BioDrugs. 2002;16(5):380-6. doi: 10.2165/00063030-200216050-00009.
Omalizumab [anti-IgE monoclonal antibody E25, E25, humanised anti-IgE MAb, IGE 025, monoclonal antibody E25, olizumab, rhuMAb-E25, Xolair] is a chimeric monoclonal antibody. It binds specifically to the Cepsilon3 domain of immunoglobulin E (IgE). Cepsilon3 is the site of high-affinity IgE receptor binding. IgE plays a major role in allergic disease by causing the release of histamine and other inflammatory mediators from mast cells. Omalizumab binds to and neutralises circulating IgE by preventing IgE from binding to its high-affinity mast-cell receptor. In addition, omalizumab does not bind to or induce histamine release from basophils, nor does it bind to or recognise IgG. The immune complexes formed between IgE and omalizumab in vivo are relatively small (molecular weight <1 million) and are therefore unlikely to cause organ damage. COLLABORATION BETWEEN GENETECH NOVARTIS AND TANOX: omalizumab is very similar to the Tanox product CGP 51901. Genentech (Roche), Novartis and Tanox (formerly Tanox Biosystems) were developing both antibodies in phase II studies, with an agreement to collaborate on phase III development of the most promising one. The Genentech product, omalizumab, was selected for further development. Tanox has marketing rights to the drug in some Asian markets. Novartis and Genentech have marketing rights in the USA. Roche has an option to participate in the commercialisation of omalizumab and other anti-IgE products of the collaboration in Japan and Europe. Roche may exercise this option if specific events relating to commercialisation of the product occur; Roche has waived this option for omalizumab in Japan. If Genentech withdraws from the collaboration, Roche has an option to assume its place. Either Novartis or Genentech may withdraw from the collaboration on short notice, in which case rights to omalizumab revert to Tanox and the remaining collaborator unless Roche exercises its option in the event of withdrawal by Genentech. PATENTS: Protein Design Labs holds fundamental antibody humanisation patents. Protein Design Labs stated in its Annual Report for 2000 that Genentech may elect to take a patent licence for Xolair under a 1998 patent rights agreement.
Phase III clinical trials of omalizumab for the treatment of allergic rhinitis and allergic asthma were in progress with Genentech (Roche) in the USA, Canada, Europe and Japan, and are now completed. In New Zealand, the antibody was investigated in clinical trials for the treatment of allergic asthma at the Wellington School of Medicine. In the phase III trials, omalizumab was administered as a subcutaneous injection. It may also be administered intravenously. In additional phase I and II studies, the safety and efficacy of aerosol administration for allergic asthma was tested. Initial results of these studies indicated that aerosol administration is less effective than intravenous or subcutaneous administration. TEMPORARY SUSPENSION OF TRIALS: In September 2000, the US FDA requested that Genentech and Novartis suspend new trials of omalizumab. Existing long-term trials, however, could continue. The hold on new trials was due to concerns about the preclinical toxicity of omalizumab and the follow-up antibody E26. Thrombocytopenia was reported in studies in monkeys for omalizumab at 5-27 times the maximum clinical dose and for E26 at 3-15 times the maximum dose. In response to FDA requests, Novartis and Genentech carried out additional preclinical trials so that a specific explanation of the toxicity could be obtained; Novartis suspected a species specificity for the adverse events, as no thrombocytopenic events occurred in the completed phase III clinical trials. The supplementary data were submitted to the FDA and the hold on clinical trials was lifted in November 2000. REGULATORY FILINGS: in June 2000, Genentech, Novartis and Tanox submitted a Biologics Licence Application (BLA) to the US FDA for approval of omalizumab for the treatment of allergic asthma and allergic rhinitis. Novartis fileiled for marketing approval of omalizumab in the European Union, Switzerland, Australia and New Zealand. INDICATION NARROWED TO ADULT ALLERGIC ASTHMA: In July 2001, the FDA requested additional data, both preclinical and clinical, for Xolair, as well as more detailed information concerning the effect of prolonged action of the drug. Genentech is to satisfy the FDA's request with data from the ALTO platelet monitoring safety study and with ongoing open-label studies. Genentech, Novartis and Tanox believe that substantial information can be provided from continuing trials, but additional trials on specific subgroups may be necessary. The new data will be submitted to both the US FDA and the EMEA in the European Union. The application for approval of Xolair that was submitted to the EMEA was withdrawn when it became clear that there would be a delay in approval in the USA. Tanox had originally anticipated that Xolair would be launched in mid-2001 in the USA and Europe. In November 2001, Genentech and Novartis stated that an amended BLA would be submitted to the FDA in the fourth quarter of 2002. The amended approval application will focus on the use of Xolair in adults only with allergic asthma. The original application was for treatment of both adults and children, and included allergic rhinitis. Genentech has stated that it will first pursue the narrower indication before filing supplemental BLAs. Approval of the drug in the USA may now be delayed until as late as the end of 2003. In Europe, Novartis is planning to develop Xolair for use only in asthmatic patients who are classed as being 'at risk', i.e. those who have been hospitalised or have visited an emergency department. Clinical studies are to be carried out, with submission for regulatory approval planned for 2003. APPROVAL IN AUSTRALIA: In June 2002, Xolair was approved by the Therapeutic Goods Administration in Australia for the treatment of adults and adolescents with moderate allergic asthma. This is the first marketing approval for Xolair.
奥马珠单抗[抗IgE单克隆抗体E25、E25、人源化抗IgE单克隆抗体、IGE 025、单克隆抗体E25、奥立珠单抗、重组人源化抗IgE单克隆抗体、Xolair]是一种嵌合单克隆抗体。它特异性结合免疫球蛋白E（IgE）的Cε3结构域。Cε3是IgE高亲和力受体结合位点。IgE通过促使肥大细胞释放组胺和其他炎症介质在过敏性疾病中起主要作用。奥马珠单抗通过阻止IgE与其高亲和力肥大细胞受体结合来结合并中和循环中的IgE。此外，奥马珠单抗不与嗜碱性粒细胞结合或诱导其释放组胺，也不与IgG结合或识别IgG。体内IgE与奥马珠单抗形成的免疫复合物相对较小（分子量<100万），因此不太可能导致器官损伤。基因泰克、诺华与Tanox的合作：奥马珠单抗与Tanox产品CGP 51901非常相似。基因泰克（罗氏）、诺华和Tanox（原Tanox生物系统公司）在II期研究中同时开发这两种抗体，并达成协议，对最有前景的一种进行III期联合开发。基因泰克的产品奥马珠单抗被选中进行进一步开发。Tanox在一些亚洲市场拥有该药物的营销权。诺华和基因泰克在美国拥有营销权。罗氏有权选择参与奥马珠单抗及合作中的其他抗IgE产品在日本和欧洲的商业化。如果发生与该产品商业化相关的特定事件，罗氏可以行使这一选择权；罗氏已放弃在日本对奥马珠单抗的这一选择权。如果基因泰克退出合作，罗氏有权取而代之。诺华或基因泰克均可在短时间内退出合作，在这种情况下，奥马珠单抗的权利将归还给Tanox和其余合作伙伴，除非罗氏在基因泰克退出时行使其选择权。专利：蛋白质设计实验室拥有基础抗体人源化专利。蛋白质设计实验室在其2000年年度报告中表示，基因泰克可能会根据1998年的专利权协议选择获得Xolair的专利许可。
基因泰克（罗氏）在美国、加拿大、欧洲和日本进行的奥马珠单抗治疗过敏性鼻炎和过敏性哮喘的III期临床试验正在进行，现已完成。在新西兰，惠灵顿医学院对该抗体进行了治疗过敏性哮喘的临床试验研究。在III期试验中，奥马珠单抗通过皮下注射给药。它也可以静脉注射给药。在另外的I期和II期研究中，测试了雾化吸入给药治疗过敏性哮喘的安全性和有效性。这些研究的初步结果表明，雾化吸入给药不如静脉或皮下给药有效。试验的临时暂停：2000年9月，美国食品药品监督管理局要求基因泰克和诺华暂停奥马珠单抗的新试验。然而，现有的长期试验可以继续。暂停新试验是因为担心奥马珠单抗和后续抗体E26的临床前毒性。在猴子研究中，奥马珠单抗在5至27倍最大临床剂量时以及E26在3至15倍最大剂量时均报告有血小板减少症。为回应美国食品药品监督管理局的要求，诺华和基因泰克进行了额外的临床前试验，以便获得毒性的具体解释；诺华怀疑这些不良事件具有种属特异性，因为在已完成的III期临床试验中未发生血小板减少事件。补充数据已提交给美国食品药品监督管理局，2000年11月临床试验的暂停被解除。监管申报：2000年6月，基因泰克、诺华和Tanox向美国食品药品监督管理局提交了生物制品许可申请（BLA），以批准奥马珠单抗用于治疗过敏性哮喘和过敏性鼻炎。诺华在欧盟、瑞士、澳大利亚和新西兰申请奥马珠单抗的上市许可。适应证缩小至成人过敏性哮喘：2001年7月，美国食品药品监督管理局要求提供关于Xolair的临床前和临床额外数据，以及关于该药物延长作用效果的更详细信息。基因泰克将通过ALTO血小板监测安全性研究的数据和正在进行的开放标签研究来满足美国食品药品监督管理局的要求。基因泰克、诺华和Tanox认为持续试验可以提供大量信息，但可能需要对特定亚组进行额外试验。新数据将提交给美国食品药品监督管理局和欧盟的欧洲药品管理局。当明确在美国的批准将延迟时，提交给欧洲药品管理局的Xolair批准申请被撤回。Tanox最初预计Xolair将于2001年年中在美国和欧洲上市。2001年11月，基因泰克和诺华表示将在2002年第四季度向美国食品药品监督管理局提交修订后的生物制品许可申请。修订后的批准申请将只专注于Xolair在仅患有过敏性哮喘的成人中的使用。最初的申请是用于治疗成人和儿童，包括过敏性鼻炎。基因泰克表示将在提交补充生物制品许可申请之前首先寻求更窄的适应证。该药物在美国的批准现在可能会延迟至2003年底。在欧洲，诺华计划开发Xolair，仅用于被归类为“有风险”的哮喘患者，即那些已住院或去过急诊科的患者。将进行临床研究，计划于2003年提交监管批准申请。在澳大利亚的批准：2002年6月，Xolair被澳大利亚治疗用品管理局批准用于治疗患有中度过敏性哮喘的成人和青少年。这是Xolair的首个上市许可。
