Annals of Allergy Asthma & Immunology最新文献_第10页

GARADACIMAB ELICITS ATTACK-FREE STATUS IN HEREDITARY ANGIOEDEMA INDEPENDENT OF BASELINE CHARACTERISTICS garadacimab可诱发遗传性血管性水肿的无发作状态，与基线特征无关

IF 5.8 2区医学 Q1 ALLERGY

Annals of Allergy Asthma & Immunology

Pub Date : 2024-10-25 DOI: 10.1016/j.anai.2024.08.127

J. Anderson , J. Bernstein , W. Yang , K. Kohga , K. Sitz , I. Jacobs , H. Feuersenger , R. Tachdjian

Introduction

Hereditary angioedema (HAE) attacks are recurrent, unpredictable, debilitating, and potentially life-threatening. Current guidelines state HAE treatment goals are complete disease control and normalization of life. Garadacimab, a fully human, once-monthly, anti-activated factor XII monoclonal antibody, was evaluated as HAE long-term prophylaxis in the pivotal Phase 3 (VANGUARD) study, and 62% of garadacimab-treated patients were attack-free (all patients receiving placebo experienced attacks). This post hoc analysis evaluated potential association between baseline patient characteristics and attack-free status.

Methods

In the 6-month, randomized, pivotal Phase 3 (VANGUARD) study, patients received garadacimab 200 mg subcutaneously (n=39) or placebo (n=25) once monthly. Patients treated with garadacimab who were attack-free (n=24) vs those with ≥1 attack (n=15) were compared across patient characteristics: age, body mass index, age at diagnosis, attacks per month during the run-in period, rate of mild/moderate/severe attacks during the run-in period, and combined rate of moderate/severe attacks during the run-in period. Youden-index was calculated for each characteristic, whereby 0 indicates no predictive ability for attack-free status and 1 indicates perfect predictive ability.

Results

All evaluated characteristics had low predictive ability for attack-free status (Youden-index range 0.18–0.39; sensitivity 25.0–79.2%; specificity 53.3–93.3%; Table). Attacks per month during the run-in period had the highest predictive power, but still had a low ability to predict attack-free status (Youden-index 0.39).

Conclusion

In the pivotal Phase 3 (VANGUARD) study, patients with HAE achieved attack-free status with garadacimab independently of evaluated baseline patient characteristics. Regardless of baseline characteristics, patients with HAE have the potential to achieve attack-free status with garadacimab.

导言遗传性血管性水肿（HAE）发作反复、难以预测、使人衰弱并可能危及生命。现行指南规定，HAE 的治疗目标是完全控制病情和恢复正常生活。加拉达西单抗是一种全人源、每月一次的抗活化因子 XII 单克隆抗体，在关键的三期（VANGUARD）研究中被评估为 HAE 长期预防药物，62% 的加拉达西单抗治疗患者不再发作（所有接受安慰剂治疗的患者均发作）。在为期 6 个月的随机关键性 3 期（VANGUARD）研究中，患者每月一次皮下注射加拉达西单抗 200 毫克（39 人）或安慰剂（25 人）。比较了接受加拉达单抗治疗的无发作患者（24人）与发作次数≥1次的患者（15人）的不同患者特征：年龄、体重指数、确诊年龄、磨合期内每月发作次数、磨合期内轻度/中度/重度发作率以及磨合期内中度/重度合并发作率。结果所有评估特征对无发作状态的预测能力均较低（尤登指数范围为 0.18-0.39；敏感性为 25.0-79.2%；特异性为 53.3-93.3%；表）。结论在关键的 3 期（VANGUARD）研究中，HAE 患者使用加拉达西单抗后可达到无发作状态，与评估的患者基线特征无关。无论基线特征如何，HAE患者都有可能通过使用加拉达单抗达到无发作状态。

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引用次数: 0

HYPERSENSITIVITY REACTIONS TO PLATINUMS: SYSTEMATIC REVIEW OF EFFICACY AND SAFETY OF DESENSITIZATION 对铂类药物的超敏反应：脱敏疗效和安全性的系统回顾

IF 5.8 2区医学 Q1 ALLERGY

Annals of Allergy Asthma & Immunology

Pub Date : 2024-10-25 DOI: 10.1016/j.anai.2024.08.057

R. Villarreal Gonzalez , E. Guadarrama-Rendón , C. de la Cruz-de la Cruz , D. Cadenas-García , M. Madrazo-Morales , K. Sáenz-Cantú , A. Treviño-Morales , M. Castells

Introduction

Platinum compounds are associated with a high incidence of hypersensitivity reactions (HSR) and IgE sensitization occurs after multiple exposures, leading to allergic symptoms and anaphylaxis. Drug desensitization induces a temporary immunological tolerance, permitting safe re-administration of platinums in allergic individuals.

Methods

To assess the safety and efficacy of rapid drug desensitization (RDD) for platinum hypersensitivity reactions we underwent a systematic review. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and registered the study in PROSPERO(CRD42023473211). The comprehensive search was conducted in Medline, Embase, Web of Science and Scopus databases.

Results

A total of 53 studies were included (n=2853 cases) from 11 countries between 1998-2024 of patients with initial HSR to platinums, carboplatin (n=44), oxaliplatin (n=30) and cisplatin (n=23) that underwent desensitization. The most frequent symptoms of HSR to platinum were skin and respiratory. There was variability in the type of desensitization protocols used, the most frequent being 4 bags-4 steps and 3-4 bags and 12-16 steps, with an average duration of 2.5-5.7 hours. Premedication was reported in most cases (n=49). Patients tolerated the desensitization protocol; the success rate at desensitization with carboplatin and oxaliplatin varied between 67-100%, while it was 100% in all cases of desensitization for cisplatin. An incidence of HSR during desensitization was reported, ranging from 4.4% to 96.7% (median of 24%), and no associated deaths.

Conclusion

RDD is a safe and effective procedure in patients with platinum HSR, helping to improve quality of life and safely providing treatment with first line therapy.

导言铂化合物与超敏反应（HSR）的高发生率有关，多次接触后会发生 IgE 致敏，导致过敏症状和过敏性休克。为了评估快速药物脱敏（RDD）治疗铂类超敏反应的安全性和有效性，我们进行了一项系统综述。我们遵循了系统综述和荟萃分析首选报告项目（PRISMA）指南，并在 PROSPERO（CRD42023473211）上注册了该研究。结果 1998-2024年间，来自11个国家的53项研究（n=2853例）纳入了对铂、卡铂（n=44）、奥沙利铂（n=30）和顺铂（n=23）进行脱敏治疗的初次HSR患者。铂类 HSR 最常见的症状是皮肤和呼吸道症状。使用的脱敏方案类型各不相同，最常见的是4袋-4步和3-4袋-12-16步，平均持续时间为2.5-5.7小时。大多数病例（49 例）都进行了预先药物治疗。患者对脱敏方案的耐受性良好；卡铂和奥沙利铂的脱敏成功率在67%-100%之间，而顺铂的脱敏成功率为100%。据报道，脱敏过程中 HSR 的发生率从 4.4% 到 96.7%（中位数为 24%）不等，没有相关死亡病例。

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引用次数: 0

SUBLINGUAL EPINEPHRINE FILM'S MUCOADHESIVE PROPERTIES ENSURES CONSISTENT ORAL PLACEMENT AND DRUG RELEASE 舌下肾上腺素薄膜的粘液黏附特性可确保稳定的口腔放置和药物释放

IF 5.8 2区医学 Q1 ALLERGY

Annals of Allergy Asthma & Immunology

Pub Date : 2024-10-25 DOI: 10.1016/j.anai.2024.08.064

C. Kraus , D. Golden , M. Greenhawt , J. Lieberman , D. Bernstein , J. Oppenheimer , S. Wargacki

Introduction

Epinephrine is the first-line treatment for severe allergic reactions including anaphylaxis. Prompt and reliable action are critical for patient outcomes. Recent advancements have led to the development of DESF, a sublingual film containing a novel epinephrine prodrug.

Methods

AQ109301, a randomized, cross-over trial in healthy adults evaluated the pharmacokinetics (PK) and pharmacodynamics (PD) of epinephrine delivered via sublingual film (DESF) compared to epinephrine autoinjectors (EAI) and manual IM injection (IM). Intraoral film placement and movement were evaluated to assess any impact on variability in PK and PD.

Results

DESF delivery resulted in epinephrine PK comparable to EAIs or IM injection. DESF PK and PD remained consistent independent of small variations in film location. Analysis of residual film location between 1.5 to 3 minutes post-administration revealed minimal displacement, with 87.5% of subjects having no change in film location between timepoints. When movement was noted, there were no significant differences between subjects with or without film movement for geometric mean Cmax (351.2 and 489.4 pg/mL, respectively; p = 0.52) or median Tmax (12 and 12 minutes, respectively, p = 0.99). Similarly, there were no significant differences in median change in systolic blood pressure between subjects with or without film movement (27.33 and 23.00 mmHg, respectively; p = 0.46).

Conclusion

The initial placement or subsequent movement of the sublingual film had no impact on epinephrine pharmacokinetics or pharmacodynamics, with all results comparable to injection. These findings suggest that sublingual epinephrine film offers a consistent, robust and permissive method of drug delivery in anaphylaxis management.

导言肾上腺素是治疗包括过敏性休克在内的严重过敏反应的一线药物。及时可靠的治疗对患者的预后至关重要。方法AQ109301是一项在健康成人中进行的随机交叉试验，评估了通过舌下含膜（DESF）给药的肾上腺素的药代动力学（PK）和药效学（PD），并与肾上腺素自动注射器（EAI）和手动IM注射（IM）进行了比较。对口内胶片的放置和移动进行了评估，以评估其对 PK 和 PD 变异的影响。DESF 的 PK 和 PD 保持一致，与胶片位置的微小变化无关。对给药后 1.5 到 3 分钟之间残留药膜位置的分析表明，移位极小，87.5% 的受试者在不同时间点之间的药膜位置没有变化。注意到移动时，在几何平均 Cmax（分别为 351.2 和 489.4 pg/mL；p = 0.52）或中位数 Tmax（分别为 12 和 12 分钟；p = 0.99）方面，有无胶片移动的受试者之间没有显著差异。结论舌下胶片的初始放置或随后移动对肾上腺素药代动力学或药效学没有影响，所有结果均与注射相当。这些研究结果表明，在过敏性休克的治疗中，舌下含膜肾上腺素是一种稳定、可靠和有效的给药方法。

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引用次数: 0

SUBCUTANEOUS IMMUNOTHERAPY – A DOUBLE-EDGED SWORD IN EOSINOPHILIC ESOPHAGITIS? A SYSTEMATIC LITERATURE REVIEW 皮下免疫疗法--嗜酸性粒细胞食管炎的双刃剑？系统性文献综述

IF 5.8 2区医学 Q1 ALLERGY

Annals of Allergy Asthma & Immunology

Pub Date : 2024-10-25 DOI: 10.1016/j.anai.2024.08.097

K. Karpinska-Leydier , A. Khorochkov , L. Veras Mena , E. Steinbach

Introduction

Eosinophilic esophagitis (EoE) is marked by histological eosinophilic infiltration and may have concurrent aero-allergen sensitization. While evidence suggests oral and sublingual immunotherapy (SLIT) may instigate EoE, data on subcutaneous immunotherapy (SCIT) is lacking.

Methods

A literature review of PubMed, Science Direct, and Embase was conducted in May 2024 for unique case reports, controlled clinical trials, and observational studies regarding SCIT in EoE patients with endoscopic or clinical follow-up.

Results

From an initial 152 results, nine studies were relevant: four retrospective cohorts, three case reports, one longitudinal-observational study, and one prospective cohort. The four retrospective cohorts showed histologic improvement post-SCIT-treatment compared with initial endoscopy. Fewer topical steroids were required post-SCIT compared to controls. Two cases described improvement in EoE symptoms after achieving maintenance phase and in one case showed complete clinical and histologic remission. The remaining case report described recurrence of EoE with SCIT; however, this was after initial use and cessation of SLIT. The observational study assessed patients given either SCIT or SLIT who had positive IgE to grass or wheat while following dietary recommendations and were monitored for three years with endoscopy and clinical follow-up clinical follow-up; these patients had reduced steroid-use. The prospective cohort assessed 39 EoE patients for two years treated with SCIT and elimination diet who had allergies to group 1 grasses and lipid transfer proteins (hazelnut, walnut, mugwort, peach), showing clinical EoE improvement at two-years.

Conclusion

Significant subjective and histologic improvement in coexisting allergy and EoE is documented in the evaluated reports; SCIT requires further consideration in EoE patients.

导言嗜酸性粒细胞食管炎（EoE）以组织学上的嗜酸性粒细胞浸润为特征，并可能同时伴有空气过敏原致敏。尽管有证据表明口服和舌下免疫疗法（SLIT）可能会诱发 EoE，但皮下免疫疗法（SCIT）方面的数据却很缺乏。研究方法 2024 年 5 月，研究人员对 PubMed、Science Direct 和 Embase 进行了文献综述，以寻找与内镜或临床随访 EoE 患者皮下免疫疗法有关的独特病例报告、临床对照试验和观察性研究。四项回顾性队列研究显示，与最初的内镜检查相比，SCIT 治疗后组织学状况有所改善。与对照组相比，SCIT 治疗后所需的局部类固醇用量更少。两个病例描述了在达到维持阶段后咽喉炎症状的改善，其中一个病例显示临床和组织学完全缓解。剩下的一份病例报告描述了使用 SCIT 后的咽喉炎复发情况；不过，这是在首次使用和停止 SLIT 后的情况。观察性研究评估了使用 SCIT 或 SLIT 的患者，这些患者在遵循饮食建议的情况下对草或小麦的 IgE 呈阳性，并接受了为期三年的内窥镜检查和临床随访；这些患者减少了类固醇的使用。前瞻性队列研究对 39 名接受 SCIT 和消除性饮食治疗两年的咽喉炎患者进行了评估，这些患者对 1 类草和脂质转移蛋白（榛子、核桃、艾草、桃子）过敏，两年后临床咽喉炎有所改善。

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引用次数: 0

MUSCLE INSTABILITY ASSOCIATED WITH HEREDITARY ANGIOEDEMA 与遗传性血管性水肿相关的肌肉不稳定性

IF 5.8 2区医学 Q1 ALLERGY

Annals of Allergy Asthma & Immunology

Pub Date : 2024-10-25 DOI: 10.1016/j.anai.2024.08.102

Y. Yu , E. Hollers , L. Luong , H. Hitomi , K. Richwine , K. Grim , T. Craig

Introduction

Hereditary angioedema (HAE) is caused by C1 inhibitor deficiency or dysfunction, leading to increased prekallikrein activity and bradykinin production. HAE is associated with vasodilation and edema which could result in obstruction of the upper airway, GI symptoms, and skin swelling. Evidence of involvement of other organ systems has been sparse. Herein we demonstrate evidence of creatinine kinase (CK) elevation in HAE patients suggesting an effect of bradykinin on skeletal muscle.

Methods

During a study after IRB approval we followed CK results in patients with HAE. We assessed patients with and without exercise and with and without therapy. We included one patient with a clinical indication to check CK levels.

Results

In most studies we have not assessed CK, however, in a recent study CK was assessed and we found that some patients with HAE have persistently elevated CK. In others, even minor exercise caused CK to rise. We also noted patients on long term prophylaxis (LTP) had lower CK levels than those not on LTP. In one of these patients, muscle symptoms were profound and caused limited exercise, minimal exercise led to elevated CK, and isoenzymes were MM, confirming skeletal muscle origin.

Conclusion

Bradykinin appears to cause instability of skeletal muscle, causing CK release with even minor exercise. The effect of increases in bradykinin in HAE on muscle needs further research, but may account for some of the typical HAE symptoms. LTP may therefore have more benefits by stabilizing skeletal muscle along with decreasing skin and mucus membrane attacks.

导言遗传性血管性水肿（HAE）是由于 C1 抑制剂缺乏或功能障碍导致前胰激肽原活性和缓激肽分泌增加引起的。HAE 与血管扩张和水肿有关，可导致上呼吸道阻塞、消化道症状和皮肤肿胀。其他器官系统受累的证据还很少。在此，我们证明了 HAE 患者肌酸激酶 (CK) 升高的证据，这表明缓激肽对骨骼肌有影响。方法在一项经 IRB 批准的研究中，我们跟踪了 HAE 患者的肌酸激酶结果。我们对有无运动、有无治疗的患者进行了评估。结果在大多数研究中，我们都没有对肌酸激酶进行评估，但在最近的一项研究中，我们对肌酸激酶进行了评估，并发现一些 HAE 患者的肌酸激酶持续升高。在其他患者中，即使是轻微的运动也会导致肌酸激酶升高。我们还注意到，接受长期预防治疗（LTP）的患者的肌酸激酶水平低于未接受长期预防治疗的患者。结论缓激肽似乎会导致骨骼肌不稳定，即使是轻微运动也会导致 CK 释放。HAE 中缓激肽的增加对肌肉的影响还需要进一步研究，但可能是某些典型 HAE 症状的原因。因此，LTP 在稳定骨骼肌的同时，还能减少皮肤和粘膜的损伤，从而带来更多益处。

{"title":"MUSCLE INSTABILITY ASSOCIATED WITH HEREDITARY ANGIOEDEMA","authors":"Y. Yu , E. Hollers , L. Luong , H. Hitomi , K. Richwine , K. Grim , T. Craig","doi":"10.1016/j.anai.2024.08.102","DOIUrl":"10.1016/j.anai.2024.08.102","url":null,"abstract":"<div><h3>Introduction</h3><div>Hereditary angioedema (HAE) is caused by C1 inhibitor deficiency or dysfunction, leading to increased prekallikrein activity and bradykinin production. HAE is associated with vasodilation and edema which could result in obstruction of the upper airway, GI symptoms, and skin swelling. Evidence of involvement of other organ systems has been sparse. Herein we demonstrate evidence of creatinine kinase (CK) elevation in HAE patients suggesting an effect of bradykinin on skeletal muscle.</div></div><div><h3>Methods</h3><div>During a study after IRB approval we followed CK results in patients with HAE. We assessed patients with and without exercise and with and without therapy. We included one patient with a clinical indication to check CK levels.</div></div><div><h3>Results</h3><div>In most studies we have not assessed CK, however, in a recent study CK was assessed and we found that some patients with HAE have persistently elevated CK. In others, even minor exercise caused CK to rise. We also noted patients on long term prophylaxis (LTP) had lower CK levels than those not on LTP. In one of these patients, muscle symptoms were profound and caused limited exercise, minimal exercise led to elevated CK, and isoenzymes were MM, confirming skeletal muscle origin.</div></div><div><h3>Conclusion</h3><div>Bradykinin appears to cause instability of skeletal muscle, causing CK release with even minor exercise. The effect of increases in bradykinin in HAE on muscle needs further research, but may account for some of the typical HAE symptoms. LTP may therefore have more benefits by stabilizing skeletal muscle along with decreasing skin and mucus membrane attacks.</div></div>","PeriodicalId":50773,"journal":{"name":"Annals of Allergy Asthma & Immunology","volume":"133 6","pages":"Pages S24-S25"},"PeriodicalIF":5.8,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142529747","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

CLUSTERING OF TREE COMPONENTS IN SENSITIZATION PROFILES SUGGESTS KEY COMBINATIONS FOR ALLERGEN IMMUNOTHERAPY 致敏图谱中树状成分的聚类提示了过敏原免疫疗法的关键组合

IF 5.8 2区医学 Q1 ALLERGY

Annals of Allergy Asthma & Immunology

Pub Date : 2024-10-25 DOI: 10.1016/j.anai.2024.08.088

M. Yasniuk , V. Rodinkova , V. Mokin , S. Yuriev , L. DuBuske

Introduction

Patient sensitization patterns need to be understood to optimize allergen immunotherapy.

Methods

20,033 individuals were tested by ALEX methods in 17 regions of Ukraine in 2020-2022.

Results

7518 patients (37.53 %) were sensitive to at least one tree allergen. Sensitization to Sec c dominated (1404) followed by sensitivity to Cupressus arizonica Cup a 1( 1147). This cluster included half – 13 -of all tree-related molecules and extracts – (Bet v 6, Bro pa, Cup a 1, Cup s, Fra e, Fra e 1, Jun a, Mor r, Ole e 1, Ole e 9, Pla a 1, Pla a 2, Pla a 3). Populus nigra extract was clustered with Alternaria, dog, cat, horse allergens and timothy grass molecule Phl p 2. Cluster 4 comprised all PR-10 proteins including pollen and food associated including Aln g 1, Api g 1, Ara h 8, Bet v 1, Cor a 1.0103, Cor a 1.0401, Cor a_pollen, Dau c, Dau c 1, Fag s 1, Fra a 1+3, Gly m 4 and Mal d 1. Agglomerative clustering showed close relations between these component allergens. Bet v 1, Cor a 1.0103 and Fag s 1 were in one subcluster, while Aln g 1 associated most closely with Cor a_pollen extract and with Mad d 1 and Cor a 1.0401.

Conclusions

Analysis of patterns of sensitization suggests there are groups of allergen components to which tree sensitized patients are most commonly sensitized potentially useful for allergen immunotherapy strategies.

结果 7518 名患者（37.53%）对至少一种树木过敏原敏感。对 Sec c 敏感的患者占大多数（1404 人），其次是对 Cupressus arizonica Cup a 1 敏感的患者（1147 人）。这个群组包括了所有树木相关分子和提取物的一半--13 种（Bet v 6、Bro pa、Cup a 1、Cup s、Fra e、Fra e 1、Jun a、Mor r、Ole e 1、Ole e 9、Pla a 1、Pla a 2、Pla a 3）。黑杨提取物与 Alternaria、狗、猫、马过敏原和梯牧草分子 Phl p 2 聚类。聚类 4 包括所有 PR-10 蛋白质，包括花粉和与食物相关的 Aln g 1、Api g 1、Ara h 8、Bet v 1、Cor a 1.0103、Cor a 1.0401、Cor a_pollen、Dau c、Dau c 1、Fag s 1、Fra a 1+3、Gly m 4 和 Mal d 1。聚类分析显示这些过敏原成分之间关系密切。Bet v 1、Cor a 1.0103 和 Fag s 1 位于一个亚簇中，而 Aln g 1 与 Cor a_pollen 提取物、Mad d 1 和 Cor a 1.0401 的关系最为密切。

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引用次数: 0

BRIQUILIMAB IS WELL-TOLERATED AND EFFECTIVELY DEPLETES TISSUE RESIDENT MAST CELLS IN NON-HUMAN PRIMATES 在非人灵长类动物体内，briquilimab 具有良好的耐受性，并能有效消耗组织中的肥大细胞

IF 5.8 2区医学 Q1 ALLERGY

Annals of Allergy Asthma & Immunology

Pub Date : 2024-10-25 DOI: 10.1016/j.anai.2024.08.096

S. Lee , C. Banfield , J. Parnes , M. Yu , E. Tucker , H. Kwon , W. Pang

Introduction

Mast cells (MCs) are key players in many allergic and other inflammatory diseases. Briquilimab is a monoclonal antibody that binds to c-Kit, and blocks SCF to prevent c-Kit activation and signaling, leading to MC apoptosis and depletion. We evaluated briquilimab pharmacokinetics (PK), pharmacodynamics (PD), and safety in non-human primates (NHPs).

Methods

African Green monkeys (AGMs) were administered subcutaneous (SC) single- (0.1 to 10 mg/kg) or repeat-dose (0.3 to 3 mg/kg, weekly for 4 weeks) of briquilimab for PK and PD assessments. GLP-compliant toxicology studies were evaluated in cynomolgus monkeys administered 1- and 6-month weekly (1 to 300 mg/kg/dose) briquilimab SC. Clinical changes and MC depletion were monitored.

Results

After single administration of briquilimab in AGMs, non-linear, dose-dependent clearance of briquilimab and dose-dependent reduction of MC numbers in the colon submucosa and MC recruitment adjacent to wounded skin were observed. Dose-dependent decreases in colon submucosal MCs, interstitial and peribronchial lung MCs, and dermal MCs migrating into adjacent wounded skin were also observed after repeat dosing of briquilimab in AGMs. Chronic, high dosing of briquilimab in cynomolgus monkeys was well-tolerated with no significant changes in body weight, clinical chemistry, ophthalmology, electrocardiography, respiratory or neurological function. Transient and reversible reductions in reticulocyte count, red cell mass, and testis and epididymis weights were observed, while no microscopic abnormalities were noted among the female reproductive tissues. Further, there were no correlative bone marrow cytologic findings.

Conclusion

Briquilimab was well-tolerated at weekly SC doses up to 300 mg/kg and significantly depleted tissue resident MCs in NHPs.

导言桅杆细胞（MC）是许多过敏性疾病和其他炎症性疾病的关键因素。Briquilimab是一种单克隆抗体，能与c-Kit结合，阻断SCF以阻止c-Kit的激活和信号传导，从而导致MC凋亡和耗竭。我们评估了非人灵长类动物（NHPs）体内briquilimab的药代动力学（PK）、药效学（PD）和安全性。方法非洲绿猴（AGMs）皮下注射（SC）单剂量（0.1-10 mg/kg）或重复剂量（0.3-3 mg/kg，每周一次，连续4周）的briquilimab，进行PK和PD评估。在符合 GLP 标准的毒理学研究中，对每周一次（1 至 300 毫克/千克/剂量）静脉注射 briquilimab 1 个月和 6 个月的猴进行了评估。结果在 AGMs 中单次给予 briquilimab 后，观察到 briquilimab 非线性、剂量依赖性清除，以及结肠粘膜下 MC 数量和损伤皮肤附近 MC 募集的剂量依赖性减少。在对 AGMs 重复施用溴喹利单抗后，还观察到结肠粘膜下 MC、肺间质和支气管周围 MC 以及移入邻近损伤皮肤的皮肤 MC 的剂量依赖性减少。犬科猴长期大量服用溴喹利单抗后耐受性良好，体重、临床化学、眼科、心电图、呼吸或神经功能均无明显变化。观察到网织红细胞计数、红细胞质量、睾丸和附睾重量出现短暂和可逆的减少，但未发现雌性生殖组织出现显微异常。此外，也没有相关的骨髓细胞学检查结果。结论：NHP 每周使用的 SC 剂量高达 300 毫克/千克时，Briquilimab 的耐受性良好，并能显著消耗组织中的常住 MCs。

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引用次数: 0

BRIQUILIMAB POTENTLY INHIBITS STEM CELL FACTOR (SCF)/C-KIT SIGNALING, AND MAST CELL (MC) DEGRANULATION AND SURVIVAL briquilimab能有效抑制干细胞因子（scf）/c-kit信号传导、肥大细胞（mc）脱颗粒和存活

IF 5.8 2区医学 Q1 ALLERGY

Annals of Allergy Asthma & Immunology

Pub Date : 2024-10-25 DOI: 10.1016/j.anai.2024.08.098

H. Bouzid , C. Kwan , C. Yanagiba , S. Lee , M. Youn , M. Yu , H. Kwon , W. Pang

Introduction

SCF binding to c-Kit receptor regulates MC activation and survival. Briquilimab is an aglycosylated IgG1, antagonistic c-Kit monoclonal antibody (mAb) that blocks SCF binding to c-Kit and inhibits SCF/c-Kit signaling leading to MC apoptosis. We evaluated briquilimab's inhibition of MC degranulation and survival in comparison to a tool compound mAb that blocks c-Kit dimerization (JSP084) and the small molecule multi-tyrosine kinase inhibitor, imatinib. Briquilimab's effects on FcγR-mediated MC degranulation, antibody-dependent-cellular-cytotoxicity (ADCC), and complement-dependent cytotoxicity (CDC) were also evaluated.

Methods

The primary human MC (CD34^-FcεRI⁺c-Kit⁺) cells were differentiated from mobilized peripheral CD34⁺ cells and used to assess MC degranulation, cytokine release assay and MC survival rate. ADCC and CDC were measured using M-07e and UT-7 cells.

Results

Both briquilimab and JSP084 inhibited in vitro IgE/FcεRI-mediated MC degranulation significantly more potently than imatinib. Briquilimab exhibited lower IC₅₀ and was more potent than JSP084 at inhibiting MC degranulation. Briquilimab also reduced MC cytokine release, including TNFα and Th2-associated cytokines at 6h and 24h after IgE/anti-IgE challenge. Briquilimab at 100 nM almost completely inhibited SCF-dependent MC survival, but 100 nM of JSP084 only partially inhibited MC survival after 6 days of culture. Antibodies containing either wildtype Fc or a modified Fc region with enhanced FcγR binding affinity, but not briquilimab lacking FcγR binding ability via aglycosylation, induced FcγR-mediated MC degranulation. Additionally, briquilimab did not induce FcγR-mediated ADCC nor CDC.

Conclusion

Briquilimab potently inhibits human IgE/FcεRI-mediated MC degranulation and MC survival in culture, and it does not induce FcγR-mediated MC degranulation, ADCC or CDC.

导言SCF与c-Kit受体的结合调节MC的活化和存活。Briquilimab是一种糖基化IgG1、拮抗c-Kit的单克隆抗体（mAb），它能阻断SCF与c-Kit的结合，抑制SCF/c-Kit信号传导，导致MC凋亡。我们将 briquilimab 对 MC 脱颗粒和存活的抑制作用与阻断 c-Kit 二聚化的工具化合物 mAb（JSP084）和小分子多酪氨酸激酶抑制剂伊马替尼进行了比较评估。方法从动员的外周CD34+细胞分化出原代人MC（CD34-FcεRI+c-Kit+）细胞，用于评估MC脱颗粒、细胞因子释放检测和MC存活率。结果Briquilimab和JSP084对体外IgE/FcεRI介导的MC脱颗粒的抑制作用明显强于伊马替尼。布利喹单抗的IC50更低，抑制MC脱颗粒的作用比JSP084更强。在IgE/抗IgE挑战后6小时和24小时，布利喹单抗还能减少MC细胞因子的释放，包括TNFα和Th2相关细胞因子。100 nM 的 Briquilimab 几乎完全抑制了 SCF 依赖性 MC 的存活，但 100 nM 的 JSP084 在培养 6 天后只能部分抑制 MC 的存活。含有野生型Fc或具有增强FcγR结合亲和力的修饰Fc区的抗体，但不含通过糖基化缺乏FcγR结合能力的briquilimab，可诱导FcγR介导的MC脱颗粒。结论Briquilimab能有效抑制人IgE/FcεRI介导的MC脱颗粒和MC在培养液中的存活，而且不会诱导FcγR介导的MC脱颗粒、ADCC或CDC。

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引用次数: 0

PHARMACOMETRIC ANALYSIS SUPPORTS EARLY ONSET OF PROTECTION WITH GARADACIMAB AGAINST HEREDITARY ANGIOEDEMA ATTACKS 药效学分析支持加拉达西单抗对遗传性血管性水肿发作的早期保护作用

IF 5.8 2区医学 Q1 ALLERGY

Annals of Allergy Asthma & Immunology

Pub Date : 2024-10-25 DOI: 10.1016/j.anai.2024.08.126

F. Glassman , A. Sharma , R. Garcia , J. Lawo , C. Nenci , I. Pragst , D. Polhamus , T. Puchalski

Introduction

Garadacimab (anti-activated factor XII antibody) demonstrated durable protection against hereditary angioedema (HAE) attacks with favorable long-term safety/tolerability profiles in clinical studies. Pharmacometric analyses assessed the relationship between garadacimab pharmacokinetics (PK) and attack rate (AR).

Methods

A repeated-time-to-event exposure–response (ER) model relating longitudinal garadacimab concentration with AR was built with data from 177 unique patients with HAE who received garadacimab/placebo across Phase 2 and Phase 3 (pivotal and open-label extension) studies. Simulations (n=1000) were used to infer efficacy (i.e., predicted AR and relative risk of attacks) of garadacimab 200 mg subcutaneous (SC) once-monthly dosing regimen with 2x200 mg SC loading dose (LD) as first administration.

Results

Per pivotal Phase 3 PK data, garadacimab achieved steady-state exposures as early as Week 1 after LD (first administration) and remained at steady state between subsequent once-monthly dosing intervals. ER predictions demonstrated increasing efficacy with increasing exposure, with higher probability of exceeding and remaining above the target therapeutic threshold of ≥90% relative-risk reduction in attacks after LD (first administration). Population predictions demonstrated exposures above target therapeutic threshold for most patients, with 75% predicted to achieve ≥90% AR reduction vs run-in at steady state. ER-predicted ARs rapidly declined after LD (first administration) and remained consistently low throughout treatment.

Conclusion

PK data and ER predictions demonstrated garadacimab achieving steady-state exposures after LD (first administration) and maintaining steady–state exposures over subsequent once-monthly dosing intervals. LD maximizes the likelihood of reaching target therapeutic threshold resulting in early onset of protection against attacks as early as Week 1 after first administration.

导言：在临床研究中，加拉达西单抗（抗活化因子 XII 抗体）对遗传性血管性水肿（HAE）发作具有持久的保护作用，并且具有良好的长期安全性/耐受性。方法利用177名独特的HAE患者在2期和3期（关键期和开放标签延长期）研究中接受加拉达单抗/安慰剂治疗的数据，建立了一个将纵向加拉达单抗浓度与AR相关联的重复时间到事件暴露-反应（ER）模型。模拟结果（n=1000）被用于推断加拉达西单抗 200 毫克皮下注射（SC）每月一次给药方案的疗效（即预测的 AR 和发作的相对风险），首次给药为 2x200 毫克 SC 负荷剂量（LD）。ER预测表明，随着暴露量的增加，疗效也会增加，在LD（首次给药）后，发作相对风险降低≥90%的目标治疗阈值更有可能超过并保持在该阈值之上。人群预测显示，大多数患者的暴露量都高于目标治疗阈值，其中75%的患者在稳态时的相对风险降低率与运行期相比可达到≥90%。结论PK数据和ER预测显示，加拉地单抗在LD（首次给药）后达到稳态暴露，并在随后每月一次的给药间隔中保持稳态暴露。LD最大程度地提高了达到目标治疗阈值的可能性，从而在首次给药后的第1周就能及早预防疾病发作。

{"title":"PHARMACOMETRIC ANALYSIS SUPPORTS EARLY ONSET OF PROTECTION WITH GARADACIMAB AGAINST HEREDITARY ANGIOEDEMA ATTACKS","authors":"F. Glassman , A. Sharma , R. Garcia , J. Lawo , C. Nenci , I. Pragst , D. Polhamus , T. Puchalski","doi":"10.1016/j.anai.2024.08.126","DOIUrl":"10.1016/j.anai.2024.08.126","url":null,"abstract":"<div><h3>Introduction</h3><div>Garadacimab (anti-activated factor XII antibody) demonstrated durable protection against hereditary angioedema (HAE) attacks with favorable long-term safety/tolerability profiles in clinical studies. Pharmacometric analyses assessed the relationship between garadacimab pharmacokinetics (PK) and attack rate (AR).</div></div><div><h3>Methods</h3><div>A repeated-time-to-event exposure–response (ER) model relating longitudinal garadacimab concentration with AR was built with data from 177 unique patients with HAE who received garadacimab/placebo across Phase 2 and Phase 3 (pivotal and open-label extension) studies. Simulations (n=1000) were used to infer efficacy (i.e., predicted AR and relative risk of attacks) of garadacimab 200 mg subcutaneous (SC) once-monthly dosing regimen with 2x200 mg SC loading dose (LD) as first administration.</div></div><div><h3>Results</h3><div>Per pivotal Phase 3 PK data, garadacimab achieved steady-state exposures as early as Week 1 after LD (first administration) and remained at steady state between subsequent once-monthly dosing intervals. ER predictions demonstrated increasing efficacy with increasing exposure, with higher probability of exceeding and remaining above the target therapeutic threshold of ≥90% relative-risk reduction in attacks after LD (first administration). Population predictions demonstrated exposures above target therapeutic threshold for most patients, with 75% predicted to achieve ≥90% AR reduction vs run-in at steady state. ER-predicted ARs rapidly declined after LD (first administration) and remained consistently low throughout treatment.</div></div><div><h3>Conclusion</h3><div>PK data and ER predictions demonstrated garadacimab achieving steady-state exposures after LD (first administration) and maintaining steady–state exposures over subsequent once-monthly dosing intervals. LD maximizes the likelihood of reaching target therapeutic threshold resulting in early onset of protection against attacks as early as Week 1 after first administration.</div></div>","PeriodicalId":50773,"journal":{"name":"Annals of Allergy Asthma & Immunology","volume":"133 6","pages":"Pages S32-S33"},"PeriodicalIF":5.8,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142529634","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

CHAPTER-1 PHASE 2 TRIAL OF ORAL BRADYKININ B2 RECEPTOR ANTAGONIST DEUCRICTIBANT FOR HEREDITARY ANGIOEDEMA PROPHYLAXIS 第 1 章缓激肽 b2 受体拮抗剂 deucrictibant 口服预防遗传性血管性水肿的 2 期试验

IF 5.8 2区医学 Q1 ALLERGY

Annals of Allergy Asthma & Immunology

Pub Date : 2024-10-25 DOI: 10.1016/j.anai.2024.08.130

H. Wedner , J. Anderson , H. Chapdelaine , M. Magerl , M. Manning , M. Riedl , P. Lu , E. Aygoren-Pursun

Introduction

Deucrictibant is an orally-administered bradykinin B2 receptor antagonist under development for on-demand and prophylactic treatment of HAE attacks.

Methods

CHAPTER-1 (NCT05047185) is an ongoing 2-part Phase 2 study evaluating deucrictibant for long-term prophylaxis of HAE attacks. In part 1, participants received double-blind treatment with placebo or deucrictibant 20mg/day or 40mg/day (immediate-release capsule formulation) for 12 weeks. Thirty-four participants were enrolled. In part 2 (ongoing), participants may receive treatment with open-label deucrictibant 40mg/day. Participants were aged ≥18 and ≤75 years, diagnosed with HAE-1/2, not receiving other prophylactic treatments at the time of screening, and experienced ≥3 attacks within 3 months prior to screening or ≥2 attacks during screening (up to 8 weeks).

Results

In placebo-controlled part 1, the monthly attack rate (primary endpoint) was reduced by 84.5% (P=0.0008) by deucrictibant 40mg/day (least squares mean: 0.30; 95% CI: 0.11, 0.82) vs placebo (1.94; 1.31, 2.87). A ≥50%, ≥70%, and ≥90% reduction in attack rate from baseline was achieved in 9, 8, and 6 of 10 participants receiving deucrictibant 40mg/day vs 2, 2, and 0 of 11 receiving placebo. Forty percent of participants receiving deucrictibant 40mg/day vs 0 receiving placebo were attack-free. Both deucrictibant doses were well-tolerated. Four mild treatment-related treatment-emergent adverse events (TEAEs) were reported by 4 participants: 1 receiving placebo, 2 deucrictibant 20mg/day, and 1 deucrictibant 40mg/day. There were no serious TEAEs, severe TEAEs, or TEAEs leading to treatment discontinuation.

Conclusion

CHAPTER-1 provides evidence on efficacy and safety of deucrictibant for the prevention of HAE attacks, supporting its further development.

方法CHAPTER-1 (NCT05047185)是一项正在进行的2期研究，由两部分组成，评估缓激肽B2受体拮抗剂用于HAE发作的长期预防治疗。在第一部分中，参与者接受安慰剂或20毫克/天或40毫克/天（速释胶囊配方）的双盲治疗，为期12周。共有 34 人参加。在第2部分（进行中）中，参与者可接受开放标签的地屈孕酮40毫克/天治疗。参与者年龄≥18岁且≤75岁，确诊为HAE-1/2，筛查时未接受其他预防性治疗，筛查前3个月内发作≥3次或筛查期间发作≥2次（最多8周）。结果在安慰剂对照第1部分中，杜冷丁40毫克/天（最小二乘法平均值：0.30；95% CI：0.11，0.82）与安慰剂（1.94；1.31，2.87）相比，每月发作率（主要终点）降低了84.5%（P=0.0008）。在接受杜冷丁 40 毫克/天治疗的 10 名参与者中，分别有 9 人、8 人和 6 人的发病率比基线降低了≥50%、≥70% 和≥90%；在接受安慰剂治疗的 11 名参与者中，分别有 2 人、2 人和 0 人的发病率比基线降低了≥50%、≥70% 和≥90%。每天服用 40 毫克地屈孕酮的患者中有 40% 不再发作，而服用安慰剂的患者中仅有 0 人不再发作。两种剂量的杜冷丁均耐受良好。4名参与者报告了4起与治疗相关的轻度治疗突发不良事件（TEAE）：其中1人服用安慰剂，2人服用20毫克/天的右旋糖利班特，1人服用40毫克/天的右旋糖利班特。结论CHAPTER-1提供了预防HAE发作的右旋瑞班的有效性和安全性证据，支持其进一步发展。

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引用次数: 0