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首个帕金森氏病疫苗一期临床试验获得成功

来源:生物谷 2014-08-06 09:19

2014年8月6日讯 /生物谷BIOON/--用于帕金森氏病(PD)治疗的首个疫苗,一期临床试验获得初步成功。在奥地利维也纳单中心进行的1期试验,研究人员发现皮下注射疫苗PD01A后,该疫苗耐受性良好,并且安全。其诱导患者免疫应答,患者免疫应答功能似乎得到改进。

疫苗PD01A由Austrian pharmaceutical company开发,疫苗针对α-突触核蛋白,α-突触核蛋白高度表达于患者大脑,在帕金森氏病患者大脑中趋于聚集。PD01A的目的是刺激机体产生抗体,以结合和清除多余的α-突触核蛋白。

由于疫苗的目的是预防帕金森病,所以尽早鉴别该疾病十分重要。目前研究人员正在寻找标志物,如嗅觉丧失,睡眠障碍等,并分析这些标志物是否可能会在PD发病之前就出现。

这项新的研究包括32名男性和女性患者,年龄介于45至65岁(平均年龄约55岁)之间,患者全是白人,这些人在过去4年被诊断为帕金森病,并正在接受稳定剂量的帕金森病药物(如左旋多巴)治疗。

纳入试验的患者是“典型的早期PD患者”,他们被随机分配,两组注射疫苗组:15微克(n =12)或75微克(n =12),注射疫苗4个月。以及对照组(n =8),这些患者持续得到定期的PD相关的医疗服务。

在52周的研究期间,没有中途退出的病例,完成率为100%。所有患者都按计划接受疫苗接种。疫苗的目的是“培养”免疫系统产生针对α-突触核蛋白的抗体。在24名接种疫苗的患者中,15名患者有α-突触核蛋白反应(alpha-synuclein reactivity)。重要的是,这些抗体被发现存在于接种疫苗患者的脑脊髓液中。总体而言,研究分析了17例病例,结果发现疫苗组的6名患者脑脊液中有抗体(PD01A的目的是刺激机体产生抗体,以结合和清除多余的α-突触核蛋白)。

虽然研究并未检测患者最终临床结果,也没评测Movement Disorder Society-Unified Parkinson's Disease Rating Scale III 评分(运动功能)的改变和非机动帕金森病症状包括认知,生活质量等的改变,但这些结果是非常令人兴奋的,因为似乎抗体的存在和患者较好的临床结果有一些功能相关性。不过,研究者强调,这是第一阶段的研究,样本数量也少。(生物谷Bioon.com)

英文原文报导:

Parkinson's Vaccine Looks Promising

The first vaccine being developed for Parkinson's disease (PD) is showing early promise.

A phase 1 pilot trial of subcutaneous injections of PD01A, carried out at a single center in Vienna, Austria, shows that the vaccine was well tolerated and safe, that it induced an immune response, and that the immune response appeared to be improving function.

"If you add all this together, I think we have the first evidence that would tell us that these findings are compatible with what we look for with disease modification," Achim Schneeberger, MD, chief medical officer of AFFiRiS, the Austrian pharmaceutical company developing the drug, told a press conference where the top-line results were released.


At the press conference in New York: left to right: Dr. Frank Mattner, Dr. Todd Sherer, Dr. Walter Schmidt, Dr. Achim Schneeberger.
The vaccine targets alpha-synuclein, a protein that is highly expressed in the brain and that tends to aggregate in patients with PD. It is thought that this process either interferes with normal alpha-synuclein function or is itself toxic to cells. PD01A is designed to stimulate the body to produce antibodies that bind to and clear excess alpha-synuclein.

Because the vaccine is intended to prevent PD, it is important to identify the disease as early as possible. Researchers are looking at markers such as loss of sense of smell, sleep disorders, and other signs that might predate the onset of PD, said Todd Sherer, PhD, chief executive officer of the Michael J. Fox Foundation, which provided $1.5 million in funding for the study.

"There is an ongoing effort to see not only if we can improve the diagnosis of PD and the tracking of PD, but if we can identify people prior to the diagnosis of the disease with the hope that ultimately you'd be able to apply a preventive therapy."

Typical PD

The new study included 32 male and female patients aged 45 to 65 years (mean age, about 55 years), all white, who had been diagnosed with PD during the previous 4 years and who were receiving stable doses of PD medications (eg, levodopa).

Patients included in the trial were "typical of early PD," said Dr. Schneeberger. They were randomly assigned to receive 4 monthly injections of 15 μg (n = 12) or 75 μg (n = 12) of the vaccine or to a control group (n = 8) that continued to get regular PD-related medical care.

The groups were well balanced in terms of baseline functional status. There were no dropouts during the 52-week study; the completion rate was 100%. All patients received all vaccinations as planned.

An independent data safety monitoring board assessed safety and tolerability. There were 235 adverse events (AEs), all of which were mild to moderate and were equally distributed between study groups. The most frequent AE was a local reaction that typically lasted 2 to 4 days. The 3 serious AEs (SAEs) were all judged not related to the vaccine.

"We clearly see that there is no safety signal for PD01A in this phase 1 study," said Dr. Schneeberger.

The study also showed "clearly" that the injections induced antibodies directed toward vaccine components, said Dr. Schneeberger. "Both groups developed a specific immune response."

Fifteen of the 24 patients who were immunized had alpha-synuclein reactivity.

Importantly, these antibodies were found in the cerebrospinal fluid of patients. "In total, we were able to analyze 17 patients and in 6 of them, we found these antibodies in their [cerebrospinal fluid]," said Dr. Schneeberger.

Although the study was not powered to detect clinical outcomes, changes in Movement Disorder Society–Unified Parkinson's Disease Rating Scale III scores (motor function) and nonmotor PD symptoms including cognition, quality of life, and investigator-rated global evaluation, all showed "statistically significant or sometimes highly statistically significant results in favor of the antibody responders in this population," said Dr. Schneeberger.

"The most convincing" piece of evidence from the study is that "immune responders show a clinically better response than immunological non-responders" he said, and he emphasized the "consistency over all clinical endpoints"

"These results are quite exciting," added Walter Schmidt, PhD, chief executive officer of AFFiRiS, in a later interview with Medscape Medical News. "There seems to be some functional correlation between the presence of antibodies and beneficial clinical impact for patients."

However, he stressed that this is a phase 1 study and the numbers are small.

The company is planning a follow-up study to assess the safety and immunological consequences of a booster shot of the low- and high-dose vaccine.

Dr. Schneeberger predicted "optimistically" that it will take 6 years before the vaccine completes subsequent trial phases.

The study was funded by the Michael J. Fox Foundation. Dr. Schneeberger and Dr. Schmidt are employees of AFFiRiS.

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