艾替班特治疗HAE急性发作获准

Firazyr (通用名：艾替班特)注射剂获美国食品和药物管理局（FDA）批准治疗年龄≥18岁成人的一种罕见疾病——遗传性血管性水肿（HAE）的急性发作。

HAE是由于一种称为C1抑制剂的蛋白水平低或功能障碍引起的，这种蛋白涉及免疫系统的调节和凝血通路的功能。病人通常有该病的家族史。美国的HAE患者不到3万人。

HAE病人可出现手、足、四肢、面部、肠道、喉头或气管的快速水肿，这可能导致毁容、失能或死亡。消化道水肿可引起腹痛、恶心和呕吐，而呼吸道水肿则使病人有窒息的危险。

美国FDA药物评价与研究中心药物评价Ⅱ办公室主任Curtis Rosebraugh说：“Firazyr给治疗HAE急性发作提供了一个新选择，因其能通过在腹部注射自我给药，病人可在意识到HAE急性发作时自我治疗。”

Firazyr的安全性和有效性在3项对照临床试验（开放标签扩展期）中得到证实，试验中225例病人接受了1076剂30 mg的Firazyr。接受Firazyr治疗的病人至症状缓解的中位时间为2小时，而用安慰剂者接近20小时。

在美国Firazyr是获准用于治疗HAE发作的第三个药物。2009年10月，FDA批准Berinert治疗HAE的面部和腹部发作，2009年12月，Kalbitor获准用于治疗≥16岁病人的HAE急性发作。

FDA批准了Firazyr的病人用药指导，包括注射说明。Firazyr最常见的副作用是注射部位反应、发热、肝酶升高、眩晕和皮疹。

本品推荐剂量为一次性注射，若症状持续或复发，可在用药后6小时第2次注射。按需，可再过6小时第3次注射，但24小时内不可多于3剂。

FIRAZYR

Indication(s):

Treatment of acute attacks of hereditary angioedema (HAE).

Pharmacology:

Icatibant is a competitive antagonist selective for the bradykinin B2 receptor, with an affinity similar to bradykinin. Hereditary angioedema is caused by an absence or dysfunction of C1-esterase-inhibitor, a key regulator of the Factor XII/kallikrein proteolytic cascade that leads to bradykinin production. Bradykinin is a vasodilator which is thought to be responsible for the characteristic HAE symptoms of localized swelling, inflammation, and pain. Icatibant inhibits bradykinin from binding the B2 receptor and thereby treats the clinical symptoms of an acute, episodic attack of HAE.

Clinical Trials:

The efficacy and safety of Firazyr for the treatment of acute attacks of HAE in adults were studied in three controlled clinical trials. Response to therapy was primarily assessed using visual analog scores on a 100 mm scale and patient- and physician-reported symptom scores for abdominal and cutaneous pain and swelling.

Trial 1 was a randomized, placebo-controlled, double-blind, parallel-group study of 98 adult patients. Patients who had developed moderate-to-severe cutaneous or abdominal or mild-to-moderate laryngeal attacks of HAE were randomized to receive either Firazyr 30mg or placebo by SC injection. Patients with severe laryngeal attacks of HAE received open-label Firazyr 30mg. The primary endpoint was assessed using a 3-item composite visual analog score (VAS), comprised of averaged assessments of skin swelling, skin pain, and abdominal pain. Response was defined as at least a 50% reduction from the pretreatment composite 3-itemVAS score. The median time to 50% reduction in symptoms for patients with cutaneous or abdominal attacks treated with Firazyr (n=43) compared to placebo (n=45) was 2 hours versus 19.8 hours, respectively. Other evaluated endpoints included time to almost complete symptom relief (VAS<10 mm) and rescue medication use. In Trial 1, the median times to almost complete symptom relief were 8 versus 36 hours for Firazyr and placebo, respectively. In terms of rescue medication use, 3/43 (7%) patients treated with Firazyr used additional rescue medication in comparison to 18/45 (40%) patients treated with placebo.

In a second placebo-controlled trial and an active-controlled trial, a total of 26 and 35 patients, respectively, received Firazyr 30mg for the treatment of an acute HAE attack. Across the three trials, Firazyr had a median time to 50% reduction from baseline symptoms ranging from 2 to 2.3 hours.

In all three controlled trials, patients were eligible for treatment of subsequent attacks in an open-label extension. Patients were treated with Firazyr 30mg and could receive up to 3 doses of Firazyr 30mg administered at least 6 hours apart for each attack. A total of 225 patients were treated with 1,076 doses of 30mg Firazyr for 987 attacks of acute HAE in these trials. In an assessment of the first 5 Firazyr-treated attacks (621 doses for 582 attacks), the median times to a 50% reduction from the pretreatment composite 3-item VAS score were similar across attacks (2, 2, 2.4, 2, 1.5 hours). The majority (93%) of these attacks of HAE were treated with a single dose of Firazyr.

Legal Classification:

Rx

Adults:

≥18yrs: 30mg SC in abdominal area; may give additional doses at intervals of at least 6 hours if response inadequate or symptoms recur. Max 3 doses/24hrs.

Children:

<18yrs: not recommended.

Warnings/Precautions:

Advise patients to seek medical attention after treating laryngeal attack given the potential for airway obstruction. Elderly. Labor & delivery. Pregnancy (Cat.C). Nursing mothers.

Interaction(s):

May attenuate the antihypertensive effect of ACE inhibitors.

Adverse Reaction(s):

Inj site reactions, pyrexia, transaminase increase, dizziness, rash.

How Supplied:

Single-use prefilled syringe (3mL)—1, 3

Last Updated:

11/18/2011

遗传性血管水肿新药—艾替班特预填充注射剂(Firazyr,icatibant)

为了研究遗传性血管水肿（HAE）新药—艾替班特疗效和安全性。一项名为FAST-3的大型Ⅲ期试验，将88例中重度皮肤和（或）腹部症状的HAE在双盲期入组，而有严重喉头水肿的患者接受艾替班特治疗。第一次发作后，患者在后续病情发作中可以选择艾替班特治疗。

结果显示，与安慰剂相比，艾替班特能更快缓解症状；根据自评的复合症状得分降低50%所需时间评估，艾替班特组中位缓解症状所需时间为2.0h，而安慰剂组需要19.8h。而根据症状评分降低30%来判断；艾替班特中位所需时间为1.5h，而安慰剂组需要18.5h。研究显示，艾替班特能快速缓解疾病的临床症状。

遗传性血管水肿是罕见的由遗传缺陷引起的遗传性疾病，其特征是不可预知的手、脚、脸、喉头和腹部的发作性水肿和肿胀。喉部肿胀能导致窒息。另外，因为肠道肿胀患者经常会出现胃部严重疼痛，恶心和呕吐。

艾替班特是Jerini AG公司开发的特异性的肽模性缓激肽B2受体拮抗剂。早前艾替班特被美国FDA授予罕用药资格并已进入快速审批通道。