2014年6月，灵北（Lundbeck）新一代溶栓药物去氨普酶（desmoteplase）首个III期研究（DIAS-3）失败，为该药临床项目的推进蒙上了阴影。此前，业界曾对该药寄予厚望，FDA也已授予该药快车道地位。近日，desmoteplase临床项目似乎迎来转机，采用新的分析方法发现，desmoteplase与较好的功能预后相关。新分析数据同时表明，检测早期缺血性损伤时，与电脑断层扫描（CT）相比，现代核磁共振成像（MRI）是一种更优良的方法。
在临床中，急性缺血性脑卒中（AIS）从症状发作到治疗的中位时间为7.0个小时，考虑到目前尚无药物用于9小时治疗窗，以及desmoteplase在符合方案集患者群体中表现出的疗效及优越安全性和耐受性，灵北表示，未来几个月，将征询关键临床和监管专家的意见对desmoteplase项目进一步评估。
灵北曾于今年6月底公布了III期DIAS-3研究的疗效和安全性数据，该研究调查了desmoteplase治疗急性缺血性脑卒中（AIS）成人患者的疗效和安全性。当时的通报显示，该研究在主要终点——改良Rankin量表（mRS）评测的功能改善方面，安慰剂与desmoteplase治疗组无统计学显著差异。然而，进一步采取符合方案数据分析(PPP：Per-Protocol Population)发现，与安慰剂相比，desmoteplase与更好的功能预后相关。所观察到的desmoteplase益处的临床意义在于，患者将经历更少的日常活动相关的残疾。相关数据已提交至2014年10月25日在土耳其伊斯坦布尔举行的第9届世界卒中大会（WSC）。
利用电脑断层扫描（CT）或核磁共振成像（MRI）评估早期缺血性组织损伤和颅内脑动脉阻塞非常具有挑战性。由此导致，有一些不符合研究方案所定义关键成像入选标准的患者进入了DIAS-3研究。采用符合方案集（Per-protocol，PP）分析时，在符合入选标准的患者群体中，第90天（Day 90）改良Rankin量表（MRS）评估的有利预后方面，与安慰剂相比，desmoteplase与更好的预后相关。这些额外分析数据表明，用于检测处于扩展时间窗的患者缺血性损伤时，核磁共振成像（MRI）比电脑断层扫描（CT）更敏感。对早期缺血性损伤＜25毫升的患者的预先定义分析中，经MRI确定的患者中，desmoteplase与更好的功能预后相关，但在经CT确定的患者中，数据无统计学显著差异。正如此前所公布的，desmoteplase具有与安慰剂相媲美的安全性，尤其是，死亡率及症状性颅内出血率在各组相当。
目前，大多数中风患者采用CT扫描评估，该技术可显示大脑中的出血，但可能不足以确定脑组织缺血性损伤的程度。而现代MRI是用于检测早期缺血性损伤的一种优良方法，可帮助临床医生确定哪些患者可能受益于治疗。
关于DIAS-3研究：
DIAS-3是一项多中心、随机、双盲、安慰剂对照研究，在欧洲和亚洲18个国家开展，调查了desmoteplase用于急性缺血性脑卒中成人患者的治疗。该研究涉及479例经磁共振成像（MRI）或电脑断层扫描（CT）证实伴有脑卒中症状及可治疗缺血性脑卒中病理的成人患者。研究中，患者在症状发作后的3-9小时内（时间窗）随机接受desmoteplase（90 μg/kg）或安慰剂治疗。今年7月公布的数据表明，desmoteplase治疗组和安慰剂组在第90天（Day 90）改良Rankin量表（MRS）具有有利预后的患者比例无统计学显著差异（51.3% vs 49.8%），未能达到研究的主要终点；安全性和耐受性数据证实desmoteplase具有良好的安全性。
关于desmoteplase：
去氨普酶（desmoteplase）是一种纤维蛋白依赖型纤溶酶原激活剂，是吸血蝙蝠（Desmodus rotundus）唾液中发现的纤溶酶原激活剂的基因工程产物，该药是在研的新一代溶栓药物，与其他溶栓剂相比，具有治疗窗宽、特异性强、毒副作用小等特点。此前，FDA已授予desmoteplase快车道地位。
英文原文：Lundbeck presents new efficacy and safety data analyses for desmoteplase in patients with acute ischaemic stroke
Valby, Denmark, 25 October 2014 - H. Lundbeck A/S (Lundbeck) today presented additional results from the Desmoteplase in Acute Ischaemic Stroke (DIAS-3) study in patients with acute ischaemic stroke treated in the time window of 3 to 9 hours after onset of symptoms. As communicated on 27 June 2014 there was no significant difference in the primary endpoint, the functional outcome measured by modified Rankin scale (mRS), between patients treated with desmoteplase or placebo at day 90 in the Full Analysis Set (FAS). However, among patients in the per-protocol population treatment with desmoteplase was associated with better functional outcome compared to placebo. The clinical meaning of the observed benefit of desmoteplase is that patients will experience less disability with regard to activities of daily living, even when treated in the extended time-window of up to nine hours.
These findings were presented as a late-breaking session at the 9th World Stroke Congress (WSC) in Istanbul, Turkey on 25 October 2014.
The assessment of early ischaemic tissue injury and of intracranial cerebral artery obstruction with either computerized tomography (CT) or magnetic resonance imaging (MRI) can be challenging. As a result, several patients were enrolled in the DIAS-3 study who did not meet key imaging inclusion criteria as defined in the study protocol. In the per-protocol population, i.e. among patients who fulfilled pre-specified enrolment criteria, desmoteplase was associated with better functional outcome compared to placebo as measured by mRS at day 90. The scale measures disability or dependence in activities of daily living.
The additional data analyses suggest that MRI is more sensitive than CT for detecting ischaemic injury in patients presenting in the extended time-window. In the pre-specified analysis of patients with <25 ml of early ischaemic injury, treatment with desmoteplase was associated with better functional outcome in those patients who were identified with MRI, however not in those who were seleced with CT.
"Today most stroke patients are evaluated with a CT scan which can show bleeding in the brain, but may be insufficient for determining the extent of ischaemic injury of the brain tissue", said Anders Gersel Pedersen, EVP and head of R&D in Lundbeck. "Modern MRI technology is a superior method for detecting early ischaemic damage and can help clinicians to determine which patients are likely to benefit from treatment."
As previously announced the safety profile of desmoteplase was comparable to that of placebo. The symptomatic intracerebral haemorrhage (sICH) rates in all treated patients were 2.5% (desmoteplase) and 2.1% (placebo) after completion of the study follow-up period to day 90. Further, mortality rates and other safety outcomes were similar in both treatment groups.
Median time from symptom onset to treatment was 7.0 hours.
Considering that no other medication is available for treatment within the nine hour treatment window, the demonstrated effect in the per-protocol population, and the safety and tolerability profile seen in the clinical trials with desmoteplase, further development will be evaluated with advice from key clinical and regulatory experts during the next few months. This evaluation will not be concluded in 2014, but if the outcome is negative a write-down of DKK 330 million will be recognised in the R&D cost line in 2015.
about the DIAS-3 study
DIAS-3 was a multi-centre, randomised, double-blind, placebo-controlled study in 479 patients from 18 countries in Europe and Asia. Patients with symptoms of stroke and a treatable ischaemic stroke pathology (proximal cerebral vessel occlusion/high-grade stenosis without signs of extensive infarction, intracranial haemorrhage or sub-acute infarction), as assessed by magnetic resonance imaging (MRI) or computerised tomography (CT) scanning were randomised to receive either desmoteplase (90 μg/kg) or placebo within three to nine hours of symptom onset.
about desmoteplase
Desmoteplase, a fibrin-dependent plasminogen activator, is a genetically engineered version of a clot-dissolving protein found in the saliva of the vampire bat Desmodus rotundus. It has received fast-track designation from the U.S. Food and Drug Administration (FDA) for the treatment of acute ischaemic stroke.
about acute ischaemic stroke (AIS)
Stroke is a medical emergency bringing an enormous burden. The annual incidence rate of stroke in the US varies between 150-200 cases per 100,000 people, corresponding to 795,000 cases. For major 5 European countries (France, Germany, Italy, Spain, UK) the incidence rate is estimated at 110-220 cases per 100,000 people a year, resulting in approximately 700,000 cases annually. In Japan, the reported incidence rate is twice as high as that in Europe and the US, i.e. 410 cases per 100,000 people a year, leading to approximately 350,000 cases annually. The overall incidence rate in the less developed countries, traditionally lower than that in the developed countries, has surpassed the latter and is still rising.
Stroke is the third leading cause of disability and the second largest cause of mortality globally.
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