2012年4月25日，欧委会批准Signiror用于治疗无法手术或手术治疗失败的成人库欣病患者。库欣病是由于垂体肿瘤大量分泌促肾上腺皮质激素（ACTH）导致肾上腺皮质醇过量分泌而引起的疾病。Signifor为一种生长激素抑制剂类似物，可通过与其受体结合抑制ACTH的释放从而减少皮质醇分泌。
SIGNIFOR
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 evaluate 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
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”。
