2012年12月14日美国食品药品监督管理局(FDA)批准Signifor(pasireotide diaspartate)注射液为治疗不能通过手术得到帮助的库欣氏病患者。 库欣氏病是肾上腺制造的皮质醇激素过度生成引起。在垂体腺的肿瘤导致肾上腺过度刺激，它导致皮质醇过度生成. 皮质醇调节机体内许多重要功能，包括对应急和损伤的反应。有库欣氏病患者可能有体重，葡萄糖不能耐受或糖尿病，高血压，容易挫伤增加，和增加对感染风险。 在一项162例库欣氏病患者临床试验中评价Signifor的安全性和有效性。试验参加者被随机地选择两个剂量水平Signifor之一经历一个6个月治疗期。有些患者对药物安全反应允许基线治疗。Signifor导致历时24-小时期间采集尿中测定皮质醇水平减低。这个减低早达开始治疗后1个月见到。在临床试验中约20 %患者能减低尿皮质醇水平至正常范围。 Signifor引起血糖水平增高，可早在开始后2周后被检测到。在有些患者中继续治疗致或恶化糖尿病；因此，患者需要仔细监测这个副作用和用抗糖尿病治疗，包括胰岛素适当治疗。 FDA要求对Signifor三项上市后研究：一项临床试验评估高血糖处理；一项长期前瞻性观察队列研究用Signifor治疗有库欣氏病患者(注册)；和集中安全性监视严重高血糖，急性肝损伤，和肾上腺皮质功能不全。 Signifor是皮下给药每天2次，病发送用药指南，包括指导患者和护理人员描述使用产品时要记住的风险和不良反应。 在临床试验中观察到最常见不良反应包括高血糖，腹泻，恶心，腹痛，和胆结石。 Signifor是由瑞士，Stein的Novartis Pharma Stein AG，制造。 批准日期：2012年 12月14日；公司：Novartis Pharmaceuticals Corporation 库欣氏病[Cushing’s disease]新孤儿药物 美国FDA药物评价和研究中心代谢和内分泌产品部主任Mary Parks，M.D. 说：“尽管手术往往是治疗库欣氏病的一线治疗，对患者当手术不起作用或不是一种选择时Signifor是一种新的治疗选择。” FDA要求对Signifor三项上市后研究：一项临床试验评估高血糖处理；一项长期前瞻性观察队列研究用Signifor治疗有库欣氏病患者(注册)；和集中安全性监视严重高血糖，急性肝损伤，和肾上腺皮质功能不全。 请参阅下文SIGNIFOR的部份处方资料 美国初次批准：2012 作用机制 SIGNIFOR是一种可注射的环六肽生长抑素类似物。Pasireotide通过与生长抑素受体(ssts)结合发挥其药理学活性。已知5个人生长抑素受体亚型：hsst 1，2，3，4，和5。在正常生理情况下这些受体亚型在不同组织中表达。来自库欣氏病患者促肾上腺皮质激素肿瘤细胞经常过表达hsst5而常常不表达其他受体亚型或在低水平表达。Pasireotide结合和激活hsst受体导致ACTH分泌的抑制，导致皮质醇分泌减低。表2中显示内源性生长抑素和pasireotide的结合亲和力。 适应证和用途 SIGNIFOR是一个生长抑素类似物适用于有库欣氏病不选择垂体手术或手术为治愈成年患者的治疗。 剂量和给药方法 ● 推荐的初始剂量是或0.6 mg或0.9 mg皮下注射1天2次；推荐剂量范围是0.3 mg至0.9 mg 1天2次。 ●剂量根据治疗反应点滴调整[24-小时尿游离皮质醇(UFC)临床意义减低和/或疾病体征和症状改善]和耐受性。 ● 给药前测试：空腹血糖，血红蛋白A1c，肝检验，心电图(ECG)，和胆囊超声。 ● 肝受损患者： o Child Pugh B：推荐初始剂量是0.3mg 1天2次和最大剂量是0.6mg 1天2次。 o Child Pugh C：在这些患者中避免使用。 剂型和规格 注射：0.3mg/mL，0.6mg/mL，和0.9mg/mL在单剂量安瓿。 禁忌证 无。 警告和注意事项 ● 肾上腺皮质功能减退：可能发生皮质醇循环水平减低导致生化和/或临床肾上腺皮质功能减退。SIGNIFOR剂量减低或中断和/或增添低剂量短期糖皮质激素 ● 高血糖和糖尿病(岁开始发生)：建议强化血糖监测和可能需要开始或调整抗糖尿病治疗。 ● 心动过缓和QT延长：在风险患者中谨慎使用。给药前和用治疗测试ECG。 ● 肝检验升高：治疗前和期间评价肝检验。 ● 胆石病：开始治疗前和在6-个月间隔进行胆囊超声检验。 不良反应 最常见不良反应发生 ≥20%患者是腹泻, 恶心，高血糖，胆石病，头痛，腹痛，疲乏，和糖尿病。 药物相互作用 ● 延长QT药物：发生QTc延长显著风险患者中谨慎使用。 ● 环孢霉素[Cyclosporine]：考虑增加监测。 ●溴隐亭[Bromocriptine]：考虑溴隐亭剂量减低。 在特殊人群中使用 尚未确定18岁以下儿童中SIGNIFOR的安全性和有效性。 SIGNIFOR (pasireotide diaspartate)注射液 Signifor: new treatment for Cushing's disease 01 October 2012, 8:56amSignifor is the first targeted treatment for Cushing's disease, an endocrine disorder caused by excessive cortisol production resulting from an underlying pituitary tumour. PHARMACOLOGY Pasireotide is a novel cyclohexapeptide somatostatin analogue. It binds with high affinity to four of the five somatostatin receptor subtypes.1 Activation of these receptors on ACTH-secreting pituitary tumours inhibits the excessive production of ACTH that leads to the symptoms of Cushing’s disease. CLINICAL STUDIES The efficacy and safety of pasireotide in the treatment of Cushing’s disease were assessed in a randomised, double-blind phase III trial (n=162), involving adult patients with urinary-free cortisol (UFC) levels at least 1.5 times the upper limit of normal.2 Pasireotide was administered by subcutaneous injection twice daily. The primary endpoint was normalisation of UFC at six months, defined as a level at or below the upper limit of normal, with no prior dose increase. After six months, mean UFC levels had normalised in 14.6% (95% CI 7.0–22.3) of patients receiving pasireotide 600 microgram twice daily and in 26.3% (95% CI 16.6–35.9) of those receiving 900 microgram twice daily. The primary endpoint was therefore determined to have been met in the 900 microgram group.1,2 Decreases in blood pressure, BMI and total cholesterol were observed at six months in patients with both full and partial mean UFC control.1 Pasireotide was associated with hyperglycaemia-related adverse events in 73% of patients; other adverse effects were similar to those observed with other somatostatin analogues.2 Novartis is currently undertaking a phase III trial to evaluate a longer-acting form of pasireotide that only requires injection once a month. Signifor (SOM230 / Pasireotide) is a somatostatin analogue indicated for the treatment of patients with Cushing's disease for whom surgery has failed. The drug is developed and manufactured by Novartis. In April 2012, Signifor was approved by the European Commission (EC) for treating adult patients with Cushing's disease. About Cushing's Disease Cushing disease is an endocrine disorder caused by a tumour on the pituitary gland. It is a serious condition where the pituitary gland releases excessive adrenocorticotropic hormone (ACTH). It occurs due to excessive urinary-free cortisol (UFC) levels in the body, and affects adults aged between 20 and 50 years. Women are three times more likely to be affected than men. The disease is estimated to affect about 10 to 15 of every million people each year. Signifor's mechanism of action Signifor contains a somatostatin analogue. The drug works by activating somatostatin receptors in the pituitary adenoma, which results in inhibiting the excessive ACTH and lowering urinary-free cortisol (UFC) levels. The drug is available as a 0.6mg injection. Signifor clinical trial phases I and II Novartis conducted phase I clinical trials on Signifor between July 2008 and April 2009. It was an open label, interventional and single-group assignment which evaluated the safety and efficacy of Signifor. The study enrolled 34 patients. The primary outcome measure was determining the pharmacokinetic profile of a Signifor single dose injection. The secondary outcome measure was determining safety after a single Signifor injection. "The drug works by activating somatostatin receptors in the pituitary adenoma, which results in inhibiting the excessive ACTH and lowering urinary-free cortisol levels." Novartis conducted phase II clinical trials on Signifor in an open label, interventional and single-group assignment that enrolled 26 patients with Cushing's disease. The primary outcome measure was finding UFC after 15 days of treatment. The secondary outcome measures included safety, tolerability, ACTH, serum cortisol and pharmacokinetics. Phase III clinical trials on Signifor/Pasireotide The EU approval for Signifor was based on phase III clinical trial known as Pasport-Cushings. It was a prospective, randomised, double-blind study, conducted in 68 sites across 18 countries. The 12-month study evaluated the efficacy and safety of Signifor in 162 patients who were administered with a 900μg and 600μg injection twice a day. The study's results, announced in March 2012, showed that Signifor 900μg and 600μg drug doses normalised the mean UFC levels in the body by 26.3% and 14.6% respectively. The patients met the primary endpoint, normalisation of UFC, after six months. The study also demonstrated that the median reduction of mean UFC was 47.9% in both dose groups of the drug. The results further showed that Signifor reduced the manifestations of Cushing's disease, which included the blood pressure, total cholesterol, as well as weight and body mass index in twelve months. The most commonly reported adverse events for Signifor included nausea, hyperglycemia, diarrhea, diabetes mellitus, injection site reactions, abdominal pain and fatigue. Novartis initiated another phase III clinical trial on Signifor in November 2011. It is a randomised, double-blind, multicenter, phase III study which evaluates the efficacy and safety of Signifor in two dosing regimens of long acting release (LAR). The study enrolled 148 patients. The primary outcome measure of the study will include finding the proportion of responders in each of the two Signifor LAR regimens. The secondary outcome measure will include finding change in mean UFC from the base line and change in controlled mUFC. The results of the study are expected by January 2016. Marketing commentary Signifor is the only pituitary-targeting medicine available on the market for Cushing's disease. The drug is expected to capture a $90.8m market by 2019. A medication approved for the same indication is Korlym (mifepristone) which was developed by Corcept Therapeutics.