Pignolo Robert J, Hsiao Edward C, Al Mukaddam Mona, Baujat Geneviève, Berglund Staffan K, Brown Matthew A, Cheung Angela M, De Cunto Carmen, Delai Patricia, Haga Nobuhiko, Kannu Peter, Keen Richard, Le Quan Sang Kim-Hanh, Mancilla Edna E, Marino Rose, Strahs Andrew, Kaplan Frederick S
Department of Medicine, Mayo Clinic, Rochester, MN, USA.
Division of Endocrinology and Metabolism, the UCSF Metabolic Bone Clinic, the Eli and Edythe Broad Institute for Regeneration Medicine, and the Institute of Human Genetics, Department of Medicine, and the UCSF Program in Craniofacial Biology, University of California-San Francisco, San Francisco, CA, USA.
J Bone Miner Res. 2023 Mar;38(3):381-394. doi: 10.1002/jbmr.4762. Epub 2023 Jan 25.
Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare, severely disabling genetic disorder of progressive heterotopic ossification (HO). The single-arm, open-label, phase 3 MOVE trial (NCT03312634) assessed efficacy and safety of palovarotene, a selective retinoic acid receptor gamma agonist, in patients with FOP. Findings were compared with FOP natural history study (NHS; NCT02322255) participants untreated beyond standard of care. Patients aged ≥4 years received palovarotene once daily (chronic: 5 mg; flare-up: 20 mg for 4 weeks, then 10 mg for ≥8 weeks; weight-adjusted if skeletally immature). The primary endpoint was annualized change in new HO volume versus NHS participants (by low-dose whole-body computed tomography [WBCT]), analyzed using a Bayesian compound Poisson model (BcPM) with square-root transformation. Twelve-month interim analyses met futility criteria; dosing was paused. An independent Data Monitoring Committee recommended trial continuation. Post hoc 18-month interim analyses utilized BcPM with square-root transformation and HO data collapsed to equalize MOVE and NHS visit schedules, BcPM without transformation, and weighted linear mixed-effects (wLME) models, alongside prespecified analysis. Safety was assessed throughout. Eighteen-month interim analyses included 97 MOVE and 101 NHS individuals with post-baseline WBCT. BcPM analyses without transformation showed 99.4% probability of any reduction in new HO with palovarotene versus NHS participants (with transformation: 65.4%). Mean annualized new HO volume was 60% lower in MOVE versus the NHS. wLME results were similar (54% reduction fitted; nominal p = 0.039). All palovarotene-treated patients reported ≥1 adverse event (AE); 97.0% reported ≥1 retinoid-associated AE; 29.3% reported ≥1 serious AE, including premature physeal closure (PPC)/epiphyseal disorder in 21/57 (36.8%) patients aged <14 years. Post hoc computational analyses using WBCT showed decreased vertebral bone mineral density, content, and strength, and increased vertebral fracture risk in palovarotene-treated patients. Thus, post hoc analyses showed evidence for efficacy of palovarotene in reducing new HO in FOP, but high risk of PPC in skeletally immature patients. © 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）是一种极其罕见、严重致残的进行性异位骨化（HO）遗传性疾病。单臂、开放标签的3期MOVE试验（NCT03312634）评估了选择性维甲酸受体γ激动剂帕罗西汀对FOP患者的疗效和安全性。将研究结果与FOP自然史研究（NHS；NCT02322255）中未接受标准治疗以外治疗的参与者进行比较。年龄≥4岁的患者每天服用一次帕罗西汀（慢性：5mg；病情发作：20mg，持续4周，然后10mg，持续≥8周；骨骼未成熟者根据体重调整剂量）。主要终点是与NHS参与者相比，新的HO体积的年化变化（通过低剂量全身计算机断层扫描[WBCT]），使用贝叶斯复合泊松模型（BcPM）和平方根变换进行分析。12个月的中期分析达到了无效标准；给药暂停。一个独立的数据监测委员会建议继续试验。事后18个月的中期分析使用了带有平方根变换的BcPM，并将HO数据合并以平衡MOVE和NHS的访视时间表，未进行变换的BcPM，以及加权线性混合效应（wLME）模型，以及预先指定的分析。在整个过程中评估安全性。18个月的中期分析包括97名MOVE参与者和101名NHS参与者，他们在基线后进行了WBCT检查。未进行变换的BcPM分析显示，与NHS参与者相比，帕罗西汀使新的HO减少的概率为99.4%（进行变换时为65.4%）。MOVE组的平均年化新HO体积比NHS组低60%。wLME结果相似（拟合减少54%；名义p=0.039）。所有接受帕罗西汀治疗的患者均报告了≥1次不良事件（AE）；97.0%的患者报告了≥1次与类维生素A相关的AE；29.3%的患者报告了≥1次严重AE，包括21/57（36.8%）年龄<14岁的患者出现过早骨骺闭合（PPC）/骨骺疾病。使用WBCT进行的事后计算分析显示，帕罗西汀治疗的患者椎骨骨矿物质密度、含量和强度降低，椎骨骨折风险增加。因此，事后分析显示有证据表明帕罗西汀在减少FOP中新的HO方面有效，但在骨骼未成熟的患者中PPC风险很高。©2022作者。《骨与矿物质研究杂志》由Wiley Periodicals LLC代表美国骨与矿物质研究协会（ASBMR）出版。
