A Randomized, Double-blind, Multicenter Study to Evaluate the Efficacy and Safety of ALX 0171 Versus Placebo, in Addition to Standard of Care, in Adults Who Have Undergone Hematopoietic Stem Cell Transplantation and Present With a Respiratory Syncytial Virus Respiratory Tract Infection

The primary objective of the study is to evaluate the antiviral effect and safety of inhaled ALX-0171 in adults diagnosed with respiratory syncytial virus (RSV) respiratory tract infection after hematopoietic stem cell transplantation (HSCT).
The secondary objective is to assess the clinical activity, pharmacokinetics (PK), virology, and immunogenicity of inhaled ALX 0171 in adults diagnosed with RSV respiratory tract infection after HSCT.

开始日期2019-02-01

申办/合作机构

Ablynx NV

NCT03418571 / Terminated临床2期

A Randomized, Double-blind, Multicenter, Multiple-dose Study of ALX-0171 Versus Placebo Along With Standard of Care in Japanese Infants and Young Children Hospitalized for Respiratory Syncytial Virus Lower Respiratory Tract Infection

This was a randomized, double-blind, multicenter, Phase II study (NCT03418571) designed to support the selection of an optimal dose of inhaled ALX-0171 for further clinical development, taking ethnicity into consideration.
Based on the results of the Phase IIb dose-ranging study ALX0171-C201 (RESPIRE), the Sponsor decided to discontinue ALX-0171 development in infants and to early terminate the ALX0171-C203 study.

开始日期2018-03-01

申办/合作机构

Ablynx NV

NCT02979431 / Completed临床2期

A Randomized, Double-blind, Placebo-controlled, Multicenter Dose Ranging Study of ALX-0171 in Infants and Young Children Hospitalized for Respiratory Syncytial Virus Lower Respiratory Tract Infection

The primary objective is to evaluate the anti-viral effect and safety of different doses of inhaled ALX-0171 in subjects hospitalized for Respiratory Syncytial Virus Lower Respiratory Tract Infection (RSV LRTI). The secondary objective is to evaluate the clinical activity, pharmacokinetic (PK) properties, pharmacodynamic (PD) effect and immunogenicity of different doses of inhaled ALX-0171.

开始日期2017-01-11

申办/合作机构

Ablynx NV

100 项与 ALX-0171 相关的临床结果

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100 项与 ALX-0171 相关的转化医学

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100 项与 ALX-0171 相关的专利（医药）

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项与 ALX-0171 相关的文献（医药）

2024-01-01·Protein expression and purification

The construction of long-acting exendin-4 analog and its hypoglycemic effect in diabetic mice

Article

作者: Wu, Xueman ; Li, Huangjin ; Zang, Linquan ; Zhao, Lin ; Zheng, Ke ; Liang, Zhiwen ; Cai, Jingmin

Exendin-4 is a glucagon-like polypeptide-1 (GLP-1) analog derived from lizard venom, but its short half-life affects drug administration compliance. An anti-HSA nanobody with a smaller size to guide the peptide coupling to Human Serum Albumin(HSA) in vivo may be a feasible strategy for constructing inexpensive, long-acting exendin-4 analogs. For this purpose, a fusion protein (exendin-4-(G4S)3-sdAbHSA), in which a humanized anti-HSA nanobody to the C-terminal of exendin-4 through the (Gly₄Ser)₃ flexible joint, was constructed. The target gene was designed according to the preferred codons and cloned into expression vector pET21b of Escherichia coli. The fusion protein could be efficiently expressed as a soluble protein, and purified to a purity over 98% by two steps of chromatography columns. In the streptozotocin-induced mouse diabetes model, the purified product had similar hypoglycemic activity as exendin-4, but dropped to the lowest value from 1 to 2 h to more than 8-10 h. The results show that this construction form does not interfere with the binding of exendin-4 to GLP-1 receptor, and can significantly prolong its half-life in vivo. This study has important reference value for constructing long-acting exendin-4 analogs and establishing efficient and green production process.

2021-02-01·British journal of pharmacology2区 · 医学

Neutrophils in respiratory syncytial virus infection: From harmful effects to therapeutic opportunities

2区 · 医学

Review

作者: Rastegar, Mostafa ; Samadizadeh, Saeed ; Besteman, Sjanna ; Bont, Louis ; Tahamtan, Alireza ; Salimi, Vahid

Respiratory syncytial virus (RSV) is an important infectious agent in infants and young children. In most cases, RSV infection only causes mild disease, but in some, it requires invasive ventilation. Although antiviral drugs are obvious candidates to treat viral illness, and some have shown antiviral effects in humans, antivirals such as GS‐5806, ALX‐0171 and ALS‐8176 have not yet met their expectations. Since the inappropriate or dysregulated immune response against RSV leads to harmful immune pathology, a robust immune cascade is probably underway by the time patients reach the hospital. RSV infection is associated with a strong neutrophil influx into the airway. It not clear if these cells contribute to antiviral defence or to lung pathology. This article discusses the protective and harmful roles of neutrophils during RSV infection and provides an overview of mechanisms by which neutrophil function could be targeted to prevent tissue injury and preserve homeostasis.

2021-01-01·The Lancet. Respiratory medicine1区 · 医学

Nebulised ALX-0171 for respiratory syncytial virus lower respiratory tract infection in hospitalised children: a double-blind, randomised, placebo-controlled, phase 2b trial

1区 · 医学

Article

作者: Ashkenazi, Shai ; Cunningham, Steve ; Oberdorfer, Peninnah ; Toh, Teck Hock ; Piedra, Pedra A ; Martinon-Torres, Federico ; Salamanca de la Cueva, Ignacio ; Bene, Zsolt ; Warachit, Boonyarat ; Repko, Miroslav ; Goldbart, Aviv ; Fleurinck, Carmen ; Sablan, Benjamin, Junior ; Nikolova, Olga ; Kolosa, Nadezda ; Khaw, Poh Guan ; Martinón-Torres, Federico ; Piedra, Pedro A ; Rodrigo Gonzalo de Liria, Carlos ; Chakarova, Petranka ; Verhulst, Stijn ; Gacs, Éva ; Kalocsai, Krisztina ; Ivkovic-Jurekovic, Irena ; Turkalj, Mirjana ; Skalova, Sylva ; Kljaic Bukvic, Blazenka ; Kovacs, Lajos ; Brackeva, Benedicte ; Bosheva, Miroslava ; Szymanski, Henryk ; Puthanakit, Thanyawee ; Matthijs, Inge ; De Bruyne, Jessie Anne ; Vogelberg, Christian ; Cicak, Biserka ; Madarasi, Anna ; Wu Hupat, Elba ; Bentur, Lea ; Dombrecht, Evelyne ; SIPL, Mirna ; Tesovic, Goran ; Mesaric Antoncic, Natasa ; Gardovska, Dace ; Teeratakulpisarn, Jamaree ; Detalle, Laurent ; Tan, Kah Kee ; Novak, Zoltan ; Dosev, Svilen ; Goetghebuer, Tessa ; Cedena Romero, María Pilar ; Alberto, Edison ; Kralinsky, Karol ; Monteagudo Montesinos, Emilio ; Mesa Monsalve, Juan ; de Leon, Anjanette ; Horneff, Gerd ; Proesmans, Marijke

BACKGROUND:

Respiratory syncytial virus (RSV) is the most common cause of severe lower respiratory tract infection, with a high global health burden. There are no effective treatments available. ALX-0171 is a novel trivalent Nanobody with antiviral properties against RSV. We aimed to assess the safety and antiviral activity of nebulised ALX-0171 in children admitted to hospital with RSV lower respiratory tract infection.

METHODS:

This double-blind, randomised, placebo-controlled, phase 2b trial was done in 50 hospital paediatric departments across 16 countries. Previously healthy children aged between 28 days to younger than 24 months who were admitted to hospital with RSV acute severe lower respiratory tract infection were randomly assigned in three sequential safety cohorts (3:1) to receive nebulised ALX-0171 (cohort 1 received 3 mg/kg, cohort 2 received 6 mg/kg, and cohort 3 received 9 mg/kg) or placebo once daily for 3 days using web-based randomisation in the sequential safety part (first block size 12, subsequently four). In a parallel part of the study, participants (cohort 4) were randomly assigned (parallel 1:1:1:1) to receive nebulised ALX-0171 3 mg/kg, 6 mg/kg, 9 mg/kg, or placebo (blocks of eight by restricted randomisation). Study drug masking was by two consecutive nebulisations (each either ALX-0171 or placebo) depending on assigned treatment group. The primary outcome was to evaluate time for the RSV viral load to drop to below quantifiable limit, measured by plaque assay on mid-turbinate nasal swabs. Safety, clinical efficacy, pharmacokinetics, viral load by RT-qPCR, and immunogenicity were secondary outcomes. Analysis, including of the primary outcome, was by modified intention to treat (participants receiving at least one dose of study drug as assigned), and safety was assessed in all children who received at least one administration of study drug, as treated. This trial is registered with EudraCT, 2016-001651-49.

FINDINGS:

Between Jan 10, 2017, and April 26, 2018, 175 children (median age 4·8 months [IQR 2·0-10·8]), received at least one dose of study drug (45 received 3 mg/kg of ALX-0171, 43 received 6 mg/kg of ALX-0171, 45 received 9 mg/kg of ALX-0171, and 42 received placebo; the modified intention-to-treat population) commencing at a mean 3·3 days (SD 1·1) from symptom onset. Median time for the viral load to drop to below quantifiable limit on plaque assay was significantly faster for the 3 mg/kg group (median 14·2 h [IQR 5·0-28·0]), 6 mg/kg group (5·1 h [4·7-28·5]), and 9 mg/kg group (5·1 h [4·6-5·9]) than the placebo group (46·1 h [25·2-116·7]; hazard ratio [HR] all ALX-0171 groups vs placebo 2·6 [1·7-3·9]; p<0·0001). Median time for the viral load to drop below quantification limit with RT-qPCR was 95·9 h (IQR 26·7 to not estimable) for the placebo group (n=35) versus 49·4 h (25·1 to 351·4) for all ALX-0171 groups (n=118). Clinical outcomes were not improved by ALX-0171 compared with placebo, with no difference in time to clinical response (oxygen saturation >92% for 4 h in room air and adequate oral feeding) in ALX-0171 groups and the placebo group (median 43·8 h [IQR 21·7-68·5] vs 47·9 h [22·5-76·4]; HR 1·1 [95% CI 0·8-1·6]) or change in the global severity score from baseline to 5 h post-dose on day 2 (-4 [IQR -6 to -2] vs -4 [-6 to -1]; difference in least-squares mean -0·45 [95% CI -1·39 to 0·49]). Serum concentrations of ALX-0171 on day 2 exceeded the concentration estimated to give full RSV neutralisation in the lung at 6 mg/kg and 9 mg/kg doses. Treatment-emergent antidrug antibodies were detected at day 14 in 46 (34%) of 135 patients who received ALX-0171 and ten (26%) of 39 patients who received placebo. Serious adverse events were reported in five (13%) of 40 children in the placebo group and ten (7%) of 135 children in all ALX-0171 groups, leading to study drug discontinuation in three children (two in the 3 mg/kg group and one in the 6 mg/kg group). 13 of 15 serious adverse events (three of four in the 3 mg/kg group, two of three in the 6 mg/kg group, three of three in the 9 mg/kg group, and five of five in the placebo group) were related to worsening respiratory status, and none were considered to be related to the study drug.

INTERPRETATION:

Antivirals against RSV might be unable to improve clinical course once RSV lower respiratory tract infection is established. Future studies of RSV antivirals should focus on earlier intervention and more precise measurement of objective outcomes before the onset of significant lower respiratory tract inflammation.

FUNDING:

Ablynx, a Sanofi Company.

项与 ALX-0171 相关的新闻（医药）

2024-05-13

·生物制品圈

吸入性生物制剂在哮喘疾病中的开发进展及前景

摘要：全球超过3亿人饱受哮喘困扰，且发病率逐年增加，作为最常见的慢性疾病之一，哮喘激发机制复杂，异质性强，是一类免疫介导的炎症疾病。随着基于生理、病理等机制深入研究，陆续推出的治疗性小分子和激素药物已实现对大多数患者的控制和治疗，但仍有5%~10%的患者为难控制、难治疗性哮喘，即重度哮喘。近十年来，得益于生物医药的迅猛发展，蛋白、抗体类药物凭借高有效性、高特异性、高安全性成为关键的重度哮喘治疗药物，然而由于生物制剂通常经注射给药，不可无创、快速地递送药物直接入肺迅速吸收起效，故而临床中亟需起效快、便捷、经济、安全的吸入式生物制剂。本综述通过对哮喘发病机制的阐释，概括现行的小分子、激素类和生物类治疗药物，并总结吸入式哮喘生物制剂的研发历程，对其未来前景进行分析，旨在加深对大分子吸入药物研究方向的认知，更新该领域前沿动态，以期为更多吸入式生物制剂的开发提供参考。关键词：哮喘；给药途径；吸入给药；生物制剂_正文_支气管哮喘简称哮喘，以呼吸急促、咳嗽和胸闷等多种症状为特征，与慢性气道炎症，广泛、可逆性呼气性气流阻塞和气道高反应性等症状有关[1]。全球超过3亿人饱受哮喘困扰，且发病率逐年增加。根据全球哮喘指南全球哮喘防治创议（global initiative for asthma，GINA）建议，需对患者采用阶梯式治疗方案，尤其推荐个性化治疗方案。随着生物制剂的发展，抗体类生物制剂已成功应用至哮喘治疗，为中重度哮喘患者带来了更有效、更安全的药物选择，但其注射的给药方式，缓慢的起效速度，频繁的入院用药、高昂的用药成本在很大程度上限制了药物的推广，故而吸入式抗体药物的临床呼声日益高涨。本综述对哮喘机制、现有治疗药物及吸入抗体药物的开发历程进行了调查研究，以期加深对哮喘发病机制及治疗药物的全面认识，同时对吸入式抗体药物的开发必要性、开发难度、研发现状进行汇总更新。1哮喘发病机制哮喘传统上被分为两类，外源性哮喘和内源性哮喘，外源性哮喘又被称为过敏性哮喘，由过敏原引起，主要归因于异常的辅助性T细胞（helper T lymphocyte，Th）2型炎症。内源性哮喘是由多种因素引发的，如阿司匹林、肺部感染、运动、寒冷、压力、肥胖等[2]。根据Th2炎症的状态，哮喘疾病又被分为高Th2和低Th2哮喘[3]。高Th2哮喘的特征是嗜酸性气道炎症，这与血液中嗜酸性粒细胞数目的增加或呼出一氧化氮（fractional exhaled nitric oxide，FeNO）分数升高有关，而低Th2哮喘包括中性粒细胞哮喘和寡粒细胞性哮喘。哮喘的病理机制是复杂的，新研究表明，哮喘的发病机制也可不依赖于非免疫应答/炎症发生，但相关研究有限[4]。2哮喘标志物由于丰富的异质性外源、内源表型特征，哮喘非常适合精准治疗方案，因而非侵入性生物标志物的鉴别将有助于其诊断和治疗。Th2和2型固有淋巴细胞（innate lymphoid cells，ILC2）通路的激活是2型炎症哮喘发生的核心，Th2型细胞因子主要有一系列白介素（interleukin，IL），如IL-4、IL-5、IL-9、IL-13、IL-31，而ILC2s产生的2型细胞因子主要有IL-5、IL-9和IL-13，上述因子均为哮喘有效标志物。嗜酸性粒（eosinophil，EOS）细胞、免疫球蛋白（immunoglobulin，Ig）E、表达ILC2s的循环趋化因子受体（cyclic chemokine receptor，CCR）10、血浆CCL（CC chemokine ligand）27水平和Fe-NO是哮喘诊断和预后的常见生物标志物。此外，如图1所示，IgE、IgG亚族，血清IgE抑制活性，嗜碱性粒细胞活化，趋化因子和细胞因子，调节性T（regulatory T，Treg）细胞，调节性B（regulatory B，Breg）细胞和树突状细胞等标记物已被推荐作为跟踪过敏原耐受诱导治疗的生物标记物[5]。3哮喘现有小分子、激素治疗药物GINA指南推荐使用药物种类包括糖皮质激素、β2-受体激动剂、胆碱能受体阻断药物、茶碱类药物、白三烯受体拮抗剂和生物靶向制剂[6]。除上述药物外，基于创新机制的新型小分子药物研发处于临床研究不同阶段，如正大天晴的前列腺素D2受体拮抗剂（又称为CRTH2拮抗剂）TQC3564正在中国临床I期研究阶段；针对磷酸二酯酶4（PDE4）抑制剂的NCT04108377正处于临床I期患者招募阶段。此外，基于蛋白激酶抑制剂（NCT00676572）、选择性糖皮质激素受体调节剂（AZD7594）、他汀类药物（NCT02433535）均以控制哮喘为目标并处于临床开发中[7]。新型小分子哮喘治疗药物的有效开发离不开对哮喘机制以及哮喘的不同表型和内型的理解，但从临床效果上看，针对中重度哮喘，生物制剂展现出更加明确的应用前景，因此在另一方向上，生物靶向药物的发展也在高歌猛进，力求在新维度上实现哮喘疾病的控制及治疗。4哮喘现有靶向治疗药物随着病情严重，在以糖皮质激素为基础治疗后仍会出现控制不佳、反复重症发作等情况，此时患者即可被认定是重度患者，高达10%的成人和2.5%的儿童哮喘群体患有重度哮喘，因固定气流受限、病情恶化、常年就医、住院和死亡风险的增加等因素致使生活质量严重下降。因此，在整个哮喘患者谱系中，重症哮喘患者是临床中最迫切的未满足医疗需求群体，目前推荐的有效控制方案是生物制剂添加疗法。目前共6款针对Th2通路的哮喘治疗性单克隆抗体获批，包括靶向IgE的奥马珠单抗（omali-zumab）、靶向IL-5的瑞替珠单抗（reslizumab）、IL-5受体药物贝那利珠单抗（benralizumab）、针对IL-4Rα的度普利尤单抗（dupilumab）以及靶向TSLP的特泽鲁单抗（tezepelumab）。目前针对低Th2型、中性粒细胞为主的重度哮喘发病机制相关分子靶点的试验性药物非常稀缺，因此，针对不同表型基础生物学机制的深入研究将对临床有关重度哮喘治疗方案的开发起到关键性驱动作用[8]。抗体类生物制剂的获批为重度哮喘病人带来了更新、更安全、更有效的治疗方式，表1对Th2通路相关靶点哮喘治疗药物关键信息进行统计，以期对哮喘生物制品有更为系统的理解。上述靶向药物已在临床试验及疾病用药过程中验证了有效性和安全性，多种潜在疾病治疗靶点药物研发正在进展中，包括细胞因子、膜分子和细胞内信号通路，如IL-37、IL-11，基质相互作用分子1（STIM1），CD200R、OX40L和CD30L、HMGB等[9]。5吸入式大分子哮喘治疗药物发展现状5.1 药物通过吸入途径递送的优势吸入给药（肺给药）可快速、无创地输送至呼吸道并传导至肺部，肺内巨大的表面积和广泛的血管分布能使药物快速吸收并发挥治疗效果，其剂量对身体其他部位的暴露量较低，可最大限度地减少全身性不良反应。吸入给药是一种无创的局部和全身给药方式，在治疗多种疾病方面具有巨大的潜力，已应用于包括哮喘、慢性阻塞性肺疾病、呼吸道病毒感染和糖尿病、囊性纤维化等多种疾病领域[10]。吸入给药作为治疗呼吸系统疾病优选的给药方案，可满足如下几项对给药方式的特殊需求[11]：（1）药物通过系统性给药在肺内很难达到有效富集的药物浓度，生物利用度低，而吸入给药具有肺内高浓度的优势。（2）当以达到肺部有效治疗浓度为目标给药时，药物剂量通常较大并呈现全身性毒性，吸入给药用药量低，规避胃肠降解作用和肝脏首过效应，安全性更好。（3）需要快速起效的肺部疾病治疗药物，吸入给药可快速实现肺部药物沉降，并由于肺部表面积大、血管化丰富、组织通透性好，药物可以快速吸收并起效。（4）在确保肺部疾病治疗药物药效的同时，若对用药成本关注，亦通过吸入给药的方式改进。5.2 吸入制剂的临床应用吸入型产品可分为雾化溶液吸入、干粉吸入和软雾吸入三大种类，吸入制剂被广泛应用于多种呼吸系统疾病领域[11]：如（1）糖皮质激素、β2受体激动剂、毒蕈碱乙酰胆碱受体拮抗剂等激素和小分子类吸入制剂（组合）用于哮喘和慢性阻塞性肺疾病治疗。（2）妥布霉素、氨曲南赖氨酸盐、左氧氟沙星、阿米卡星、多粘菌素、神经氨酸酶抑制剂、利巴韦林、喷他脒等吸入制剂在抗感染领域的应用。（3）吸入重组人脱氧核糖核酸酶在囊性纤维化适应症的治疗应用。（4）吸入甘露醇在气道黏液清除、囊性纤维化及支气管扩张中的应用。（5）吸入前列腺环素发挥血管扩张机制用于肺动脉高压的治疗。（6）吸入肺表面活性剂用于呼吸窘迫综合征的治疗。（7）吸入核酸药物如重组新型冠状疫苗在抗病毒感染领域的开发应用。吸入制剂主要应用在呼吸系统疾病领域，但从口鼻吸入通过呼吸道将药物递送至肺部并交换进入体循环，也为系统性疾病的治疗提供了创新性的方案[11]。在中枢神经系统领域，尼古丁吸入剂（器）已在尼古丁替代疗法中得到成功应用以减轻或摆脱尼古丁依赖。全球首款左旋多巴吸入粉雾剂INBRIJA®已在美国和欧盟获批上市用于帕金森的吸入治疗。糖尿病领域，辉瑞与Mannkind曾先后获批两种吸入胰岛素药物Exu-bera®与Afrezza®，为糖尿病治疗提供了新的治疗选择。5.3 吸入大分子药物在哮喘治疗领域的开发现状抗体具有高特异性、高亲和力和高安全性等优势，已被广泛用于治疗肺部疾病，如肺癌和严重哮喘。目前共有6款针对重度哮喘的单克隆抗体上市，并取得了优异的临床治疗效果。然而，已上市产品均以皮下注射或静脉输注方式递送，其局限性包括侵入性、系统毒性（如细胞因子风暴），需专业医师操作等因素使得大量患者难以院外治疗。因此，吸入给药凭借直接呼吸道给药，无创、局部效应增强、全身暴露最小和易于自我给药等优点，已在多个吸入性单克隆抗体及其衍生物在临床试验中得到治疗潜力的评估[12]，表2汇总了吸入式生物制剂在哮喘领域的简要总结。5.3.1 吸入单克隆抗体/片段诺和诺德及诺华曾在轻度过敏性哮喘患者中开展了奥马珠单抗自我雾化给药疗效研究，虽然33名受试者在分别连续雾化用药2周和8周后血清中均检测到奥马珠单抗，但血清IgE水平无明显变化，变应原诱导的气道反应不受抑制，推测无效的原因是肺组织中覆盖IgE效应细胞的奥马珠单抗浓度不足，无法中和肺部产生的IgE。此外，一名受试者产生了抗奥马珠单抗抗体，这也令人担心吸入单抗可能比注射给药免疫原性更强[13]。2014年，来自比利时的研究团队发表了关于雾化吸入抗原结合片段（fragment of antigen binding，Fab）在哮喘小鼠模型（NMRI）中的研究结果[14]，该研究通过聚乙二醇化延长了IL-17A Fab2和IL-13Fab双抗在呼吸道局部停留时间，肺内聚乙二醇化抗体含量在给药后4h达到平台期，而未成功偶联聚乙二醇的抗体则入肺后就开始清除，研究阐释了聚乙二醇化修饰对治疗性蛋白局部递送到肺部后的长效具有显著效果。此后，该团队又相继针对不同分子量聚乙二醇分别对IL-17A Fab和IL-13Fab长效后肺部沉积进行了探索，上述研究主要聚焦肺部药物长效化机制研究，并未对抗体靶点组合的药效及成效性进行深入探索，但初步论证了吸入抗体给药途径的可行性。比利时布鲁塞尔的优时比制药（UCB Pharma）在食蟹猴过敏性哮喘模型中布局了针对雾化吸入IL-13靶点Fab抗体CDP7766的研究，该研究发现通过振动网筛雾化器产生的气溶胶仍保持优异的分子活性及纯度，没有明显的降解和聚体产生，并且在动物模型中表现出良好的耐受性，未观察到局部刺激相关的不良反应，并显著抑制了肺泡灌洗液中过敏原诱导的细胞因子和趋化因子的上调，临床上可快速持久地抑制FeNO，健康和哮喘受试者均表现出良好的耐受性（NCT02473939），证明了吸入性抗IL-13抗体片段药物治疗过敏性哮喘的潜力[15]。Faghihi等通过喷雾干燥将肿瘤坏死因子α（tumor necrosis factorα，TNFα）单克隆抗体Infliximab开发成干燥粉剂，用于局部炎症性哮喘治疗，探讨通过吸入给药途径抑制肺部分泌TNFα的可行性，但其粉剂分子与TNFα结合降低了21%，在卵清蛋白刺激小鼠哮喘模型中表现出的TNFα分子抑制活性相对于单抗降低了2个数量级，虽然抗体干粉开发成功与否主要取决于喷雾干燥条件、配方成分及抗体雾化稳定性，但该研究初步提示了单克隆抗体并不合适用于吸入制剂开发[16]。CSJ117是诺华布局的一款针对TSLP靶点的Fab拮抗剂（Ecleralimab），CSJ117采用粉雾剂药物开发方式用以治疗成人轻度特应性哮喘，在其I期临床研究（NCT03138811）中，CSJ117耐受性良好，并减轻过敏原激发后的支气管收缩[17]。2020年诺华启动了一项II期试验，目的是研究CSJ117治疗未得到控制的重度哮喘的药效和安全性研究（NCT04410523），II期临床研究已完成，但暂未数据揭盲，并且由于诺华产业战略调整，该项目暂停了后续开发，正在积极寻求合作转让。安进及阿斯利康在携手成功推出TSLP单克隆抗体Tez-epelumab商业化上市后，快速对上市药物分子进行工程化改造将单克隆抗体皮下注射液开发成为Fab干粉吸入剂型，项目代码为AMG104/AZD8630，该项目已于2022年启动临床I期研究，以评估安全性、耐受性和药代动力学（NCT05110976）。5.3.2 吸入纳米抗体除了单克隆抗体及抗体片段外，诸如Nanobodies®、Anticalin®、Affibody®等新型蛋白骨架类型在基于蛋白质的吸入治疗领域引起了轰动。与全长单克隆抗体相比，新型蛋白骨架体积较小、结构简单，更容易结合隐蔽结合位点、组织渗透面积更大、药物聚集更方便、热稳定性更强[18]。纳米抗体是由驼科动物体内重链抗体（95kDa）可变区扩增而来的单域抗体，又称为VHH抗体（variable domain of heavy chain of heavy-chain antibody，VHH），从属于基因工程抗体范畴。纳米抗体晶体尺寸直径2.5nm，长4nm，是目前可与抗原结合的最小片段。2018年，首创的Nano-body®caplacizumab（Cablivi®）获得欧洲药品管理局的首个上市许可，用于治疗获得性血栓性血小板减少性紫癜，虽然caplacizumab是肠外用药，但吸入型Nanobody®平台及产品一直在临床开发中。吸入型抗合胞病毒纳米抗体药物ALX-0171的安全性和耐受性已在一项首次婴儿I/IIa期临床试验中得到证实，并观察到抗病毒活性[19]。尽管IIb期剂量范围研究已经完成（NCT02979431），但在下呼吸道感染和炎症发生的基础上，继续雾化ALX-0171并不能改善临床治疗结果，所以该项目未达预期而被搁置研究，但该研究表明ALX-0171在早期的使用干预可产生重要的临床抗病毒作用。随着新冠疫情爆发，许多纳米抗体也被开发成吸入制剂以对抗SARS-CoV-2感染，如洛启生物的Nb11-59表现出强效的体外真病毒中和活性[20]。在哮喘类领域，目前有两款来自洛启生物的纳米抗体吸入产品处于中国临床I期开发阶段，洛启生物靶向IL-4Rα的LQ036产品适应症为嗜酸性粒细胞哮喘，LQ043H靶向TSLP，其适应症为非嗜酸性粒细胞哮喘。LQ036与LQ043H是目前全球推进速度最快的同靶点吸入纳米抗体产品。LQ036及LQ043H均具有优异的体外阻断活性，并按照吸入制剂开发标准进行了完整的空气动力学研究，具有雾化后粒径均匀、生物活性完整保留、药物纯度稳定等优势，同时两款产品均采用毕赤酵母生产系统表达，产量高，工艺简单，药物成本优势明显。LQ036已完成针对安全性、耐受性、免疫原性和药代动力学的澳洲临床I期研究（NCT04993443），安全性、耐受性优异，无药物相关免疫原性发生；目前该项目正处于中国临床I期开发阶段，评价雾化经口吸入LQ036在中国健康受试者体内的耐受性、安全性、免疫原性和药代动力学（CTR20223011）。洛启LQ043H项目同期处于中国临床I期研究阶段，评价LQ043H单域抗体雾化液在中国健康受试者中单次给药后的耐受性、安全性、药代动力学和免疫原性（CTR20230092）。此外，LQ036的慢性阻塞性肺疾病适应症IND申请获得国家药监局药品审评中心（CDE）受理（受理号：CXSL2300435）。LQ036和LQ043H的顺利推进将为纳米抗体在吸入给药方向上的临床应用提供有力支持，并创新性地为哮喘和慢性阻塞性肺疾病患者提供更有效、更安全、更便捷、更经济的治疗方案。5.3.3 吸入类抗体骨架蛋白Anticalin®是Astra Zeneca与Pieris公司蛋白研发平台推出的一类基于丰富血浆及体液来源脂质运载蛋白骨架修饰开发而成的工程化蛋白，通过对脂质运载蛋白1进行定向蛋白质突变，经过系统性修饰推出了Elarekibep项目（PRS-060），Elarekibep是一款靶向IL-4Rα的高亲和力、缓慢解离、长效拮抗剂，用于治疗中度至重度哮喘。Elarekibep的小尺寸和稳定性使其可以被直接吸入肺部，其临床I期以雾化液方式开展，试验显示轻度哮喘患者的FeNO水平显著降低（NCT03384290，NCT03574805）。在其干粉吸入制剂临床II期向3mg及1mg更低剂量组进行药效探索时，其非人类灵长类动物长期毒性研究出现了非药物剂量依赖的炎症介导的肺组织损伤，随即其合作方阿斯利康终止了该项目后续临床开发（NCT04643158）。该项目的失败原因更多指向于Anticalin®平台分子自身结构毒性问题，这一结论为类抗体支架蛋白Anticalin®的未来研发应用蒙上了阴影[21]。Affibody®是Affibody公司推出的一类新型抗体模拟物，该类药物是由58个氨基酸残基组成的新型亲和配体，相对分子质量约为6500，由3个螺旋结构组成，功能与抗体相似，但具备相对分子质量小、折叠速度快、选择性和亲和力高、结构稳定等优势。Affibody最近宣布接受Chiesi投资，使用Affibody专有技术布局开发呼吸系统疾病吸入性创新疗法，根据公司最新官网更新，ABY-062作为一种靶向TSLP的候选药物，很有可能是按照吸入式治疗药物方向开发，这也意味着吸入大分子药物开发行列迎来了新抗体骨架Affibody®的加入，我们期待其在吸入性创新疗法上的表现。5.3.4 吸入重组蛋白除吸入抗体类药物之外，重组蛋白也曾尝试开发成吸入制剂。拜耳医药曾尝试过IL-4蛋白突变体雾化吸入开发方向，Pitrakinra（AER-001，BAY-16-9996）是IL-4蛋白的变体，具有2个氨基酸变化，使其能够结合IL-4Rα链并抑制IL-4Rα与γC或IL-13Rα1的相互作用。在Pitrakinra的一项II期临床研究中，吸入Pitrakinra可减弱过敏原激发后哮喘受试者的晚期哮喘反应和气道炎症，但对哮喘患者应对过敏原挑战的肺功能没有显著影响[22]。虽然在一项药物遗传学研究中，在携带IL-4Rα基因特异性单核苷酸多态性的患者中，Pitrakinra显著降低哮喘急性发作的频率，但最终其临床III期不明原因并未继续推进。Altrakincept是一款通过雾化给药开发的竞争性重组人可溶性IL-4Rα蛋白，已在临床试验中进行了测试，并证明可预防中重度哮喘患者因停用皮质类固醇而导致的肺功能恶化，但进一步的长期研究结果令人失望，该项目也未再进一步推进[23]。6小结在过去的15年里，生物制剂的开发和临床应用显著扩大，但这些药物的给药途径仍主要以局部或系统性注射为主，吸入抗体是一种明显的无创替代方案，为多种疾病的局部治疗提供了机会，尤其对于呼吸系统疾病治疗，同时也尝试应用于系统性疾病的治疗。但由于抗体三维结构复杂，三级结构是其作用的核心，在吸入给药过程中遭受各种应力下容易产生降解和聚体，这种结构的破坏严重影响产品有效性和安全性等性能的评估，所以维持其结构完整性和生物活性对于成功开发吸入性生物制剂至关重要，这无疑对分子特性、配方设计、辅料选择、加工工艺和吸入装置等方面提出了系统性挑战。后续基础研究对上皮细胞转运机制的理解，辅助抗体稳定性、吸收和雾化性能的相容性赋形剂的开发，适配性更高、便携性更好、操作更便捷吸入装置的开发等都会对吸入抗体药物的开发提供更坚实的开发基础。并且随着纳米抗体、抗体片段、抗体骨架等新形式生物制剂的诞生为更多创新药物的开发提供了保障，未来我们期待更多吸入相关创新技术的诞生。总而言之，吸入型生物制剂的开发是一个系统过程，需要全面、充分考虑发病机理、患者群体、药物分子类型选择及其与肺内生物屏障的相互作用等因素，并合理地选择制剂、赋形剂和装置，同时也涉及上述学科和领域的共同发展。我们希望未来会有治疗效果更佳、安全数据更好、自行用药更便捷、药物价格更低廉的吸入生物制剂产品的诞生以满足日渐复杂、日益壮大的临床未满足需求。参考文献详见《中国临床药理学与治疗学》 2024 Apr; 29(4)识别微信二维码，添加生物制品圈小编，符合条件者即可加入生物制品微信群！请注明：姓名+研究方向！版权声明本公众号所有转载文章系出于传递更多信息之目的，且明确注明来源和作者，不希望被转载的媒体或个人可与我们联系(cbplib@163.com)，我们将立即进行删除处理。所有文章仅代表作者观点，不代表本站立场。

2024-04-24

·精准药物

第一批吃到螃蟹的药企

第一批开悟的药企，已率先享受RSV药物的时代红利。作为RSV药物的商业化元年，2023年有2款RSV疫苗和1款预防抗体药物合计斩获30亿美元销售额。随着市场竞争大幕缓缓拉开，更多药企持续开悟中。01国产不再“静悄悄”就中国市场而言，RSV药物赛道可谓是“蓝海中的蓝海”。目前，全球已获批的3款RSV药物，仅赛诺菲/阿斯利康的Beyfortus（尼塞韦单抗）于今年1月在中国上市，而GSK的Arexvy尚处于Ⅰ期临床，预计2026年实现商业化落地。尽管国内市场尚处于萌芽阶段，但潜力巨大。据灼识咨询数据，到2030年，中国RSV药物市场规模预计增至15亿美元，年复合增长率高达75.8%，远超全球同期增速（21.4%）。其中，针对儿童的RSV药物预计约占整个中国RSV药物市场的89.4%。这无疑吸引了众多国产企业布局，包括艾棣维欣、三叶草生物、沃森生物、艾美疫苗、智飞生物等，多数技术路线为已验证成药性的重组蛋白和mRNA。图片来源：中航证券研报进度最快的是艾棣维欣重组蛋白亚单位疫苗ADV110（BARS13），针对60-80岁老年人的II期临床试验，以及针对18-45岁成人的I期临床试验，均显示出良好的安全性、耐受性和免疫原性。三叶草生物基于其独有的Trimer-Tag（蛋白质三聚体化）疫苗技术平台开发的二价重组蛋白RSV候选疫苗SCB-1019，在针对18-59岁成人的I期试验中取得了积极初步数据。另外，处于临床早期阶段的还有康乐卫士、康泰生物布局的重组蛋白疫苗，以及百克生物布局的重组亚单位疫苗。mRNA疫苗方面，艾美疫苗、沃森生物/蓝鹬生物、石药集团和嘉晨西海等均已布局，目前处于临床早期阶段。值得一提的是，智飞生物与GSK于去年10月签订了在中国独家销售带状疱疹疫苗Shingrix的合作，同时还就后者的RSV疫苗Arexvy达成初步合作意向。除此以外，也有一些国产企业选择布局RSV预防药物。例如，爱科百发的RSV抗病毒特效药AK0529已向国家药监局递交上市申请，用于治疗婴幼儿、成人患者中RSV感染，有望成为全球首个获批的特效抗RSV病毒感染的临床药品；智翔金泰研发的重组RSV单抗GR2102，于今年2月获批临床，拟用于预防RSV感染。02全球争夺“大蛋糕”据不完全统计，目前全球有近70条在研RSV预防管线，涉及技术路线包括减毒活疫苗、亚单位疫苗、mRNA疫苗和针对不同病毒蛋白的重组载体候选疫苗，参与者不乏强生、默沙东等MNC巨头。其中，Moderna的mRNA-1345进展最快，对60岁以上老人效果显著，目前已申请在欧盟、瑞士、澳大利亚和美国等多地上市，并开展了针对儿科人群的临床试验。格外值得一提的是，已拥有RSV预防药物的阿斯利康，也顺势打入了RSV疫苗赛道：于2023年底斥资11亿美元溢价收购Icosavax，后者的核心产品IVX-A12是一种针对RSV和人偏肺病毒（hMPV）的潜在FIC的VLP组合候选疫苗，已被FDA授予针对60岁以上成人的快速通道资格，可与Synagis和Beyfortus形成互补，覆盖更多人群，且即将开展Ⅲ期临床试验。除技术创新外，一些企业还选择开发疫苗联合疗法。例如，近日GSK启动了RSV重组蛋白疫苗+新冠mRNA疫苗联合免疫的三期临床试验；Moderna也布局了一款流感/新冠/RSV三联mRNA疫苗mRNA-1230，目前处于临床前阶段。RSV预防药物的在研管线也不在少数，包括默沙东的clesrovimab、珠海泰诺麦博TNM001和赛诺菲的gontivimab等，均已处于临床Ⅱ期及以上阶段。从上述管线的进度不难看出，未来几年RSV药物的市场竞争将进入白热化阶段。全球RSV抗体管线丰富图片来源：开源证券研报由于RSV可感染广泛人群，扩大适用年龄范围成为推动RSV疫苗增长的关键。这点与HPV疫苗类似。默沙东的九价HPV疫苗之所以能爆卖，正是由于扩龄策略，将适用人群从16-26岁拓展至9-45岁适龄女性，使得潜在消费者基数大幅增加，市场空间实现了翻倍。除了老年人，RSV疫苗的适用人群还在持续拓展。今年1月底，欧盟已受理GSK的Arexvy扩龄至50-59岁成人的上市申请，预计今年下半年可获批上市。只是很可惜，Arexvy针对婴幼儿和孕妇的临床试验均未成功。另一边，辉瑞的Abrysvo也在扩龄：去年8月获得FDA批准新增胎龄32-36周孕妇适应症，以保护新生儿免受RSV感染。而且，Abrysvo针对18-59岁人群的III期研究已经成功，即将申请上市，同时正在开展针对2-17岁高危儿童及青少年的Ⅲ期临床试验。可见，无论GSK还是辉瑞，都在想方设法攻克儿童人群，尤其5岁以下婴幼儿。毕竟，该年龄段是RSV的最核心易感人群，市场前景更佳。据灼识咨询数据显示，针对儿童的RSV药物预计2030年将增至117亿美元，将占全球RSV药物市场的91.1%。基于此，不少药企布局了儿童RSV疫苗，包括赛诺菲的鼻喷减毒活疫苗LID/ΔM2-2/1030s（Ⅲ期，预计2026年提交上市申请）、BlueLake（蓝湖生物）的BLB-201（Ⅱ期）等。值得一提的是，赛诺菲的LID/ΔM2-2/1030s可以保护新生儿在第二个RSV流行季（次年4月-次年9月）不受感染，而与阿斯利康联合研发的Beyfortus，可保护新生儿在第一个RSV流行季（当年10月-次年3月）不受感染，可谓进行了全方位的布局。图片来源：民生证券研报03百亿美元赛道作为新晋明星赛道，RSV疫苗市场需求大、增长潜力足，被誉为“下一个HPV疫苗”。呼吸道合胞病毒（RSV）感染范围广泛，具有明显的季节性，尤其在秋末初冬时高发，对所有年龄段的人群都构成威胁，特别是婴幼儿、成年免疫缺陷者和老年人等高危人群。根据WHO统计数据显示，RSV每年导致全球约6400万儿童感染、36万成人入院。针对RSV感染的治疗，主要分为主动免疫（RSV疫苗）和被动免疫（RSV预防药物）两种治疗手段。1998年，诞生了全球首款RSV预防药物，MedImmune公司（后被阿斯利康收购）研发的Synagis（帕利珠单抗）获FDA批准上市，用于预防早产儿RSV引起的下呼吸道疾病。但由于价格昂贵、覆盖病患群体小（仅在美国获批用于治疗早产儿），且需每月注射一次，直到上市后的第10年，Synagis才跻身“重磅炸弹药物”行列。近两年，RSV预防药物迎来了重大突破：由阿斯利康和赛诺菲联合开发的Beyfortus（尼塞韦单抗），分别于2022年、2023年获欧盟、FDA批准上市，用于预防婴幼儿RSV引起的下呼吸道疾病。图片来源：平安证券研报相较之下，RSV疫苗的研发之路更加坎坷，耗时60多年才终于迎来曙光。2023年5月，葛兰素史克（GSK）的Arexvy、辉瑞的二价RSV疫苗Abrysvo相继获FDA批准上市，用于预防60岁及以上人群由RSV引起的下呼吸道疾病。至此，2023年成为了RSV药物的商业化元年，且销售表现不俗。其中，Arexvy仅销售7个月便大卖15.66亿美元，Abrysvo在6个月的时间实现销售额8.9亿美元，Beyfortus的营收也达到了5.98亿美元。GSK预测，Arexvy销售峰值将超过30亿英镑，彰显RSV疫苗市场的巨大潜力。由于感染广泛、疾病负担重、市场尚处蓝海，RSV药物市场具备百亿美元级别的潜力。据灼识咨询研究数据显示，RSV药物全球整体市场规模预计到2030年将增长至128亿美元。参考资料：1.各家公司的财报、公告、官微2.《11亿美元AZ入新局，与辉瑞、GSK开启“三国杀”？RSV赛道谁是国内第一玩家？》，E药经理人，2023-12-163.平安证券、民生证券、开源证券、中航证券研报声明：本内容仅用作医药行业信息传播，为作者独立观点，不代表药智网立场。如需转载，请务必注明文章作者和来源。对本文有异议或投诉，请联系maxuelian@yaozh.com。责任编辑 | 金银花转载开白 | 马老师 18996384680（同微信）商务合作 | 王存星 19922864877（同微信）阅读原文，是受欢迎的文章哦

疫苗临床1期信使RNA临床2期

2018-02-22

·GlobeNewswire

ABLYNX ANNOUNCES 2017 FULL YEAR RESULTS

REGULATED INFORMATION A year of many momentous moments GHENT, Belgium, 22 February 2018 - Ablynx [Euronext Brussels and Nasdaq: ABLX] today announced its financial results for the year ended 31 st December 2017, which have been prepared in accordance with IFRS as issued by the IASB and adopted by the European Union, business highlights year-to-date and the outlook for the remainder of the year. 2017 Highlights Compelling Phase III data for caplacizumab (wholly-owned, anti-vWF Nanobody®) for the treatment of acquired thrombotic thrombocytopenic purpura (aTTP), a potential €1.2 billion per annum market, which will support both the ongoing regulatory review process in Europe and the planned Biologics License Application (BLA) in the USA Successful US initial public offering (IPO) raising $230 million Completed the dose escalation part of the Phase IIb RESPIRE study in 36 infants with the wholly-owned anti-RSV (respiratory syncytial virus) Nanobody, ALX-0171, and initiated the parallel dose part in 144 infants, with topline results expected in Q4 2018 Research collaboration with Sanofi on up to eight new programmes, focussed on immune-mediated inflammatory diseases, with €23 million in upfront payments and up to €2.4 billion in potential milestones plus tiered royalties Received €15 million milestone payment from Merck KGaA for the completion of a pre-clinical package for ALX-1141, targeting ADAMTS-5 in osteoarthritis, which has since entered Phase I trials Total revenues of €55.5 million and net cash burn [1] of €60.4 million resulting in a cash position, including cash, other financial assets, restricted cash and deposits of €354.3 million On 29 th January 2018, Ablynx announced an offer by Sanofi to acquire all its outstanding ordinary shares (including shares represented by American Depository Shares (ADSs), warrants and convertible bonds) at a price of €45 per share, which represents an aggregate equity value of approximately €3.9 billion. This proposed transaction was unanimously approved by both the Sanofi and Ablynx Board of Directors. The tender offer is expected to be launched in the beginning of the second quarter of 2018. Sanofi will publish an offer document in which it will set out the full details of its tender offer, and the Board of Directors of Ablynx will publish a response memorandum (' memorie van antwoord '), in which it will set out its position on the tender offer. Dr Edwin Moses, CEO of Ablynx said: "We experienced many momentous moments this year including the compelling Phase III results for our lead product caplacizumab and our successful US initial public offering. Caplacizumab has the potential to change the lives of patients affected by aTTP, a devastating disease for which there is currently no approved drug available. We are proud to be pioneers in the treatment of aTTP and are working with the regulatory authorities to obtain marketing approval and make caplacizumab rapidly available to patients." "We are also pleased with the progress made with our anti-RSV Nanobody, ALX-0171, that is delivered via nebulisation, a technique with potential in other pulmonary diseases, and we look forward to the results from our Phase IIb RESPIRE study which should be available before the end of this year." "The offer made by Sanofi on 29 th January 2018 to acquire Ablynx for €3.9 billion represents compelling value for shareholders and builds on a successful existing partnership. We strongly believe that Sanofi's global infrastructure, commitment to innovation and commercial capabilities will accelerate Ablynx's therapeutic programmes and maximise the potential of our pipeline and unique Nanobody technology platform to the benefit of all stakeholders." Operational review R&D update In January , Ablynx's partner, Merck KGaA, reported encouraging results from their Phase Ib study of the bi-specific anti-IL-17A/F Nanobody, in patients with moderate to severe psoriasis. In February , Ablynx submitted a marketing authorisation application (MAA) to the European Medicines Agency (EMA) for caplacizumab, its wholly-owned anti-vWF-Nanobody, caplacizumab, for the treatment of aTTP, including data from the Phase II TITAN study. In November, the MAA was further updated with the positive results of the Phase III HERCULES study that were announced in October . In May , Ablynx received a €15 million milestone payment from Merck KGaA for the completion of a pre-clinical package for a novel Nanobody (ALX-1141) targeting ADAMTS-5 in osteoarthritis, with Merck KGaA subsequently starting a Phase I study. In June , Ablynx achieved a second milestone in the immuno-oncology collaboration with Merck & Co., Inc., (known as MSD outside the USA and Canada) triggering a €2.5 million payment to Ablynx. In July , Ablynx received Fast Track designation from the FDA for caplacizumab for the treatment of aTTP. In August , Ablynx announced the completion of the sequential dose escalation part of the Phase IIb RESPIRE study in 36 infants hospitalised as a result of a RSV infection and the initiation of the parallel dose part in 144 infants with ALX-0171, the Company's inhaled anti-RSV Nanobody. Results from this Phase IIb study are expected in Q4 2018. In October , Ablynx announced positive topline results from the Phase III HERCULES study of caplacizumab, in 145 patients with aTTP. The study met its primary and two key secondary endpoints and reported a favourable safety profile. In December , Ablynx reported additional clinically important benefits of caplacizumab from its Phase III HERCULES study in aTTP at the 59 th Annual Meeting of the American Society of Hematology (ASH) as part of the late-breaking abstracts session. Also in December , Ablynx announced positive data from a single and multiple dose Phase I study of caplacizumab, demonstrating comparable pharmacokinetics in 60 healthy Japanese and Caucasian subjects. Corporate developments In June , Ablynx appointed Dr Markus Ewert as Chief Business Officer to lead Ablynx's business development activities and become a member of the Executive Committee. In July , Ablynx announced a research collaboration and global exclusive licensing agreement with Sanofi to develop up to eight Nanobody product candidates initially focused on immune-mediated inflammatory diseases. Ablynx received an upfront payment of €23 million plus research funding for the initially selected targets and is eligible to receive further option exercise fees from additional targets and up to €2.4 billion in potential future milestone payments and royalties on the net sales of any products originating from the collaboration. In October , following the positive Phase III data of caplacizumab, Ablynx completed its initial US public offering, raising $230 million in gross proceeds from the sale of 13,144,500 ordinary shares in the form of ADSs, including the full exercise of the underwriters' option, at a price of $17.50 per ADS. The US public offering was nearly three times oversubscribed and was upsized from the $175 million initially targeted. Also in October , Ablynx established Ablynx, Inc., its subsidiary in the USA and appointed Mr Daniel Schneider as the General Manager to lead the commercialisation of caplacizumab in North America. Post-period highlights In January 2018 , Ablynx announced the appointment of Robert Friesen, PhD, as Chief Scientific Officer, effective 1 st March 2018. Dr Friesen will lead the Company's scientific, research and technology activities and become a member of the Executive Committee. In January and February 2018, Ablynx announced changes to its Board of Directors with the departures of Dr Peter Fellner and Dr Bo Jesper Hansen respectively. Dr Russell G. Greig, who has been a non-executive Director of Ablynx since 2012, is now the new Chairman of the Board. On 16 th February 2018 , Ablynx announced that as part of the research collaboration signed in July 2017, Sanofi has exercised its options for two additional multi-specific Nanobody product candidates, triggering the payment to Ablynx of €13 million in exercise fees. On 1 st March 2018, Piet Houwen will join Ablynx as Chief Operating Officer. Mr Houwen will be responsible for the support of Ablynx's business and R&D processes and become a member of the Executive Committee. Outlook for the remainder of 2018 During H1 2018, a BLA will be submitted for caplacizumab in the USA. In Europe, the Company has the potential to receive marketing authorisation for caplacizumab in aTTP in Q3 2018 followed by potential first commercial sales in Germany. For ALX-0171, a Phase II study in Japanese infants, hospitalised as a result of a RSV infection, and a global Phase II study in hematopoietic stem cell transplant patients who become infected with RSV, are expected to be initiated in H1 2018. Results from the ongoing Phase IIb study in RSV-infected hospitalised infants are expected in Q4 2018. The Phase II study results for vobarilizumab (anti-IL6R Nanobody) in 312 systemic lupus erythematosus (SLE) patients are expected in H1 2018 followed by AbbVie's decision on whether to opt-in and license the compound. The Company expects up to three Nanobodies to enter Phase I studies from our collaborative programmes during the year. Detailed financial review (€ million) FY 2017 FY 2016 Variance Total revenue and grant income 55.5 85.2 (35%) R&D income 55.5 84.8 (35%) Grants - 0.4 Operating expenses (109.7) (113.8) (4%) R&D (90.9) (100.3) (9%) G&A (18.8) (13.5) 39% Operating loss (54.2) (28.6) (90%) Net financial result (54.3) 27.5 < (100%) Net loss (108.5) (1.1) < (100%) Net cash burn* (60.4) (1) (72.2) (3) 16% Cash position** at 31 December 354.3 (2) 235.4 (4) 51% (1) excluding €179.3 million net proceeds from Nasdaq IPO (2) including €1.6 million in restricted cash (3) excluding €71.4 million net proceeds from the private placement announced on 1 June 2016 (4) including €1.6 million in restricted cash * Net cash burn is the difference between the cash position of the current year and the previous year minus the proceeds (net of issue costs) from the issue of ordinary shares ** Cash position includes cash, other financial assets, restricted cash and deposits Income statement Total revenues and grant income decreased by 35% to €55.5 million (2016: €85.2 million), mainly driven by lower recognition of upfront payments from the ongoing collaborations with AbbVie and Merck & Co., Inc. Total research and development costs decreased to €90.9 million (2016: €100.3 million) in line with the decrease in external development costs, largely related to lower clinical trials expenditure for vobarilizumab. General and administrative costs increased to €18.8 million (2016: €13.5 million), related to expenditure for consultancies and staff, including pre-commercialisation costs for caplacizumab and costs related to the IPO on Nasdaq completed in October 2017. As a result of the above, the operating loss was €54.2 million (2016: €28.6 million). The net financial loss of €54.3 million comprises finance expenses of €46.6 million resulting from an increase in the fair value of the derivative associated with the convertible bond (following an increase in the Ablynx share price at year-end compared to that at the end of 2016), and finance costs of €7.4 million (mainly related to the amortisation of the debt component of the convertible bond). As a result, the net loss for 2017 increased to €108.5 million (2016: net loss of €1.1 million). Balance sheet The Company's non-current assets of €78.5 million are €53.9 million higher than at 31 December 2016, mainly driven by the purchase of Interest Structured Notes with a maturity of two years and higher receivables for research and development incentives. Ablynx's current assets of €311.3 million consist mainly of cash and cash equivalents and other financial assets. Cash and cash equivalents consist of cash and deposits held on call with several banks. The Company also places cash in term accounts with maturities limited to a maximum of one year. Shareholders' equity increased from €103.1 million at the end of 2016 to €179.9 million at the end of 2017, mainly as a result of the €179.3 million net proceeds from the IPO on Nasdaq and the incorporation of the €108.5 million loss for the period. Non-current liabilities relate to the senior unsecured bonds due on 27 May 2020 with a principal value of €100 million. Current liabilities consist mainly of trade payables and deferred income related to the upfront payments received from partners. Cash flow statement Net cash outflow from operating activities was €57.8 million as compared to a net outflow of €66.6million in 2016. The difference primarily relates to lower operating expenses for the current period. Cash flow from investing activities resulted in a net outflow of €160.0 million as compared to a net inflow of €45.9 million in 2016. The net cash outflow primarily relates to the movements from deposits with a term of less than 1 month to deposits with a term greater than 1 month. Cash flow from financing activities represented a net inflow of €179.5 million compared to a net inflow of €70.4 million in 2016. The difference primarily relates to higher net proceeds from the issue of new shares on Nasdaq in 2017 compared to the net proceeds raised via an accelerated book building procedure in 2016. The Company ended the period with a total liquidity position of €354.3 million (2016: €235.4 million) which consists of cash and cash equivalents of €14.9 million, other financial assets of €337.8 million and restricted cash of €1.6 million. Investor Conference Call and Webcast In light of the pending transaction with Sanofi, Ablynx will not be hosting a conference call to discuss its 2017 full year results. Next financial events 27 March 2018 - online publication Annual Report 2017 26 April 2018 - Annual General Meeting 2018 Glossary of terms ADS American Depositary Shares ASH American Society of Hematology aTTP acquired thrombotic thrombocytopenic purpura BLA biologics license application EMA European Medicines Agency IPO Initial Public Offering MAA marketing authorisation application RA rheumatoid arthritis RSV respiratory syncytial virus SLE systemic lupus erythematosus About Ablynx Ablynx is a biopharmaceutical company engaged in the development of Nanobodies , proprietary therapeutic proteins based on single-domain antibody fragments, which combine the advantages of conventional antibody drugs with some of the features of small-molecule drugs. Ablynx is dedicated to creating new medicines which will make a real difference to society. Today, the Company has more than 45 proprietary and partnered programmes in development in various therapeutic areas including inflammation, haematology, immuno-oncology, oncology and respiratory disease. The Company has collaborations with multiple pharmaceutical companies including AbbVie; Boehringer Ingelheim; Eddingpharm; Merck & Co., Inc., Kenilworth, New Jersey, USA; Merck KGaA; Novo Nordisk; Sanofi and Taisho Pharmaceuticals. The Company is headquartered in Ghent, Belgium. More information can be found on www.ablynx.com . For more information, please contact Ablynx: Dr Edwin Moses CEO t: +32 (0)9 262 00 07 m: +32 (0)473 39 50 68 e: edwin.moses@ablynx.com Lies Vanneste Director Investor Relations t: +32 (0)9 262 01 37 m: +32 (0)498 05 35 79 e: lies.vanneste@ablynx.com Follow us on Twitter @AblynxABLX Ablynx media relations: Consilium Strategic Communications Mary-Jane Elliott, Philippa Gardner, Sukaina Virji t: +44 (0)20 3709 5700 e: ablynx@consilium-comms.com Joele Frank, Wilkinson Brimmer Katcher Dan Katcher or Joseph Sala t: +1 212-355-4449 Disclaimer Certain statements, beliefs and opinions in this press release are forward-looking, which reflect the Company or, as appropriate, the Company directors' current expectations and projections about future events. By their nature, forward-looking statements involve a number of risks, uncertainties and assumptions that could cause actual results or events to differ materially from those expressed or implied by the forward-looking statements. These risks, uncertainties and assumptions could adversely affect the outcome and financial effects of the plans and events described herein. A multitude of factors including, but not limited to, changes in demand, competition and technology, can cause actual events, performance or results to differ significantly from any anticipated development. Forward looking statements contained in this press release regarding past trends or activities should not be taken as a representation that such trends or activities will continue in the future. As a result, the Company expressly disclaims any obligation or undertaking to release any update or revisions to any forward-looking statements in this press release as a result of any change in expectations or any change in events, conditions, assumptions or circumstances on which these forward-looking statements are based. Neither the Company nor its advisers or representatives nor any of its parent or subsidiary undertakings or any such person's officers or employees guarantees that the assumptions underlying such forward-looking statements are free from errors nor does either accept any responsibility for the future accuracy of the forward-looking statements contained in this press release or the actual occurrence of the forecasted developments. You should not place undue reliance on forward-looking statements, which speak only as of the date of this press release. Additional Information for US Investors The tender offer for the outstanding ordinary shares ("Shares"), American Depositary Shares issued by J.P. Morgan Chase Bank, N.A., acting as depositary ("ADSs"), warrants ("Warrants") and convertible bonds of Ablynx ("Bonds" and, together with the Shares, ADSs and Warrants, the "Securities") has not yet commenced. This communication is for informational purposes only and is neither a recommendation, an offer to purchase nor a solicitation of an offer to sell any Securities of Ablynx. At the time the tender offer is commenced, Sanofi will file, or cause to be filed, a tender offer statement on Schedule TO with the SEC and thereafter, Ablynx will file a solicitation/recommendation statement on Schedule 14D-9. Holders of Securities are urged to carefully review the documents that will be filed by Sanofi and Ablynx with the SEC because these documents will contain important information, including the terms and conditions of the tender offer. The offer to purchase, the related letter of transmittal and certain other tender offer documents, as well as the solicitation/recommendation statement, are available to all holders of Securities of Ablynx at no expense to them. These documents are available for free at the SEC's website at www.sec.gov. Additional copies may be obtained for free by contacting Sanofi at ir@Sanofi.com or on Sanofi's website at https://en.Sanofi.com/investors. You should read the filings made by Sanofi and Ablynx with the SEC carefully before making a decision concerning the U.S. Offer. [1] Net cash burn is the difference between the cash position of the current year and the previous year minus the proceeds (net of issue costs) from the issue of ordinary shares Attachments: http://www.globenewswire.com/NewsRoom/AttachmentNg/2d4f2974-6e82-4d3d-9220-4d622bf87dcf

合作财报抗体快速通道IPO

100 项与 ALX-0171 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB16179

研发状态

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适应症	最高研发状态	国家/地区	公司	日期
下呼吸道感染	临床2期	澳大利亚	Ablynx NV	2014-12-01
下呼吸道感染	临床2期	比利时	Ablynx NV	2014-12-01
下呼吸道感染	临床2期	保加利亚	Ablynx NV	2014-12-01
下呼吸道感染	临床2期	爱沙尼亚	Ablynx NV	2014-12-01
下呼吸道感染	临床2期	匈牙利	Ablynx NV	2014-12-01
下呼吸道感染	临床2期	以色列	Ablynx NV	2014-12-01
下呼吸道感染	临床2期	拉脱维亚	Ablynx NV	2014-12-01
下呼吸道感染	临床2期	马来西亚	Ablynx NV	2014-12-01
下呼吸道感染	临床2期	菲律宾	Ablynx NV	2014-12-01
下呼吸道感染	临床2期	波兰	Ablynx NV	2014-12-01

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临床结果

适应症

分期

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT02979431 (CTgov)	临床2期	呼吸道合胞体病毒感染	180	Placebo (Placebo)	廠範遞夢遞齋蓋衊壓鹽(顧膚獵網憲顧鹽蓋繭鹹) = 觸觸淵簾夢鹽積築壓觸餘鏇範築積憲鏇廠鹽願 (廠襯鏇鑰壓窪廠齋夢糧, 艱鏇衊艱鏇糧憲艱衊夢 ~ 憲鏇觸醖網選簾遞餘廠) 更多	-	2019-10-18
				ALX-0171 3.0 mg/kg (ALX-0171 3.0 mg/kg)	廠範遞夢遞齋蓋衊壓鹽(顧膚獵網憲顧鹽蓋繭鹹) = 醖糧觸製膚淵遞餘衊積餘鏇範築積憲鏇廠鹽願 (廠襯鏇鑰壓窪廠齋夢糧, 獵鏇醖積淵繭繭餘網選 ~ 壓製築壓遞淵鬱範獵艱) 更多
NCT03418571 (CTgov)	临床2期	呼吸道合胞体病毒感染	15	ALX-0171 1.5 mg/kg (ALX-0171 1.5 mg/kg)	構鬱觸積餘願壓範壓淵(齋壓構夢餘衊憲蓋艱廠) = 範鏇襯製憲遞糧壓遞淵選夢獵壓壓製簾遞繭簾 (憲顧繭構蓋鏇觸獵蓋襯, 蓋夢艱願構蓋膚鏇築選 ~ 襯鹽築淵艱簾壓壓夢醖) 更多	-	2019-07-15
				Placebo (Placebo)	構鬱觸積餘願壓範壓淵(齋壓構夢餘衊憲蓋艱廠) = 廠淵壓選獵積鏇餘積膚選夢獵壓壓製簾遞繭簾 (憲顧繭構蓋鏇觸獵蓋襯, 淵齋製壓糧壓願蓋壓製 ~ 鏇襯繭網餘衊齋鹽鏇獵) 更多