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【medical-news】DNA疫苗改变多发性硬化病程

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DNA Vaccine Alters Natural Course of Multiple Sclerosis

October 5, 2007 — A newly developed DNA vaccine appears to fundamentally alter the disease course of multiple sclerosis in patients with relapsing remitting multiple sclerosis (RRMS).

Phase 2 results of the investigational drug BHT 3009 (Bayhill Therapeutics, Palo Alto, California), a tolerizing vaccine encoding full-length human myelin basic protein (MBP), induced a 50% to 60% reduction in gadolinium-enhancing brain lesions as well as volume reductions in T2 volumes and T1 black holes in MS patients treated with 0.5 mg of the drug, compared with placebo.

Furthermore, the investigators observed statistically significant reductions in several cerebral spinal fluid (CSF) autoantibodies in the BHT 3009 0.5-mg group. The CSF analysis also revealed that the highest impact of BHT 3009 occurred in those with the highest tier of anti-MBP autoantibodies.

"This is a significant step in advancing one of the first antigen specific therapies for use in the clinic. We're a step closer to providing MS patients with a treatment that fundamentally alters the course of the disease," vaccine inventor Hideki Garren, MD, PhD, from Stanford University, in Palo Alto, California, and Bayhill Therapeutics, told Medscape.

Major Advantages Over Traditional Treatment

Invented by Dr. Garren and 3 other colleagues at Stanford, BHT 3009 offers several advantages over established MS treatments such as beta interferon. Most important, rather than targeting the entire immune system, BHT-3009 targets only disease-causing antigen-specific T-cells that attack the myelin.

In addition, he said, the drug's dosing schedule is only once per month. In contrast, beta interferon treatment protocols range from every other day to once per week. Furthermore, adverse effects, including flulike symptoms, associated with beta interferon can make it difficult to tolerate. In contrast, he said, the tolerability of BHT 3009 is "excellent."

The study will be presented at the American Neurological Association 132nd Annual Meeting on October 9 in Washington, DC and again at the 23rd Congress of the European Committee for Treatment and Research on October 12 in Prague, Czech Republic.

The multicenter randomized, placebo-controlled trial, which was predominantly conducted at more than 40 centers in Eastern Europe, included 289 RRMS patients, the vast majority of whom had never been treated with disease-modifying therapy.

Low-Zone Tolerance

Inclusion criteria included Expanded Disability Status Scale (EDSS) score of 0 to 3.5. In addition, patients were required to have a minimum of 1 relapse within the year prior to study enrollment and 5 or fewer gadolinium-enhancing brain lesions.

Exclusion criteria were individuals with greater than 5 brain lesions and who had received more than a lifetime total of 180 days of previous disease-modifying therapy.

Study subjects were randomized to 1 of 3 study groups — placebo, 0.5-mg BHT 3009, or 1.5-mg BHT 3009 administered monthly by intramuscular injection for 1 year.

The trial's primary end point was the reduction in the number of gadolinium-enhancing lesions. Secondary end points included various other magnetic resonance imaging (MRI) measures, including gadolinium lesion volume and T2 and T1 black hole volume. Other non-MRI secondary end points included relapses and disability.

Results of the study's secondary MRI end points were generally consistent with reductions seen in the primary end point, which was limited to patients in the 0.5-mg group.

"There was no effect with the higher dose of the vaccine. This finding is consistent with the hypothesis that lower doses, given chronically in MS, will tolerize the immune system, a phenomenon known as 'low-zone tolerance.' We did not see any worsening of the disease with the higher dose; there was just no effect," he said.

No Clinical Impact

In addition, the study showed no statistically significant clinical impact of lesion reduction with either dose of the vaccine.

"Unfortunately, we did not see an effect on disability or relapse rates. Although the overall relapse rate was relatively low [compared with trials of other therapies], the study was not sufficiently powered to reveal such an effect. We need another, much larger phase 3 trial to answer this question," said Dr. Garren.

He added plans are currently under way to conduct such a trial, which is expected to launch by the end of 2008.

"In this current trial, we've shown a reduction in lesions and an antigen-specific effect. In the next trial, we want to replicate these results and demonstrate clinical efficacy," he said.

The researchers are also looking at a second, similar experimental agent in type 1 diabetes.

"We have started a safety and proof-of-concept trial using another investigational agent, BHT-3021 in type 1 diabetic patients. We don't have any data to report as of yet, but the initial results are encouraging," he said.

The study was funded by Bayhill Therapeutics Inc. Dr. Garren discloses that he is cofounder of and has received salary, stock, and/or stock options from Bayhill Therapeutics, Inc.

American Neurological Association 132nd Annual Meeting: Abstract T84. Presented October 9, 2007.

23rd Congress of the European Committee for the Treatment and Research in Multiple Sclerosis. Presented October 12, 2007.

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2007-10-08 09:49 浏览 : 1559 回复 : 6

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2007-10-12 14:27

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DNA Vaccine Alters Natural Course of Multiple Sclerosis
DNA疫苗改变多发性硬化症的天然进程

October 5, 2007 — A newly developed DNA vaccine appears to fundamentally alter the disease course of multiple sclerosis in patients with relapsing remitting multiple sclerosis.
2007年10月5日，一种新开发的基因疫苗似乎是从根本上改变缓解型多发性硬化症(RRMS)患者的疾病进程。

Phase 2 results of the investigational drug BHT 3009 (Bayhill Therapeutics, Palo Alto, California), a tolerizing vaccine encoding full-length human myelin basic protein (MBP), induced a 50% to 60% reduction in gadolinium-enhancing brain lesions as well as volume reductions in T2 volumes and T1 black holes in MS patients treated with 0.5 mg of the drug, compared with placebo.
试验药物BHT 3009 （Bayhill Therapeutics, Palo Alto, California），是一种能够对完整长度的人类髓磷脂碱蛋白 (MBP) 进行编码的耐受化疫苗，其二期研究结果表明对于MS患者采用0.5毫克的治疗剂量以后，与安慰剂组相比较，能够减少50%-60的钆增强脑部病变，同样t2脑容积和t1黑洞的容积也减少了50%-60%。

Furthermore, the investigators observed statistically significant reductions in several cerebral spinal fluid (CSF) autoantibodies in the BHT 3009 0.5-mg group. The CSF analysis also revealed that the highest impact of BHT 3009 occurred in those with the highest tier of anti-MBP autoantibodies.
此外，研究人员发现，BHT 30090.5毫克药物组的一些脑脊髓液(CSF) 自身抗体明显减少，与对照组相比差别有统计学意义。CSF分析也发现BHT 3009 在最高序列的髓磷酯碱性蛋白抗体中发生了强烈的排斥反应。

"This is a significant step in advancing one of the first antigen specific therapies for use in the clinic. We're a step closer to providing MS patients with a treatment that fundamentally alters the course of the disease," vaccine inventor Hideki Garren, MD, PhD, from Stanford University, in Palo Alto, California, and Bayhill Therapeutics, told Medscape.
疫苗发明者美国斯坦福大学（Bayhill Therapeutics, Palo Alto）Hideki Garren博士接受Medscape网站采访说：“对于推进将第一个抗原特异性疗法用于临床而言这是一个有意义的阶段。”

Major Advantages Over Traditional Treatment
与传统治疗方法相比的主要优点

Invented by Dr. Garren and 3 other colleagues at Stanford, BHT 3009 offers several advantages over established MS treatments such as beta interferon. Most important, rather than targeting the entire immune system, BHT-3009 targets only disease-causing antigen-specific T-cells that attack the myelin.
Garren博士和另外3个斯坦福大学的同事发明的BHT 3009较目前确定的多发性硬化症治疗方法（如β干扰素）有一些优点。最重要的，BHT-3009只针对攻击髓鞘的致病抗原特异性T细胞，而不是针对整个免疫系统。

In addition, he said, the drug's dosing schedule is only once per month. In contrast, beta interferon treatment protocols range from every other day to once per week. Furthermore, adverse effects, including flulike symptoms, associated with beta interferon can make it difficult to tolerate. In contrast, he said, the tolerability of BHT 3009 is "excellent."
此外，这种药物的给药方案只能是每月一次。相比之下， β干扰素的治疗范围从每两天一次到每星期一次。而且β干扰素导致的过敏症状等不良反应使患者难以忍受。相反，BHT 3009的耐受性却是"极好的"。

The study will be presented at the American Neurological Association 132nd Annual Meeting on October 9 in Washington, DC and again at the 23rd Congress of the European Committee for Treatment and Research on October 12 in Prague, Czech Republic.
这项研究将在10月9日华盛顿举行的美国神经学协会132次年会上公布，随后也要在10月12日捷克共和国布拉格召开的治疗和研究欧洲委员会第23次会议上公布。

The multicenter randomized, placebo-controlled trial, which was predominantly conducted at more than 40 centers in Eastern Europe, included 289 RRMS patients, the vast majority of whom had never been treated with disease-modifying therapy.
主要在东欧40多个临床中心开展了多中心随机、安慰剂对照试验，包括289名RRMS患者，其中绝大多数人从未接受过疾病修饰治疗。

Low-Zone Tolerance
低区带耐受性

Inclusion criteria included Expanded Disability Status Scale (EDSS) score of 0 to 3.5. In addition, patients were required to have a minimum of 1 relapse within the year prior to study enrollment and 5 or fewer gadolinium-enhancing brain lesions.
入选标准：扩大残疾状态量表（EDS）评分为0至3.5分。此外，病人在进入研究试验前一年最好有一次复发和等于（或少于）5个的钆增强脑部病变。

Exclusion criteria were individuals with greater than 5 brain lesions and who had received more than a lifetime total of 180 days of previous disease-modifying therapy.
排除标准：患者大于5个脑部病变；之前接受疾病修饰治疗超过180天。

Study subjects were randomized to 1 of 3 study groups — placebo, 0.5-mg BHT 3009, or 1.5-mg BHT 3009 administered monthly by intramuscular injection for 1 year.
研究对象被随机分到3个研究小组当中：安慰剂组；0 .5毫克BHT 3009组；1.5毫克BHT 3009肌肉注射每月一次，持续一年。

The trial's primary end point was the reduction in the number of gadolinium-enhancing lesions. Secondary end points included various other magnetic resonance imaging (MRI) measures, including gadolinium lesion volume and T2 and T1 black hole volume. Other non-MRI secondary end points included relapses and disability.
试验的主要终点是钆增强病变数目的减少。次要终点包括其他各种磁共振成像（MRI）的措施、钆病变的体积、T2和T1黑洞的体积。其他非磁共振成像次要终点包括复发和残疾。

Results of the study's secondary MRI end points were generally consistent with reductions seen in the primary end point, which was limited to patients in the 0.5-mg group.
研究结果的二次磁共振成像终点一般都符合首先观察终点中出现的好转，这局限于0.5毫克组患者当中。

"There was no effect with the higher dose of the vaccine. This finding is consistent with the hypothesis that lower doses, given chronically in MS, will tolerize the immune system, a phenomenon known as 'low-zone tolerance.' We did not see any worsening of the disease with the higher dose; there was just no effect," he said.
"大剂量的疫苗没有效果。这一调查结果与假设是一致的：即长期给予MS患者低剂量，免疫系统将耐受，这一现象被称为“低区带耐受性”。高剂量组没有发生任何疾病恶化，仅仅是没有效果。”

No Clinical Impact
没有临床影响

In addition, the study showed no statistically significant clinical impact of lesion reduction with either dose of the vaccine.
此外，研究结果显示，不论使用何种剂量的疫苗，其损害减少的临床改变差别没有统计学意义。

"Unfortunately, we did not see an effect on disability or relapse rates. Although the overall relapse rate was relatively low [compared with trials of other therapies], the study was not sufficiently powered to reveal such an effect. We need another, much larger phase 3 trial to answer this question," said Dr. Garren.
不幸的是，我们没有看到对残疾或复发率方面有效果。虽然总体复发率相对降低（与其他疗法的试验相比），这项研究没有足够的证据证明这一效果。我们需要另一个规模更大的第3阶段试验来回答这个问题。

He added plans are currently under way to conduct such a trial, which is expected to launch by the end of 2008.
目前补充计划正在进行这样的试验，预计到2008年底能够发表。

"In this current trial, we've shown a reduction in lesions and an antigen-specific effect. In the next trial, we want to replicate these results and demonstrate clinical efficacy," he said.
他说：“在这目前的试验，我们已经观察到减少病变与抗原特异性作用。在接下来的试验中，我们要重复这些成果，并证明临床疗效。”

The researchers are also looking at a second, similar experimental agent in type 1 diabetes.
研究人员也正在对1型糖尿病进行类似的第二阶段研究。

"We have started a safety and proof-of-concept trial using another investigational agent, BHT-3021 in type 1 diabetic patients. We don't have any data to report as of yet, but the initial results are encouraging," he said.
我们已经对1型糖尿病患者采用另外一种试验药BHT-3021，开始了一项安全的、设想性试验。目前我们没有任何数据可以报告，但是初步结果是令人鼓舞的。

The study was funded by Bayhill Therapeutics Inc. Dr. Garren discloses that he is cofounder of and has received salary, stock, and/or stock options from Bayhill Therapeutics, Inc.
这项研究是由bayhilltherapeutics公司支助的，盖博士披露说作为合伙人，他已经从bayhill therapeutics公司收到薪金、股票和股票期权。

American Neurological Association 132nd Annual Meeting: Abstract T84. Presented October 9, 2007.
美国神经学协会第132次年度会议：摘要T84。 2007年10月9日出版。

2007-10-19 16:52

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编译：DNA疫苗改变多发性硬化症的天然进程

　　10月9日在华盛顿举行的美国神经学协会132次年会上公布一种新开发的有望从根本上改变缓解型多发性硬化症(RRMS)患者疾病进程的基因疫苗。这项研究随后要在10月12日捷克共和国布拉格召开的治疗和研究欧洲委员会第23次会议上公布。

　　疫苗发明者美国斯坦福大学（Bayhill Therapeutics, Palo Alto）Hideki Garren博士接受Medscape网站采访说：“这对于推进将第一个抗原特异性疗法用于临床而言是一个有意义的阶段。”

　　该项目主要在东欧40多个临床中心开展了多中心随机、安慰剂对照试验，包括289名RRMS患者，其中绝大多数人从未接受过疾病修饰治疗。

　　入选标准：扩大残疾状态量表（EDS）评分为0至3.5分。此外，病人在进入研究试验前一年最好有一次复发和等于（或少于）5个的钆增强脑部病变。排除标准：患者大于5个脑部病变；之前接受疾病修饰治疗超过180天。研究对象被随机分到3个研究小组当中：安慰剂组；0 .5毫克BHT 3009组；1.5毫克BHT 3009肌肉注射每月一次，持续一年。试验的主要终点是钆增强病变数目的减少。次要终点包括其他各种磁共振成像（MRI）的措施、钆病变的体积、T2和T1黑洞的体积。其他非磁共振成像次要终点包括复发和残疾。研究结果的二次磁共振成像终点一般都符合首先观察终点中出现的好转，这局限于0.5毫克组患者当中。

　　试验药物BHT 3009 （Bayhill Therapeutics, Palo Alto, California）是一种能够对完整长度的人类髓磷脂碱蛋白 (MBP) 进行编码的耐受化疫苗，其二期研究结果表明对于MS患者采用0.5毫克的治疗剂量以后，与安慰剂组相比较，能够减少50%-60的钆增强脑部病变，同样t2脑容积和t1黑洞的容积也减少了50%-60%。此外，研究人员发现，BHT 30090.5毫克药物组的一些脑脊髓液(CSF) 自身抗体明显减少，与对照组相比差别有统计学意义。CSF分析也发现BHT 3009 在最高序列的髓磷酯碱性蛋白抗体中发生了强烈的排斥反应。

　　Garren博士和另外3个斯坦福大学的同事发明的BHT 3009较目前确定的多发性硬化症治疗方法（如β干扰素）与传统治疗方法相比有一些优点。最重要的，BHT-3009只针对攻击髓鞘的致病抗原特异性T细胞，而不是针对整个免疫系统。

　　这种药物的给药方案只能是每月一次。相比之下，β干扰素的治疗范围从每两天一次到每星期一次。而且β干扰素导致的过敏症状等不良反应使患者难以忍受。相反，BHT 3009的耐受性却是"极好的"。

　　大剂量的疫苗没有效果，这一调查结果与假设是一致的：即长期给予MS患者低剂量，免疫系统将耐受，这一现象被称为“低区带耐受性”。高剂量组没有发生任何疾病恶化，仅仅是没有效果。

　　研究结果显示，不论使用何种剂量的疫苗，其损害减少的临床改变差别没有统计学意义。但看到对残疾或复发率方面有效果。虽然总体复发率相对降低（与其他疗法的试验相比），这项研究没有足够的证据证明这一效果。因此需要另一个规模更大的第3阶段试验来回答这个问题。目前补充计划正在进行这样的试验，预计到2008年底能够发表。

　　在这目前的试验中已经观察到减少病变与抗原特异性作用。在接下来的试验中，需要重复这些成果，并证明临床疗效。研究人员也正在对1型糖尿病进行类似的第二阶段研究。研究人员已经对1型糖尿病患者采用另外一种试验药BHT-3021，开始了一项安全的、设想性试验。目前还没有任何数据可以报告，但是初步结果是令人鼓舞的。

　　这项研究是由bayhilltherapeutics公司支助的，盖博士披露说作为合伙人，他已经从bayhill therapeutics公司收到薪金、股票和股票期权。

2007-10-19 16:56

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