首个遗传性血管水肿治疗药物ecallantide FDA咨询委员会涉险过关

周三，FDA专家咨询委员会以6-5的投票结果同意支持FDA批准首个遗传性血管水肿（HAE）药物ecallantide。如最终获得批准，本品将是Dyax公司首个上市产品，也将是FDA批准的首个治疗HAE急性发作的药物。FDA通常会尊重专家委员会的意见，最后裁决日为3月23日。

遗传性血管水肿是一种罕见但可致命的遗传性疾病，发作时以皮肤、小肠、口腔、咽喉等处水肿为特征。喉部水肿可致命。Dyax公司称本病美国约有10000例患者。

专家委员会中支持者认为临床对这一药物需求的紧迫性盖过了本品临床研究数据的瑕疵以及存在严重过敏反应的担忧。而FDA审核员则对临床数据是否清楚证明本品有效提出了质疑，例如他们提到其中一个临床研究中的52例患者以及后来募集的44例患者前后结果不一致的问题。一些专家组成员也认为临床研究数据有太多问题，不能因为是罕用药而降低标准。

Dyax公司总裁在会后对结果表示满意，并称将研究本品的安全使用条件。Dyax公司正寻求将本品用于10岁及10岁以上HAE患者，而专家委员会大部分成员认为没有充分证据证明本品在10～17岁患者中的安全性及有效性。

目前有数家公司正在研发HAE药物，ViroPharma公司的Cinryze已获FDA批准用于预防HAE发作，目前正在申请用于治疗HAE急性发作。
Kalbitor approved for acute attacks of hereditary angioedema (HAE) Kalbitor (ecallantide for injection, from Dyax) has been approved by the FDA for the treatment of acute attacks of hereditary angioedema (HAE) in patients ≥16 years of age. This approval was based on data from EDEMA3 and EDEMA4, two Phase 3, placebo-controlled clinical studies that evaluated the efficacy of Kalbitor in patients having an attack of HAE at any anatomic location, with at least one moderate or severe symptom. In both trials, the effects of Kalbitor were evaluated using the Mean Symptom Complex Severity (MSCS) score and the Treatment Outcome Score (TOS), two HAE-specific patient-reported outcome endpoints developed by Dyax.

Kalbitor-treated patients demonstrated a greater decrease from baseline in the mean MSCS than placebo (-0.8 vs. -0.4) and a greater mean TOS (53 vs. 8) in the EDEMA4 trial at 4 hours. In the EDEMA4 trial at 24 hours, Kalbitor treatment also resulted in a greater decrease from baseline in the mean MSCS than placebo (-1.5 vs. -1.1) and a greater mean TOS (89 vs. 55). The results in the EDEMA3 trial were consistent with that of EDEMA4.
Kalbitor will be made available in 10mg/mL single-use vials.
DX-88（ecallantide）显示能缓解遗传性血管水肿所有位急性发作症状2009年11月7日，在迈阿密海滩的年度ACAAI会议上，展示了DX - 88（ecallantide），一个口服的用于缓解所有部位急性发作的严重的遗传性血管水肿（HAC）症状的药物。

所导致血管性水肿的发作位置在临床疗效的响应时间似乎不同。腹部发作，通常是最痛苦的，喉部的发作，可威胁生命，临床效应响应速度超过外围发作，服用DX-88与安慰剂相比在4个小时内显示出明显的效果。DX - 88在治疗周边发作的显效时间约24小时。
Dyax公司和Genzyme公司称，Dyax公司的重组血管舒缓素酶抑制剂DX-88关键的Ⅲ期临床试验已经开始。

这种皮下注射药将在遗传性血管神经性水肿患者的治疗中进行疗效和安全性评估，血管神经性水肿这种罕见的遗传病可引起急性局部水肿和炎症。

KALBITOR (ecallantide) 10mg/mL single-use vials by DyaxCAMBRIDGE, Mass.--(BUSINESS WIRE)--Dyax Corp. (NASDAQ:DYAX - News) announced today that the U.S. Food and Drug Administration (FDA) has granted approval for KALBITOR® (ecallantide) for the treatment of acute attacks of hereditary angioedema (HAE) in patients 16 years of age andolder.
HAE is a rare, genetic disorder characterized by severe, debilitating and often painful swelling, which can occur in the abdomen, face, hands, feet and airway. KALBITOR, a potent, selective and reversible plasma kallikrein inhibitor discovered and developed by Dyax, is the first subcutaneous HAE treatment approved in the U.S.As part of product approval, Dyax has, together with the FDA, established a Risk Evaluation and Mitigation Strategy (REMS) program to communicate the risk of anaphylaxis and the importance of distinguishing between a hypersensitivity reaction and HAE attack symptoms.
“The approval of KALBITOR represents an important milestone in our ongoing commitment to the HAE community,” said Gustav A. Christensen, President
and Chief Executive Officer of Dyax. “Furthermore, bringing KALBITOR to market validates our mission to discover, develop, and commercialize innovative biopharmaceuticals for unmet medical needs.”
“By specifically affecting a key mediator of the inflammation, pain and edema that are characteristic of HAE attacks, KALBITOR may be advantageous in offering physicians a targeted approach for treating acute attacks,” said professor Jonathan Bernstein, MD, department of internal medicine, division of immunology/allergy, at the University of Cincinnati College of Medicine. “Additionally, the subcutaneous route of administration and efficacy in treating acute attacks in patients 16 years of age and older, regardless of anatomic location, make KALBITOR an important treatment option.”
HAE attacks, which occur on average more than 20 times yearly, are unpredictable and range in progression and severity. An acute episode may occur in one or more anatomical sites, sometimes moving from one site to another.
“HAE is a highly unpredictable disease because most attacks occur spontaneously with no identifiable trigger. KALBITOR will provide patients 16 years of age and older and their physicians with an FDA-approved subcutaneous therapy for treating painful and debilitating HAE acute attacks,” stated Anthony J. Castaldo, President of the United States Hereditary Angioedema Association (HAEA), a nonprofit patient advocacy organization that represents approximately 6,500 HAE patients in the United States.
KALBITOR HAE Program
The approval of KALBITOR is based on the results of two placebo-controlled Phase 3 clinical studies, known as EDEMA3® and EDEMA4®. Patients having an
attack of HAE, at any anatomic location, with at least one moderate or severe symptom, were treated with 30 mg subcutaneous KALBITOR or placebo.
Because patients could participate in both trials, a total of 143 unique patients participated.

There were 64 patients with abdominal attacks, 55 with peripheral attacks, and 24 with laryngeal attacks. In both trials, the effects of KALBITOR were evaluated using the Mean Symptom Complex Severity (MSCS) score and the Treatment Outcome Score (TOS), two HAE-specific patient-reported outcome endpoints developed by Dyax.
These measures evaluated the severity of attack symptoms at all anatomical locations (MSCS score) and response to therapy (TOS). In the EDEMA4 trial at 4 hours, patients treated with KALBITOR demonstrated a greater decrease from baseline in the mean MSCS than placebo (-0.8 vs. -0.4; p = 0.010) and a greater mean TOS (53 vs. 8, p = 0.003). In the EDEMA4 trial at 24 hours, patients treated with KALBITOR also demonstrated a greater decrease from baseline in the mean MSCS than placebo (-1.5 vs. -1.1; p = 0.04) and a greater mean TOS (89 vs. 55, p = 0.03).

The results in the EDEMA3 trial were consistent with the EDEMA4 trial results.
Potentially serious hypersensitivity reactions, including anaphylaxis, have occurred in patients treated with KALBITOR. In 255 HAE patients treated with intravenous or subcutaneous KALBITOR in clinical studies, 10 patients (3.9%) experienced anaphylaxis. For the subgroup of 187 patients treated with subcutaneous KALBITOR, 5 patients (2.7%) experienced anaphylaxis. Symptoms associated with these reactions have included chest discomfort, flushing, pharyngeal edema, pruritus, rhinorrhea, sneezing, nasal congestion, throat irritation, urticaria, wheezing, and hypotension.
These reactions occurred within the first hour after dosing.
The most common adverse reactions occurring in ≥3% of KALBITOR-treated patients and greater than placebo were headache, nausea, diarrhea, pyrexia, injection site reactions, and nasopharyngitis.

什么是遗传性血管水肿
遗传性血管性水肿是一种常染色体显性遗传性疾病，分为I型(C1抑制蛋白的生成较低)和Ⅱ型(C1抑制因子有功能缺陷，而血浆水平正常)两种。大多数患者是由于C1抑制基因的突变，C1胆碱酯酶的血清仅2球蛋白抑制物的缺乏而引起的。也有少数患者是因其功能失常而发生的，而在血清中的含量是正常的。这种有缺陷的基因使得在血浆中不能产生足够的C1酯酶抑制因子，不能抑制其他血清酶和血管活性肽包括纤维蛋白溶酶、激肽酶等。在遗传性血管性水肿患者，激肽酶引起局部血管渗透性增强，进而纤维蛋白溶酶，甚至激肽酶能活化C1，从而导致C 1的自活化，以及C1酶解物C2和C4补体的消耗，因此受累部位的血管通透性增加，促使血管外液体潴留的速度加快。由Cl酯酶抑制因子作用于C2和C4所释放的一种激肽样渗透因子是本病发病的致病因素。遗传性血管性水肿患者的C1酯酶抑制因子的缺乏是经常的，但发作是阵发性的。

本病发作是自发的，但拔牙等外伤、剧烈运动或情绪激动等往往可诱发。

遗传性血管性水肿常在10岁前开始发作，很少到20～30岁时才开始发病，发病的年龄在各个家庭不同，而在一个家庭中通常几乎是相似的。临床表现为突然发生的局限性皮下水肿，非凹陷性，不痒，仅有发胀、不适感。常为单发，局限在面部或一个肢体，偶尔累及外生殖器，可伴有暂时性形状、环状或网状红斑，常有外伤或感染等为先驱，水肿于1～2天消失。除皮肤外，各种靶器官的黏膜皆可受累，如累及消化道，可呈腹绞痛、呕吐、腹胀和水样腹泻。上呼吸道不常累及，但有产生喉头或咽喉部水肿导致窒息的危险。偶尔肌肉、膀胱、子宫和肺部等都可发生水肿。本病可反复发作，甚至终生存在，但在中年后发作的频率与严重程度往往较前为轻。
常规检查未见异常，血清C1酯酶抑制因子、C4和C2的补体值均下降，在发作时尤为显著。当胃肠道累及时，白细胞计数增高，达16～20×109/L，血细胞比容值增高可能继发于大量液体渗入到血管外组织间隙。腹部X线摄片可见肠梗阻，有气体充盈、空隙和液体平段，钡剂灌肠累及部位示病变节段有水泡样圆形水肿性黏膜印影，偶尔亦可见肠套叠表现。

对遗传性血管性水肿的治疗一般的药物如抗组胺剂、类固醇或肾上腺素等都收效甚微，尤其在急性发作时。对已确定的发作，在可能的情况下，可采用净化的C1酯酶抑制因子浓缩物治疗。如果在紧急情况下没有这种合成的抑制因子，输正常新鲜血浆可顺利度过危象。在没有任何其他方法时，需立即采取急救措施，进行气管切开术，以保持呼吸道通畅，在发作频繁患者，有时需做永久性气管切开术。

短期预防最好用雄激素如康力龙或达那唑，它们可减少C1抑制因子的产生、增加C4的效能。但雄性激素长期服用可产生男性化、低密度胆固醇增加等副作用，尤其对妇女和孩子影响较大，不能长期使用。为使病人相对地不易发作，可采用间歇性小剂量使用方法。也可试服6一氨基己酸或其同类物，可有预防及减少发作的效能，但比雄性激素效果要差些。预防遗传性血管性水肿患者急性发作的进一步加剧，以防止死亡是尤为重要的。在现代治疗法发明之前，遗传性血管性水肿的死亡。