首个获批的新药Evenity（romosozumab）即将上市。Evenity是一种全人源化单抗，通过抑制骨硬化蛋白（sclerostin）的活性发挥作用。Evenity是一种骨形成剂，具有双重作用，既能增加骨形成，又能减少骨吸收，从而增加骨密度（BMD），降低骨折风险。

  2019年1月9日，日本厚生劳动省批准了安进和UCB共同开发的EVENITY™ (通用名romosozumab)、用于骨折高危老年男性和绝经后女性的骨质疏松治疗。这个批准是根据两个分别叫做Frame和Bridge的三期临床结果，前者招募7180位绝经女性、后者招募245位老年男性。另一个与Fosamax比较的三期临床ARCH提供了部分安全性数据。这个产品在日本由安进与安斯泰来的一个生物制药合资公司（AABP）开发，这是该公司上市的第三个新药。EVENITY在美国和欧洲上市申请正在评审中。
  [药源解析]
  日本是世界最长寿国家，与其它国家比骨质疏松当然也是更为严重的问题。据估计日本有1200万骨质疏松患者，骨折是生活自理的最大障碍之一。骨折不仅因患者活动受限影响生活质量、也可能造成内出血等严重后果，直接增加死亡率。当然日本审批相对宽松，虽然黑色素瘤可能比欧美发病率略低、但当年率先批准了第一个PD-1药物Opdivo。
  EVENITY是第一个既抑制骨组织再吸收也加快骨组织形成的骨质疏松药物，是一个叫做硬皮蛋白（sclerostin）信号分子的抗体。现在已经完成三个三期临床试验，基本达到主要临床终点。但去年申请在美国上市被拒，具体信息没有公布。早期数据显示硬皮蛋白只有骨细胞分泌，但过去几年发现心脏组织也对这个信号蛋白应答，降低组织钙化速度。在ARCH试验中，使用1年Romo、一年Fosamax比使用两年Fosamax显著降低各类骨折，但增加30%心血管风险，这可能是FDA担心的地方。今天厂家特别提到日本药监部门仔细研究了这个产品的安全性、包括ARCH试验数据。
  EVENITY是安进产品线中最重要产品之一，除了其机理的独特性（同时抑制骨重吸收和促进骨生产）目前也无同机理竞争产品在晚期临床，时间上有较大优势。但现在市场上已有若干骨质疏松药物、包括Radius前年上市的甲状旁腺素相关蛋白类似物Tymlos（通用名abaloparatide），所以竞争还是存在的。除了ARCH试验中的安全性问题，EVENITY在FRAME试验中错过一个二级终点（非脊柱骨折）、疗效也不是滴水不漏。当然只靠日本市场是不够的，这个产品必须在欧美上市才能成为大药。
EVENITY™ (romosozumab) receives approval in Japan for the treatment of osteoporosis in patients at high risk of fracture
Amgen and UCB announced that the Japanese Ministry of Health, Labor and Welfare has granted a marketing authorization for Evenity (romosozumab) for the treatment of osteoporosis in patients at high risk of fracture. Amgen and UCB are co-developing Evenity worldwide, with development in Japan being led by Amgen Astellas BioPharma K.K, a joint venture between Amgen and Astellas Pharma Inc., headquartered in Tokyo.
"The approval of Evenity in Japan is a significant milestone that reinforces our commitment to bringing effective treatments to the millions of patients who suffer from osteoporosis," said David M. Reese, M.D., executive vice president of research and development at Amgen. "A patient with a prior osteoporotic fracture is twice as likely to suffer another fracture if left undiagnosed and without appropriate treatment. With this approval, physicians in Japan now have a new medicine to help patients reduce their risk of fracture."
Evenity is a bone forming agent that both increases bone formation and reduces bone resorption to increase bone mineral density (BMD) and reduce the risk of fracture. The approval is based on results from two pivotal phase 3 studies: FRAME, which included 7,180 postmenopausal women with osteoporosis, and BRIDGE, which included 245 men with osteoporosis. The Japanese Pharmaceuticals and Medical Devices Agency undertook a thorough review of the safety profile of Evenity, including the cardiovascular safety findings in the ARCH trial.
"In Japan, osteoporotic fracture is one of the leading causes for patients losing independence and needing nursing care. As the aged population of Japan increases, preventing such fractures should be given high priority," said Steve Sugino, Amgen vice president and president and representative director of AABP. "Japanese patients will be the first in the world to have a new therapeutic option for osteoporosis that reduces the risk of fracture by not only increasing bone formation but also decreasing bone resorption."
"Patients with a prior fracture face the risk of having another fracture and particularly stand to benefit from the option of a new bone-forming agent," said Toshio Matsumoto, MD, PhD, emeritus professor of Tokushima University and the advisor of the university's Fujii Memorial Institute of Medical Sciences. "Physicians have been waiting for a new therapeutic option. I have great hope that the approval of Evenity will help reduce the fracture risk for patients in Japan."
Japan has one of the longest life expectancy rates in the world, and it is believed that by 2050, over 37 percent of the population will be aged 60 or older. Age is one of the most common risk factors associated with developing osteoporosis, as bone mass is lost over time.Today, the prevalence of osteoporosis in the country is around 12 million, and the hip fracture incidence rate in the population over 75 is increasing dramatically in both men and women.
"With one of the longest life expectancy rates in the world, Japan is a country of longevity, but this means that the rate of osteoporosis will increase, leaving many people at high risk for fracture due to the condition," said Dr Pascale Richetta, head of bone and executive vice president, UCB. "We are proud that Evenity is now approved as a new treatment to help address this important public health issue and help people with their osteoporosis."
This is the first approval for Evenity in the world, and the third approval of a new medicine through AABP.
FRAME (FRActure Study In Postmenopausal WoMen With OstEoporosis) is a randomized, double-blind, placebo-controlled study that evaluated 7,180 postmenopausal women with osteoporosis. The study evaluated the effectiveness of Evenity treatment (210 mg), compared with placebo, in reducing the risk of new vertebral fractures through 12 months. The study also evaluated the effectiveness of treating with Evenity for 12 months followed by denosumab for 12 months, compared with placebo followed by denosumab, in reducing the risk of new vertebral fractures through 24 months.
ARCH (Active-ContRolled FraCture Study In Postmenopausal Women With Osteoporosis At High Risk Of Fracture) is a randomized, double-blind, alendronate-controlled study of Evenity in 4,093 postmenopausal women with osteoporosis at high risk for fracture based on previous fracture history. The study evaluated 12 months of Evenity treatment (210 mg) followed by at least 12 months of alendronate treatment (70 mg), compared with alendronate treatment alone, to determine effectiveness in reducing the incidence of clinical fracture (non-vertebral fracture and clinical vertebral fracture) and new vertebral fracture.
BRIDGE (PlaceBo-ContRolled Study EvaluatIng The Efficacy AnD Safety Of Romosozumab In TreatinG MEn With Osteoporosis) is a randomized, double-blind, placebo-controlled study of 245 men aged 55-90 years with osteoporosis and a history of fragility fracture (excluding hip fracture) or vertebral fracture. The study evaluated the effectiveness of Evenity treatment for 12 months, compared with placebo, in increasing BMD at the lumbar spine and the effect on BMD at the femoral neck and total hip.
Worldwide, one in three women and one in five men, over the age of 50, will suffer a fragility fracture due to osteoporosis and with an aging population these numbers will rise.Yet despite this, we are currently seeing a large gap in the management and treatment of osteoporosis, especially in the post-fracture setting, with an estimated four out of five patients remaining undiagnosed and untreated after a fracture. Without proper care or access to effective intervention options, they remain at risk of painful and disabling fractures in the future.
Evenity is an bone-forming monoclonal antibody approved in Japan.. It is designed to work by inhibiting the activity of sclerostin, which enables Evenity to both rapidly increase bone formation and reduce bone resorption simultaneously. Evenity has been studied for its potential to reduce the risk of fractures in an extensive global Phase 3 program. This program included two large fracture trials comparing Evenity to either placebo or active comparator in more than 10,000 postmenopausal women with osteoporosis. Amgen and UCB are co-developing Evenity.
https://www.astellas.com/system/files/news/2019-01/190109_1_Eg.pdf