Department of Medicine, Divisions of Geriatric Medicine and Gerontology, Hospital Internal Medicine, and Endocrinology, Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA.
Departement de Genetique, Institut IMAGINE and Hôpital Necker-Enfants Malades, Paris, France.
J Bone Miner Res. 2022 Oct;37(10):1891-1902. doi: 10.1002/jbmr.4655. Epub 2022 Aug 17.
Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare genetic disorder characterized by progressive heterotopic ossification (HO), often heralded by flare-ups, leading to reduced movement and life expectancy. This placebo-controlled, double-blind trial (NCT02190747) evaluated palovarotene, an orally bioavailable selective retinoic acid receptor gamma agonist, for prevention of HO in patients with FOP. Patients experiencing a flare-up were enrolled in two cohorts: (1) patients ≥15 years were randomized 3:1 to palovarotene 10/5 mg (weeks 1-2/3-6) or placebo; (2) patients ≥6 years were randomized 3:3:2 to palovarotene 10/5 mg, palovarotene 5/2.5 mg (weeks 1-2/3-6), or placebo. Cohort data were pooled. The primary endpoint was the proportion of responders (no/minimal new HO at flare-up body region by plain radiograph) at week 6. Change from baseline in HO volume and new HO incidence were assessed by computed tomography (CT) at week 12. Tissue edema was assessed by magnetic resonance imaging (MRI) or ultrasound. Forty patients (aged 7-53 years) were enrolled (placebo: n = 10; palovarotene 5/2.5 mg: n = 9; palovarotene 10/5 mg: n = 21). Disease history was similar between groups. In the per-protocol population, the proportion of responders at week 6 by plain radiograph was 100% with palovarotene 10/5 mg; 88.9% with palovarotene 5/2.5 mg; 88.9% with placebo (Cochran-Armitage trend test: p = 0.17). At week 12, the proportions were 95.0% with palovarotene 10/5 mg; 88.9% with palovarotene 5/2.5 mg; 77.8% with placebo (Cochran-Armitage trend test: p = 0.15). Week 12 least-squares mean (LSmean) new HO volume, assessed by CT, was 3.8 × 10 mm with palovarotene 10/5 mg; 1.3 × 10 mm with palovarotene 5/2.5 mg; 18.0 × 10 mm with placebo (pairwise tests versus placebo: p ≤ 0.12). Palovarotene was well-tolerated. No patients discontinued treatment or required dose reduction; one patient had dose interruption due to elevated lipase. Although these findings were not statistically significant, they support further evaluation of palovarotene for prevention of HO in FOP in larger studies. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
进行性骨化性纤维发育不良（FOP）是一种超罕见的遗传疾病，其特征为进行性异位骨化（HO），常以 flare-ups 为前驱症状，导致运动能力下降和预期寿命缩短。这项安慰剂对照、双盲试验（NCT02190747）评估了 palovarotene，一种口服生物利用度的选择性维甲酸受体γ激动剂，用于预防 FOP 患者的 HO。出现 flare-ups 的患者被纳入两个队列：（1）≥15 岁的患者以 3:1 的比例随机分配至 palovarotene 10/5mg（第 1-2 周/第 3-6 周）或安慰剂；（2）≥6 岁的患者以 3:3:2 的比例随机分配至 palovarotene 10/5mg、palovarotene 5/2.5mg（第 1-2 周/第 3-6 周）或安慰剂。汇总了两个队列的数据。主要终点是在 flare-up 身体区域的平片上，无/最小新 HO 的患者比例（反应者）在第 6 周。第 12 周通过 CT 评估 HO 体积和新 HO 发生率的变化。HO 组织水肿通过 MRI 或超声进行评估。共纳入 40 名患者（年龄 7-53 岁）（安慰剂：n=10；palovarotene 5/2.5mg：n=9；palovarotene 10/5mg：n=21）。各组之间的疾病史相似。在符合方案人群中，第 6 周平片上的反应者比例，palovarotene 10/5mg 组为 100%；palovarotene 5/2.5mg 组为 88.9%；安慰剂组为 88.9%（Cochran-Armitage 趋势检验：p=0.17）。第 12 周，palovarotene 10/5mg 组的比例为 95.0%；palovarotene 5/2.5mg 组为 88.9%；安慰剂组为 77.8%（Cochran-Armitage 趋势检验：p=0.15）。第 12 周 CT 评估的最小二乘均值（LSmean）新 HO 体积，palovarotene 10/5mg 组为 3.8×10mm；palovarotene 5/2.5mg 组为 1.3×10mm；安慰剂组为 18.0×10mm（与安慰剂相比，两两比较：p≤0.12）。Palovarotene 耐受性良好。无患者停止治疗或需要减少剂量；1 名患者因脂肪酶升高而中断治疗。尽管这些发现没有统计学意义，但它们支持在更大规模的研究中进一步评估 palovarotene 预防 FOP 中的 HO。
