OREANDA-NEWS. November 11, 2015. Amgen (NASDAQ:AMGN) today presented the findings from a head-to-head Phase 3 study comparing intravenous etelcalcetide (AMG 416) with oral cinacalcet for the treatment of secondary hyperparathyroidism (SHPT) in adult patients with chronic kidney disease (CKD) receiving hemodialysis. The findings were presented today at the American Society of Nephrology (ASN) Kidney Week in San Diego.

The study met the primary endpoint of non-inferiority of etelcalcetide compared to cinacalcet, measured as the proportion of patients achieving a greater than 30 percent reduction from baseline in mean pre-dialysis serum intact parathyroid hormone (PTH) levels during the Efficacy Assessment Phase (EAP), defined as the period between weeks 20 and 27.

Etelcalcetide is a novel calcimimetic agent that suppresses the secretion of parathyroid hormone and is in clinical development for the treatment of SHPT in patients with CKD on hemodialysis. Etelcalcetide is administered intravenously three times per week at the end of each dialysis session. It 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 be associated with significant clinical consequences for patients with CKD.

In addition, etelcalcetide was superior to cinacalcet in the secondary endpoints of the proportion of patients achieving greater than 30 percent (68.2 percent versus 57.7 percent, p=0.004) and greater than 50 percent (52.4 percent versus 40.2 percent, p=0.001) reduction in PTH from baseline during the EAP. These differences were statistically significant. There was no difference between the treatment arms in the mean number of days of vomiting or nausea per week in the first eight weeks, another secondary endpoint.

"Treating SHPT in patients with chronic kidney disease on hemodialysis is associated with a number of challenges, and a high unmet need remains when it comes to the management of this complex disease," said

Sean E. Harper, M.D., executive vice president of Research and Development at Amgen. "We believe etelcalcetide has the potential to be an important new treatment option, and we look forward to working with regulatory authorities to bring this novel intravenous calcimimetic to market."

In the study presented at ASN, treatment-emergent adverse events (TEAEs) were reported in 92.9 and 90.0 percent of patients who received etelcalcetide and cinacalcet, respectively. TEAEs that were reported in greater than 10 percent of patients in either arm included (etelcalcetide versus cinacalcet, respectively): blood calcium decreased (68.9 and 59.8 percent), nausea (18.3 and 22.6 percent), vomiting (13.3 and 13.8 percent) and diarrhea (6.2 and 10.3 percent). TEAEs of hypocalcemia (symptomatic) were reported in 5.0 percent of patients who received etelcalcetide versus 2.3 percent in the cinacalcet group. Treatment-emergent events related to cardiac failure were reported in 3.0 percent of patients who received etelcalcetide versus 0.6 percent in the cinacalcet group. Serious adverse events were reported in 25.1 and 27.3 percent of patients who received etelcalcetide and cinacalcet, respectively. Fatal adverse events were reported in 2.7 percent for the etelcalcetide arm and 1.8 percent for the cinacalcet arm.

Amgen submitted data from the three Phase 3 studies of etelcalcetide as part of a New Drug Application (NDA) with the U.S. Food and Drug Administration (FDA) for the treatment of SHPT in patients with CKD on hemodialysis, which was accepted on Nov. 6, 2015. The FDA has set a Prescription Drug User Fee Act (PDUFA) target action date of Aug. 24, 2016. In addition, Amgen also submitted a Marketing Authorization Application (MAA) to the European Medicines Agency (EMA) via the centralized procedure for etelcalcetide for the treatment of secondary hyperparathyroidism (SHPT) in adult patients with chronic kidney disease (CKD) on hemodialysis therapy. If approved, etelcalcetide will be the first calcimimetic agent that can be administered intravenously.

Study Design
This was a randomized, active-controlled, double-blind, double-dummy study over 26 weeks that compared the efficacy and safety of etelcalcetide with cinacalcet for the treatment of SHPT in 683 patients with CKD receiving hemodialysis.

Patients randomized to treatment with etelcalcetide received intravenous (IV) doses of etelcalcetide three times per week at the end of each dialysis session and daily oral doses of placebo tablets. Subjects randomized to treatment with cinacalcet received daily oral doses of cinacalcet tablets and IV doses of placebo three times per week at the end of each dialysis session. Patients also received standard of care, which could include calcium supplements, vitamin D sterols and phosphate binders, if prescribed by the individual physician.

The primary endpoint was the proportion of patients with greater than 30 percent reduction from baseline in mean PTH levels during weeks 20 and 27, with the objective of demonstrating non-inferiority of etelcalcetide to cinacalcet.

Key and other secondary endpoints included the achievement of a greater than 30 percent and greater than 50 percent reductions from baseline PTH during the EAP, and the mean number of days of vomiting or nausea per week in the first eight weeks. Nausea or vomiting days were collected by the Nausea/Vomiting Symptom Assessment (NVSA) patient assessment daily questionnaires.

About Secondary Hyperparathyroidism
SHPT is a common and serious condition that is often progressive among patients with CKD, and it affects many of the approximately two million people throughout the world who are receiving dialysis, including 450,000 people in the U.S. The disorder develops early in the course of CKD and usually manifests as increased levels of parathyroid hormone (PTH) as a result of increased production from the parathyroid glands (four small glands in the neck).

Patients with end stage renal disease who require maintenance dialysis often have substantial elevations of PTH that are commonly associated with abnormal calcium and phosphorus levels and an increased risk of significant clinical consequences.

About Etelcalcetide (formerly AMG 416)
Etelcalcetide is a novel calcimimetic agent in clinical development for the treatment of SHPT in CKD patients on hemodialysis that is administered intravenously at the end of the dialysis session. Etelcalcetide binds to and activates the calcium-sensing receptor on the parathyroid gland, thereby decreasing PTH levels.

About Sensipar® (cinacalcet)
Sensipar® (cinacalcet) is the first oral calcimimetic agent approved by the FDA for the treatment of SHPT in adult patients with CKD on dialysis. Sensipar is not indicated for use in adult patients with CKD who are not on dialysis because of an increased risk of hypocalcemia. The therapy is also approved in the U.S. for treatment of hypercalcemia in adult patients with parathyroid carcinoma and hypercalcemia in adult patients with primary HPT for whom parathyroidectomy would be indicated on the basis of serum calcium levels, but who are unable to undergo parathyroidectomy. Sensipar binds to the calcium-sensing receptor, resulting in a drop in PTH levels by inhibiting PTH synthesis and secretion. In addition, the reductions in PTH lower serum calcium and phosphorus levels.

Important Safety Information
Sensipar® (cinacalcet) treatment initiation is contraindicated if serum calcium is less than the lower limit of the normal range (8.4 mg/dL).

Sensipar® lowers serum calcium; therefore, it is important that patients are carefully monitored for the occurrence of hypocalcemia. Life threatening events and fatal outcomes associated with hypocalcemia have been reported in patients treated with Sensipar®, including pediatric patients. Decreases in serum calcium can prolong the QT interval, potentially resulting in ventricular arrhythmia. Cases of QT prolongation and ventricular arrhythmia secondary to hypocalcemia have been reported in patients treated with Sensipar®.

Significant reductions in calcium may lower the threshold for seizures. Patients, particularly those with a history of seizure disorder, should be carefully monitored for the occurrence of low serum calcium or symptoms of hypocalcemia.

In Sensipar® postmarketing use, isolated, idiosyncratic cases of hypotension, worsening heart failure, and/or arrhythmia were reported in patients with impaired cardiac function. The causal relationship to Sensipar® therapy could not be completely excluded and may be mediated by reductions in serum calcium levels.

Adynamic bone disease may develop if intact parathyroid hormone (iPTH) levels are suppressed below 100 pg/mL. Patients with moderate to severe hepatic impairment should be monitored throughout treatment with Sensipar®, as cinacalcet exposure assessed by area under the curve (AUC) was higher than in patients with normal hepatic function. Patients with secondary HPT: Serum calcium and serum phosphorus should be measured within 1 week and PTH should be measured 1 to 4 weeks after initiation or dose adjustment of Sensipar®. Once the maintenance dose has been established, serum calcium and serum phosphorus should be measured approximately monthly, and PTH every 1 to 3 months. Patients with primary HPT or parathyroid carcinoma: Serum calcium should be measured within 1 week after initiation or dose adjustment of Sensipar®. Once maintenance dose levels have been established, serum calcium should be measured every 2 months. In clinical trials of patients with secondary HPT comparing Sensipar® to placebo, the most commonly reported side effects were nausea (31 percent vs. 19 percent), vomiting (27 percent vs. 15 percent), and diarrhea (21 percent vs. 20 percent). In clinical trials of patients with primary HPT and parathyroid carcinoma treated with Sensipar®, the most commonly reported side effects were nausea (63 percent), vomiting (46 percent), and paresthesia (20 percent).

Please see Full Prescribing Information.

About Amgen
Amgen is committed to unlocking the potential of biology for patients suffering from serious illnesses by discovering, developing, manufacturing and delivering innovative human therapeutics. This approach begins by using tools like advanced human genetics to unravel the complexities of disease and understand the fundamentals of human biology.

Amgen focuses on areas of high unmet medical need and leverages its biologics manufacturing expertise to strive for solutions that improve health outcomes and dramatically improve people's lives. A biotechnology pioneer since 1980, Amgen has grown to be one of the world's leading independent biotechnology companies, has reached millions of patients around the world and is developing a pipeline of medicines with breakaway potential. 

For more information, visit www.amgen.com and follow us on www.twitter.com/amgen.

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