Xadago（沙芬酰胺）沙芬酰胺甲磺酸盐(Safinamide mesilate)
通用名：沙非酰胺（safinamide）
商品名称：Xadago
剂型：薄膜衣片
规格：50毫克和100毫克

Name	Xadago
INN or common name	safinamide
Therapeutic area	Parkinson Disease
Active substance	safinamide
Date opinion adopted	18/12/2014
Company name	Zambon SpA.
Status	Positive
Application type	Initial authorisation

On 18 December 2014, the Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion, recommending the granting of a marketing authorisation for the medicinal product Xadago, 50mg and 100mg, film-coated tablet intended for the treatment of Parkinson’s disease. The applicant for this medicinal product is Zambon SpA. They may request a re-examination of any CHMP opinion, provided they notify the European Medicines Agency in writing of their intention within 15 days of receipt of the opinion.
The active substance of Xadago is safinamide, a highly selective and reversible MAO-B inhibitor causing an increase in extracellular levels of dopamine in the striatum. Xadago is also associated with state-dependent inhibition of voltage-gated sodium (Na+) channels, and modulation of stimulated release of glutamate.
The benefits with Xadago are its ability to improve the ON time in patients with motor fluctuations, currently receiving L-dopa alone or in combination with other PD medications. The most common side effects are dyskinesia, somnolence, dizziness, headache, insomnia, nausea and orthostatic hypotension.
A pharmacovigilance plan for Xadago will be implemented as part of the marketing authorisation.
The approved indication is: “Xadago is indicated for the treatment of adult patients with idiopathic Parkinson’s disease (PD) as add-on therapy to a stable dose of Levodopa (L-dopa) alone or in combination with other PD medicinal products in mid-to late-stage fluctuating patients.”
Detailed recommendations for the use of this product will be described in the summary of product characteristics (SmPC), which will be published in the European public assessment report (EPAR) and made available in all official European Union languages after the marketing authorisation has been granted by the European Commission.
The CHMP, on the basis of quality, safety and efficacy data submitted, considers there to be a favourable benefit-to-risk balance for Xadago and therefore recommends the granting of the marketing authorisation.

Name	Language	First published	Last updated
CHMP summary of positive opinion for Xadago

New Drugs Online Report for safinamide
Information
Generic Name: safinamide  
Trade Name: Xadago 
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
Dec 14: EU positive opinion for treatment of adult patients with idiopathic PD as add-on therapy to a stable dose of Levodopa (L-dopa) alone or in combination with other PD medicinal products in mid-to late-stage fluctuating patients [16].
19/12/2014 12:54:22 
May 14: Filed in the US for use as add-on therapy for early and mid-to-late stage PD [15].
30/05/2014 13:37:26 
Dec 13: Filed for marketing approval in the EU. The submission covers the indications add-on therapy to 1) a stable dose of a single dopamine agonist in early Parkinson’s disease patients and 2) and to levodopa alone or in combination with other Parkinson’s disease treatments in mid-to late stage Parkinson’s disease patients. The rapporteur and co-rapporteur for safinamide are the Netherlands and the UK, respectively. Zambon will be the Marketing Authorization holder [14].
09/12/2013 09:04:01 
Jun 13: Newron announces PIII SETTLE results will be part of the EU & US regulatory submissions [12].
21/06/2013 10:46:20 
Mar 13: Newron and its partner Zambon plan to submit in the US and EU in Q4/2013 [11].
20/03/2013 19:16:24 
Safinamide no longer listed in Merck Serono-s pipeline (7).
08/12/2011 15:26:13 
Safinamide in PIII trials for mid-to-late stage PD (2).
30/11/2009 16:59:08 
Trial or other data
Jun 13: Newron presents data from the PIII SETTLE study at the 2013 MDS meeting. Results presented showed that safinamide significantly improved "super responder" rates in fluctuating PD pts as add-on to levodopa & other dopaminergic therapies. Safinamide was also associated with clinically important improvement in motor symptoms in fluctuating PD patients as add-on to levodopa & other dopaminergic therapies [12].
21/06/2013 10:44:36
Mar 13: Results from the PIII SETTLE study presented at the 65th AAN meeting. The 24-week international trial enrolled 549 patients with mid-to late-stage idiopathic PD (>3 years of disease duration) treated with optimized, stable doses of levodopa and standard of care (dopamine agonist, COMT inhibitor, anticholinergic and/or amantadine) for at least 4 weeks. Patients who were experiencing a minimum of 1.5 hours of OFF time during the day were randomized to once a day safinamide (50-100mg) or placebo (standard of care including levodopa), as adjunctive treatment. Based on discussions with the regulatory authorities, the primary endpoint was the change in daily ON time, as assessed by the patient completed daily diary cards (18 hours/day). Analyses of the ITT population showed treatment with safinamide 50-100 mg/day significantly improved ON-Time without troublesome dyskinesia vs placebo by 0.96 ± 0.21 hours (p<0.01). Significant benefits of safinamide 50-100 mg/day were also reported in OFF-time, Motor symptoms (UPDRS III), PDQ39, EQ-5D, clinical global impression of change and severity, and OFF-time post morning dose of levodopa. 484 patients completed the trial; the drop-out rate was similar in both treatment groups (approx. 12%). The most commonly reported adverse events were nausea, urinary tract infections, falls, back pain and dyskinesia. Transient dyskinesia occurred more frequently with safinamide, but was mainly mild, and was not associated with treatment discontinuation. The incidence of treatment induced abnormalities in laboratory results, ophthalmological examinations, vital signs and ECG was similar in all groups [11]. 
20/03/2013 19:16:38
May 12: Top line results reported from the last two PIII studies of safinamide as an add-on treatment in early (MOTION) and advanced (SETTLE) patients with PD. The results with those from previous PII/III studies in early (studies 009 and 015) and advanced (study 016) PD (no details given). Safinamide was well tolerated with no significant difference in the incidence of drop outs, serious AEs, treatment emergentAEs, laboratory abnormalities and ophthalmologic findings between safinamide and placebo. The 24-week SETTLE study enrolled 549 patients with mid- to late-stage idiopathic PD (> 3 years of disease duration) treated with a stable dose of levodopa for at least four weeks, who had motor fluctuations with more than 1.5 hours of ‘OFF’ time during the day. Concomitant treatment with stable doses of a dopamine agonist, a COMT inhibitor, an anticholinergic and/or amantadine were allowed. The primary endpoint was the change in daily ‘ON’ time, as assessed by the recordings of diary cards maintained by patients after prior training, from baseline to week 24 [10].
19/05/2012 20:00:48
Apr 12: Merck Serono will return the global rights to safinamide to Newron this month. Newron has now signed a strategic collaboration and licence option with Zambon will meet the costs of completing safinamide´s clinical development and the preparation of the application for marketing approval in Europe and the US [8].
06/04/2012 17:10:02
Oct 11: Merck Serono is to return all rights for safinamide to Newron Pharmaceuticals from April 2012. The decision was made as part of the ongoing review of its R&D pipeline. In Merck Serono´s view, safinamide has a more limited market potential than originally anticipated [6].
24/10/2011 14:51:51
Jul 11: Patient enrollment in the SETTLE1 study has been completed [5].
01/08/2011 09:43:59
April 11: Results of a two-year study of 50mg or 100mg safinamide or placebo in 669 patients with mid-to-late stage Parkinson´s disease who were already taking levodopa and other dopaminergic treatments. Movement ability was rated on the United Parkinson´s disease rating scale (measures e.g. tremor, speech, behavior, mood and daily activities including swallowing, dressing and walking). Average scores at start of study were 3.9 (50mg), 3.7 (100mg) and 3.4 (placebo). After 2 years, safinamide 100mg/day was shown to reduce dyskinesia by 24% in the one-third of pts who had score 4 or more on the dyskinesia rating scale at baseline, vs. placebo. There were no significant differences for people who took the 50 milligram dose. There were no significant differences in the primary efficacy measure (movement control, i.e., dyskinesia) scores in the overall population. Side effects were comparable among the three treatment groups. [4] 
18/04/2011 13:04:34
Nov 10: Top-line results reported of an 18-month, double-blind, placebo-controlled extension study (study 018) of a previously completed and reported 6-month PIII study (study 016). 544 patients with advanced PD were randomised to one of two doses of safinamide (50 or 100mg once daily) or placebo as add-on therapy to levodopa. The primary efficacy endpoint - mean change in the ratings of the Dyskinesia Rating Scale1 (DRS) after 24 months - was not met. Mean improvements in the DRS score of 0.19 and 0.28 were observed in those on safinamide 50mg and 100mg vs a worsening of 0.32 for the placebo group (respectively p=0.21 and p=0.15 vs placebo). An exploratory analysis of the pre-specified main secondary endpoint suggested that the significant effect on "ON" 2 time without troublesome or minor dyskinesia observed in study 016 (primary endpoint) was maintained at the end of the 24-month period for both safinamide doses (1.01 and 1.18 hours respectively vs 0.34 hours for placebo; p=0.0031 and p=0.0002 vs placebo). The incidences of dropouts, serious adverse events or clinically notable events among were comparable among the 3 groups [3]. 
05/11/2010 09:10:12
May 09: A further 24 week PIII study, SETTLE (SafinamidE Treatment as add-on To LEvodopa in idiopathic Parkinson´s disease with motor fluctuations), is to start. It will evaluate a flexible dose of safinamide (50-100mg once daily) vs placebo, as add-on therapy to a stable dose of levodopa, in >450 patients with mid- to late-stage Parkinson´s disease with motor fluctuations and more than 1.5 hours of ‘OFF’ time/day. Stable doses of a dopamine agonist, a COMT inhibitor, an anticholinergic and/or amantadine will be permitted. The primary endpoint is the change in daily ‘ON’ time from baseline to week 24 (2)
07/05/2009 21:47:47
May 09: Some additional results from study 016 below. As well as the benefit on motor fluctuations (increase in ‘ON’ time) reported previously, there was a statistically significant reduction in the UPDRS part IV scale with both 50 and 100mg doses. The 100 mg dose also improved depressive symptoms as measured by the GRID-HAMD scale total score, and improved emotional well-being as measured by a subscale of the PDQ-39 (2).
07/05/2009 21:37:11
Feb 09: Headline results released of a pivotal PIII 6 mo trial in 699 patients with mid- to late stage parkinson´s disease stabilised on levodopa, who were randomised to safinamide 50mg or 100mg daily or placebo. Patients on safinamide experienced an average increase of "ON" time of 1.3 hours per day vs baseline, compared to 0.7 hour for those on placebo vs. baseline; the difference was statistically significant (1)
16/04/2009 11:54:59
References  
Available only to registered users
 Category
BNF Category: Drugs used in parkinsonism and related disorders (04.09)
Pharmacology: MAOB, dopamine reuptake, glutamate inhibitor  
Epidemiology: The incidence of the disease rises steeply with age; from 17.4 in 100,000 person years between 50 and 59 years of age to 93.1 in 100,000 person years between 70 and 79 years. Prevalence is 65.6 per 100,000 to 125 per 100,000. [9]  
Indication: Parkinson's disease 
Additional Details: Mid-to-late stage 
Method(s) of Administration  
Oral 
Company Information
Name: Newron 
US Name: Newron 
Further Information
Anticipated Commissioning route (England) - 
In timetable: -  
PbR Awaiting Update
2013年12月5日，致力开发中枢神经系统疾病药物的制药公司Newron及其市场合作伙伴赞邦（Zambon）公布了其治疗帕金森病（PD）的先导候选药品沙芬酰胺（safinamide）的研发进展。在上周向欧洲药品管理局（EMA）提交了上市许可申请（MAA）后，赞邦和Newron计划在2014年第一季度向美国食品和药物管理局（FDA） 提交的新药申请（NDA）。
沙芬酰胺在2014年和2015年之间在美国和欧洲被批准上市似乎已经是板上定钉的事情。作为一个“me-too”的药物，它和Teva公司的Azilect（雷沙吉兰）和司来吉兰（selegiline）一样是单胺氧化酶B（MAO-B）抑制剂。MAO-B抑制剂通常作为单药治疗早期PD患者，或者被添加到晚期PD患者的治疗方案中以能更好地控制症状并减少所需的其他帕金森病药物的剂量。2012年5月完成了针对早期和晚期病人的四个关键性III期临床试验，从超过2000位PD患者中得到长期和短期数据，证明沙芬酰胺具有很好的安全谱以及类似于同类其他药物的疗效。
沙芬酰胺与其竞争产品相比具有两个优点
第一，它对MAO-B具有高度特异性，因此可以限制或消除饮食限制（dietary restrictions），这在同类的其它药品中仍然是一个很大的问题；
第二，沙非酰胺有双重作用机制，除可抑制MAO-B外，还具有抑制谷氨酸释放（glutamate release ）的附加功能，理论上，这可能会产生神经保护作用，相比目前只提供对症治疗的情况，沙非酰胺更能满足市场上的关键未得到满足需求，目前的MAO-B抑制剂，特别是的Azilect，也已经提出了具有神经保护作用，但临床数据并不能充分支持这一假设。
因此，沙芬酰胺很可能会成为更受医生青睐的药品。无论如何，医生对这个药物药寄予厚望，相信它能减缓疾病的进展。
Newron过去的几年里已经克服了逆境。其与默克公司的营销协议在执行五年后于2011年结束，因此safinamide的各项权益也于2012年被该公司收回。默克公司对于导致这个决定的有关事件并没有完全公开，给出的理由是战略变化和高估了该药物的市场。在此之前，沙芬酰胺未能在2010年完成的3期临床试验中达到其主要终点，该试验的目的是评估沙芬酰胺在减少运动障碍（dyskinesia）方面的疗效，运动障碍是中晚期帕金森病患者常见的并发症。另一个问题是，沙非酰胺作为第一个谷氨酸释放抑制剂目前也被一些关键意见领袖质疑。
虽然Newron的新营销合作伙伴赞邦可能没有与制药巨头默克公司同等规模的销售团队，但是safinamide的采购速度证明了该引人注目的药物是让人们振奋的。作为MAO-B抑制剂，沙芬酰胺可能直接窃取Azilect的患者份额。Azilect 通常优于司来吉兰，Azilect在2012年的销售额是3.3亿美元，这个药的专利在美国要持续到2017年，在欧洲持续到2019年。
沙非酰胺在欧洲和美国市场的推出，将是Newron和赞邦的一个重大的胜利，这两个企业在医药行业中是相对较小的“玩家”。对照研究数据支持沙非酰胺具有神经保护作用，这将有利于沙芬酰胺在竞争激烈的MAO-B抑制剂占据一席之地，而目前的治疗选择又十分有根，相信医生也乐于使用这一具有新机制的药物。