高血压疫苗于第2a期临床试验中显示出安全且耐受性良好


  November 6, 2007(奥兰多讯)-根据一项第2a期临床试验结果显示,一种研究中对抗血管张力素II的疫苗,对轻中度高血压病患是安全的、且耐受性良好;该疫苗可以产生长时间的抗体免疫反应,半衰期约为4个月。
  
  研究作者瑞士洛桑Vaudois大学医院中心的Jurg Nussberger医师在美国心脏医学会2007年科学座谈会向听众表示,高剂量治疗可以显著地降低白天居家测量血压、且显著降低早晨血压;凌晨是最常发生不良心血管事件的时候。
  
  他附带表示,未来的研究将应用这个划时代的剂型以及治疗疗程,来开创这个策略的所有潜力。
  
  【凌晨高血压】
  Nussberger医师表示,血压的控制良好会因为病患对降血压药物顺应性的问题而受影响,虽然现在有许多种降血压药物,但仅有25%病患的血压控制良好,这可能与这些药物必须每天服用且终生服用有关。
  
  然而,他表示,这些药物中许多的半衰期短于24小时,所以如果病患早晨服用这些药物,这些药物的血中浓度将会在凌晨降到最低,这个时间刚好是正常血压开始上升且最常发生心血管事件的时候。
  
  Nussberger医师表示,如果有一个疫苗是可以对抗血管张力素II的,抗体的效果可以持续终生,你可能就不会有血中浓度不定的问题,且病患可能每年仅需看医生2或3次。
  
  过去由英国剑桥大学Morris J. Brown与同事进行的研究,他们测试一种对抗血管张力素I的疫苗,显示可以些微降低醛固酮的浓度,但是并没有降低血压的作用。
  
  目前这项安慰剂控制第2a期临床研究针对CYT006-AngQb,一种针对血管张力素II、类似病毒颗粒的接合疫苗,在这项研究中比较两种不同剂量的效果;他表示,这项研究中收纳72位轻中度高血压病患,以收缩压140至179 mmHg、舒张压90至109 mmHg定义;其中5位病患因为与试验无关的理由退出。
  
  这项研究为期4个月;病患在试验前接受100 μg或是300 μg的抗原或是安慰剂,接著,在1个月与3个月后再进行一次,之后共追踪8个月,以研究其安全性;试验终点为安全性与耐受性,"探索性地"测量居家血压以及血清肾素浓度。
  
  两组的所有病患都有不良反应,这样的发现并不令人意外,因为即使是被分派到安慰剂组的病患都有接受氢氧化铝乳剂的注射,且因此报导注射位置有疼痛、红肿、或是水肿的不良反应;接受疫苗注射组的病患发生头痛的比例较高,但这些不良反应都发生在注射的前1或是2天,且都是可逆的。
  
  CYT006-AngQb相较于安慰剂组的不良反应事件(AE)

试验终点

安慰剂

100 μg

300 μg

任何 AE 的盛行率( % )

100

100

100

AE 的严重度(事件 % )

 

轻度的

91

94

90

中度的

8

5

8

重度的

1

1

2

与治疗相关的( % )

70

83

86

与治疗相关的严重 AE

0

0

0


  所有病患的抗体效价都显示对于对抗血管张力素II有很强的反应,在第1次注射后就很明显;在第1个月时,第2次注射的抗体效价达到最高峰,接著在第3个月时,也就是第3次注射时,开始下降;使用300 μg剂量所引起的抗体反应更为显著,最终半衰期为123天,或大约是4个月。
  
  相较于安慰剂,第14周时量测居家血压显示使用300 μg剂量,白天血压显著下降;相较于试验前,收缩压下降5.6 mmHg、舒张压下降2.8 mmHg;低剂量有下降血压的趋势,但未达显著差异;Nussberger医师表示,所以高剂量300μg是有效的。
  
  特别的,这对于凌晨血压波动有强烈的疗效;将凌晨5点的血压求平均值,与安慰剂相比是有差异的,且300 μg组在第14周时凌晨血压比安慰剂组低25/13 mmHg。
  
  Nussberger医师表示,许多进一步研究该疫苗安全性与疗效的研究目前正在计画中。
  
  【血压控制良好潜在的好处】
  座谈会引言人密西根底特律韦恩州立大学John M. Flack医师应Medscape神经学与神经外科学的邀请表示,他认为这种治疗高血压的策略有很大的潜力。
  
  Flack医师表示,有一些潜在的安全性问题,举例来说,对怀孕妇女来说,血管张力素II是胚胎发育所必须的;另一方面,在适当选择的族群中,这确实是克服了一个显著的障碍,也就是每天服用降血压药物的顺应性。
  
  他表示,我认为一旦发现了正确的剂量、以及对于免疫反应及血压之间的连结有进一步的了解,这是我们治疗高血压能力上一个非常有希望的分隔点,这是一个慢性的情况,要经过很长的努力。
  
  这项研究由瑞士休伦Cytos生物科技,该疫苗的研发厂商赞助;Nussberger医师表示,他接受Cytos公司进行这项研究生物化学分析的资金。

Hypertension Vaccine Safe, Wel

By Susan Jeffrey
Medscape Medical News

November 6, 2007 (Orlando) — Results of a phase 2 study suggest that an investigational vaccine against angiotensin II was safe and well tolerated in patients with mild to moderate hypertension. The vaccine produced a long-lived antibody response with a half-life of about 4 months.

"Treatment with the high dose produced a significant reduction of daytime ambulatory blood pressure [BP] and a marked reduction in the early morning hours, when most adverse cardiovascular events occur," study author Jürg Nussberger, MD, from Centre Hospitalier Université Vaudois, in Lausanne, Switzerland, told attendees at the American Heart Association 2007 Scientific Sessions here.

"Future studies will apply state-of-the-art formulations and treatment regimens to explore the full potential of this approach," he said.

Early Riser

Good control of hypertension has been undermined by problems of patient compliance with antihypertensive medications. Although many effective drugs are available, only about 25% of patients are optimally controlled, Dr. Nussberger said. "This has probably something to do with the fact that these drugs have to be taken daily and lifelong."

However, many of these drugs have a half-life of less than 24 hours, so if patients take them in the morning, the medications are at a trough in the early-morning hours, he said, just as the normal rise in blood pressure takes place and when most cardiovascular events occur.

"With a vaccine against angiotensin II, where there is a long-lasting effect with antibodies, you may not have this problem of peak-trough, and the patient has to come to the doctor maybe only 2 or 3 times a year," Dr. Nussberger said.

Previous work by Morris J. Brown and colleagues at the University of Cambridge, United Kingdom, had tested a vaccine against angiotensin I and shown some reduction of aldosterone, but no blood pressure–lowering effect.

The current study explored the safety and tolerability of CYT006-AngQb, a viruslike particle-based conjugate vaccine that targets angiotensin II in a placebo-controlled phase 2a sequential 2-dose comparison trial. In the study, 72 patients with mild to moderate hypertension, defined as a systolic pressure of 140 to 179 mm Hg and a diastolic pressure of 90 to 109 mm Hg, were enrolled; 5 patients dropped out for reasons unrelated to the study, he noted.

The study was done over 4 months; patients were given 100 µg or 300 µg of the antigen or placebo at time zero, then at 1 month and 3 months, after which they were followed for 8 months for safety. End points were safety and tolerability, with an "exploratory" look at efficacy with ambulatory blood pressure measurements and plasma renin concentrations.

Adverse events occurred in all patients in both groups, a finding that was not unexpected, since even placebo patients received an injection of aluminum hydroxide emulsion and so reported pain, erythema, or edema at the injection site. Headache was also more frequent in the vaccination group, but all of these effects occurred over the first 1 or 2 days and were reversible.

Adverse Events (AE) With CYT006-AngQb vs Placebo
End point
Placebo
100 µg
300 µg
Incidence of any AE (%)
100
100
100
Severity of AEs (% of events)

    Mild
91
94
90
    Moderate
8
5
8
    Severe
1
1
2
Relationship to treatment (%)
70
83
86
Severe AEs related to treatment
0
0
0

Antibody titers showed a strong response against angiotensin II in all patients, evident after the first injection. At 1 month, the second injection showed a strong peak in titers, followed by a decrease to 3 months, when the third injection was given. The antibody response was significantly higher with the 300-µg dose, with a terminal half-life of 123 days, or about 4 months.

Ambulatory BP measurements at week 14 showed a significant reduction in daytime blood pressure with the 300-µg dose vs placebo; systolic BP was reduced by 5.6 mm Hg and the diastolic pressure by 2.8 mm Hg compared with baseline measures. The low dose showed some trend toward a reduction in BP but did not reach significance. "So the high dose, 300 µg, worked," Dr. Nussberger said.

Particularly, there appeared to be strong efficacy during the early-morning pressor surge. When measures were averaged for each hour of 5 AM to 8 AM, there was a differential between placebo and the 300-µg group of 25/13 mm Hg at week 14.

Several studies to investigate further the safety and efficacy of the vaccine are now being planned, Dr. Nussberger said.

Potential Benefit of Good BP Control

Asked for comment on this work by Medscape Neurology & Neurosurgery, session moderator John M. Flack, MD, from Wayne State University, in Detroit, Michigan, said he thinks there is significant potential for this kind of approach to treating hypertension.

"There are potential safety issues — for example, in pregnant women, where angiotensin II is nee

    
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