Abstract：
Dystrophic epidermolysis bullosa is a rare genetic blistering skin disease caused by mutations in COL7A1, which encodes type VII collagen (C7). Beremagene geperpavec (B-VEC) is a topical investigational herpes simplex virus type 1 (HSV-1)-based gene therapy designed to restore C7 protein by delivering COL7A1.
We conducted a phase 3, double-blind, intrapatient randomized, placebo-controlled trial involving patients 6 months of age or older with genetically confirmed dystrophic epidermolysis bullosa. For each patient, a primary wound pair was selected, with the wounds matched according to size, region, and appearance. The wounds within each pair were randomly assigned in a 1:1 ratio to receive weekly application of either B-VEC or placebo for 26 weeks. The primary end point was complete wound healing of treated as compared with untreated wounds at 6 months. Secondary end points included complete wound healing at 3 months and the change from baseline to weeks 22, 24, and 26 in pain severity during changes in wound dressing, assessed with the use of a visual analogue scale (scores range from 0 to 10, with higher scores indicating greater pain).
Primary wound pairs were exposed to B-VEC and placebo in 31 patients. At 6 months, complete wound healing occurred in 67% of the wounds exposed to B-VEC as compared with 22% of those exposed to placebo (difference, 46 percentage points; 95% confidence interval [CI], 24 to 68; P = 0.002). Complete wound healing at 3 months occurred in 71% of the wounds exposed to B-VEC as compared with 20% of those exposed to placebo (difference, 51 percentage points; 95% CI, 29 to 73; P<0.001). The mean change from baseline to week 22 in pain severity during wound-dressing changes was -0.88 with B-VEC and -0.71 with placebo (adjusted least-squares mean difference, -0.61; 95% CI, -1.10 to -0.13); similar mean changes were observed at weeks 24 and 26. Adverse events with B-VEC and placebo included pruritus and chills.
Complete wound healing at 3 and 6 months in patients with dystrophic epidermolysis bullosa was more likely with topical administration of B-VEC than with placebo. Pruritus and mild systemic side effects were observed in patients treated with B-VEC. Longer and larger trials are warranted to determine the durability and side effects of B-VEC for this disease. (Funded by Krystal Biotech; GEM-3 ClinicalTrials.gov number, NCT04491604.).
We conducted a phase 3, double-blind, intrapatient randomized, placebo-controlled trial involving patients 6 months of age or older with genetically confirmed dystrophic epidermolysis bullosa. For each patient, a primary wound pair was selected, with the wounds matched according to size, region, and appearance. The wounds within each pair were randomly assigned in a 1:1 ratio to receive weekly application of either B-VEC or placebo for 26 weeks. The primary end point was complete wound healing of treated as compared with untreated wounds at 6 months. Secondary end points included complete wound healing at 3 months and the change from baseline to weeks 22, 24, and 26 in pain severity during changes in wound dressing, assessed with the use of a visual analogue scale (scores range from 0 to 10, with higher scores indicating greater pain).
Primary wound pairs were exposed to B-VEC and placebo in 31 patients. At 6 months, complete wound healing occurred in 67% of the wounds exposed to B-VEC as compared with 22% of those exposed to placebo (difference, 46 percentage points; 95% confidence interval [CI], 24 to 68; P = 0.002). Complete wound healing at 3 months occurred in 71% of the wounds exposed to B-VEC as compared with 20% of those exposed to placebo (difference, 51 percentage points; 95% CI, 29 to 73; P<0.001). The mean change from baseline to week 22 in pain severity during wound-dressing changes was -0.88 with B-VEC and -0.71 with placebo (adjusted least-squares mean difference, -0.61; 95% CI, -1.10 to -0.13); similar mean changes were observed at weeks 24 and 26. Adverse events with B-VEC and placebo included pruritus and chills.
Complete wound healing at 3 and 6 months in patients with dystrophic epidermolysis bullosa was more likely with topical administration of B-VEC than with placebo. Pruritus and mild systemic side effects were observed in patients treated with B-VEC. Longer and larger trials are warranted to determine the durability and side effects of B-VEC for this disease. (Funded by Krystal Biotech; GEM-3 ClinicalTrials.gov number, NCT04491604.).
摘要：
背景：营养不良性大疱性表皮松解症是由编码VII型胶原（C7）的COL7A1突变引起的一种罕见的遗传性起泡性皮肤病。Beremagenegeperpavec（B-VEC）是一种基于1型单纯疱疹病毒（HSV-1）的局部研究基因疗法，旨在通过提供COL7A1来恢复C7蛋白。
方法：我们进行了第3阶段，双盲，患者内部随机，安慰剂对照试验纳入6个月或以上基因证实患有营养不良性大疱性表皮松解症的患者。对于每个病人来说,选择了一对主要伤口，伤口根据大小匹配，区域,和外观。每对伤口以1:1的比例随机分配以接受每周施用B-VEC或安慰剂26周。主要终点是在6个月时与未治疗的伤口相比,治疗的伤口完全愈合。次要终点包括3个月时伤口完全愈合，以及在伤口敷料改变期间疼痛严重程度从基线到第22、24和26周的变化。使用视觉模拟量表进行评估(评分范围为0~10分,评分越高表示疼痛越大).
结果：31例患者的主要伤口对暴露于B-VEC和安慰剂。6个月时,暴露于B-VEC的伤口中有67％的伤口完全愈合，而暴露于安慰剂的伤口中有22％（差异，46个百分点；95%置信区间[CI]，24至68；P=0.002）。暴露于B-VEC的伤口中有71％在3个月时完全愈合，而暴露于安慰剂的伤口中有20％（差异，51个百分点；95%CI，29~73；P<0.001）。从基线到第22周，伤口敷料更换期间疼痛严重程度的平均变化为B-VEC为-0.88，安慰剂为-0.71（调整后的最小二乘平均差，-0.61；95％CI，-1.10至-0.13）；在第24周和第26周观察到相似的平均变化。B-VEC和安慰剂的不良事件包括瘙痒和寒战。
结论：在患有营养不良性大疱性表皮松解症的患者中，局部给药B-VEC比安慰剂更可能在3个月和6个月时完全伤口愈合。在用B-VEC治疗的患者中观察到瘙痒和轻度全身副作用。需要更长和更大的试验来确定B-VEC对这种疾病的耐久性和副作用。（由KrystalBiotech资助；GEM-3ClinicalTrials.gov编号，NCT04491604。).
方法：我们进行了第3阶段，双盲，患者内部随机，安慰剂对照试验纳入6个月或以上基因证实患有营养不良性大疱性表皮松解症的患者。对于每个病人来说,选择了一对主要伤口，伤口根据大小匹配，区域,和外观。每对伤口以1:1的比例随机分配以接受每周施用B-VEC或安慰剂26周。主要终点是在6个月时与未治疗的伤口相比,治疗的伤口完全愈合。次要终点包括3个月时伤口完全愈合，以及在伤口敷料改变期间疼痛严重程度从基线到第22、24和26周的变化。使用视觉模拟量表进行评估(评分范围为0~10分,评分越高表示疼痛越大).
结果：31例患者的主要伤口对暴露于B-VEC和安慰剂。6个月时,暴露于B-VEC的伤口中有67％的伤口完全愈合，而暴露于安慰剂的伤口中有22％（差异，46个百分点；95%置信区间[CI]，24至68；P=0.002）。暴露于B-VEC的伤口中有71％在3个月时完全愈合，而暴露于安慰剂的伤口中有20％（差异，51个百分点；95%CI，29~73；P<0.001）。从基线到第22周，伤口敷料更换期间疼痛严重程度的平均变化为B-VEC为-0.88，安慰剂为-0.71（调整后的最小二乘平均差，-0.61；95％CI，-1.10至-0.13）；在第24周和第26周观察到相似的平均变化。B-VEC和安慰剂的不良事件包括瘙痒和寒战。
结论：在患有营养不良性大疱性表皮松解症的患者中，局部给药B-VEC比安慰剂更可能在3个月和6个月时完全伤口愈合。在用B-VEC治疗的患者中观察到瘙痒和轻度全身副作用。需要更长和更大的试验来确定B-VEC对这种疾病的耐久性和副作用。（由KrystalBiotech资助；GEM-3ClinicalTrials.gov编号，NCT04491604。).
