Safety and efficacy of fordadistrogene movaparvovec in ambulatory participants with Duchenne muscular dystrophy (CIFFREO): a phase 3, double-blind, randomised, placebo-controlled study.

Fordadistrogene movaparvovec is an investigational recombinant adeno-associated virus 9 (rAAV9)-based vector encoding a mini-dystrophin transgene protein for Duchenne muscular dystrophy .

Fordadistrogene movaparvovec 是一种正在研究中的重组腺相关病毒9型（rAAV9）载体，它编码了一种迷你肌营养不良蛋白，用于治疗杜氏肌营养不良症。

We aimed to assess the safety and efficacy of fordadistrogene movaparvovec in slowing the functional decline experienced by individuals with Duchenne muscular dystrophy.

我们的目标是评估fordadistrogene movaparvovec在减缓杜氏肌营养不良症患者功能衰退方面的安全性和疗效。

Methods

CIFFREO was a phase 3, double-blind, randomised, placebo-controlledstudy done at 45 academic and hospital sites in Australia, Belgium, Canada, France, Germany, Israel, Italy, Japan, Russia, South Korea, Spain, Switzerland, Taiwan, the UK, and the USA.

CIFFREO是一项在澳大利亚、比利时、加拿大、法国、德国、以色列、意大利、日本、俄罗斯、韩国、西班牙、瑞士、台湾、英国和美国的45个学术和医院场所进行的3期、双盲、随机、安慰剂对照研究。

Eligible participants were male, ambulatory, aged 4 years to younger than 8 years, with a genetic diagnosis of Duchenne muscular dystrophy.

符合条件的参与者为男性，能够行走，年龄在4岁至未满8岁之间，具有杜氏肌营养不良症的遗传诊断。

Participants were randomly assigned (2:1) using interactive response technology, stratified by age (<6 years or ≥6 years), to cohort 1 (intravenous fordadistrogene movaparvovec 2 × 1014 vector genomes [vg]/kg on day 1, placebo on day 390) or cohort 2 (placebo on day 1, intravenous fordadistrogene movaparvovec 2 × 1014 vg/kg on day 390).

参与者使用交互式响应技术随机分配（2:1），按年龄（<6岁或≥6岁）分层，分为第1组（第1天静脉注射fordadistrogene movaparvovec 2 × 10^14向量基因组[vgs]/kg，第390天给予安慰剂）或第2组（第1天给予安慰剂，第390天静脉注射fordadistrogene movaparvovec 2 × 10^14 vg/kg）。

Placebo vials were provided and prepared identically to fordadistrogene movaparvovec.

提供了与fordadistrogene movaparvovec相同制备的安慰剂小瓶。

Participants, investigators, and outcome assessors were masked to treatment assignments.

参与者、研究者和结果评估者对治疗分配情况进行了盲法处理。

The primary endpoint was change from baseline to week 52 in the North Star Ambulatory Assessment (NSAA) total score, assessed in patients in the full analysis set (all participants who were randomly assigned and received a single dose of fordadistrogene movaparvovec or placebo on day 1, excluding siblings and those meeting genetic exclusion criteria), analysed using a mixed model for repeated measures.

主要终点是从基线到第52周北星步态评估（NSAA）总分的变化，评估对象为全分析集中的患者（所有被随机分配并接受fordadistrogene movaparvovec或安慰剂单剂量治疗的参与者，第1天接受治疗，排除同胞和符合遗传排除标准的个体），使用重复测量混合模型进行分析。

Participants were analysed according the cohort to which they were assigned and analysis only included participants who completed the 1-year follow-up.

参与者按照他们被分配的队列进行分析，且仅包括完成1年随访的参与者。

The safety analysis set comprised all participants who were randomly assigned and received a single dose of fordadistrogene movaparvovec or placebo on day 1.

安全性分析集包括所有被随机分配并在第1天接受单剂量fordadistrogene movaparvovec或安慰剂的参与者。

The trial was registered at ClinicalTrials.gov (NCT04281485) and is active, not recruiting.

该试验已在ClinicalTrials.gov注册（NCT04281485），目前正在进行中，但不再招募新参与者。

Results

Between Nov 5, 2020, and April 20, 2023, 226 participants were screened for eligibility, 122 of whom were randomly assigned (81 to cohort 1 and 41 to cohort 2).

2020年11月5日至2023年4月20日期间，共有226名参与者接受了资格筛查，其中122人被随机分配（81人进入队列1，41人进入队列2）。

The primary outcome was analysed in 64 participants in the fordadistrogene movaparvovec group and 28 in the placebo group.

主要结果在fordadistrogene movaparvovec组的64名参与者和安慰剂组的28名参与者中进行了分析。

At screening, mean age was 6·3 years (SD 1·3) in participants in the fordadistrogene movaparvovec group and 6·5 years (1·2) in participants in the placebo group; mean NSAA total score was 22·5 (SD 3·6) in the fordadistrogene movaparvovec group and 23·5 (3·9) in the placebo group.

在筛查时，fordadistrogene movaparvovec组的参与者的平均年龄为6.3岁（标准差1.3岁），安慰剂组的参与者的平均年龄为6.5岁（标准差1.2岁）；fordadistrogene movaparvovec组的NSAA总分平均值为22.5（标准差3.6），安慰剂组的NSAA总分平均值为23.5（标准差3.9）。

At week 52, the least squares mean change from baseline in NSAA total score was 1·46 (SE 0·43) for fordadistrogene movaparvovec and 1·37 (0·65) for placebo (difference between groups 0·09 [95% CI -1·46 to 1·64]; p=0·91).

在第52周时，fordadistrogene movaparvovec组的NSAA总分基线变化的最小二乘平均值为1.46（标准误0.43），安慰剂组为1.37（标准误0.65）（两组差异为0.09 [95% 置信区间-1.46至1.64]；p=0.91）。

Adverse events occurred in 78 (99%) of 79 participants in the fordadistrogene movaparvovec group versus 27 (77%) of 35 in the placebo group.

在79名fordadistrogene movaparvovec组的参与者中，有78人（99%）发生了不良事件，而在35名安慰剂组的参与者中，有27人（77%）发生了不良事件。

The most common adverse events in the fordadistrogene movaparvovec group versus the placebo group were vomiting (60 [76%] vs five [14%]), pyrexia (49 [62%] vs three [9%]), decreased appetite (26 [33%] vs one [3%]), nausea (23 [29%] vs three [9%]), increased liver glutamate dehydrogenase (19 [24%] vs zero), nasopharyngitis (19 [24%] vs six [17%]), and abdominal pain (17 [22%] vs three [9%]).

fordadistrogene movaparvovec组与安慰剂组最常见的不良事件分别是呕吐（60 [76%] vs 五 [14%]）、发热（49 [62%] vs 三 [9%]）、食欲减退（26 [33%] vs 一 [3%]）、恶心（23 [29%] vs 三 [9%]）、肝谷氨酸脱氢酶增加（19 [24%] vs 零）、鼻咽炎（19 [24%] vs 六 [17%]）以及腹痛（17 [22%] vs 三 [9%]）。

Serious adverse events occurred in 25 (32%) participants in the fordadistrogene movaparvovec group versus five (14%) in the placebo group.

在fordadistrogene movaparvovec组中，有25名（32%）参与者出现了严重不良事件，而安慰剂组有五名（14%）参与者出现了严重不良事件。

There were no deaths in the study.

研究中没有发生死亡事件。

interpretation

The study did not meet its primary efficacy endpoint.

该研究未达到其主要疗效终点。

Based on the efficacy and safety data from this phase 3 study, the benefit-risk profile of fordadistrogene movaparvovec was determined to be negative.

基于这项第三阶段研究的疗效和安全性数据，fordadistrogene movaparvovec的效益-风险比被确定为负面。

Thus, the study sponsor has discontinued any further clinical development of this investigational gene therapy agent.

因此，研究赞助商已停止进一步的临床开发此研究性基因治疗剂。

funding

Pfizer.

辉瑞制药有限公司。