Gonadal Dysgenesis

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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选对技术，需要战略性眼光；斩难关，需要屡败屡战的坚韧；让价值无可替代，需要扎实的积累。什么样的企业能在艰难期打造有临床价值的创新产品？首支PEG长效生长激素的故事，就是一种答案。20年前，当看到公司用自己差不多一年半的工资，从国外堪堪买回5g的聚乙二醇(PEG)，以作为研发长效生长激素的原材料时，金赛药业原核工艺部负责人王俊才不免感叹：太金贵了！但没办法，当时国内没有一家公司有能力生产PEG，唯一的途径是从国外极少的生产商处购买。王俊才至今也忘不了：“1gPEG的价格约为3200元，我那时1个月工资才1000多块钱。每次做实验，都十分谨慎，称量都是毫克计。”拿着这昂贵又稀缺的原材料，金赛要做鲜少企业愿意做、能做成的事——自研出全球第一支PEG化长效重组人生长激素。这注定是条艰险、孤独的道路。2002年专利阻击战，2004年临床I期，2006年陆续进入临床II、III期，2009年起长达4、5年艰难的审评及GMP核查过程……12年曲折岁月，嵌进整个研发团队一生。终在2014年，金赛上市了全球首创长效生长激素产品金赛增，用于内源性生长激素缺乏所引起的儿童生长缓慢（GHD），结束了60年来生长激素需每天注射一次的历史，开启了生长激素周治疗时代。“12年磨一剑”，这是最好的注解。近10年，纵使有不少药企纷纷参与到研发中来，金赛增所在的市场仍无任何竞品上市。2024年，国产长效生长激素研发竞争态势变得相当激烈，但仍唯独金赛增，具备长时间的安全性临床研究，拥有10年注册临床、10年真实世界数据以及超10万例中国患儿临床应用的独家优势。作为生长激素的赛道引领者，金赛接下来要做的，仍如20年前一样：创造趋势。基于未被满足的临床需求，不断拓宽产品应用的边界，这也确保了金赛增的价值不可替代、可长期持续。01选择PEG技术后的12年从2002年递交PEG化学修饰技术的专利申请，到2014年金赛增上市，共12年。金赛能跑赢全球大药企，造出全球首创长效生长激素产品，离不开这曲折的12年，更离不开PEG这一技术底层逻辑。金赛药业成立之初的金磊金赛创始人金磊，20年前决定战略性研发长效生长激素时，具备了两大前提优势。一是，长效生长激素已在国际上有了理论基础，而金磊用数年时间“吃透”了生长激素研究，其扎实的基本功基础和经验助其成为了开拓者；二是千禧年后PEG开始逐渐成为蛋白质长效化主流技术，FDA已验证其技术可行性。但在当时的国内，选择PEG来研发长效生长激素，仍是一场巨大的冒险。全球上市的PEG修饰药物当时能用一只手数过来，且基本都是在2010年后才陆续上市，在此之前算是空白。“当时，国内还没有人进行PEG化药物修饰技术研究，我们是第一家。同时我们还是国际上第一家试做生物大分子长效制剂的企业。”王俊才回忆道。这意味着，PEG这一原材料是稀缺的，只能依赖进口，价格高昂，且对PEG标准要求很高，必须保证其均匀性和纯度。尽管起初金赛一次性通过了技术审评，顺利进入到临床试验研究阶段，但这条路还没有成功的应用先例。能否保持较长的浓度，保留生物学活性，以及确保长期使用的安全性，是待解决的研发难点。可以说，这条路走对了是殿堂，走错了，便是深渊。但金磊及研发团队仍坚定选择了这一路径，原因不止是掌握的技术优势，更是需求使然。短效产品的局限性就摆在那里：儿童需每日注射，但频繁注射会造成心理压力，漏针现象严重，依从性欠佳，治疗效果有的大打折扣。而如果“从众”选择缓释微球作为主流的长效技术，由于技术限制，注射的针头很粗，易让患者非常疼痛，有效性和安全性也都缺乏。曾有海外明星公司沿该技术推出了长效生长激素，但上市没几年便退出市场，且其工艺极其复杂。而PEG长效生长激素的核心原理是什么？简单来说，通过天然肽键键合方式，将天然结构的生长激素和惰性PEG相连，如同为生长激素加了一层“金钟罩”，大大降低了被肾脏过滤的速度，同时减少蛋白酶降解作用，可更长时间发挥药效。每周注射一次，能达到每天注射治疗的效果。2004年开始，金赛陆续启动了I到III期的临床试验。在此之前，金赛遇到了首个棘手的问题——专利。与知名MNC间关于PEG化生长激素的专利抗衡，倏然而至。要想“以小胜大”，必须抢占时间，非常懂行，兼具勇气。仔细研究专利法后，金赛最终提供了确切的原始研发资料，证实了在该领域研发时间最早、技术更领先、更具有开创性，打赢了专利战。但几年后，自2009年迎来首次专家上会会审起，真正漫长而艰难的质控及审评一关，又悄然开始。“药监局出台了新的政策，增加新药上会评审和生产现场核查。药审中心组织了药学、非临床研究、临床及统计学的专家，对药品的安全性，有效性和质量可控性进行再评价。”王俊才向E药经理人分享道。面对这款全球首创产品，审评又格外严格谨慎。金赛按要求数次提交了补充材料，期间，“我们完善了质量可控性和产品一致性，以及完善了相关蛋白的分析方法、PEG残留质控方法、PEG修饰度检测方法……很多方法都得突破常规思维，带有很大的挑战性。”王俊才感慨道。让他印象最深的时间段，是在最后一次补充资料研究期间。那时正值春节，金磊带着整个项目组不舍昼夜地做实验、整理材料，最终终于通过了技术审评和生产现场核查，完成了国内首个PEG修饰药物的分析方法和标准建立。金赛药业“重组人生长激素系列产品研制与产业化”项目获得国家科技进步二等奖10年的“煎熬”及屡败屡战，王俊才记忆犹新，每一位研发技术人员也都毕生难忘。60年来，全球生长激素产品需每天注射一次，这对于儿童及背后家庭来说都是种痛苦。而PEG无毒，具有良好的水溶性，可增大生长激素分子量的作用，使肾脏代谢速度变慢，更长时间发挥药效。难得的技术突破，为金赛增提供了莫大的科学及社会价值。02用真实世界数据说话克服了专利、研发及审评难题后，首款长效生长激素还要面临从零开始打开市场的问题。当时，在医生和患者的认知里，有关长效生长激素的知识几乎是一片空白。上市初期，对于此类一周注射一次的产品，不少医生对此抱有怀疑，甚至不认为中国具备推出全球“首个且唯一一个”创新产品的能力，患者及家庭了解的匮乏更不必多说。而让市场了解、熟悉和信任的最好方式，是用充分、扎实的临床数据证明长期应用的疗效与安全性。一款药品必须经过至少5年上市后临床验证，才能充分证明安全性，很多药品虽获批上市，但在真实世界应用中因出现严重不良反应而退市。此外，对在中国首次申请上市的药品医疗器械，注册申请人应提供是否存在人种差异的临床试验数据。所以自2014年产品上市起，金赛没有急着去追求商业化成绩，而以大的研发投入和精力放在了IV期真实世界临床及其他适应证的拓展上。经过10年的积累，至今，金赛增是国内唯一拥有长达3年及以上安全性临床研究的长效生长激素，也是全球唯一在真实世界中超过10万例临床应用的长效生长激素。试验样本量最为庞大，在全国多地80余家医院展开。且研究人种是中国患儿，唯一具备中国人群长时间的用药经验，另在不良反应和抗体两大指标表现上，也可谓同行最优。长时间的临床也有力证明了，一方面，PEG技术的确能规避其他主流长效制剂技术一定的缺陷。以蛋白质融合技术为例，多项试验发现，这项技术存在免疫原性、纯化困难等诸多安全隐患，需长期监测尚未发现的细胞毒性等副作用。另一方面，金赛增的分子量和PEG结构（40 kda ，U型）相较于同类型产品表现更好，且是迄今唯一经长时间临床验证具有良好安全性的经典PEG化技术应用，既可保证生长激素的稳定性和安全性，也可保证制备过程中产物的高度均一性。据悉，金赛增的半衰期长达32小时，U形PEG形成的空间位阻又可以使药物免疫原性变得极低。一项关键III期临床数据显示，金赛增的年化生长速率可达13.41cm/y，较短效明显改善，也优于已公布的其他长效生长激素研究结果。2023年，国际著名期刊Journal of Clinical Endocrinology& Metabolism发表了金赛增治疗生长激素缺乏症儿童最大样本量、多中心、前瞻性、长达3年随访的真实世界研究数据，研究旨在评估在真实世界中使用该产品的长期有效性、安全性以及剂量对患者结局的影响。结果显示，身高标准差、年生长速率、安全性等关键指标表现均为积极，0.2mg/kg/w组获益尤其突出。10年注册临床和10年真实世界数据积打下的“基本盘”，让金赛增获得了业内的权威认可，为其打造了差异化的长期竞争优势，其临床突破也可谓是全球重组生长激素研发领域的重大进步。03未来如何赢？知来路，明未来。金赛药业的成立与成长，始终伴随着创始人及研发团队对初心的坚守。很多年前，金磊回国探亲时，他在教育部组织的社会实践考察中走访了一些贫困地区，看到许多十几岁的儿童身高还不足1米，其上学、就业、心理状态被严重影响。然而，很多人从未听过生长激素，即使知道有矮小治疗产品，由于被进口垄断，也无力承担高昂的治疗费用。医生端也是极其匮乏，在那个年代国内有能力治疗矮小疾病的医生，还不到20个人。强大的需求，让金磊毅然回国创立了金赛药业，先让国人有了自己的生长激素，再是推动了生长激素从短效粉针、水针再到长效水针的迭代升级。首款国产生长激素（赛增）问世截至目前，我国现存4-15 岁需治疗的矮小症人口仍超700万，但接受规范生长激素治疗的人群比例低于5％，渗透率仍处于较低水平，具有更高依从性的长效水针，依然具备很大的拓展空间。临床需求是一家低调做研发、求突破的药企最大的动力，几年前开始，金赛药业关于超长效水针生长激素的研发工作便已如火如荼地进行。另在几大极具市场规模的重磅适应证拓展上，金赛增已先于全球同类型产品取得了领先的研发成果。生长激素主要适应证有生长激素缺乏症（GHD），特发性矮身材（ISS），先天性卵巢发育不全综合征（Turner综合征），小于胎龄儿（SGA），以及PraderWilli综合征。截至目前，金赛增治疗ISS、Turner综合征所致儿童生长障碍等适应证已进入上市评审阶段，2024年有望获批上市，另外小于胎龄儿适应证也已完成II期临床。可以看到，未来覆盖更多重磅适应证的金赛增，其市场渗透率将进一步提高，继续占领强大的市场份额。其中，ISS尤其有望带来可观的市场空间。ISS是由多种尚无可认知病因引起，约占所有身材矮小儿童的60%-80%。临床研究表明，经过52周的治疗，ISS患者对金赛增的治疗耐受性良好，糖脂代谢指标均正常，且保持稳定。其中0.2 mg/kg/w的高剂量组金赛增治疗后HV（生长速率）增长5.88cm/y，达到10.04cm/y，充分地验证了产品的安全性与疗效。另值得注意的是，金赛增，以及金赛研发的所有生长激素产品，在出海国际化上蕴含了很大的市场机遇。国内的生长激素产品有较强的海外价格竞争力和毛利率表现，其中，金赛药业很早布局海外市场，金赛增有望直接进入美国III期临床，并有望在几年内上市，这将成为其新的重磅增长空间，持续扩充想象边界。且正如金磊所盼，通过在生长激素领域的迭代升级，横向扩展和纵深，以及在生产工艺上的不断优化，一切都会有效带领行业站在新的起点，迈入新的发展阶段，于整个行业的进步来说意义非凡。2024年，中国医药创新也迎来了一个里程碑式的转折和开端。复盘金赛增20年的成长历程，同样有利于在这一关键时间节点，回答“什么样的企业能做出有价值的创新产品”这一问题。精彩推荐CM10 | 集采 | 国谈 | 医保动态 | 药审 | 人才 | 薪资 | 榜单 | CAR-T | PD-1 | mRNA | 单抗 | 商业化 | 国际化 ｜ 猎药人系列专题 | 出海启思会 | 声音·责任 | 创百汇 | E药经理人理事会 | 微解药直播 | 大国新药 | 营销硬观点 | 投资人去哪儿 | 分析师看赛道 | 药事每周谈 | 医药界·E药经理人 | 中国医药手册创新100强榜单 | 恒瑞 | 中国生物制药 | 百济 | 石药 | 信达 | 君实 | 复宏汉霖 ｜翰森 | 康方生物 | 上海医药 | 和黄医药 | 东阳光药 |  荣昌 | 亚盛医药 | 齐鲁制药 | 康宁杰瑞 | 贝达药业 | 微芯生物 | 复星医药 ｜再鼎医药｜亚虹医药跨国药企50强榜单 | 辉瑞 | 艾伯维 | 诺华 | 强生 | 罗氏 | BMS | 默克 | 赛诺菲 | AZ | GSK | 武田 | 吉利德科学 | 礼来 | 安进 | 诺和诺德 | 拜耳 | 莫德纳 | BI | 晖致 | 再生元

Ad hoc announcement pursuant to Art. 53 LR MILAN--(BUSINESS WIRE)-- Newron Pharmaceuticals S.p.A. (“Newron”) (SIX: NWRN, XETRA: NP5), a biopharmaceutical company focused on the development of novel therapies for patients with diseases of the central and peripheral nervous system, today announced its financial results and operational highlights for the business year ended December 31, 2023, and provided an outlook for 2024. Highlights 2023: Evenamide (Schizophrenia) Compelling efficacy results across multiple investigation timepoints up to and including one-year from study 014/015 evaluating evenamide as an add-on therapy to a single antipsychotic in patients with treatment-resistant schizophrenia (TRS) Presentation of data to the medical community at several international scientific conferences, highlighting the clinically meaningful response to evenamide in TRS patients, across various timepoints Publication of data from study 014 and results from first 100 patients of study 015 in peer-reviewed journal, the International Journal of Neuropsychopharmacology, outlining the continued improvement in symptoms of psychosis in TRS patients treated with evenamide The findings from study 014/015 support the initiation of a potentially pivotal, Phase III, randomized, double-blind, placebo-controlled study with evenamide as an add-on treatment in patients with TRS Study 008A, a potentially pivotal study of evenamide (30 mg bid) in patients with chronic schizophrenia demonstrating inadequate benefit to their current second-generation antipsychotic, completed patient enrollment; top-line results are expected in April 2024 Xadago®/safinamide (Parkinson’s disease) Newron and its partners reached agreement with generic pharmaceutical manufacturers who submitted Paragraph IV Notice Letters regarding Abbreviated New Drug Applications in the US In Europe, Supplementary Protection Certificates (SPCs) have been approved in most territories of relevance Corporate Newron’s senior management team strengthened by two key promotions: Laura Faravelli, previously Director Business Development at Newron, was promoted to Vice President Business Development; Roberto Galli, Vice President Finance since 2012, was promoted to Chief Financial Officer Gillian Dines appointed as Non-Executive Director to the Board of Newron at the AGM 2023 Margarita Chavez appointed as advisor to the Board of Newron; she is nominated for election as Non-Executive Director to the Board at the next Ordinary AGM on April 17, 2024 Post-period, Newron entered into an agreement for the subscription of up to 2.05 million newly issued shares with an institutional investor focused on investing in high-growth firms across sectors including biotech and healthcare, to finance the Company’s operations beyond the current key inflection points in its pipeline Post-period, agreement with European Investment Bank (EIB) to extend the near-term tranche repayment dates of Newron’s 2018 financing agreement Stefan Weber, CEO of Newron, commented: “Against a backdrop of challenging global biotechnology market conditions, we have continued to make huge strides in advancing our evenamide development program for treatment-resistant schizophrenia (TRS) through the clinic. We have reported multiple data sets across three different study timepoints, each showing compelling evidence of the benefit of evenamide in schizophrenia patients no longer responding to their first- or second-generation antipsychotic treatments. Post-period, we also optimized our financing structure by agreeing with the EIB to extend the near-term tranche repayment dates of our financing agreement. And we welcomed an institutional investor that signed a subscription agreement for new shares to finance our operations beyond the current key inflection points in the pipeline. We thank our shareholders for their ongoing support and for sharing our vision to improve the lives of patients suffering from diseases of the CNS, by now for 25 years, since Newron was founded.” Evenamide Newron made substantial progress across its evenamide development program over the reporting year and into early 2024. The published compelling data is demonstrating the benefit of the Company’s new chemical entity for patients with TRS: In Q1 2023, Newron disclosed interim analyses of study 014, a Phase II, international, randomized, open label, rater-blinded trial evaluating evenamide (7.5, 15 or 30 mg bid) as an add-on to a single antipsychotic (excluding clozapine) in patients with moderate to severe TRS, not responding to their current antipsychotic medication, and study 015, its extension to one year of treatment. Results from the first 100 patients to complete six months (30 weeks) of treatment with evenamide were reported in January, followed by results in February 2023 from the same 100-person cohort at the one-year (52 weeks) timepoint. The results at the six-week, six-month and one-year timepoints demonstrated a clinically important and sustained improvement in symptoms, and importantly, a substantially greater benefit at one-year than at the six-week and six-month datapoints. Topline data from all 161 patients at the six-week primary endpoint were reported in March. Although the primary objective of the study was safety and tolerability of evenamide, efficacy over baseline was also assessed. The mean Positive and Negative Syndrome Scale (PANSS) total score, Clinical Global Impression of Severity (CGI-S) rating, and the Strauss-Carpenter Level of Functioning (LOF) total score significantly improved compared to baseline (p<0.001). The results from the complete study population of 161 patients were fully consistent with the findings from the first 100 patients at this timepoint. Notably, evenamide was safe and well-tolerated at all doses, with almost all (95%) patients completing six weeks of treatment. The incidence of treatment-emergent adverse events was very low, and more than 90% of the completers chose to continue with evenamide treatment into the long-term extension study (study 015). In the beginning of Q4, Newron provided data from the full study population in the extension study (study 015) at the 36th ECNP Congress in Barcelona, Spain, demonstrating the positive effect of evenamide at six months of treatment. Results showed that benefits continued to accrue over time, and many patients who did not respond early achieved clinically important benefits later on in the study. Remarkably, following treatment with evenamide, approximately 40% of patients at six months no longer met the protocol severity criteria used to diagnose TRS. These data were further strengthened, post-period in January 2024, with the final results from study 015 reviewing all study participants after one year of treatment. The data showed that treatment with evenamide was associated with sustained, clinically significant benefit that increased throughout the one-year course of treatment. Gradual and sustained improvement was demonstrated across all efficacy scales used. More than 70% of patients experienced clinically important reduction in disease severity. Review of the efficacy data indicated that treatment with evenamide resulted in approximately 50% of patients at one-year no longer meeting any of the protocol severity criteria used to diagnose treatment resistance. Significantly 25% of all patients achieved “remission” (no/minimal symptoms for at least six months), never described before in TRS patients. Moreover, in contrast to common clinical experience, no patient relapsed during the one-year treatment period. The durability and longevity of these clinical benefits is unprecedented in this indication and suggest that the glutamate modulating effect of evenamide could lead to a progressive and long-standing alteration in brain processes, synergizing with the effect of the antipsychotic to which the patient had become resistant. The next R&D activities will be: In their totality, the results from study 014/015 support the initiation of a potentially pivotal Phase III, randomized, double-blind, placebo-controlled study of evenamide as an add-on treatment in patients with TRS, which will hopefully confirm the benefit of evenamide seen so far. If approved, the compound would be the first add-on drug that improves the symptoms of TRS, offering a much-needed new therapeutic option for those who are not responding to existing antipsychotics. Newron is also investigating evenamide in a potentially pivotal study (study 008A) in a separate indication, in patients with chronic schizophrenia currently being treated with a second-generation antipsychotic, but who demonstrate an inadequate response to that treatment. Study 008A is a four-week, randomized, double-blind and placebo-controlled study assessing the efficacy, tolerability, and safety of evenamide (30 mg bid). Patient enrollment has completed and results from this study are expected in April 2024. Xadago®/safinamide In partnership with Zambon and Supernus, Newron continued to further develop and market its product, Xadago®/safinamide. In reference to the receipt of several Paragraph IV Notice Letters in May 2021 regarding the submission by some generic manufacturers of an Abbreviated New Drug Application ANDA to the US Food and Drug Administration (FDA), seeking approval to engage in the commercial manufacture, use or sale of safinamide mesylate drug product in the US before expiration of the three US patents listed in the FDA Orange Book for Xadago®, Newron and its partners Zambon and Supernus have reached settlement agreement with said generic manufacturers, thus resolving the legal action. All three patents remain valid and in force. Under the agreement, the generic manufacturers will be allowed to enter the US market with a safinamide mesylate drug product no earlier than December 1, 2027. In the EU, Supplementary Protection Certificates (SPCs) have already been approved in most territories of relevance; Newron and Zambon are confident that upon completion of the still ongoing procedures and targeted activities, the SPCs will be granted in all key territories. ESG reporting The Annual Report 2023 provides further transparency on Newron’s corporate ESG commitments. The relevant section covers information on the following topics: employee aspects, environmental aspects including climate, social aspects, human rights, and anti-corruption as well as cyber security – given their relevance to Newron and its stakeholders and given the Company’s ability as a company to have a positive impact on the listed areas. Newron’s 2023 ESG Report follows the most recent edition of the Directive on Information relating to Corporate Governance (Annex 7) of SIX Exchange Regulation (SER). Financial key takeaways 2023: In 2023, Newron reported a net loss of EUR 16.2 million, slightly lower compared to EUR 17.5 million in 2022 Cash used in operating activities has decreased to EUR 10.1 million from EUR 11.1 million in 2022 Xadago® revenues from Zambon increased from EUR 6.0 million in 2022 to EUR 9.0 million in the reporting year Newron’s R&D expenses have risen to EUR 13.2 million from EUR 12.0 million in 2022 G&A expenses slightly increased from EUR 7.4 million in 2022 to EUR 7.5 million Cash and Other current financial assets as of December 31, 2023 were at EUR 12.6 million, compared to EUR 22.8 million at the beginning of the year Post-period, in March 2024, Newron announced it has entered into an agreement for the subscription of up to 2.05 million shares with an institutional investor focused on investing in high-growth firms across sectors including biotech and healthcare, raising gross proceeds of up to EUR 15.0 million (at current exchange rate CHF-EUR). Under the agreement, the fund subscribes to an initial 750,000 newly issued shares at a subscription price of EUR 7.33 per share, which corresponds to gross proceeds of approximately EUR 5.5 million. In addition, the fund has a right to subscribe to an additional up to 1,300,000 newly issued shares until no later than January 31, 2025, at a subscription price to be calculated pursuant to an agreed formula. The share subscriptions are governed by the capital increase authorised by Newron’s shareholders in 2018 and approved and empowered by the Company’s Board of Directors in 2023. Newron intends to use the net proceeds of the fundraise for general corporate purposes, including the financing of its operations and research programs and for the development of current and future pipeline products. Newron also continues to seek opportunistic additions to its pipeline portfolio. Post-period, and also in March 2024, Newron announced that the Company has agreed with the European Investment Bank (EIB) to extend the near-term tranche repayment dates of its loan agreement. Under the amendment to certain terms of the financing agreement with the EIB, the repayment of tranches one to three (out of a total of five) has been shifted substantially, with tranche one now scheduled for repayment by 25 November 2025, tranche two by April 2026 and tranche three by June 2026. The EIB qualifies now for certain performance-based remuneration. Newron appreciates the support of the EIB in helping the Company to align its contractual obligations with the potential timing of certain upcoming inflection points from its pipeline. Financial Summary (IFRS) 2023 and 2022: In thousand EUR (except per share information) 2023 2022 Licence income from contracts with customers 58 14 Royalties from contracts with customers 6,735 5,936 Other income from contracts with customers 2,264 144 Revenue 9,057 6,094 Research and development expenses, net (13,152) (12,005) Operating Result (11,629) (13,302) Financial result, net (4,571) (4,170) Net loss (16,224) (17,493) Loss per share (0.91) (0.98) Cash used in operating activities (10,140) (11,092) Cash, cash equivalents and Other current financial assets 12,599 22,774 Total assets 25,866 37,195 Newron’s Annual Report 2023 is available for download on the Company’s website at: Outlook 2024: Following the remarkable evenamide data to date, Newron plans to initiate a potentially pivotal trial evaluating evenamide in TRS, once preparations are completed and a partner has been identified. If this trial replicates the data published in study 014/015, the Company believes there will be substantial improvements in the treatment paradigm and outlook for TRS patients. Newron is also primed to report data from study 008A, a potentially pivotal study assessing evenamide in schizophrenia patients not deemed to be treatment resistant. If positive, this would be the first well-controlled study to demonstrate the clinical utility of evenamide in schizophrenia patients who show an inadequate response to treatment with atypical antipsychotics. Newron is continuing to have a productive dialogue with industry players around potential future collaboration opportunities for evenamide. The Company also continues to review the CNS landscape for opportunities to expand its drug development pipeline. Newron’s total available cash resources together with the initial proceeds deriving from the subscription agreement signed post-period, will fund the Company’s planned development programs and operations well into 2025 and well beyond the current key value inflection points in our pipeline. Media/analyst/investor Conference Call today at 3 pm CET Newron’s management team will present today the 2023 full-year results and provide an update and guidance for 2024. Please dial in five to ten minutes prior to the beginning of the call using one of the following telephone numbers: Switzerland/Europe: +41 (0)58 310 50 00 United Kingdom: +44 (0)207 107 0613 United States: +1 (1)631 570 5613 The presentation is available at 2024 Shareholders’ Meeting Agenda: Newron’s Board of Directors has approved the below agenda for the April 17, 2024, Shareholders’ Ordinary and Extraordinary meeting, which will take place at the Company’s registered office (Via Antonio Meucci 3) in Bresso (Mi), Italy, starting at 10 am CET. The formal invitation to shareholders will be issued and disclosed in the statutory papers on or around March 26, 2023. The full invitation and supporting material will be made available on the Company’s website ( ) on the same day. The agenda is as follows: Ordinary part Approval of the financial statements as at 31 December 2023. Update – as per art. 2447 Civil Code - regarding the freezing of 2022 Newron’ standalone losses. Connected and consequent resolutions; Appointment of a new members of the Board of Directors, for the financial years 2024 and 2025 and, therefore, until the approval of the financial statements as of December 31st, 2025, as follows: determination of the relevant number, proposal to appoint Margarita Chavez*, in quality of new non-executive director Determination of the remuneration Connected and consequent resolutions. Extraordinary part Proposal to amend Art 14 of the by-laws. Related and consequential resolutions; Proposal of attribution to the Board of Directors of powers, pursuant to art. 2443 of the Civil Code, exercisable during the next 5 years, to increase the share capital, in one or more times, for a maximum amount of Euro 357.636,00, in addition to any premium, with or without option rights, pursuant to art. 2441, paragraphs 1 and/or 4, first and second part, and/or 5, 6 of the Civil Code. Related and consequential resolutions; Proposal of attribution to the Board of Directors of powers, pursuant to art. 2443 of the Civil Code, exercisable during the next 5 years, to increase the share capital, in one or more times, for a maximum amount of Euro 107.291,00, in addition to any premium, with exclusion of the option rights, pursuant to art. 2441, paragraphs 5, 6 and/or 8 of the Civil Code, for one or more stock option plans. Related and consequential resolutions; * Margarita Chavez brings to Newron over 20 years of dealmaking expertise and leadership in the pharmaceutical industry. Most recently, she was Managing Director of AbbVie Ventures, where she led investments and built biotech companies across the US and Europe. Ms. Chavez also served as a board member for several biotech companies across the US and Europe. As a Director in Abbott’s Global Pharmaceutical Licensing & Acquisitions Division, she was involved in the successful in-licensing of Elagolix and the acquisitions of Solvay, ImmuVen and the Lupron franchise. Before joining Abbott, Ms. Chavez practiced as a corporate and securities lawyer in the Silicon Valley, advising tech and biotech companies on strategic transactions including IPOs and mergers and acquisitions. She received her bachelor’s degree from Santa Clara University and her juris doctor from Santa Clara University School of Law (both California). Ms. Chavez is currently a Venture Partner at Wellington Partners and has been acting as advisor to Newron’s board since October 1, 2023. Financial calendar AGM and EGM 2024: April 17, 2024 Half-year report 2024: September 19, 2024 About Newron Pharmaceuticals Newron (SIX: NWRN, XETRA: NP5) is a biopharmaceutical company focused on the development of novel therapies for patients with diseases of the central and peripheral nervous system. The Company is headquartered in Bresso near Milan, Italy. Xadago®/safinamide has received marketing authorization for the treatment of Parkinson’s disease in the European Union, Switzerland, the UK, the USA, Australia, Canada, Latin America, Israel, the United Arab Emirates, Japan and South Korea, and is commercialized by Newron’s Partner Zambon. Supernus Pharmaceuticals holds the commercialization rights in the USA. Meiji Seika has the rights to develop and commercialize the compound in Japan and other key Asian territories. Newron is also developing evenamide as the potential first add-on therapy for the treatment of patients with symptoms of schizophrenia. For more information, please visit: Important Notices This document contains forward-looking statements, including (without limitation) about (1) Newron’s ability to develop and expand its business, successfully complete development of its current product candidates, the timing of commencement of various clinical trials and receipt of data and current and future collaborations for the development and commercialization of its product candidates, (2) the market for drugs to treat CNS diseases and pain conditions, (3) Newron’s financial resources, and (4) assumptions underlying any such statements. In some cases, these statements and assumptions can be identified by the fact that they use words such as “will”, “anticipate”, “estimate”, “expect”, “project”, “intend”, “plan”, “believe”, “target”, and other words and terms of similar meaning. All statements, other than historical facts, contained herein regarding Newron's strategy, goals, plans, future financial position, projected revenues and costs and prospects are forward-looking statements. By their very nature, such statements and assumptions involve inherent risks and uncertainties, both general and specific, and risks exist that predictions, forecasts, projections and other outcomes described, assumed or implied therein will not be achieved. Future events and actual results could differ materially from those set out in, contemplated by or underlying the forward-looking statements due to a number of important factors. These factors include (without limitation) (1) uncertainties in the discovery, development or marketing of products, including without limitation difficulties in enrolling clinical trials, negative results of clinical trials or research projects or unexpected side effects, (2) delay or inability in obtaining regulatory approvals or bringing products to market, (3) future market acceptance of products, (4) loss of or inability to obtain adequate protection for intellectual property rights, (5) inability to raise additional funds, (6) success of existing and entry into future collaborations and licensing agreements, (7) litigation, (8) loss of key executive or other employees, (9) adverse publicity and news coverage, and (10) competition, regulatory, legislative and judicial developments or changes in market and/or overall economic conditions. Newron may not actually achieve the plans, intentions or expectations disclosed in forward-looking statements and assumptions underlying any such statements may prove wrong. Investors should therefore not place undue reliance on them. There can be no assurance that actual results of Newron's research programs, development activities, commercialization plans, collaborations and operations will not differ materially from the expectations set out in such forward-looking statements or underlying assumptions. Newron does not undertake any obligation to publicly update or revise forward-looking statements except as may be required by applicable regulations of the SIX Swiss Exchange or the Dusseldorf Stock Exchange where the shares of Newron are listed. This document does not contain or constitute an offer or invitation to purchase or subscribe for any securities of Newron and no part of it shall form the basis of or be relied upon in connection with any contract or commitment whatsoever. View source version on businesswire.com: Contacts For more information: Newron Stefan Weber – CEO, +39 02 6103 46 26, pr@newron.com UK/Europe Simon Conway / Ciara Martin / Natalie Garland-Collins, FTI Consulting, +44 20 3727 1000, SCnewron@fticonsulting.com Switzerland Valentin Handschin, IRF , +41 43 244 81 54, handschin@irf-reputation.ch Germany/Europe Anne Hennecke / Caroline Bergmann, MC Services, +49 211 52925222, newron@mc-services.eu USA Paul Sagan, LaVoieHealthScience, +1 617 374 8800, Ext. 112, psagan@lavoiehealthscience.com Source: Newron Pharmaceuticals S.p.A. View this news release online at: