安进甲旁亢新药AMG416 III期临床实现三连胜，头对头研究轻松击败Sensipar

美国生物技术巨头安进（Amgen）研发的继发性甲旁亢（SHPT）药物AMG416 III期临床项目实现圆满成功。根据该公司消息，在一项头对头III期研究中，AMG416轻而易举地击败了自身已上市产品Sensipar（cinacalcet，西那卡塞）。该项研究的成功，也标志着AMG416 III期临床取得了三连胜。业界对AMG416十分看好，认为该药将成为安进管线中又一枚重磅产品，年销售额将超过10亿美元。

该头对头研究（Study 20120360）是AMG416 III期项目的最后一个研究，在683例正接受血液透析治疗的慢性肾脏病（CKD）患者中开展，评估了AMG 416治疗继发性甲状旁腺功能亢进（SHPT）的疗效和安全性，并与上市药物Sensipar进行了对比；主要终点为疗效评估阶段（EAP，定义为20-27周），2个治疗组实现甲状旁腺激素（PTH）水平从基线下降幅度≥30%的患者比例。研究数据证明了AMG416相对于Sensipar的非劣效性（68.2% vs 57.7%），达到了研究的主要终点。此外，与Sensipar治疗组相比，AMG416治疗组有更高比例的患者实现PTH水平降幅≥50%（52.4% vs 40.2%），达到了研究的次要终点。在另一个次要终点（每周呕吐或恶心平均天数）方面，2个治疗组无差异。

这些数据，加上此前已公布的2项安慰剂对照III期临床数据，进一步加强了AMG416有效治疗血液透析患者继发性甲状旁腺功能亢进（SHPT）的临床证据。不过，AMG416也不是没有副作用。临床研究中，AMG416治疗组血钙下降及恶心不良事件发生率高于安慰剂组，但安慰剂组严重不良事件发生率更高。此次头对头研究中，AMG416的安全性数据与Sensipar相似。

继发性甲状旁腺功能亢进（SHPT，简称继发性甲旁亢），是指在慢性肾功能不全、肠吸收不良综合征、Fanconi综合征和肾小管酸中毒、维生素D缺乏或抵抗以及妊娠、哺乳等情况下，甲状旁腺长期受到低血钙、低血镁或高血磷的刺激而分泌过量的PTH，以提高血钙、血镁和降低血磷的一种慢性代偿性临床表现，长期的甲状旁腺增生最终导致形成功能自主的腺瘤。

AMG416是一种新颖的拟钙剂（calcimimetic agent），该药通过静脉给药，开发用于正接受血液透析治疗的慢性肾脏病（CKD）患者。AMG416结合并激活对甲状旁腺上的钙敏感受体，从而导致实现甲状旁腺激素（PTH）水平的降低。

英文原文：

Amgen Announces Positive Results From Head-To-Head Study Comparing The Efficacy And Safety Of AMG 416 With Cinacalcet In Patients With Secondary Hyperparathyroidism Receiving Hemodialysis

Third Phase 3 Study Met Non-Inferiority and Superiority Endpoints in the Reduction of Parathyroid Hormone

THOUSAND OAKS, Calif., Feb. 25, 2015 /PRNewswire/ -- Amgen (AMGN) today announced results from the head-to-head Phase 3 study comparing AMG 416 with cinacalcet for the treatment of secondary hyperparathyroidism (SHPT) in patients with chronic kidney disease (CKD) receiving hemodialysis. The study met the primary endpoint of non-inferiority of AMG 416 compared to cinacalcet, measured as the achievement of 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.

Further, AMG 416 was statistically significantly superior to cinacalcet in the secondary endpoints of the proportion of patients achieving greater than 50 percent (52.4 percent versus 40.2 percent) and greater than 30 percent (68.2 percent versus 57.7 percent) PTH reduction from baseline during the EAP. 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.

"These findings, combined with results from two positive placebo-controlled studies of more than 1,000 patients, add to the growing body of evidence that reinforce the promise of AMG 416 for hemodialysis patients with secondary hyperparathyroidism," said Sean E. Harper, M.D., executive vice president of Research and Development at Amgen. "The management of this disease in patients with chronic kidney disease is a complex process, and at Amgen, we are committed to building upon our leadership in nephrology to provide patients with an innovative therapy that can be administered intravenously along with hemodialysis."

Treatment-emergent adverse events (TEAEs) were reported in 92.9 and 90.0 percent of patients who received AMG 416 and cinacalcet, respectively. TEAEs that were reported in greater than 10 percent of patients in either arm included (AMG 416 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 AMG 416 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 AMG 416 versus 0.6 percent in the cinacalcet group. Serious adverse events were reported in 25.1 and 27.3 percent of patients who received AMG 416 and cinacalcet, respectively. Fatal adverse events were reported in 2.7 percent for the AMG 416 arm and 1.8 percent for the cinacalcet arm.

Study Design
This was a randomized, active-controlled, double-blind, double-dummy study (study number 20120360) over 26 weeks that compared the efficacy and safety of AMG 416 with cinacalcet for the treatment of SHPT in 683 patients with CKD receiving hemodialysis.

Patients randomized to treatment with AMG 416 received intravenous (IV) doses of AMG 416 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 PTH levels during weeks 20 and 27, with the objective of demonstrating non-inferiority of AMG 416 to cinacalcet.

Key and other secondary endpoints included the achievement of a greater than 50 percent reduction from baseline in mean pre-dialysis serum intact PTH during the EAP, achievement of a greater than 30 percent reduction from baseline in mean pre-dialysis serum intact PTH during the EAP, and the mean number of days of vomiting or nausea per week in the first eight weeks. Nausea or vomiting 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. 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 in an effort to maintain normal levels of calcium and phosphorus. Ultimately, excess PTH production proves inadequate for maintaining normal serum calcium and phosphorus levels. When kidney disease progresses to the point where dialysis is needed to sustain life, SHPT manifests as abnormal PTH, calcium and phosphorus levels that, in turn, can lead to significant clinical consequences.

About AMG 416
AMG 416 is a novel calcimimetic agent in Phase 3 clinical development for the treatment of SHPT that is administered intravenously in patients with CKD who are receiving hemodialysis. AMG 416 binds to and activates the calcium-sensing receptor on the parathyroid gland, thereby decreasing serum intact PTH levels.