Immune Globulin (Human)(Grifols)

Clinical trial met primary endpoint demonstrating comparable total immunoglobulin (Ig) levels when administering XEMBIFY® (Grifols’ subcutaneous Ig) every two weeks, compared with weekly, in patients with primary immunodeficienciesStudy designed to support extending U.S. Food and Drug Administration labeling of XEMBIFY® to include biweekly dosing, providing added flexibility and convenience for patientsGrifols is accelerating adoption of XEMBIFY® as part of its broader immunoglobulin business strategy focused on treating immunodeficiency disorders, which represent up to 55% of the total market for Ig, a category experiencing single-digit growth rates BARCELONA, Spain, July 20, 2023 (GLOBE NEWSWIRE) -- Grifols (MCE: GRF, MCE: GRF.P NASDAQ: GRFS), one of the world’s leading producers of plasma-derived medicines, today announced that its recently concluded phase 4 trial (NCT04566692) evaluating a biweekly dosing of XEMBIFY® has met its primary endpoint. It has demonstrated that patients with primary immunodeficiencies (PIDs) treated with this subcutaneous 20% immunoglobulin (SCIg) product every two weeks achieved non-inferiority in total Ig levels compared with those who received the medication weekly. The phase 4 trial also demonstrated similarly good safety and tolerability profiles between biweekly and weekly administration. It was a multicenter, single-sequence, open-label clinical study that included 27 subjects across 18 U.S. sites. Results will support the potential product labeling extension of XEMBIFY® to include biweekly dosing, pending review and approval by the United States Food and Drug Administration. This option is already available in the European markets where it is authorized. “Patients using XEMBIFY® could have an additional dosing option to choose from, providing more convenience and flexibility when controlling their immunodeficiencies,” said Kim Hanna, Grifols Senior Director Clinical Development. “Grifols is committed to strengthening its portfolio of leading immunoglobulin therapeutics to meet the growing demand as the number of people living with immunodeficiencies continues to increase.” With demonstrated efficacy and tolerability, XEMBIFY® is indicated for PIDs in the U.S. and both primary and select secondary immunodeficiencies (SIDs) in Europe, Canada and Australia. The global market for Ig is expected to grow in the high single digits in the coming years as a result of the increase in PIDs and SIDs, which together account for up to 55% of the total Ig market.1 SIDs have notably risen due to an aging population and the use of immunosuppressive therapies, such as immuno-oncology treatments, for which Ig is the preferred and only option. About XEMBIFY® Grifols XEMBIFY® is a 20% solution of purified human immunoglobulin (primarily immune globulin G [IgG]) made from large pools of human plasma via modifications of the Immune Globulin (Human), 10% Caprylate/Chromatography Purified (IGIV-C 10%) manufacturing process. INDICATION XEMBIFY® (immune globulin subcutaneous human–klhw) is a 20% immune globulin indicated for treatment of primary humoral immunodeficiency disease (PIDD) in patients 2 years of age and older. XEMBIFY® is for subcutaneous administration only. IMPORTANT SAFETY INFORMATION WARNING: THROMBOSIS Thrombosis may occur with immune globulin products, including XEMBIFY®. Risk factors may include: advanced age, prolonged immobilization, estrogens, indwelling vascular catheters, hyperviscosity, and cardiovascular risk factors. Thrombosis may occur in the absence of known risk factorsFor patients at risk of thrombosis, administer XEMBIFY® at the minimum dose and infusion rate practicable. Ensure adequate hydration in patients before administration. Monitor for signs and symptoms of thrombosis and assess blood viscosity in patients at risk of hyperviscosity Contraindications XEMBIFY® is contraindicated in patients who have had an anaphylactic or severe systemic reaction to the administration of human immune globulin. It is contraindicated in IgA-deficient patients with antibodies against IgA and a history of hypersensitivity. Warnings and Precautions Hypersensitivity. Severe hypersensitivity reactions may occur with immune globulin products, including XEMBIFY®. In case of hypersensitivity, discontinue infusion immediately and institute appropriate treatment. XEMBIFY contains IgA. Patients with known antibodies to IgA may have a greater risk of developing potentially severe hypersensitivity and anaphylactic reactions. Thrombosis. Thrombosis may occur following treatment with immune globulin products, including XEMBIFY®. Thrombosis may occur in the absence of known risk factors. In patients at risk, administer at the minimum dose and infusion rate practicable. Ensure adequate hydration before administration. Monitor for signs and symptoms of thrombosis and assess blood viscosity in patients at risk of hyperviscosity. Aseptic meningitis syndrome (AMS). AMS may occur with human immune globulin treatment, including XEMBIFY®. Conduct a thorough neurological exam on patients exhibiting signs and symptoms to rule out other causes of meningitis. Discontinuation of treatment has resulted in remission within several days without sequelae. Renal dysfunction/failure. Acute renal dysfunction/failure, acute tubular necrosis, proximal tubular nephropathy, osmotic nephrosis, and death may occur with use of human immune globulin products, especially those containing sucrose. XEMBIFY® does not contain sucrose. Ensure patients are not volume-depleted prior to starting infusion. In patients at risk due to preexisting renal insufficiency or predisposition to acute renal failure, assess renal function prior to the initial infusion of XEMBIFY® and again at appropriate intervals thereafter. If renal function deteriorates, consider discontinuation. Hemolysis. XEMBIFY® may contain blood group antibodies that may cause a positive direct antiglobulin reaction and hemolysis. Monitor patients for clinical signs and symptoms of hemolysis. If signs and symptoms are present after infusion, perform confirmatory lab testing. Transfusion-related acute lung injury (TRALI). Noncardiogenic pulmonary edema may occur in patients following treatment with immune globulin products, including XEMBIFY®. Monitor patients for pulmonary adverse reactions. If TRALI is suspected, perform appropriate tests for the presence of antineutrophil and anti-HLA antibodies in both the product and patient serum. TRALI may be managed using oxygen therapy with adequate ventilatory support. Transmissible infectious agents. Because XEMBIFY® is made from human blood, it may carry a risk of transmitting infectious agents, eg, viruses, the variant Creutzfeldt-Jakob disease (vCJD) agent, and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent. No cases of transmission of viral diseases, vCJD, or CJD have ever been associated with the use of XEMBIFY®. Interference with lab tests. After infusion of XEMBIFY®, passively transferred antibodies in the patient’s blood may yield positive serological testing results, with the potential for misleading interpretation. Adverse Reactions The most common adverse reactions in ≥ 5% of subjects in the clinical trial were local adverse reactions, including infusion-site erythema (redness), infusion-site pain, infusion-site swelling (puffiness), infusion-site bruising, infusion-site nodule, infusion-site pruritus (itching), infusion-site induration (firmness), infusion-site scab, infusion-site edema, and systemic reactions including cough and diarrhea. Drug InteractionsPassive transfer of antibodies may transiently interfere with the immune responses to live attenuated virus vaccines (eg, measles, mumps, rubella, and varicella). You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch or call 1-800-FDA-1088. Please see full Prescribing Information for XEMBIFY® or visit www.xembify.com Globally, prescribing information varies; refer to the individual country product label for complete information. About Grifols Grifols is a global healthcare company founded in Barcelona in 1909 committed to improving the health and well-being of people around the world. A leader in essential plasma-derived medicines and transfusion medicine, the company develops, produces and provides innovative healthcare services and solutions in more than 110 countries. Patient needs and Grifols’ ever-growing knowledge of many chronic, rare and prevalent conditions, at times life-threatening, drive the company’s innovation in both plasma and other biopharmaceuticals to enhance quality of life. Grifols is focused on treating conditions across a broad range of therapeutic areas: immunology, hepatology and intensive care, pulmonology, hematology, neurology and infectious diseases. A pioneer in the plasma industry, Grifols continues to grow its network of donation centers, the world’s largest with over 390 across North America, Europe, Africa and the Middle East and China. As a recognized leader in transfusion medicine, Grifols offers a comprehensive portfolio of solutions designed to enhance safety from donation to transfusion, in addition to clinical diagnostic technologies. It provides high-quality biological supplies for life-science research, clinical trials, and for manufacturing pharmaceutical and diagnostic products. The company also supplies tools, information and services that enable hospitals, pharmacies and healthcare professionals to efficiently deliver expert medical care. Grifols, with more than 24,000 employees in more than 30 countries and regions, is committed to a sustainable business model that sets the standard for continuous innovation, quality, safety and ethical leadership. In 2022, Grifols’ economic impact in its core countries of operation was EUR 9.6 billion. The company also generated 193,000 jobs, including indirect and induced. The company’s class A shares are listed on the Spanish Stock Exchange, where they are part of the Ibex-35 (MCE:GRF). Grifols non-voting class B shares are listed on the Mercado Continuo (MCE:GRF.P) and on the U.S. NASDAQ through ADRs (NASDAQ:GRFS). For more information, please visit www.grifols.com MEDIA CONTACT: Media Press Officemedia@grifols.comTel. +34 93 571 00 02 INVESTORS: Investors Relations Department & Sustainabilityinversores@grifols.com - investors@grifols.com Tel. +34 93 571 02 21 LEGAL DISCLAIMER The facts and figures contained in this report that do not refer to historical data are “future projections and assumptions”. Words and expressions such as “believe”, “hope”, “anticipate”, “predict”, “expect”, “intend”, “should”, “will seek to achieve”, “it is estimated”, “future” and similar expressions, insofar as they relate to the Grifols group, are used to identify future projections and assumptions. These expressions reflect the assumptions, hypotheses, expectations and predictions of the management team at the time of writing this report, and these are subject to a number of factors that mean that the actual results may be materially different. The future results of the Grifols group could be affected by events relating to its own activities, such as a shortage of supplies of raw materials for the manufacture of its products, the appearance of competitor products on the market, or changes to the regulatory framework of the markets in which it operates, among others. At the date of compiling this report, the Grifols group has adopted the necessary measures to mitigate the potential impact of these events. Grifols, S.A. does not accept any obligation to publicly report, revise or update future projections or assumptions to adapt them to events or circumstances subsequent to the date of writing this report, except where expressly required by the applicable legislation. This document does not constitute an offer or invitation to buy or subscribe shares in accordance with the provisions of the following Spanish legislation: Royal Legislative Decree 4/2015, of 23 October, approving recast text of Securities Market Law; Royal Decree Law 5/2005, of 11 March and/or Royal Decree 1310/2005, of 4 November, and any regulations developing this legislation. In addition, this document does not constitute an offer of purchase, sale or exchange, or a request for an offer of purchase, sale or exchange of securities, or a request for any vote or approval in any other jurisdiction. The information included in this document has not been verified nor reviewed by the external auditors of the Grifols group. 1 Marketing Research Bureau. Global Usage and Forecast of the Immunoglobulin Market by Region

非离子表面活性剂 Triton X-100 (C14H22O(C2H4O)n) 是用于确保生物医药产品病毒安全性的关键化学品。两个制药行业与它有着广泛的历史背景：生物制药和血浆源性产品，用于灭活脂质囊膜病毒。最近，欧盟的环境法规鼓励或强制要求逐步淘汰这种表面活性剂。该裁决的目的是保护水生生态系统免受潜在的 Triton X-100 降解产物的影响，这些降解产物可以作为具有雌激素模拟活性的内分泌干扰物。逐步淘汰将影响欧洲市场的医药产品，具体取决于批准状态和进入欧盟的生产点。下面，我们将讨论这些法规对两个关键行业的潜在影响。对于血浆源性产品溶剂/去污剂 (S/D) 灭活是行业标准单元操作，用于确保源自人血浆的产品的病毒安全性。为了加强由于“窗口期”而无法提供 100% 覆盖率的测试，该方法是在 1980 年代开发的，作为该行业对血浆供应中人类免疫缺陷病毒 (HIV) 污染的反应的一部分。这个想法是去污剂（例如胆酸盐、Triton X-100 或聚山梨酯 80）和溶剂（通常是三（正丁基）磷酸盐，TNBP）共同作用可以溶解逆转录病毒（如 HIV）周围的脂质囊膜，从而导致失活。这项工作由纽约血液中心率先开展，其中第一个 S/D 治疗使用了胆酸盐。随后，Baxter 的 Hyland 部门开发了所谓的“方法 M”，该方法使用 Triton X-100 处理，因为它被认为具有改进的动力学。血浆蛋白治疗协会 (PPTA) 的七名成员进行的 308 项研究的公开数据集最近强调了 S/D 的普遍重要性。这七家公司生产多种血浆源性产品，包括血液因子 VIII 和 IX、静脉内免疫球蛋白 (IVIG) 和肌内免疫球蛋白 (IMIG)。每个产品的生产方案都包括一个 S/D 步骤，其中将 Triton X-100、胆酸盐或聚山梨醇酯 80 去污剂与 TNBP 溶剂结合。聚山梨酯是最常用的；Triton X-100 表面活性剂次之，通常与聚山梨醇酯结合使用。PPTA 成员报告并评估了 S/D 在稳健性研究中的有效性，并根据其监管提交的数据在商业设定点进行了评估。这些公司使用几种模式囊膜病毒进行小规模研究：伪狂犬病病毒 (PRV)、牛病毒性腹泻病毒 (BVDV)、HIV-1、辛德毕斯病毒 (SINV)、马病毒性动脉炎病毒 (EAV)、西尼罗河病毒 (WNV) )、水疱性口炎病毒 (VSV)、痘苗病毒 (VacV) 和严重急性呼吸系统综合症冠状病毒 (SARS-CoV)。事实证明，Triton X-100 表面活性剂可有效灭活囊膜病毒，生产条件下的汇总声明如下：Triton X-100 - TNBP 组合在 >2.9 和 >6.5 log之间；对于添加了聚山梨醇酯 80 的相同组合，log >4.0 和 >6.6 之间。由于它是血浆制品行业 S/D 装置操作中第二大最常用的去污剂，显然，逐步淘汰或更换基于 Triton X-100 的 S/D 处理将具有颠覆性。使用它的现有工艺是生产许多已批准和上市药物的一部分。尽管这一变化还不是对现有产品的法律监管要求，但它需要工艺重新验证工作（包括使用一组病毒进行病毒灭活研究），然后是全球监管批准流程。此外，更改 S/D 步骤需要在不增加患者风险的情况下进行，因为 S/D 是一项关键的安全措施。需要合适的替代品。对于生物制药在生物制药行业，对 Triton X-100 潜在淘汰的主要监管关注与由啮齿动物源性的表达系统（如中国仓鼠卵巢 (CHO) 细胞）产生的囊膜逆转录病毒样颗粒 (RVLP) 有关。这些颗粒大多是非传染性的，但国际统一指南要求在下游工艺中清除它们。在生产过程中会产生大量 RVLP，在许多澄清的收获细胞培养液 (HCCF) 中可检测到高达 10^10 个颗粒/mL。幸运的是，蛋白质纯化的多个步骤可以去除或灭活病毒：例如柱层析、过滤和低 pH 孵育。HCCF 的去污剂处理已被提议作为“第五正交步骤”（在两层析柱、低 pH 灭活和除病毒过滤之后）。与逆转录病毒颗粒一样，RVLP 具有脂质囊膜，因此清除率研究可以使用密切相关的模式病毒，即异嗜性鼠白血病病毒（X-MuLV）。这第五步可能对需要额外清除脂质囊膜病毒的产品有帮助，尤其是当一个层析步骤不能提供有效结果或生产细胞产生高水平 RVLP 时。例如，已知小鼠骨髓瘤细胞系 SP2/0 会产生高水平的颗粒，其中一部分可以在体外分析中形成病灶。X-MuLV 灭活研究表明，非离子表面活性剂可有效灭活鼠类逆转录病毒，即使在 HCCF 中也是如此 (6)。为支持此类去污剂处理应用，美国材料与试验协会 (ASTM) 制定了一项标准 (E3042-16)，支持啮齿动物逆转录病毒（例如 MuLV 和 RVLP）清除率达到 4 log10 的要求。该标准主要适用于经 Triton X-100 表面活性剂处理的单克隆抗体 (MAb) 工艺料液，其范围包括澄清的无细胞中间体（0.2 µM 过滤 HCCF）。与低 pH 孵育单元操作相比，这种更广泛的范围提供了巨大的优势，低 pH 孵育单元操作只能在捕获层析之后应用。为了工艺效率，在 S/D 处理后，后续的捕获柱可以去除表面活性剂。这允许将第二个灭活步骤（例如，低 pH）应用于下游更纯化的中间体。Triton X-100灭活啮齿动物逆转录病毒ASTM标准按以下参数进行：Triton X-100浓度≥0.5%，时间≥60 min（混合），pH 6.0-8.0，温度15-25℃（根据统一指南的室温）。欧盟环境立法2006 年欧盟化学品注册、评估、授权和限制 (REACH) 法规于 2007 年 6 月生效。其目的是在欧盟内部对潜在有害化学品进行监督。为此，它涉及化学品的生产和使用及其对人类健康和环境的潜在影响。该法规还适用于商品中发现的化学物质，因此它会影响相关物质单独或作为进口商品的一部分进口到欧洲。REACH 规则的技术方面由位于芬兰赫尔辛基的欧洲化学品管理局 (ECHA) 实施和管理。该机构已经为欧盟内部使用的化学品建立了注册系统，到 2022 年初，近 23,000 种物质已输入其数据库。该立法要求公司向 ECHA 注册有关其生产或进口的化学品的危害、风险和安全使用的信息。然后，此类信息会发布在该机构的网站上。现有的全球化学品分类和标签系统可以很容易地识别与欧盟法规 1907/2006 下的特定物质相关的危害。有害物质分为许多类别。然后，高度关注物质 (SVHC) 受到控制，使其使用须经授权。最终目标是逐步用危险性较低的物质取代它们。SVHC 包括致癌、致突变和/或对生殖系统有毒的物质。对于环境问题，这些物质包括具有持久性、生物累积性和毒性的物质（PBT 物质）以及“非常持久和生物累积性”的物质（称为 vPvB 物质）。根据 REACH 法规，此类分类需要“科学证据证明可能对人类健康或环境产生严重影响，从而引起同等程度的关注。”这是根据具体情况决定的。在程序上，物质首先会在成员国发起并经过短暂的咨询期后被列入候选名单。此类清单为候选物质的供应商带来了向客户和消费者提供信息的多项义务。ECHA 审查其候选清单并确定物质的优先顺序，然后在进一步协商后将某些物质移至授权清单。一旦某种物质在授权清单上，如果获得授权，它只能用于非豁免应用。通常情况下，会设定一个截止日期，之后将不再接受进一步的授权申请。Triton X-100 “冲击”Triton X-100 表面活性剂是一组称为辛基酚乙氧基化物的化学物质的一部分，即使在低浓度下也会对水生生物产生毒性作用。它于 2012 年 12 月作为 4-(1,1,3,3-四甲基丁基) 苯酚乙氧基化物质组的一部分添加到 ECHA 候选清单中。添加该成分是基于对这些物质的非乙氧基化降解产物作为具有雌激素样活性的内分泌干扰物的环境影响的担忧，这种作用对水生动物特别有害。因此，降解产物 4-(1,1,3,3-四甲基丁基)苯酚被认为是 SVHC 和 PBT。2017 年，该表面活性剂作为 SVHC 被列入 ECHA 的授权清单（附件 XIV）。Triton X-100 生产商有机会申请授权，在“日落期”后继续使用该化合物。但申请豁免的时间现已过去，自 2023 年 12 月 22 日起，欧盟将禁止使用 Triton X-100 生产试验性医疗产品 (IMP) 和新的 MP。请注意，含有 ≤0.1% (w/w) Triton X-100 表面活性剂的物质不被视为危险物质，仍然可以进口到欧洲。由于该产品通常不用作生物制品或先进疗法的赋形剂，因此在欧洲以外生产的大多数此类药物在其开发商考虑在欧盟生产之前不需要生产变更。此外，已经获得许可的药物及其赋形剂（目前）不受该规则约束。所有其它希望在欧盟生产生物药物和研究产品的生产商都必须寻求 Triton X-100 的替代品并验证它们对各自用途的适用性，尤其是在病毒降低应用中。筛选替代品生物技术行业通过寻找合适的替代品来应对即将淘汰的问题 - 这是由已经使用基于去污剂的灭活步骤的大型生产商发起的一项活动。报告的候选物在化学、应用点和有效活动要求方面有所不同（表 1）。这些选项中的大多数在灭活生物制药基质中的 X-MuLV（RVLP 的共识模型）方面与 Triton X-100 表面活性剂一样有效。在某些情况下，灭活动力学受到冷生产或有溶剂和无溶剂比较的挑战。其它囊膜病毒（例如 HIV-1、PRV 和 BVDV）的灭活也在模式血浆产品基质中进行了评估，其结果等同于或优于生物制药研究中的结果。表 1：已发表的科学文献中 Triton X-100 的潜在替代品；PEG = 聚乙二醇，AAV = 腺相关病毒，S/D = 溶剂/去污剂，X-MuLV = 异营养性鼠白血病病毒，PRV = 伪狂犬病病毒，HIV = 人类免疫缺陷病毒，BVDV = 牛病毒性腹泻病毒，SuHV1 = 猪疱疹病毒 1 。候选去污剂的重要标准：要成为可行的候选去污剂，Triton X-100 替代品需要有效灭活病毒，最好是针对多种囊膜病毒。对于 HCCF 中可能存在的其它分子，例如脂质、宿主细胞蛋白 (HCP)、DNA 和消泡剂，灭活需要稳健。除了稳健性之外，还应考虑许多其它标准。例如，一种去污剂需要“环保”，满足全球处理要求，以取代不能满足要求的去污剂。采购方面的考虑也很关键：去污剂必须经济实惠，并且最好能从多家供应商处获得。它的生产过程必须是可扩展的，以响应生物制药开发商不断增长的生产需求。将适用制药生产的原材料纯度标准，随之而来的分析需要可以确保纯度和其它属性。如果去污剂是药典级的，那将是一种额外优势。更换应该对药品质量或生物工艺性能影响很小或没有影响。它们不得影响蛋白质原料药（例如，通过引起沉淀或变性）。应尽量减少不良或反应性副产物（例如过氧化物）。此外，混合过程中的起泡应该受到限制或不存在。预计下游工艺步骤会去除去污剂，并需进行分析，以测量宽浓度范围内替代去污剂的水平。它需要有效地溶解在水溶液中。预计生产过程中会进行安全处理，因此毒性必须最小（包括来自潜在杂质的毒性）。监管方面的考虑：从监管的角度来看，需要验证基于替代去污剂的单元操作、以清除病毒 - 如果引入替代品，则需要重新验证现有的生产工艺。除此之外，其它工艺验证方面需要小规模解决，并且可能需要工艺性能确认 (PPQ) 批次。验证研究需要表明，新的去污剂既不影响蛋白质、药物产品的稳定性，也不影响下游工艺流体中间体的保留。应证明修改后的病毒灭活单元操作可提供可接受的步骤产量，并且测试应证明去污剂不会堵塞或以其它方式影响下游步骤的效率。去污剂清除率需要小规模研究并在大规模 PPQ 运行中确认。常规清洁后，更换物应不会在层析柱基质或设备上留下任何残留物或积聚物。修订后的杂质毒理学评估需要进行临床前研究。例如，发起方应该针对他们使用替代去污剂生产的产品重新计算新的杂质安全系数。所有这些活动都需要向批准原始工艺的监管机构报告并获得批准。随着新版本获得每个监管机构的批准，世界各地的批准时间差异不可避免地会导致不同国家/地区的分阶段工艺流程版本。所有这些考虑因素可能会促使许多生物制药公司采取保守的实施方法，使一些公司产生偏见，反对改变他们现有的流程，并让现有的 Triton X-100 工艺“过时”。根据欧盟立法，这对于现有产品是可行的。但是，对于新产品，必须努力为这种转变做好准备。尽早做好准备可能是最好的选择，这不仅是为了减轻监管的复杂性，也是为了我们共享的水生生态系统的健康。原文：K. Brorson, C. Niederlaender. Triton X-100 Elimination: The Road Ahead for Viral Inactivation. Bioprocess International, 2022.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圈微信群！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。