Phase 2 trial of a DNA vaccine encoding myelin basic protein for multiple sclerosis
Phase 2 trial of a DNA vaccine encoding myelin basic protein for multiple sclerosis
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DOI：
10.1002/ana.21370
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发表时间：
2008-05-01
影响因子：
11.2
通讯作者：
Steinman, Lawrence
中科院分区：
文献类型：
--
作者：
Garren, Hideki;Robinson, William H.;Steinman, Lawrence
目的：评价BHT-3009治疗复发-缓解型多发性硬化症(MS)的疗效和安全性，证实BHT-3009可引起免疫耐受。复发-缓解型多发性硬化症患者按1：1：1随机分为三组：安慰剂、0.5 mg BHT-3009或1.5 mg BHT-3009，在0、2、4周肌肉注射，此后每4周肌肉注射一次，直到44周。主要终点是从28周到48周的脑磁共振图像上新出现的Gd增强病变的4周发生率。结果：在267例患者分析人群中，与安慰剂相比，在28-48周期间，使用0.5mgBHT-3009的患者新强化皮损的中位数降低了50%(p=0.07)，在8-48周期间，使用0.5mgBHT-3009的患者新强化皮损的中位数降低了61%(P=0.05)。与安慰剂相比，服用0.5 mg BHT-3009的患者48周时强化病变的平均体积减少了51%(p=0.02)。1.5 mg BHT-3009对磁共振成像损伤参数无明显改善。在0.5 mg BHT-3009组中，观察到23种髓鞘特异性自身抗体显著减少，但安慰剂或1.5 mg BHT-3009组未见显著下降。结论：在复发缓解期MS患者中，小剂量(0.5 mg)BHT-3009治疗44周几乎达到了降低新的增强磁共振成像病变率的主要终点(p=0.07)，并实现了几个次要终点，包括将磁共振成像增强病变率从8周降至48周(p=0.05)。预先选择的一组患者的免疫学数据也表明，0.5 mg的治疗可以诱导抗原特异性免疫耐受。剂量越大，效果越差。
Objective: To evaluate the efficacy and safety of BHT-3009 in relapsing-remitting multiple sclerosis (MS) and to confirm that BHT-3009 causes immune tolerance.Methods: BHT-3009 is a tolerizing DNA vaccine for MS, encoding full-length human myelin basic protein. Relapsing-remitting MS patients were randomized 1:1:1 into three groups: placebo, 0.5mg BHT-3009, or 1.5mg BHT-3009, given intramuscularly at weeks 0, 2, 4, and every 4 weeks thereafter until week 44. The primary end point was the 4-week rate of occurrence of new gadolinium-enhancing lesions on brain magnetic resonance images from weeks 28 to 48. Protein microarrays were used to measure levels of anti-myelin autoantibodies.Results: Compared with placebo, in the 267 patient analysis population the median 4-week rate of new enhancing lesions during weeks 28 to 48 was 50% lower with 0.5mg BHT-3009 (p = 0.07) and during weeks 8 to 48 was 61% lower with 0.5mg BHT-3009 (P = 0.05). The mean volume of enhancing lesions at week 48 was 51% lower on 0.5mg BHT-3009 compared with placebo (p = 0.02). No significant improvement in magnetic resonance imaging lesion parameters was observed with 1.5mg BHT-3009. Dramatic reductions in 23 myelin-specific autoantibodies in the 0.5mg BHT-3009 arm were observed, but not with placebo or 1.5mg BHT-3009.Conclusions: In relapsing-remitting MS patients, treatment with the lower dose (0.5mg) of BHT-3009 for 44 weeks nearly attained the primary end point for reduction of the rate of new enhancing magnetic resonance imaging lesions (p = 0.07) and achieved several secondary end points including a reduction of the rate of enhancing magnetic resonance imaging lesions from weeks 8 to 48 (p = 0.05). Immunological data in a preselected subgroup of patients also indicated that treatment with 0.5mg induced antigen-specific immune tolerance. The greater dose was ineffective.