2016年5月27日，美国食品和药品监管局(FDA)批准Zinbryta (daclizumab)为有多发性硬化症(MS)的复发型成年的治疗。Zinbryta是一个长效注射剂，可由患者每月自身给药。 FDA的药品评价和研究中心中神经学产品部主任Billy Dunn，M.D.说：“Zinbryta可能对治疗需要新选择的患者提供一个另外选择。” MS是一种中枢神经系统慢性，炎性，自身免疫病，它破坏脑和机体其他部分间交流。它是在年轻成年中神经学失能最常见原因和在妇女中比男性更频繁发生。对大多数有MS的人，初始地恶性功能(功能)的发作接着是恢复阶段(缓解)。随时间，恢复可能是不完全，导致功能中进展性下降和增加失能残疾。大多数人在年龄20和40 岁间经受其首次MS症状。 在两项临床试验中显示Zinbryta的有效性。一项试验在1,841例参加者中比较Zinbryta和Avonex，研究共144周。用Zinbryta 患者比服用Avonex患者有较少临床复发。第二项试验比较Zinbryta与安慰剂及包括412例参加者被治疗共52周。在该研究中，接受Zinbryta患者比接受安慰剂有较少复发。 Zinbryta应一般地仅被对两个或更多MS药物有反应不佳的患者中使用因为有严重安全性风险，包括肝损伤和免疫情况。因为这个风险，Zinbryta有一个黑框警告和仅通过一个受限的分发程序在风险评估和减灾战略下可得到。 黑框警告告诉处方者药物可能致严重肝损伤，包括危及生命和致命性事件。健康保健专业人员应在开始Zinbryta前，每个月每剂前，和直至目次剂量后6个月进行血液测试监视患者的肝功能。 该黑框警告还强调Zinbryta治疗的其他重要风险包括免疫情况，例如结肠炎症(非-感染性结肠炎)，皮肤反应，和淋巴结肿大， 另外被强调的警告包括超敏性反应(过敏性反应或血管水肿)，对感染增加风险，和抑郁和/或自杀意念的症状。 在临床试验中接受Zinbryta患者报道与Avonex比较最常见的不良反应包括感冒症状(鼻咽炎)，上呼吸道感染，皮疹，流感，皮炎，喉痛(口咽炎)，湿疹，和淋巴结肿大。接受Zinbryta患者当与安慰剂比较报道的最常见不良反应是抑郁，皮疹，和增加的谷丙转氨酶。 Zinbryta是由麻省剑桥的Biogen Inc.公司制造。 New Drugs Online Report for daclizumab Information Generic Name: daclizumab   Trade Name: Zinbryta  Synonym: DAC HYP, Zenapax  Entry Type: New molecular entity   Development and Regulatory status UK: Recommended for approval (Positive opinion)  EU: Recommended for approval (Positive opinion)  US: Pre-registration (Filed)  UK launch Plans: Available only to registered users Actual UK launch date:   Comments Apr 16: EU positive opinion for treating adults with relapsing forms of multiple sclerosis (RMS) [18]. 29/04/2016 14:15:50  Apr 15: The FDA has accepted application for the approval of ZINBRYTA™ for relapsing forms of multiple sclerosis. [15] 30/04/2015 09:49:51  Mar 15: Filed in the EU. The filing for Zinbryta is based on the DECIDE and SELECT trials [14]. 30/03/2015 15:03:25  Sep 14: Biogen Idec and AbbVie plan to file regulatory applications in 2015 [13]. 16/09/2014 11:17:38  May 10: First patient enrolled in the PIII DECIDE study [5]. 24/05/2010 21:25:07  PIII trial expected to started 1H 2010 [3]. 02/09/2009 08:32:45  PII study for monotherapy planned (1) Trial or other data Oct 15: Results of DECIDE, published in NEJM, show that daclizumab was associated with a lower annualised relapse rate than interferon beta-1a (0.22 vs. 0.39, respectively; P<0.001) in patients with relapsing-remitting MS. Infections, cutaneous events and LFT elevations were however more common [16]. Although the annualised relapse rate in this study was lower with daclizumab than interferon beta-1a, there was no statistically significant difference between the two groups in terms of disability progression confirmed at 12 weeks at week 144 (16% and 20%, respectively; P=0.16) [17]. 13/10/2015 10:12:12 Sept 14: Results from PIII DECIDE study. Pts taking daclizumab had a statistically significant 45% reduction in annualised relapse rate compared to pts treated with interferon beta-1a (p<0.0001). Daclizumab demonstrated superiority in reducing the number of new or newly enlarging T2-hyperintense lesions at week 96, with a 54% reduction relative to inteferon beta-1a. The risk of three-month confirmed disability progression, as measured by the Expanded Disability Status Scale (EDSS), was reduced by 16% in patients treated with daclizumab compared to those on interferon beta-1a(p=0.16).(p<0.0001). 73% of daclizumab-treated patients were relapse-free vs. 59% of interferon beta-1a treated pts (p<0.0001) at week 96. The risk of meaningful worsening in the physical impact of multiple sclerosis (MS) (> 7.5 point worsening in the Multiple Sclerosis Impact Scale [MSIS-29] physical score) was reduced by 24% in the daclizumab group compared to the interferon beta-1a group (nominal p=0.018). [12] 15/09/2014 08:50:23 Jun 14: Positive top-line results from the DECIDE study reported [11]. 11/07/2014 17:19:28 Jun 14: Biogen Idec & AbbVie announce that, in a PII study, daclizumab significantly decreased annualised relapse rate by 45% vs. once-weekly Avonex (interferon beta-1a). Daclizumab also met one of two secondary endpoints [10]. 18/06/2014 12:18:25 Mar 14: PIII SELECTION study published in The Lancet [9]. 20/03/2014 10:10:34 NCT01797965 (EXTEND) is a long-term PIII extension study in 1,841 subjects with RRMS who have completed study NCT01064401 (DECIDE). All patients will receive open-label daclizumab monthly for up to 3 years. The study starts Feb 13 and finishes Dec 16 [8] 17/07/2013 18:35:51 Apr 13: Results from the daclizumab high-yield process (DAC HYP) SELECT study published early online in The Lancet (www.thelancet.com/journals/lancet/article/PIIS0140-6736(12)62190-4/fulltext). 05/04/2013 09:33:03 Oct 12: Results from SELECTION, a 1 year extension study to the SELECT study reported at the European Committee for Treatment and Research in Multiple Sclerosis meeting. Daclizumab sustained efficacy in the 2nd year but serious autoimmune issues also emerged. Of 621 patients completing SELECT, 517 participated in SELECTION, with 92% remaining through the full year. Patients in SELECT originally taking placebo were re-randomized to either 150 or 300mg daclizumab monthly; those in the active drug arms were also re-randomized to receive either continuous treatment with the same dose, or to a 24-week washout period followed by resumption of the original dose for 24 weeks. The purpose was threefold: to confirm the drug´s efficacy in the original placebo group, to examine the durability of its effects with continuous treatment, and to see whether it would retain its efficacy when restarted after treatment interruption. Patients in the initial placebo group had a mean annualized relapse rate (ARR) of 0.434 in SELECT and an ARR of 0.179 (95% CI 1.23 to 0.261) in SELECTION (pooled data on both doses). Disability progression was also reduced (P=0.033). New or enlarging T2 MRI lesions declined by 74% and new gadolinium-enhancing T1 lesions decreased 86% after the switch. In patients continuously treated with daclizumab, ARR and the slowing of disability progression seen in SELECT was maintained. Rates of new/enlarging T2 lesions declined modestly but significantly (P=0.032). In the patients randomized to the 24-week daclizumab washout, gadolinium-enhancing lesion numbers rebounded to 3x the level seen at the end of SELECT; after 6 months daclizumab treatment mean lesion counts fell back to levels similar to those at the end of SELECT. CD56bright natural killer cell counts, a laboratory measure of daclizumab treatment, had risen roughly 10-fold from baseline during SELECT but levelled off in continuously treated patients. There were 13 serious infections, 6 skin events, 8 cases of liver enzyme elevations beyond 5X the ULN, 1 cancer, and 3 cases of autoimmune disorders (including 1 fatal hepatitis) .Some researchers think that the autoimmune problems may be serious enough to jeopardize the drug´s future in MS [7]. 17/10/2012 09:40:01 Aug 11: Top-line data from PIIb SELECT trial. Daclizumab high-yield process (DAC HYP) significantly reduced annualised relapse rate by 54% in 150mg dose arm, and by 50% in 300mg dose arm, vs. placebo, at one year. DAC HYP met secondary endpoints for the 150 mg and 300 mg arms, respectively, providing a highly statistically significant reduction in the cumulative number of new gadolinium-enhancing lesions between weeks 8 and 24 (69%; 78%); in the number of new or newly enlarging T2 hyperintense lesions at one year (70%; 79%); and in the reduction in the proportion of patients who relapsed (55%; 51%). DAC HYP also showed a trend toward improvement in quality of life measures at one year. DAC HYP reduced the risk of sustained disability progression at one year Overall incidence of adverse events and treatment discontinuations were similar in all study arms.[6]  09/08/2011 15:49:55 May 10: First patient enrolled in the global PIII DECIDE study (NCT01064401) comparing monthly subcutaneous daclizumab vs weekly IM interferon beta-1a (AVONEX®) in patients with relapsing-remitting multiple sclerosis (RRMS). The randomized, double-blind 2-3 year montherapy study is expected to enroll 1,500 RRMS patients in 28 countries. DECIDE (Daclizumab HYP Efficacy Compared to Interferon Beta 1-a Study for Multiple Sclerosis) will include patients between the ages of 18 to 55 years with an Expanded Disability Status Scale (EDSS) score ranging from 0.0 to 5.0. The primary endpoint is annualized relapse rate; other endpoints include functional decline, disability progression and quality of life. Estimated study completion date is Nov 13 [5]. 24/05/2010 21:24:44 Feb 10: PII data from the CHOICE study published in the online edition of The Lancet Neurology, ahead of publication in the April issue. The study enrolled 230 patients, ages 18 to 55 years, with active relapsing MS who had an entry score of five or less on the Expanded Disability Status Scale (EDSS). The patients had to be taking a stable IFNβ regimen for a minimum of six months prior to enrollment. During the year prior to enrollment, patients had to have experienced at least one MS relapse or incurred at least one MS lesion of the brain or spinal cord while on a stable IFNβ regimen. Patients were randomised to one of 3 groups: 2mg/kg daclizumab every two weeks (DAC high dose/ IFNβ); 1mg/kg daclizumab every four weeks (DAC low dose/ IFNβ); or placebo (placebo/ IFNβ). Compared with placebo/IFNβ therapy, there was a 72 % reduction in the number of new or enlarged gadolinium contrast-enhancing lesions (Gd-CELs – primary endpoint) between weeks eight and 24 in the DAC high dose/IFNβ group (p=0.004, 95% CI 34%, 88%) and a 25% reduction in the DAC low dose/IFNβ group (p=0.51, 95% CI -76%, 68%). In addition, treatment with daclizumab resulted in a 7-8 fold increase of CD56bright NK cells (a subset of the natural killer (NK) cells that help regulate the immune system) which was associated with a decrease in disease activity. Daclizumab was well-tolerated; common adverse events occurred with a similar frequency in each treatment group [4].  18/02/2010 08:59:25 Aug 09: The company will request a Special Protocol Assessment from the FDA for a PIII study planned to start 1H 2010. They are anticipating approval Jul 11 [3].  02/09/2009 08:41:09 The PIIb SELECT study is a placebo-controlled, dose-ranging study of monotherapy in patients with relapsing-remitting MS. 600 patients will be randomized to receive 150 mg DAC HYP, 300 mg DAC HYP or placebo every four weeks suncutaneously. The primary endpoint is reduction in the annualized relapse rate. Secondary endpoints include reductions of new or enlarged gadolinium-enhanced magnetic resonance imaging lesions. SELECT is considered to be the first of two registration-enabling trials required by regulatory authorities [3].  02/09/2009 08:40:55 The PIIb SELECT trial (NCT00390221) of DAC HYP monotherapy started in Feb 08 in EU, Russia, India and Australia and is expected to complete in Nov 11. In Mar 09, It was agreed to increase patient numbers from 300 to 600, and to change the primary endpoint to annualised relapse rate. The independent Safety Monitoring Committee has conducted a planned interim futility analysis of a subset of the data, and has recommended the continuation of the trial. Regulatory authorities have stated that a positive outcome of this phase II trial plus a phase III trial would be sufficient to support registration of daclizumab [2]. 02/09/2009 08:29:28 Facet Biotech Corporation has developed a high-yield manufacturing process for daclizumab (DAC HYP), producing a high concentration, liquid formulation for subcutaneous injection for the treatment of MS [2]. 02/09/2009 08:26:10 CHOICE trial showed benefit in reducing number of lesions when added to beta-interferon in pts with relapsing MS (1) Evidence Based Evaluations NIHR HSRIC  http://www.hsric.nihr.ac.uk/topics/daclizumab-high-yield-process-for-relapsing-forms-of-multiple-sclerosis-first-or-second-line/  References   Available only to registered users