IGF-1

点击上方的 行舟Drug ▲ 添加关注长效生长激素制剂研究现状及进展来源《中国新药杂志》 2024年 第33卷第3期作者刘清扬，张娟，后子靖，康琛，刘鑫，张波，唐彦中国医学科学院北京协和医院；烟台毓璜顶医院；北京中医药大学东直门医院；河北医科大学第二医院摘要生长激素缺乏症是一种生长激素分泌障碍所导致的内分泌疾病，主要特征是生长激素水平不足，无法维持正常的生长和代谢。其病因可能为先天性或后天性的，儿童生长激素缺乏症主要特征为身材矮小、生长障碍；成人生长激素缺乏症临床表现往往呈非特异性。目前标准治疗方案是使用外源性生长激素替代治疗，以短效重组人生长激素的使用最为常见，但需要每日皮下注射，会导致依从性差和疗效下降。长效生长激素制剂可减少给药注射频率，提高依从性和疗效，多种长效生长激素制剂目前处于不同的开发阶段。本文就长效生长激素制剂的研究现状和最新进展进行综述，以期为长效生长激素的使用提供参考。关键词生长激素缺乏症；生长激素；长效生长激素；激素替代治疗_正文_重组人生长激素（recombinant human growth hormone，rhGH）每日皮下注射治疗生长激素缺乏症（growth hormone deficiency，GHD）的长期安全性和有效性已得到充分研究[1-2]。然而，由于需要每天注射，维持最大限度的治疗依从性具有挑战性，依从性不佳会导致临床疗效下降，与每日注射的生长激素（growth hormone，GH）治疗相比，每周注射一次长效生长激素（long⁃acting growth hormone，LAGH）的治疗方案可提供更大便利性、耐受性和依从性[3]。本文介绍了不同LAGH类型、研究进展及潜在存在的安全问题，以期为更全面、更清楚地了解该领域的研究状况提供参考。1GHGH是由人脑垂体前叶中的GH细胞合成、存储和分泌的一种由191个氨基酸组成的非糖化多肽，分子量约为22kDa，全天以脉冲形式分泌，白天有几个高峰，睡眠时脉冲次数增加[4]。GH的合成和释放主要受下丘脑所分泌的生长激素释放激素（growth hormone releasing hormone，GHRH）和生长激素释放抑制激素正⁃负向调控[5]。大多数生理作用是通过GH⁃IGF轴来实现的，GH分泌后被运输到全身，通过GH受体（growth hormone receptor，GHR）几乎在身体的每个细胞发挥作用，既可直接与靶细胞中的GHR结合，刺激靶细胞生长，又可经胰岛素样生长因子（insulin⁃like growth factor，IGF⁃1）介导，作用于肝脏、骨骼肌、脂肪等多个靶器官[6]。在靶器官（如肝脏）和外周组织（如骺板）中，GH诱导产生IGF⁃1，肝脏是IGF⁃1的主要来源，IGF⁃1通过负反馈循环调节内源性GH的产生，而组织来源的IGF⁃1同时以自分泌和旁分泌的方式起作用[7]。GH和IGF⁃1协同发挥作用，IGF⁃1增强GH的合成代谢作用，同时对抗GH的高血糖和脂肪分解作用。GH具有广泛的生理学效应，其主要功能为促进身体生长和发育，此外还参与蛋白质、脂类和碳水化合物代谢及功能调节[8]。GH不同于类固醇激素，不会产生糖皮质激素或性激素样的不良反应。自20世纪50年代以来，GH的来源经历了尸源垂体提取、大肠杆菌合成、酵母菌合成、哺乳动物细胞重组DNA技术合成、基因重组修饰合成等不同阶段[9]。随着GH来源的增多，其适应证也逐渐扩展，除最早于1985年被美国FDA批准治疗GHD之外，至今已获批用于10余种疾病的治疗，包括特纳综合征、努南综合征、Prader⁃Willi综合征、特发性矮小等[10]。文章内容由凡默谷小编查阅文献选取，排版与编辑为原创。如转载，请尊重劳动成果，注明【来源：凡默谷公众号】。2GHD GHD是由于下丘脑⁃垂体功能障碍导致GH合成或分泌不足，或由于GH结构异常或受体缺陷所导致的生长发育及代谢障碍的内分泌疾病[11]。儿童生长激素缺乏症（pediatric growth hormone defi⁃ciency，PGHD）主要表现为身材矮小、生长障碍；PGHD可以是先天性的（遗传、围产期损伤、畸形、身体创伤或垂体柄发育不良），也可以是后天的（肿瘤、手术、感染或放疗）；可以是单独的，也可以合并其他垂体激素缺陷[12]。成人生长激素缺乏症（adult growth hormone deficiency，AGHD）临床表现呈非特异性，可表现为身体成分异常（体脂增加、体重减少、骨密度降低等）、基质代谢异常（血脂异常、胰岛素抵抗等）和心血管风险增加[13]，AGHD根据起病年龄分为儿童期发病和成人期发病[14]。GHD的特征是GH水平不足，无法维持正常的生长和代谢，GHD的理想治疗手段是使用GH替代治疗，替代疗法应实现每日和内源性GH相同的组织分布和效果，同时保持GH水平和产生的IGF⁃1在生理范围内。GH替代时代始于1958年[15]，随后，rhGH疗法被每天使用。研究表明，每日使用rhGH可提高GHD患者的身高增长速度并有效改善身体成分[16]。虽然GH治疗已经很成熟，但每日注射不方便，独立且无人监督的青少年不依从率高达66%~77%，会导致依从性差和疗效下降[17]。即使近年各方通过研制出方便注射的笔以及改良配方和保存方式等，期望改善注射体验、提高依从性，但仍有相当多儿童因需要每日注射而使依从性差。LAGH势在必行，在这种情况下，人们开发了LAGH制剂，可以降低给药频率，从每周到每月不等[18]，与每日注射的GH治疗相比，LAGH会提高便利性和依从性，从而提高临床疗效。3LAGH制剂LAGH制剂的制备方法可分为2种：①形成皮下贮库，使天然或改良的GH缓慢扩散到血管系统。②从皮下组织的输送部位迅速吸收，但从循环中缓慢消除[19]。可通过将未修饰的GH与延长技术[贮库、聚乙二醇（polyethylene glycol，PEG）或前药]结合或以一种方式（白蛋白结合）修饰GH来延长GH的半衰期，从而减少给药频率[18-19]。1979年Lippe等[20]通过将垂体衍生的人GH加入明胶中以延长其半衰期，首次尝试开发LAGH制剂。1999年，首个LAGH制剂（nutropin depot）在美国获批并上市，但后来由于注射量大以及注射部位反应，最终退出市场[21]。此后，许多人尝试使用不同的方法来开发LAGH制剂，主要包括如下种类：贮库制剂、PEG化分子、前体药化合物、与白蛋白非共价结合的GH分子及GH融合蛋白。多种LAGH制剂目前处于不同的开发阶段，目前有3种LAGH疗法已被批准用于PGHD治疗，其余则处于不同的临床试验阶段（见表1和图1）[22]。3.1 贮库/微球制剂微球（microspheres）是指药物溶解或分散在成球材料中形成的骨架型微小球形或类球形微粒，其粒径范围一般在1~300μm，可以实现蛋白类药物的缓慢释放，微球缓释剂是最早应用的LAGH延时技术。目前rhGH缓释微球主要以聚乳酸⁃羟基乙酸共聚物[poly（lactic⁃co⁃glycolic acid），PLGA]、聚乳酸（polylactic acid，PLA）、透明质酸（hyaluronicacid，HA）等高分子作为微球骨架材料，将未修饰的GH进行包裹而制成LAGH[23]。1999年美国Genentech公司上市了首个将rh⁃GH包载在PLGA微球中的制剂nutropin depot[24]，在美国获批治疗PGHD，但由于非常黏稠，需要大口径的针注射，易在注射部位产生硬结、红斑，且PLGA逐渐降解产生疏水作用，导致rhGH失活和释放不完全等，于2004年退市。LB03002是一种含有rhGH的HA缓释微球，在中链MCT油中重组，组织透明质酸酶分解微球，缓慢释放GH。2012年发表的一项为期3年的临床试验表明，青春期前未经治疗的GHD儿童皮下注射剂量为0.5~0.7mg·kg-1·周-1的LB03002，与每日皮下注射rhGH相比，具有相似的疗效和更高的安全性[25]。LB03002在韩国上市并获批治疗PGHD，虽2013年在欧洲获得批准，但由于3年没有在欧洲上市，其在欧洲的授权失效。3.2 PEG化合物PEG是一种无毒、无活性和高度亲水的生物惰性且无免疫原性化合物，对rhGH进行PEG化修饰，可增加溶解度、降低毒性、延长循环半衰期[26]。早期PEG⁃GH水凝胶由交联PEG单体形成，具有不理想的高初始爆发治疗效果[27]。用碳氟化合物端基修饰PEG可获得更好的缓释形式[28]。临床研究表明，Ambrx公司生产的ARX201可以提高和维持AGHD患者的血清IGF⁃I水平[29]，但在临床前实验中发现PEG在食蟹猴的脉络膜丛室管膜细胞内积聚[30]，相关药物停止研发。研究发现多个早期研发的PEG⁃GH会导致注射部位脂肪萎缩，这认为与高分子量LAGH在皮下贮库位置的延迟吸收有关[31]。金赛增（Jintrolong®）是我国长春金赛药业有限责任公司研发的一种将支链PEG分子与rhGH的氨基结合的PEG化rhGH长效制剂，于2014年在我国获批用于PGHD，成为首个用于PGHD的PEG化rhGH长效制剂[32]。Ⅰ期临床试验结果表明，12例GHD儿童单次给药后，血清IGF⁃1水平升高并能持续1周，与每日持续注射rhGH无显著差异[33]。金赛增具有更长的半衰期和较低的血浆清除率且无明显的rhGH蓄积，多项临床试验肯定了其安全性和有效性[32，34-35]。尽管PEG化修饰rhGH技术已经较为成熟，但长期给药可能会存在一些潜在不良影响。在临床前灵长动物研究中，主要潜在不良影响是出现细胞空泡化[30]，在后续的临床研究中发现IGF⁃1水平升高、影响机体代谢状态等[32，34]。未来应更多地关注大剂量PEG化rhGH长效制剂治疗安全性。3.3 前药技术（transient conjugation技术，TransCon技术）TransCon指的是“暂时连接”，通过将原形药物与惰性载体临时连接起来的技术[36]，将未经修饰的原形药物以可控的速度缓释，延缓药品在体内的代谢与排泄的速率。TransCon分子包括3个部分：未经修饰的原形药物、保护原形药物的惰性载体分子和将两者暂时连接起来的连接结构。当3个部分结合后，惰性载体分子可以使得原形药物失活并使其免受清除。当注射至人体内，在生理条件的pH和体温下，有活性的、未经修饰的原形药物将以可控的方式在1周内缓慢释放出来，抵达靶器官与受体结合后激活一系列信号转导进而发挥治疗作用，而惰性载体分子和连接体结构经肾脏清除[37-38]。lonapegsomatropin是全球唯一采用TransCon技术开发的一种非活性前药，由天然的、未修饰的rhGH通过瞬态连接剂共价连接到惰性载体分子甲氧基聚乙二醇（mPEG）上（见图2），通过最大限度减少肾排泄和受体结合的屏蔽效应，延长GH在体内的循环时间，使GH的半衰期为25h，允许每周给药1次[39]。lonapegsomatropin⁃tcgd于2021年8月25日在美国首次获批治疗PGHD，并以Skytrofa®的商品名上市，适用于年龄≥1岁及体重≥11.5kg且因内源性GH分泌不足而导致生长受限的儿童患者，建议每周服用一次0.24mg·kg-1的剂量[40-41]。lonapegsomatropin的Ⅰ期临床试验结果表明其耐受性良好，无结合抗体形成，血清GH和IGF⁃1水平与每日持续注射rhGH测量相当[43]。多个临床试验已证明对PGHD（Ⅱ期和Ⅲ期临床试验）和AGHD（Ⅱ期临床试验）有积极的疗效和良好的安全性。一项包含37例AGHD和53例未经治疗的PGHD的Ⅱ期临床试验显示，每周使用lonapegsomatropin和每日使用rhGH的安全性和有效性相似[42，44]。为期26周的Ⅲ期临床试验fliGHt Trial[45]纳入了146例GHD儿童（其中143例之前曾接受过每日rhGH治疗），所有受试者每周给药1次lonapegsomatropin（0.24mg·kg-1·周-1）来评价其安全性、耐受性，结果表明lonapegsomatropin具有良好的耐受性，并保持了日常rhGH的已知安全性。heiGHt研究[46]纳入了161例既往未治疗的GHD儿童，以2∶1的比例随机分为每周1次lonapegsomatropin治疗组（0.24mg·kg-1·周-1皮下注射，n=105）或每日1次GH治疗组（34μg·kg-1·d-1皮下注射，相当于0.24mg·kg-1·周-1，n=56），疗程52周，结果表明，lonapegsomat⁃ropin组较每日rhGH组具有非劣效性和优越性，并具有相似的安全性。enliGHten试验[47]是一项长期开放性研究，是此前heiGHt研究和fliGHt研究的扩展性研究，主要评估每周1次lonapegsomatropin治疗PGHD的长期有效性和安全性。研究结果显示，接受lonapegsomatropin治疗长达2年的受试者身高持续改善并接近父母的平均身高，安全性与每日rh⁃GH相当，包括相似的不良事件水平、耐受性和稳定的BMI。此外，研究发现与注射器/针筒给药相比，lonapegsomatropin注射装置的局部反应更少。3.4 非共价白蛋白结合生长激素延长药物半衰期的一种方法是增加其对常见血清蛋白（如白蛋白）的亲和力，somapacitan是一种可逆白蛋白结合的LAGH衍生物，由天然的rhGH经过修饰以增强其与血浆白蛋白的结合，延长半衰期，使其适合每周1次给药[48]。这是一项成熟的技术，已成功用于长效胰岛素地特胰岛素。2020年8月，somapacitan被美国FDA批准治疗AGHD，2021年1月在日本获批，2021年4月在欧洲获批。Ⅰ期临床试验结果显示somapacitan与每日rhGH有相当的耐受性和血清IGF⁃1水平[49]。Johannsson等[50]开展的一项为期26周的Ⅲ期随机对照试验证明somapacitan耐受性良好，未发现安全问题，且给药更方便。3.5 融合蛋白融合蛋白是指利用基因工程等技术将某种具有生物学活性的功能蛋白分子与其他蛋白（融合伴侣）融合而产生的新型蛋白。融合蛋白可延长rhGH的半衰期并减少清除，但可能会显著增加分子量影响组织穿透性。人们目前已经开发了多种融合蛋白技术，例如免疫球蛋白融合技术[Fc融合、可变片段（Fv）融合等]、HSA融合技术、XTEN融合技术及CTP（carboxyl terminal peptide）融合蛋白技术等[19]。Kim等[51]通过将rhGH融合到由IgD和IgG4组成的复合Fc片段中制备得到的新型rhGH 长效化制剂（GX⁃H9）。Ku等[52]报道一项临床试验结果显示其具有相当的疗效和接受的耐受性且没有发现显著的免疫原性。somatrogon是rhGH与人绒毛膜促性腺激素（hCG）β亚基的28个羧基末端残基嵌合的产物[53]，Ⅱ期临床试验表明somatrogon每周1次给药与每日rhGH给药有相当疗效和安全性[54]。PGHD相关的Ⅲ期临床试验正在进行。TV1106[55]和VRS⁃317[56]因疗效不佳和存在安全性隐患等终止相关研发。4LAGH制剂潜在安全性问题与目前每日给药的rhGH制剂相比，LAGH制剂可明显改善患者对药物的依从性，虽然多个临床试验显示了LAGH制剂同每日给药的rhGH制剂有相当的耐受性和安全性，但因LAGH制剂的临床试验是短期的，且由于GH作用延长的机制和持续时间的延长，可能存在额外的安全风险，因此临床监测LAGH制剂长期不良反应非常重要。在接受LAGH制剂治疗的患者中，最常见的不良事件包括注射部位瘙痒、贫血、甲状腺功能减退、发热、皮疹、头痛和呕吐等[57]。鉴于LAGH的非生理性特征，新的安全性问题已经提出，已经确定了一些与LAGH制剂相关的潜在安全性问题[58]：①GH和/或IGF⁃1的生理上升高。②GH的谷浓度高于正常生理水平。③波动的IGF⁃1水平。④GH缺乏生物活性时IGF⁃1升高。⑤由于产品独特的生物学特征而导致的非生理性组织分布等。GH水平长期升高可能诱导超生理性血清IGF⁃1水平并诱导医源性肢端肥大症、肿瘤和葡萄糖耐受不良[18]。然而令人欣慰的是，迄今为止在众多已发表的临床试验中，这些担忧还没有得到任何强有力的实证，由于每个单独的LAGH制剂都有其独特的药动学和药效学特征，因此在用药过程中应严密监测IGF⁃1、甲状腺水平、血糖、血脂以及选择性地检查相关肿瘤标志物等指标。5小结GHD是由于GH合成或分泌不足导致的罕见内分泌疾病，数十年以来，GHD的常规治疗方法是每日1次rhGH皮下注射，并已被证明可以恢复纵向生长，分别改善PGHD和AGHD患者的身体成分和生活质量，不良反应相对较少。然而，每天注射对一些患者来说可能是不方便和痛苦的，导致依从性和疗效下降。LAGH制剂相对于每日注射rhGH而言是一种进步，多种LAGH制剂目前处于不同的开发阶段，可以将rhGH注射频率从每天降低到每周或每月，为儿童和成人患者提供更好的接受性、耐受性和治疗灵活性。LAGH制剂的分子质量和离子电荷等属性可能会影响LAGH进入靶组织，导致疗效和安全性的差异。在LAGH给药后，血清GH峰值和谷值以及IGF⁃1水平可能会因GH延长机制而变化。GH和IGF⁃1的短暂升高与疗效和安全性的关系仍有待阐明，需要进行长期监测。参考文献详见《中国新药杂志》 2024年 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Reported positive Phase 1/2 proof-of-concept data for lonigutamab, first subcutaneous anti-IGF-1R to demonstrate clinical responses in thyroid eye disease patients Achieved primary endpoint with high statistical significance in global Phase 2b/3 clinical trial of izokibep in psoriatic arthritis with robust clinical responses also achieved for higher hurdle endpoints Announced differentiated long-term 32-week data from global Phase 2b clinical trial of izokibep in hidradenitis suppurativa – ongoing Phase 3 trial is enrolling faster than previously expected and topline data now expected in second half of 2024 Cash, cash equivalents and short-term marketable securities of $721.3 million provides runway to support key late-stage data milestones including registrational studies for multiple indications LOS ANGELES, March 28, 2024 (GLOBE NEWSWIRE) -- ACELYRIN, INC. (Nasdaq: SLRN), a late-stage clinical biopharma company focused on accelerating the development and delivery of transformative medicines in immunology, today reported financial results for the full year ended December 31, 2023 and highlighted recent corporate updates and upcoming milestones. “Our goal for ACELYRIN remains steadfast: to advance our programs across multiple autoimmune and inflammatory diseases with the goal of delivering transformative medicines for patients,” said Shao-Lee Lin, MD, PhD, Founder and CEO of ACELYRIN. “As we approach the one-year anniversary of our initial public offering last May, we are particularly excited to have announced recently positive and robust data for izokibep and lonigutamab. These data underscore our novel approach to immunology and inflammation drug development and validate the potential of our differentiated product candidates in diseases of unmet need. We look forward to a number of anticipated milestones across multiple indications throughout the balance of the year.” Full Year 2023 Financial Highlights Cash Position: Cash, cash equivalents and short-term marketable securities totaled $721.3 million at December 31, 2023. The Company expects these to fund operations into 2026, through key data milestones for late stage registrational studies and Biologic License Application submission-enabling manufacturing activities. R&D Expenses: Research and development expenses were $355.9 million for the full year ended December 31, 2023, as compared to $55.6 million for 2022. These increases were primarily a result of expansion of the izokibep program across indications and a one-time $123.1 million in-process research and development (IPR&D) expense, plus an additional $10.0 million license payment, both related to the acquisition of ValenzaBio. G&A Expenses: General and administrative expenses were $66.2 million for the full year ended December 31, 2023, as compared to $13.5 million for 2022. These increases in expenses were primarily a result of expanding our organizational capability to support the development of our broad portfolio of immunology product candidates. Net Loss: Net loss for the full year ended December 31, 2023 was $381.6 million, compared to $64.8 million for 2022. Upcoming Milestones and Recent Pipeline Highlights ACELYRIN recently reported positive data for its late-stage programs. Both the izokibep and lonigutamab programs are at the forefront in development progress as the next generation approaches to validated mechanisms in psoriatic arthritis (PsA), hidradenitis suppurativa (HS) and thyroid eye disease (TED). Upcoming Milestones Thyroid Eye Disease: On the strength of the Phase 1/2 proof-of-concept, a Phase 2b/3 trial, designed to be the first of two registrational trials in TED, is planned to be initiated in the second half of 2024. Psoriatic Arthritis: The Phase 2b/3 clinical trial is expected to serve as the first of two registrational trials in PsA and 160 mg every two weeks (Q2W) appears to be the optimal dose. A confirmatory Phase 3 trial is targeted to be initiated by year-end 2024. Hidradenitis Suppurativa: The ongoing Phase 3 trial in HS is enrolling faster than previously expected, and topline data are now expected in the second half of 2024. A confirmatory Phase 3 trial for registration is targeted to be initiated by year-end 2024. Noninfectious Uveitis: The ongoing Phase 2b/3 trial is evaluating approximately 100 participants and is expected to continue out to 48 weeks with topline data anticipated in the second half of 2024. Recent Pipeline Highlights Lonigutamab Thyroid Eye Disease ACELYRIN recently announced positive proof of concept for lonigutamab, the first reported subcutaneous anti-IGF-1R to demonstrate clinical responses in thyroid eye disease. In the Phase 1/2 trial, lonigutamab demonstrated rapid improvements in proptosis and clinical activity score (CAS) at the first measurement – within three weeks after the first subcutaneous dose. These results, along with clinically meaningful improvements in diplopia as well as mean changes in proptosis from baseline, were at least comparable to the IV approaches. Izokibep Psoriatic Arthritis Reported positive topline data from the Phase 2b/3 clinical trial evaluating izokibep in PsA. The global trial met the primary endpoint of ACR50 at 16 weeks with high statistical significance and showed significant, multi-domain responses for the high hurdles of ACR70, PASI100, as well as composite endpoints ACR50/PASI100 and Minimal Disease Activity. The improvements in magnitude of responses relative to the earlier Phase 2 study were notable given the higher burden of disease of the patients in the Phase 2b/3 trial. Further, the results demonstrated higher clinical responses than those reported by the approved IL-17A agents, and responses comparable to those reported by the IL-17A&F agents without evidence of the associated safety liabilities. Hidradenitis Suppurativa Reported differentiating long-term data for izokibep in a global Phase 2b clinical trial in HS with results demonstrating rapid, dose ordered improvement across multiple disease manifestations through week 32, with HiSCR100 consistently achieved in approximately 1/3 of patients on the 160 mg every week (QW) dose including in those patients who switched from placebo to izokibep at week 16. The results showed consistent improvement in resolution of abscesses, nodules, and draining tunnels with marked reduction in skin pain and clinically meaningful improvements in overall quality of life. Moreover, HiSCR100 was achieved earlier than reported by other IL-17A agents and the IL-17A&F agents without evidence to date for increased risk of infection, especially fungal, or suicidal ideation and behavior, in a patient population predisposed to infection and clinical depression. Noninfectious Uveitis Izokibep is also being evaluated in a Phase 2b/3 clinical trial as a treatment for noninfectious uveitis, an autoimmune inflammation of the lining of the back of the eye, which affects the cells required for vision. Leadership Updates The Company recently appointed Agnes Lee as Senior Vice President, Investor Relations and Corporate Communications and a member of the company’s Senior Leadership Team. Ms. Lee most recently served as Senior Vice President of Investor Relations and Strategic Planning at Inogen, Inc. In December 2023, the Company announced the appointment of Lynn Tetrault to its Board of Directors. Ms. Tetrault is the founder of Anahata Leadership and currently chairs the Board of Directors for NeoGenomics, Inc. About Izokibep Izokibep is a small protein therapeutic designed to inhibit IL-17A with high potency through tight binding affinity, the potential for robust tissue penetration due to its small molecular size, about one-tenth the size of a monoclonal antibody, and an albumin binding domain that extends half-life. Clinical trial data supports the hypothesis that these unique characteristics of izokibep may provide clinically meaningful and differentiated benefits for patients, including resolution of key manifestations of disease. The late-stage izokibep PsA and HS data have demonstrated levels of clinical response comparable with next generation approaches to IL-17 inhibition. These data also demonstrate that targeting IL-17A alone with greater potency can achieve the same or better clinical responses than agents targeting IL-17 subunits more broadly than IL-17A, without their associated safety liabilities. Izokibep is currently being evaluated in multiple late-stage trials in moderate-to-severe hidradenitis suppurativa (HS), moderate-to-severe psoriatic arthritis (PsA), and noninfectious uveitis. About Lonigutamab Lonigutamab is a humanized IgG1 monoclonal antibody targeting the IGF-1 receptor and is delivered subcutaneously. Relative to standard of care, lonigutamab binds to a distinct epitope, which results in internalization of the receptor within minutes, and in preclinical binding and functional laboratory assays, it has been shown to be 75-fold more potent. The characteristics of lonigutamab that enable subcutaneous delivery also enable the potential for longer-term dosing, which can potentially improve depth and durability of clinical response, while attempting to limit safety liabilities by avoiding the high maximal concentrations resulting from IV administration, while maintaining optimal therapeutic levels. About ACELYRIN, INC. ACELYRIN, INC. (Nasdaq: SLRN) is a Los Angeles area-based late-stage clinical biopharma company – with additional operations in the San Francisco Bay area – focused on providing patients life-changing new treatment options by identifying, acquiring, and accelerating the development and commercialization of transformative medicines. ACELYRIN has two programs in late-stage clinical development. Izokibep is a next generation inhibitor of IL-17A in Phase 3 development for the treatment of psoriatic arthritis, hidradenitis suppurativa and uveitis. Lonigutamab is a subcutaneously delivered monoclonal antibody targeting IGF-1R being investigated for the treatment of TED. For more information about ACELYRIN, visit us at or follow us on LinkedIn and X. Forward Looking Statements This press release contains forward-looking statements including, but not limited to, statements related to the overall advancement of ACELYRIN’s programs and ability to accelerate the development and delivery of transformative medicines; the therapeutic potential of ACELYRIN’s product candidates, including their ability to offer clinically meaningful, differentiated benefits that may improve over time, move patients towards disease resolution and limit safety liability versus other treatment options; anticipated development activities including the planned initiation of a Phase 2b/3 trial in thyroid eye disease and the ability for such trial to serve as the first of two registrational studies in TED, the expectation that the Phase 2b/3 trial in PsA will serve as the first of two registrational trials in PsA which is subject to remediation and regulatory agency review amongst other factors, targeted commencement of a second Phase 3 trial in HS, the anticipated availability of clinical data for uveitis; and other statements that are not historical fact. These forward-looking statements are based on ACELYRIN’s current plans, objectives and projections, and are inherently subject to risks and uncertainties that may cause ACELYRIN’s actual results to materially differ from those anticipated in such forward-looking statements. Such risks and uncertainties include, without limitation, those associated with the successful completion of development and regulatory activities with respect to ACELYRIN’s product candidates, the risk that future results could differ materially and adversely from early clinical data and other risks and uncertainties affecting ACELYRIN including those described from time to time under the caption “Risk Factors” and elsewhere in ACELYRIN’s current and future reports filed with the Securities and Exchange Commission. Forward-looking statements contained in this press release are made as of this date, and ACELYRIN undertakes no duty to update such information except as required under applicable law. ACELYRIN, Inc. Consolidated Statement of Operations and Comprehensive Loss (in thousands, except share and per share data) Year ended December 31, 2023 2022 2021 Operating expenses Research and development $ 355,886 $ 55,632 $ 38,230 General and administrative 66,178 13,547 3,564 Total operating expenses 422,064 69,179 41,794 Loss from operations (422,064 ) (69,179 ) (41,794 ) Change in fair value of derivative tranche liability 10,291 487 - Interest income 30,555 4,052 - Other expense, net (423 ) (132 ) (45 ) Net loss $ (381,641 ) $ (64,772 ) $ (41,839 ) Other comprehensive loss Unrealized gain (loss) on short-term marketable securities, net 248 (86 ) - Total other comprehensive gain (loss) $ 248 $ (86 ) $ - Net loss and other comprehensive loss $ (381,393 ) $ (64,858 ) $ (41,839 ) Net loss per share attributable to common stockholders, basic and diluted $ (5.43 ) $ (41.59 ) $ (60.87 ) Weighted-average common shares outstanding, basic and diluted 70,249,580 1,557,534 687,398 ACELYRIN, INC. Selected Consolidated Balance Sheet Data (in thousands) December 31, December 31, 2023 2022 Cash and cash equivalents $ 218,097 $ 267,110 Short-term marketable securities 503,229 47,510 Total assets 742,690 319,923 Total liabilities 86,353 26,192 Accumulated deficit (488,719 ) (107,078 ) ACELYRIN Contacts: investors@acelyrin.com media@acelyrin.com

▎药明康德内容团队编辑3月22日，中国国家药监局药品审评中心（CDE）官网公示，Recordati集团中国全资子公司锐康迪医药申报的注射用双羟萘酸帕瑞肽微球拟纳入优先审评，拟定适应症为：治疗无法手术或手术后未治愈和通过另一种生长抑素类似物治疗控制不佳的成人肢端肥大症患者。公开资料显示，这是一款长效帕瑞肽产品（pasireotide pamoate）。此前博鳌乐城维健罕见病临床医学中心已经引进该产品治疗肢端肥大症患者。截图来源：CDE官网肢端肥大症是由生长激素（GH）和胰岛素样生长因子-1（IGF-1）分泌过多引起的一种罕见的、使人衰弱的内分泌疾病，该病已经在中国被纳入《第二批罕见病目录》。在大多数情况下，这种疾病是由脑垂体上的非癌性肿瘤引起的。长期暴露于生长激素和IGF-1可能会导致患者经历极端的身体变化，包括手、脚和面部特征的增大。肢端肥大症使患者死亡率增加2~3倍，并和严重的健康并发症有关，包括心脏病、高血压、糖尿病、关节炎和结肠癌。肢端肥大症治疗的总体目标是抑制GH过度分泌，降低IGF-1的水平，减少并发症，降低死亡率。长效帕瑞肽（即双羟萘酸帕瑞肽）为第二代生长抑素类似物（SRL），生长抑素正是GH分泌的生理抑制剂。与第一代SRL相比，长效帕瑞肽增强了生长抑素受体（SSTR） 的结合谱，即对SSTR1、2、3和SSTR5亚型具有高亲和力，尤其对SSTR5的亲和力最高，具有更好的临床和生化控制率，且安全性良好。对于不能选择手术或手术后尚未治愈，且使用第一代SRL治疗不能充分控制的成人肢端肥大症患者，长效帕瑞肽可以作为新的治疗选择。双羟萘酸帕瑞肽于2014年相继获得欧洲药品管理局（EMA）和美国FDA批准治疗成人肢端肥大症患者。本次该药被CDE拟纳入优先审评，意味着其有望加速获批，惠及更多患者。参考资料：[1]中国国家药监局药品审评中心（CDE）官网.Retrieved Mar 22，2024, From https://www.cde.org.cn/main/xxgk/listpage/4b5255eb0a84820cef4ca3e8b6bbe20c[2]肢端肥大症患者治疗新选择！创新药长效帕瑞肽可在乐城申请使用 . Retrieved Oct 9， 2023. From https://mp.weixin.qq.com/s/6hJIqHK_P37So8FIRaJFNw[3]Recordati Rare Diseases, Inc. Announces Transfer of U.S. Marketing Rights to SIGNIFOR® (pasireotide) Injection and SIGNIFOR LAR® (pasireotide) for Injectable Suspension. Retrieved Feb 20， 2020. From https://www.recordatirarediseases.com/us/node/169本文来自药明康德内容团队，欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。转载授权请在「医药观澜」微信公众号留言联系我们。其他合作需求，请联系wuxi_media@wuxiapptec.com。免责声明：药明康德内容团队专注介绍全球生物医药健康研究进展。本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。