欧盟批准德国Jerini公司的主导药物缓激肽拮抗药艾替班特预填充注射剂（Icatibant，Firazyr）上市，用于治疗遗传性血管水肿（HAE）急性发作。HAE是退行性病变有可能威胁生命的遗传性疾病，特征是自发和复发性水肿。
2001年开始研发的本品是该类新化合物中的第1个，作为肽类激素缓激肽的拮抗剂通过阻断B2受体发挥作用。HAE患者体内的缓激肽浓度升高，HAE发作时形成水肿。欧洲药品管理局（EMEA）和美国FDA已批准艾替班特作为罕用药物对症治疗血管水肿的急性发作，并分别给予10年和7年的市场专卖权。本品迄今在临床研究中显示对患者治疗安全有效。本品皮下注射，以预填充注射器包装，室温稳定。

本品对皮肤和腹部血管水肿患者进行了2项重要的临床研究。第1项研究纳入74例患者，比较本品与另1种治疗此种疾病的氨甲环酸的作用；第2项研究56例患者，比较本品与安慰剂的作用。结果表明，本品控制症状较氨甲环酸和安慰剂有效。在这2项研究中，本品组改善患者症状的时间较氨甲环酸组和安慰剂组缩短，分别为2.0～2.5小时、12.0小时和4.6小时。

本品最常见的不良反应是红肿，温热感，灼热，瘙痒，疼痛。

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。

HAE是可能危及生命的遗传性疾病，患病率为1:10000到1:50000。疾病的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。这种疾病由遗传缺陷引起，从父辈传给子女。

Efficacy and Favourable Safety Profile of Firazyr (icatibant) for the Treatment of Hereditary Angioedema attacks

Results from two Phase III studies of Firazyr published recently in the New England Journal of Medicine demonstrate the efficacy and favourable safety profile of icatibant for the treatment of Hereditary Angioedema (HAE) attacks.

The FAST-1 and FAST-2 studies

The FAST-1 and FAST-2 studies were double-blind randomised multicenter trials designed to evaluate the effect of icatibant in adult patients with type I or type II HAE presenting with cutaneous and/or abdominal attacks.

In the FAST-2 study, 74 patients received either 30mg subcutaneous icatibant or 3g oral tranexamic acid daily for 2 days. In the FAST-1 study, 56 patients received either 30mg icatibant or placebo.

The primary efficacy end point for both studies was median time to onset of clinically significant symptom relief.

Secondary efficacy end points included the median times to first improvement of the index symptom according to the patient and according to the investigator and the median time to almost complete relief of symptoms.

In addition, a further 11 patients with laryngeal symptoms (8 in FAST-1 and 3 in FAST-2) were treated with open-label 30mg subcutaneous icatibant.

Relief from abdominal pain, cutaneous pain or cutaneous swelling

Quicker onset of symptom relief with icatibant than tranexamic acid

• The FAST-2 study demonstrated that the median time to onset of clinically significant symptom relief was significantly shorter for icatibant versus tranexamic acid (2.0 hours vs. 12.0 hours; p<0.001).
• Median time to first symptom improvement from abdominal pain, cutaneous pain or cutaneous swelling was significantly shorter for icatibant than for tranexamic acid according to both the patient (0.8 hours vs. 7.9 hours; p<0.001) and the investigator (1.5 vs. 6.9 hours; p<0.001).
• Icatibant also showed a significant difference in median time to almost complete symptom relief versus the tranexamic acid (10.0 hours for icatibant vs 51.0 hours for tranexamic acid (p<0.001).

First symptom improvement quicker with icatibant than placebo

• In the FAST-1 trial, the primary end point of median time to onset of clinically significant symptom relief was 2.5 hours for patients given icatibant and 4.6 hours for patients given placebo, a difference that was not statistically significant (p=0.14). The lack of significance for the primary endpoint may be attributed to the stringent definition of that endpoint in particular the inclusion of patients who received rescue medication in the analysis and the specification that only one symptom be assessed in defining symptom relief.
• However, median time to first symptom improvement from abdominal pain, cutaneous pain or cutaneous swelling was significantly shorter for icatibant than placebo according to both the patient (0.8 hours vs. 16.9 hours; p<0.001) and investigator (1.0 vs. 5.7 hours; p<0.001).

Treatment of laryngeal attacks

The administration of icatibant in patients with laryngeal attacks resulted in a patient reported median time to symptom improvement of 0.6 and 1.0 hours in FAST-1 and FAST-2 respectively.

Safety profile

No drug-related serious adverse events were reported. Although almost all icatibant treated patients experienced injection site reactions such as redness of skin, itching and in some cases burning and pain, these were generally mild to moderate in severity, short-lived and resolved spontaneously.

Conclusions

The FAST-2 study demonstrated that icatibant was well tolerated and provided a significant benefit in the median time to onset of clinically significant symptom relief of either abdominal pain, cutaneous pain or cutaneous swelling compared to tranexamic acid.

The findings of the placebo-controlled study, FAST-1, were consistent with respect to tolerability and showed a numerically similar, though non-statistically-significant, benefit for icatibant with respect to the primary endpoint. 

Laryngeal HAE attacks can be life threatening due to the risk of suffocation as the airways become obstructed by swelling. Open label treatment of laryngeal attacks with icatibant showed median time to first symptom improvement as reported by the patient was 0.6 hours in the FAST-1 trial and 1.0 hours in the FAST-2 trial.

 “People with HAE live with a persistent anxiety which stems from the unpredictability and variability of their disease,” said Professor Marco Cicardi of the Department of Internal Medicine at the University of Milan. “The publication of this study shows the subcutaneous injection of icatibant to be an effective and well-tolerated treatment for acute attacks of HAE in adults. In addition, patients have the reassurance of being able to carry icatibant with them at all times for any trained healthcare professional to administer subcutaneously in the eventuality of an attack.”

“Icatibant brings two exciting ‘firsts’ in the symptomatic treatment of acute HAE attacks. It is the first bradykinin B2 receptor antagonist, blocking the effects of bradykinin, the key mediator of HAE symptoms, and the first subcutaneously injectable treatment for HAE approved in Europe,” said Professor Cicardi. “Icatibant has been a positive addition to our treatment options for HAE within Europe.”

Reference:

1- Cicardi M, Banerji A et al. Icatibant, a New Bradykinin-Receptor Antagonist, in Hereditary Angioedema. N Engl J Med 2010; 363:532-41.