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2014年2月24日，美国FDA批准Myalept（注射用美曲普汀）作为替代治疗药物结合饮食用于治疗先天性或获得性全身脂肪代谢障碍患者的瘦素缺乏并发症。
全身脂肪代谢障碍是一种与脂肪组织缺乏有关的病症。先天性全身脂肪代谢障碍患者出生时很少或根本没有脂肪组织。获得性全身脂肪代谢障碍患者通常随着时间的推移失去脂肪组织。因瘦素在脂肪组织制造，所以全身脂肪代谢障碍患者的瘦素水平很低。瘦素调节进食及其它激素，如胰岛素。
患有两种形式全身脂肪代谢障碍的患者常常在很小年龄时出现严重的胰岛素抵抗，可能会有难以控制的糖尿病，或血液中含有能导致胰腺炎的高水平甘油三酯。“Myalept是首个获批用于治疗先天性或获得性全身脂肪代谢障碍有关综合症的治疗药物，它可以为患有这种孤儿病的患者提供一种需要的治疗选择，”FDA药物评价与研究中心药物评价II办公室副主任、医学博士Mary Parks说。
Myalept是通过基因重组技术制成的一种模拟瘦素，它的安全性和有效性通过一项开放式标签的单一试验研究获得评价，有48名先天性或获得性全身脂肪代谢障碍，同时患有糖尿病、高甘油三酯血症和/或高水平空腹胰岛素的患者参与了该项研究。试验显示患者糖化血红蛋白（一种血糖控制指标）、空腹血糖和甘油三酯均有降低。
对瘦素和/或Myalept有中和活性的抗药抗体可能会出现，可导致严重感染或治疗效果丧失。使用或未使用Myalept治疗的获得性全身脂肪代谢障碍患者中已有T细胞淋巴瘤报道，
所以卫生保健专业人员在使用Myalept治疗有明显血液学异常和/或获得性全身脂肪代谢障碍患者时应该认真考虑治疗的收益和风险。
Myalept被禁用于普通肥胖患者。Myalept未被批准在患有HIV相关脂肪代谢障碍患者或患有代谢性疾病（包括糖尿病和高甘油三酯血症、无并发证据的全身脂肪代谢障碍）的患者身上使用。
由于存在发生中和抗体和淋巴瘤的风险，所以Myalept只能通过Myalept风险评估及降低策略(REMS)计划获得。根据REMS计划，开药者必须参加并完成培训以获得认证。
药房必须获得该计划的认证，并在收到用于每个新处方的Myalept REMS处方授权书之后才能分发Myalept。Myalept获批时也带有一份用药指南和说明，以提供患者有关这款药物的重要信息。该指南在患者每次申请处方时一并分发。
FDA要求对Myalept进行7项上市后研究，包括一项长期的Myalept用药患者前瞻性观察研究，一项评价Myalept免疫原性（抗体形成）的研究和一项有关Myalept使用潜在严重风险自发报告的评价和分析。8项其它研究被要求作为上市后的承诺。在临床试验中，Myalept治疗患者最常见的副作用有低血糖、头痛、体重减轻和腹痛。Myalept由位于圣地亚哥的Amylin制药上市销售。
批准日期: 2014年2月24日；公司: Amylin Pharmaceuticals, Inc.
MYALEPT Rx
Pharmacological Class:
Recombinant human leptin analog.
Active Ingredient(s):
Metreleptin 11.3mg; per vial; lyophilized pwd for SC inj after reconstitution (with BWFI or WFI).
Company
Bristol-Myers Squibb and AstraZeneca
Indication(s):
Adjunct to diet as replacement therapy to treat leptin deficiency complications in patients with congenital or acquired generalized lipodystrophy. Limitations of Use: Safety and efficacy for treating partial lipodystrophy complications, or liver disease, including nonalcoholic steatohepatitis (NASH) have not been established. Not for use in HIV-related lipodystrophy or metabolic disease, including diabetes mellitus and hypertriglyceridemia, without concurrent evidence of congenital or acquired generalized lipodystrophy.
Pharmacology:
Metreleptin exerts its function by binding to and activating the human leptin receptor (ObR), which belongs to the Class I cytokine family of receptors that signals through the JAK/STAT transduction pathway.
Clinical Trials:
Myalept was eva luated in an open-label, single-arm study for treatment of patients with congenital or acquired generalized lipodystrophy and diabetes mellitus, hypertriglyceridemia, and/or increased fasting insulin.
Among the 48 patients enrolled, 32 had congenital generalized lipodystrophy and 16 had acquired generalized lipodystrophy. Myalept was administered SC either once or twice daily for a median treatment duration of 2.7 years (range: 3.6 months–10.9 years). The weighted average daily dose for patients >40kg at baseline was 3.2mg (males) and 6.3mg (females) over the entire study period. For the 12 patients <40kg at baseline, the weighted average daily dose was 0.06–0.11mg/kg over the entire study period.
Patients treated with Myalept had mean/median reductions in HbA1c (−2%), fasting glucose (−49mg/dL), and triglycerides (−184mg/dL [−55%]) at Month 12 from baseline. The changes in HbA1c, fasting glucose, and triglycerides observed at Month 4 were similar to those at Month 12.
Patients with baseline HbA1c ≥7% (n=28) showed a 2.4% mean reduction at Month 12. Patients with baseline triglyceride ≥500mg/dL (n=12) showed a 1,117mg/dL median reduction at Month 12.
Legal Classification:
Rx
Contraindication(s):
General obesity not associated with congenital leptin deficiency.
Adults & Children:
Administer by SC injection same time every day into the abdomen, thigh or upper arm. Rotate injection sites. Dose may be decreased or increased based on clinical response. ≤40kg (males and females): initially 0.06mg/kg once daily; may adjust in 0.02mg/kg increments to max 0.13mg/kg/day. >40kg: initially 2.5mg (males) or 5mg (females) once daily; may adjust in 1.25–2.5mg/day increments to max 10mg/day. If discontinuing therapy in patients with pancreatitis risk, taper dose over one-week period, monitor triglyceride levels and consider initiating or adjusting dose of lipid-lowering drugs as needed.
Warnings/Precautions:
Risk of developing anti-metreleptin neutralizing antibodies; test for antibodies if severe infections or loss of efficacy occurs. Carefully consider the benefits and risks of treatment in patients with significant hematologic abnormalities and/or acquired generalized lipodystrophy. Risk of hypoglycemia; monitor blood glucose in patients on concomitant insulin or insulin secretagogue. Autoimmune disease. Neonates and infants: use preservative-free sterile WFI to reconstitute. Elderly. Pregnancy (Cat. C). Nursing mothers: not recommended.
Interaction(s)
May affect CYP450 substrates (eg, oral contraceptives). Drugs with narrow therapeutic index (eg, warfarin, cyclosporine, theophylline); monitor and adjust dose as needed upon initiation or discontinuation of metreleptin. Concomitant insulin or insulin secretagogue (eg, sulfonylurea); adjust and reduce dose of insulin/insulin secretagogue as needed.
Adverse Reaction(s)
Headache, hypoglycemia, decreased weight, abdominal pain; hypersensitivity (discontinue if occurs), lymphomas, progression of autoimmune disorders, possible antibody formation.
Notes:
Available only through the Myalept REMS Program. Call (855) 6MYALEPT to enroll.
How Supplied:
Vial—1
LAST UPDATED:
5/2/2014
http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm387060.htm |
