抑制血浆激肽释放酶用于遗传性血管性水肿预防。

Inhibiting Plasma Kallikrein for Hereditary Angioedema Prophylaxis.

机构信息

From the Division of Rheumatology, Allergy, and Immunology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston (A.B.), Dyax, Burlington (C. Soo, R.I., D.J.S., C.T., J.A.K., R.F., H.K., R.M., C. Stevens, J.C.B., Y.C., B.A.), and ICON Clinical Research, Marlborough (J.G.S.) - all in Massachusetts; the Division of Clinical Immunology and Allergy, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York (P.B.), and Winthrop University Hospital, Mineola (M.D.-L.) - both in New York; Triumpharma, Amman, Jordan (M.S., A.A.-G.); Asthma and Allergy Research Associates, Dallas (W.L.); the Division of Allergy and Immunology, Washington University School of Medicine, St. Louis (H.J.W.); Allergy and Asthma Medical Group, Walnut Creek (J.J.), and the Department of Rheumatology, Allergy, and Immunology, University of California, San Diego, San Diego (M.R.) - both in California; Baker Allergy, Asthma, and Dermatology, Lake Oswego, OR (J.B.); the Department of Internal Medicine-Allergy Section Cincinnati, University of Cincinnati College of Medicine, Cincinnati (J.A.B.); the Division of Allergy and Immunology, Department of Internal Medicine, Morsani College of Medicine, University of South Florida, Tampa (R.L.); the Institute for Asthma and Allergy, Chevy Chase, MD (H.H.L.); the Department of Medicine and Pediatrics, Penn State Hershey Allergy, Asthma, and Immunology, Hershey, PA (T.C.); and the Department of Biomedical and Clinical Sciences, Luigi Sacco, University of Milan, and Luigi Sacco Hospital Milan, Milan (M.C.).

出版信息

N Engl J Med. 2017 Feb 23;376(8):717-728. doi: 10.1056/NEJMoa1605767.

DOI:10.1056/NEJMoa1605767

PMID:28225674

Abstract

BACKGROUND

Hereditary angioedema with C1 inhibitor deficiency is characterized by recurrent, unpredictable swelling episodes caused by uncontrolled plasma kallikrein generation and excessive bradykinin release resulting from cleavage of high-molecular-weight kininogen. Lanadelumab (DX-2930) is a new kallikrein inhibitor with the potential for prophylactic treatment of hereditary angioedema with C1 inhibitor deficiency.

METHODS

We conducted a phase 1b, multicenter, double-blind, placebo-controlled, multiple-ascending-dose trial. Patients with hereditary angioedema with C1 inhibitor deficiency were randomly assigned in a 2:1 ratio to receive either lanadelumab (24 patients) or placebo (13 patients), in two administrations 14 days apart. Patients assigned to lanadelumab were enrolled in sequential dose groups: total dose of 30 mg (4 patients), 100 mg (4 patients), 300 mg (5 patients), or 400 mg (11 patients). The pharmacodynamic profile of lanadelumab was assessed by measurement of plasma levels of cleaved high-molecular-weight kininogen, and efficacy was assessed by the rate of attacks of angioedema during a prespecified period (day 8 to day 50) in the 300-mg and 400-mg groups as compared with the placebo group.

RESULTS

No discontinuations occurred because of adverse events, serious adverse events, or deaths in patients who received lanadelumab. The most common adverse events that emerged during treatment were attacks of angioedema, injection-site pain, and headache. Dose-proportional increases in serum concentrations of lanadelumab were observed; the mean elimination half-life was approximately 2 weeks. Lanadelumab at a dose of 300 mg or 400 mg reduced cleavage of high-molecular-weight kininogen in plasma from patients with hereditary angioedema with C1 inhibitor deficiency to levels approaching that from patients without the disorder. From day 8 to day 50, the 300-mg and 400-mg groups had 100% and 88% fewer attacks, respectively, than the placebo group. All patients in the 300-mg group and 82% (9 of 11) in the 400-mg group were attack-free, as compared with 27% (3 of 11) in the placebo group.

CONCLUSIONS

In this small trial, administration of lanadelumab to patients with hereditary angioedema with C1 inhibitor deficiency reduced cleavage of high-molecular-weight kininogen and attacks of angioedema. (Funded by Dyax; ClinicalTrials.gov number, NCT02093923 .).

摘要

背景

C1 抑制剂缺乏遗传性血管性水肿的特征是反复发作、不可预测的肿胀发作，这是由不受控制的血浆激肽释放酶生成和从高分子量激肽原切割导致的过度缓激肽释放引起的。Lanadelumab（DX-2930）是一种新的激肽释放酶抑制剂，具有预防 C1 抑制剂缺乏遗传性血管性水肿的潜力。

方法

我们进行了一项 1b 期、多中心、双盲、安慰剂对照、多次递增剂量试验。C1 抑制剂缺乏遗传性血管性水肿患者以 2:1 的比例随机分配接受 lanadelumab（24 例）或安慰剂（13 例），间隔 14 天接受两次给药。分配给 lanadelumab 的患者被纳入连续剂量组：总剂量 30mg（4 例）、100mg（4 例）、300mg（5 例）或 400mg（11 例）。通过测量血浆中切割的高分子量激肽原来评估 lanadelumab 的药效学特征，并通过在 300mg 和 400mg 组与安慰剂组相比，在指定时间段（第 8 天至第 50 天）内血管性水肿发作的发生率来评估疗效。

结果

接受 lanadelumab 治疗的患者均未因不良事件、严重不良事件或死亡而停药。治疗期间出现的最常见不良事件是血管性水肿发作、注射部位疼痛和头痛。观察到血清浓度呈剂量依赖性增加；平均消除半衰期约为 2 周。Lanadelumab 剂量为 300mg 或 400mg 可降低 C1 抑制剂缺乏遗传性血管性水肿患者血浆中高分子量激肽原的切割水平，接近无该疾病患者的水平。从第 8 天到第 50 天，300mg 和 400mg 组的发作次数分别比安慰剂组减少 100%和 88%。300mg 组的所有患者和 400mg 组的 82%（9/11）患者无发作，而安慰剂组的 27%（3/11）患者无发作。