骨化性纤维发育不全(FOP)是一种非常罕见的疾病,以进行性异位骨化(HO)和疼痛性软组织炎性发作为特征。这是一项2期(NCT03188666)试验的事后分析,在该试验中,患有FOP的成年人在28周内每4周接受静脉注射抗激活素A抗体加雷托单抗10mg/kg或安慰剂(第1期),随后是28周的开放标签治疗和延长(第2期和第3期)。在这里我们描述爆发,它们与新的HO病变的关系,以及Garetosmab对突发事件的影响。通过计算机断层扫描测量新的HO病变的体积。患者报告的突然发作由以下两项定义:新发疼痛,肿胀,接头刚度,运动减少,或感知到HO的存在。71%(17/24)的安慰剂治疗患者经历了爆发,59%(10/17)的患者出现了新的HO病变,与爆发位置无关;24%的爆发位置与新的HO病变匹配。到第28周,安慰剂队列中出现了29个新的HO病变,其中12个(41%)发生在与新的或正在进行的突发相同的位置。在安慰剂治疗的患者中出现较高体积的新形成的异位骨(第28周),这些患者先前经历过发作(中位数[Q1:Q3]为16.6[12.0:31.1]cm3对3.2cm3)。先前已证明Garetosmab在第1期降低了患者报告的发作频率;此处,与安慰剂相比,garetosmab降低了患者报告的耀斑持续时间中位数(Q1:Q3)(15.0[6.0:82.0]对48.0[15.0:1.00]天)和耀斑严重程度。与安慰剂(58.3%)相比,加雷托单抗(40.0%)治疗的患者使用皮质类固醇的频率在数字上降低。在这个分析中,71%的安慰剂治疗成人FOP经历了超过28周的突然发作,与新形成的异位骨体积增加有关。Garetosmab降低了发作的严重程度和持续时间,并在整个试验期间持续了效果。
骨化性纤维发育不良(FOP)是一种非常罕见的遗传性疾病,由编码受体的基因ACVR1的突变引起。在FOP中,突变的受体被激活素A独特地激活,一种结合ACVR1的蛋白质(但通常不会激活它)。当FOP突变体ACVR1被激活素A激活时,这会导致新骨在通常不发育的地方形成。更具体地说,在FOP中,软组织(例如骨骼肌)和结缔组织(例如肌腱和韧带)逐渐被正常骨骼外部的骨骼取代-该过程称为异位骨化(HO)。在有FOP的人中,骨骼的堆积会影响他们的活动能力。此外,患有FOP的人也会经历爆发,这是软组织疼痛的肿胀。这项分析调查了突发事件,突发与新的HO病变的关系,以及在一项纳入FOP患者的临床试验中,garetosmab对突发事件的影响。Garetosmab是一种单克隆抗体,可与激活素A结合并阻止其激活有缺陷的受体,从而阻止新的异位骨形成。在这项研究中,大约一半的患者随机接受安慰剂,另一半随机接受Garetosmab,研究药物。在接受安慰剂的人中,71%的人经历了突然发作,而59%的人发生了新的HO病变,而与突然发作的位置无关。我们以前报道过garetosmab降低了患者报告的爆发频率。在这项研究中,我们表明garetosmab还可以减少爆发的持续时间和严重程度,以及皮质类固醇的使用频率和整个试验维持的治疗效果。
Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare disorder, characterized by progressive heterotopic ossification (HO) and painful soft-tissue inflammatory flare-ups. This was a post-hoc analysis from a phase 2 (NCT03188666)
trial in which adults with FOP received intravenous anti-activin A antibody garetosmab 10 mg/kg or placebo every 4 weeks over 28 weeks (Period 1), followed by a 28-week open-label treatment and extension (Period 2 and 3). Here we describe flare-ups, their relationship to new HO lesions, and the impact of garetosmab on flare-ups. Volume of new HO lesions was measured by computed tomography. Patient-reported flare-ups were defined by any two of: new onset of pain, swelling, joint stiffness, decrease in movement, or perceived presence of HO. Flare-ups were experienced by 71% (17/24) of placebo-treated patients, 59% (10/17) of whom developed a new HO lesion irrespective of flare-up location; 24% of flare-ups location-matched new HO lesions. Twenty-nine new HO lesions occurred in the placebo cohort by week 28, of which 12 (41%) occurred in the same location as new or ongoing flare-ups. A higher volume of newly formed heterotopic bone (week 28) occurred in placebo-treated patients who had experienced a prior flare-up versus those without (median [Q1:Q3] of 16.6 [12.0:31.1] cm3 versus 3.2 cm3). Garetosmab was previously shown to decrease patient-reported flare-up frequency in Period 1; here, garetosmab reduced the median (Q1:Q3) duration of patient reported flares (15.0 [6.0:82.0] versus 48.0 [15.0:1.00] days) and severity of flare-ups versus placebo. Frequency of corticosteroid use was numerically reduced in those treated with garetosmab (40.0%) versus placebo (58.3%). In this analysis, 71% of placebo-treated adults with FOP experienced flare-ups over 28 weeks, which were associated with an increased volume of newly formed heterotopic bone. Garetosmab reduced the severity and duration of flare-ups with effects sustained during the entire trial.
Fibrodysplasia ossificans progressiva (FOP) is a very rare genetic disorder caused by mutations in ACVR1, a gene that encodes for a receptor. In FOP, the mutated receptor is uniquely activated by activin A, a protein that binds ACVR1 (but does not normally activate it). When FOP-mutant ACVR1 is activated by activin A, this causes new bone to form in places where it does not usually develop. More specifically, in FOP, soft tissues (such as skeletal muscles) and connective tissues (such as tendons and ligaments) are gradually replaced by bone outside of the normal skeleton—a process referred to as heterotopic ossification (HO). In people with FOP, the build-up of bone impacts their mobility. Additionally, people with FOP also experience flare-ups, which are painful swellings of the soft tissues. This analysis investigated flare-up events, the relationship of flare-ups to new HO lesions, and the impact of garetosmab on flare-ups during a clinical trial that enrolled people with FOP. Garetosmab is a monoclonal antibody that binds to activin A and blocks it from activating the faulty receptor, hence stopping new heterotopic bone from forming. In this
study, approximately half of the patients randomly received placebo and the other half randomly received garetosmab, the
study drug. Of the people who received placebo, 71% experienced flare-ups and 59% percent of those who had flare-ups developed a new HO lesion irrespective of flare-up location. We previously reported that garetosmab decreases patient-reported flare-up frequency. In this
study, we show that garetosmab also reduces the duration and severity of flare-ups, as well as the frequency of corticosteroid use with the treatment effect maintained for the entire
trial.