Department of Pediatrics, Unit of Rare Diseases, IRCCS Istituto Giannina Gaslini, Genoa, Italy.
Regeneron Pharmaceuticals, Tarrytown, NY, USA.
Nat Med. 2023 Oct;29(10):2615-2624. doi: 10.1038/s41591-023-02561-8. Epub 2023 Sep 28.
Fibrodysplasia ossificans progressiva (FOP) is a rare disease characterized by heterotopic ossification (HO) in connective tissues and painful flare-ups. In the phase 2 LUMINA-1 trial, adult patients with FOP were randomized to garetosmab, an activin A-blocking antibody (n = 20) or placebo (n = 24) in period 1 (28 weeks), followed by an open-label period 2 (28 weeks; n = 43). The primary end points were safety and for period 1, the activity and size of HO lesions. All patients experienced at least one treatment-emergent adverse event during period 1, notably epistaxis, madarosis and skin abscesses. Five deaths (5 of 44; 11.4%) occurred in the open-label period and, while considered unlikely to be related, causality cannot be ruled out. The primary efficacy end point in period 1 (total lesion activity by PET-CT) was not met (P = 0.0741). As the development of new HO lesions was suppressed in period 1, the primary efficacy end point in period 2 was prospectively changed to the number of new HO lesions versus period 1. No placebo patients crossing over to garetosmab developed new HO lesions (0% in period 2 versus 40.9% in period 1; P = 0.0027). Further investigation of garetosmab in FOP is ongoing. ClinicalTrials.gov identifier NCT03188666 .
进行性骨化性纤维发育不良（FOP）是一种罕见疾病，其特征为结缔组织异位骨化（HO）和疼痛发作。在 2 期 LUMINA-1 试验中，FOP 成年患者在第 1 期（28 周）中被随机分配接受 garetosmab（一种激活素 A 阻断抗体，n = 20）或安慰剂（n = 24），随后进入第 2 期开放标签期（28 周；n = 43）。主要终点为安全性，第 1 期的主要终点为 HO 病变的活动度和大小。所有患者在第 1 期均至少经历了一次治疗后出现的不良事件，主要为鼻出血、睫毛缺失和皮肤脓肿。在开放标签期发生了 5 例死亡（5/44；11.4%），虽然认为不太可能与治疗相关，但无法排除因果关系。第 1 期的主要疗效终点（通过 PET-CT 评估的总病变活性）未达到（P = 0.0741）。由于在第 1 期抑制了新 HO 病变的发展，第 2 期的主要疗效终点前瞻性地更改为与第 1 期相比新 HO 病变的数量。没有安慰剂患者交叉至 garetosmab 后发生新的 HO 病变（第 2 期 0%，第 1 期 40.9%；P = 0.0027）。正在进行 garetosmab 在 FOP 中的进一步研究。临床试验标识符：NCT03188666。
