death, adjudicated major non-fatal cardiovascular events and seizures were similar in both groups.

"These positive pivotal data further underscore the potential of AMG 416 in reducing parathyroid hormone concentrations, and ultimately, in helping treat patients impacted by this challenging disease," said Sean E. Harper, M.D., executive vice president of R&D at Amgen. "We are excited to build on our leadership in nephrology and help provide patients with chronic kidney disease on hemodialysis with a new therapeutic option."

There were two 26-week, randomized, double-blind, placebo-controlled studies (study numbers 20120229 and 20120230) that evaluated the efficacy and safety of AMG 416 for the treatment of SHPT in a total of 1,023 patients with CKD receiving hemodialysis. Patients received AMG 416 or placebo three times per week by intravenous injection at the end of each hemodialysis treatment. Doses ranged from a minimum of 2.5mg to a maximum of 15mg. Patients also received standard of care which could include calcium supplements, vitamin D sterols and phosphate binders, if prescribed by the individual physician.

SHPT is a common and serious condition that often is progressive among patients with CKD, and it affects many of the approximately two million people throughout the world who are receiving dialysis. The disorder develops early as an adaptive response to declining kidney function when the parathyroid glands (four small glands in the neck) increase the production of PTH. When kidney disease progresses to the point where dialysis is needed to sustain life, SHPT usually manifests as elevated PTH and an abnormal calcium and phosphorus balance that can lead to significant clinical consequences.