2012年1月20日，欧洲药品管理署（EMA）下属人用药品委员会（CHMP）建议批准治疗库欣（Cushing）病的新药Signifor[帕瑞肽(pasireotide)]，用于治疗不能手术的病人或手术失败病人。 库欣病是一种危及病人生命的罕见病，生长在垂体的肿瘤分泌大量促肾上腺皮质激素（ACTH），ACTH刺激肾上腺生长和分泌大量皮质醇，导致病人出现很多症状，包括体重增加（特别在面部和颈部），皮肤易擦伤，面部汗毛重，肌肉和骨骼变弱，血压升高。在欧盟国家，库欣病的发生率约为0.4/10000居民，大约有20000例病人。 库欣病的一线治疗是手术切除肿瘤。但手术不能治愈的病人现在没有批准的药物治疗方法。许多治疗库欣病的药属于超适应证使用，关于这些药的安全性和疗效资料不多。 建议批准Signifor[帕瑞肽(pasireotide)]治疗库欣病，是使欧洲病人可使用此药的第一步。帕瑞肽是一种生长抑素类似物，它与生长抑素受体给合后，可阻止ACTH的释放，从而降低血液中的皮质醇水平，减轻库欣病的症状。研究发现垂体肿瘤细胞有大量生长抑素受体。 临床研究证明，用900μg帕瑞肽，有41%的病人尿液中的皮质醇水平至少降低50%，用600μg帕瑞肽，有34%的病人尿液中的皮质醇水平至少降低50%。关于帕瑞肽的安全性，CHMP指出，帕瑞肽的安全性与欧洲已批准很多年的其他生长抑素类似物相似。产品资料建议医师监测病人的肝脏和心脏不良反应。CHMP认为采取这些预防措施后，帕瑞肽用作库欣病的二线治疗的好处大于危险，建议授权在欧洲使用帕瑞肽。 CHMP的建议已提交欧盟委员会，申请批准。2009年10月8日，帕瑞肽被指定为“孤儿药”。 Pharmacological Class: Cyclohexapeptide somatostatin analog. Active Ingredient(s): Pasireotide diaspartate 0.3mg/mL, 0.6mg/mL, 0.9mg/mL; soln for SC inj. Company Novartis Pharmaceuticals Corp Indication(s): Treatment of adult patients with Cushing’s disease for whom pituitary surgery is not an option or has not been curative. Pharmacology: Pasireotide exerts its activity via binding to somatostatin receptors (ssts). Five human somatostatin receptor subtypes are known: hsst 1, 2, 3, 4, and 5. These receptor subtypes are expressed in different tissues under normal physiological conditions. Corticotroph tumor cells from Cushing’s disease patients frequently over-express hsst5 whereas the other receptor subtypes are often not expressed or are expressed at lower levels. Pasireotide binds and activates the hsst receptors resulting in inhibition of ACTH secretion, which leads to decreased cortisol secretion. Clinical Trials: A Phase 3, multicenter, randomized study was conducted to eva luate the safety and efficacy of two dose levels of Signifor over a 6-month treatment period in Cushing’s disease patients with persistent or recurrent disease despite pituitary surgery or de novo patients for whom surgery was not indicated or who had refused surgery.   Patients with a baseline 24-hour urine free cortisol (UFC) >1.5 x upper limit of normal (ULN) were randomized to receive a Signifor dosage of either 0.6mg SC b.i.d. or 0.9mg SC b.i.d. After three months of treatment, patients with a mean 24-hour UFC ≤2.0 x ULN and below or equal to their baseline values continued blinded treatment at the randomized dose until Month 6. Patients who did not meet these criteria were unblinded and the dose was increased by 0.3mg b.i.d. After the initial 6 months in the study, patients entered an additional 6-month open-label treatment period. The dosage could be reduced by 0.3mg b.i.d. at any time during the study for intolerability. The primary efficacy endpoint was the proportion of patients who achieved normalization of mean 24-hour UFC levels after 6 months of therapy and did not dose increase during this period.   At Month 6, the percentages of responders for the primary endpoint were 15% and 26% in the 0.6mg b.i.d. and 0.9mg b.i.d. groups, respectively. The percentages of patients with mUFC ≤ ULN or ≥ 50% reduction from baseline, a less stringent endpoint than the primary endpoint, were 34% in the 0.6mg bid and 41% in the 0.9mg bid groups. Dose increases appeared to have minimal effect on 24-hour UFC response. The mean and median percentage changes in UFC from baseline were -22% and -47% in the 0.6mg b.i.d. group, and -42% and -46% in the 0.9mg b.i.d. group. Legal Classification: Rx Adults: Initially 0.6mg or 0.9mg by SC inj twice daily; usual range: 0.3mg–0.9mg twice daily. Titrate based on response and tolerability. Hepatic impairment: moderate (Child-Pugh B): initially 0.3mg twice daily; max 0.6mg twice daily; severe (Child-Pugh C): avoid. Children: <18years: not established. Warnings/Precautions: Monitor for hypocortisolism; consider temporary dose reduction, interruption or steroid replacement therapy if occurs. Diabetes: risk of hyperglycemia; initiate or adjust anti-diabetic treatment if occurs. Congenital long QT prolongation. Cardiac disease (including recent MI, CHF, unstable angina, significant bradycardia). High-grade heart block. Hypokalemia. Hypomagnesemia. Correct and monitor electrolytes prior to starting and during therapy. Hepatic impairment. Monitor baseline fasting plasma glucose, HbA1c, LFTs, ECG, gallbladder ultrasound, pituitary function prior to initiation and periodically during treatment. Pregnancy (Cat. C). Nursing mothers: not recommended. Interaction(s) Caution with anti-arrhythmics or other drugs that may prolong the QT interval. May antagonize cyclosporine (adjust dose). May potentiate bromocriptine; dose reduction may be needed. Adverse Reaction(s) Diarrhea, nausea, hyperglycemia, cholelithiasis, headache, abdominal pain, fatigue, diabetes; bradycardia, QT prolongation. How Supplied: Single-dose ampule—60 LAST UPDATED: 4/9/2013 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.