Efficacy and safety of garetosmab, an activin A-blocking antibody, in fibrodysplasia ossificans progressiva (OPTIMA): a randomised, double-blind, placebo-controlled, phase 3 trial.

FOP is caused by heterozygous gain-of-function mutations in the activin receptor type 1A, allowing this receptor to be aberrantly activated by activin A (ActA), which normally inhibits this receptor, thus driving heterotopic bone formation.

FOP 是由 activin 受体类型 1A 的杂合性功能获得性突变引起的，这种突变使得该受体能够被 activin A (ActA) 异常激活，而 ActA 通常会抑制这种受体，从而驱动异位骨的形成。

In preclinical models and an earlier phase 2 trial (LUMINA-1) in FOP, an antibody blocking ActA (garetosmab) prevented heterotopic ossification.

在临床前模型和早期的 FOP 二期试验（LUMINA-1）中，阻断 ActA 的抗体（garetosmab）预防了异位骨化。

We aimed to evaluate the efficacy and safety of garetosmab in adults living with FOP.

我们的目标是评估 garetosmab 在成年 FOP 患者中的疗效和安全性。

Methods

OPTIMA is a randomised, double-blind, placebo-controlled, phase 3 trial conducted at 18 study sites across 16 countries and regions.

OPTIMA 是一项随机、双盲、安慰剂对照的三期试验，研究地点分布在全球 16 个国家和地区的 18 个研究点。

Participants aged 18 years or older with FOP were randomly assigned (1:1:1) to monthly intravenous placebo, garetosmab 3 mg/kg, or garetosmab 10 mg/kg.

年龄在 18 岁或以上的 FOP 患者被随机分配（1:1:1）接受每月一次的静脉注射安慰剂、garetosmab 3 mg/kg 或 garetosmab 10 mg/kg。

Randomisation was stratified by baseline Cumulative Analogue Joint Involvement Scale score and previous participation in the LUMINA-1 study.

随机分组根据基线累积模拟关节受累评分和是否参加过 LUMINA-1 研究进行了分层。

The primary efficacy and safety endpoints were total number of new heterotopic bone lesions at week 56 and treatment-emergent adverse events of special interest (AESIs) through week 56, analysed in all randomised participants who received at least one dose of the study drug.

主要疗效和安全性终点是第 56 周新异位骨病变的总数和第 56 周治疗后出现的特殊关注的不良事件（AESIs），在所有接受至少一次研究药物治疗的随机参与者中进行分析。

This trial is registered with ClinicalTrials.gov (NCT05394116); the trial is active (completed primary endpoint) but not recruiting participants.

该试验已在ClinicalTrials.gov注册（NCT05394116）；试验正在进行中（已完成主要终点），但不再招募参与者。

Results

Between Nov 21, 2022, and July 4, 2024, 63 participants were enrolled and randomly assigned (placebo, n=21; garetosmab 3 mg/kg, n=19; garetosmab 10 mg/kg, n=23).

在2022年11月21日至2024年7月4日期间，共有63名参与者被纳入试验并随机分配（安慰剂组，n=21；garetosmab 3 mg/kg组，n=19；garetosmab 10 mg/kg组，n=23）。

The mean age was 26·6 years (SD 6·8); 38 (60%) participants were female and 25 (40%) male. 62 participants completed 56 weeks of treatment; one participant in the placebo group discontinued at 53 weeks.

平均年龄为26.6岁（标准差6.8）；38名（60%）参与者为女性，25名（40%）为男性。62名参与者完成了56周的治疗；安慰剂组有一名参与者在53周时退出。

The total number of new heterotopic bone lesions was significantly lower with garetosmab: there were 19 lesions with placebo versus one lesion with garetosmab 3 mg/kg (rate ratio vs placebo: 0·06 [95% CI 0·00-0·73]; p=0·027) and two lesions with garetosmab 10 mg/kg (rate ratio vs placebo: 0·10 [0·01-0·76]; p=0·026).

与garetosmab相比，新的异位骨病灶总数显著降低：安慰剂组有19个病灶，而garetosmab 3 mg/kg组只有1个病灶（与安慰剂相比的比率比为0.06 [95% CI 0.00-0.73]；p=0.027），garetosmab 10 mg/kg组有2个病灶（与安慰剂相比的比率比为0.10 [0.01-0.76]；p=0.026）。

Treatment-emergent AESIs occurred in one (5%) of 21 participants receiving placebo, zero of 19 receiving garetosmab 3 mg/kg, and four (17%) of 23 receiving garetosmab 10 mg/kg; all were considered treatment-related.

治疗后出现的不良事件（AESIs）在21名接受安慰剂的参与者中有1名（5%），在19名接受garetosmab 3 mg/kg的参与者中没有，在23名接受garetosmab 10 mg/kg的参与者中有4名（17%）；所有这些都被认为与治疗有关。

No deaths occurred.

没有发生死亡事件。

interpretation

Garetosmab substantially reduced the number of new heterotopic bone lesions, providing robust evidence of its potential to be an efficacious and generally well tolerated disease-modifying therapy for FOP.

Garetosmab显著减少了新的异位骨病灶的数量，提供了强有力的证据表明其作为FOP疾病修饰性治疗的潜在有效性和良好的耐受性。

funding

Regeneron Pharmaceuticals.

Regeneron Pharmaceuticals。