背景:杜氏肌营养不良症(DMD)是一种遗传性肌肉疾病,在儿童早期表现出来,最终致命。最近批准的针对DMD遗传原因的治疗仅限于特定的患者亚群。强调需要更广泛的应用疗法。肌肉生长抑制素的药理抑制作用,一种肌肉生长的内源性抑制剂,几乎只在骨骼肌中产生,已被证明可以增加几种物种的肌肉质量,包括人类。Taldefgrobepalfa是一种抗肌肉生长抑制素重组蛋白,可结合并阻断肌肉生长抑制素信号传导。taldefrobepalfa的临床前研究表明,三种动物的肌肉生长抑制素显著减少,下肢体积增加,包括营养不良的老鼠.
方法:本手稿报告了三项单独的DMD中taldefrobepalfa临床试验的累积数据:一项健康成人志愿者的1期研究(NCT02145234),和两个随机的,双盲,在非卧床男孩中进行的安慰剂对照研究,DMD-评估安全性的1b/2期试验(NCT02515669)和包括NorthStar非卧床评估(NSAA)作为主要终点的2/3期试验(NCT03039686).
结果:在健康的成年志愿者中,taldefgrobepalfa通常具有良好的耐受性,并导致大腿肌肉体积显着增加。用taldefgrobepalfa治疗与对游离肌肉生长抑制素的强烈剂量依赖性抑制有关。在1b/2阶段试验中,肌肉生长抑制素抑制与对瘦体重的积极影响相关,虽然对肌肉质量的影响不大。2/3期试验发现,治疗效果未达到主要终点预先指定的无用分析阈值(从NSAA总分的基线变化≥1.5分)。
结论:无效性分析表明,对于患有DMD的男孩,taldefrobepalfa不会导致功能改变。该计划随后于2019年终止。总的来说,没有安全问题,无患者因治疗相关不良事件或严重不良事件而退出治疗.
背景:NCT02145234,NCT02515669,NCT03039686。
该计划的目标是开发一种治疗方法,以改善杜氏肌营养不良症(DMD)患者的肌肉功能。DMD患者的肌肉无力是进行性的,导致不可逆的步行能力丧失,最终因心肺功能衰竭而死亡。改善肌肉功能的一种潜在方法是靶向一种称为肌肉生长抑制素的蛋白质,该蛋白质在健康肌肉中起作用以调节肌肉大小。动物研究表明,阻断肌肉生长抑制素可以增加肌肉大小。Taldefgrobepalfa是一种旨在阻断肌肉生长抑制素的药物,它被证明可以诱导动物的肌肉生长。一项针对健康志愿者的研究发现,alfa能够增加人类的肌肉大小,并且与安全问题无关。在此之后,一项研究是在患有DMD的男孩中进行的,他们接受了taldefrobepalfa或安慰剂治疗.这项针对患者的首次研究发现,治疗能够降低肌肉生长抑制素水平,并且对肌肉大小的影响很小,支持更多DMD患者的更大试验。更大的试验的目的是测试taldefgrobepalfa是否对DMD患者的肌肉功能具有有意义的影响。该关键试验的结果未达到功能的目标改善,因此决定终止试验并停止使用taldefrobepalfa作为DMD的潜在治疗方法。没有患者因不良安全影响而停止taldefrobepalfa治疗,也没有发现安全问题。
BACKGROUND: Duchenne muscular dystrophy (DMD) is a genetic muscle disorder that manifests during early childhood and is ultimately fatal. Recently approved treatments targeting the genetic cause of DMD are limited to specific subpopulations of patients, highlighting the need for therapies with wider applications. Pharmacologic inhibition of myostatin, an endogenous inhibitor of muscle growth produced almost exclusively in skeletal muscle, has been shown to increase muscle mass in several species, including humans. Taldefgrobep alfa is an anti-myostatin recombinant protein engineered to bind to and block myostatin signaling. Preclinical studies of taldefgrobep alfa demonstrated significant decreases in myostatin and increased lower limb volume in three animal species, including dystrophic mice.
METHODS: This manuscript reports the cumulative data from three separate clinical trials of taldefgrobep alfa in DMD: a phase 1 study in healthy adult volunteers (NCT02145234), and two randomized, double-blind, placebo-controlled studies in ambulatory boys with DMD-a phase 1b/2 trial assessing safety (NCT02515669) and a phase 2/3 trial including the North Star Ambulatory Assessment (NSAA) as the primary endpoint (NCT03039686).
RESULTS: In healthy adult volunteers, taldefgrobep alfa was generally well tolerated and resulted in a significant increase in thigh muscle volume. Treatment with taldefgrobep alfa was associated with robust dose-dependent suppression of free myostatin. In the phase 1b/2 trial, myostatin suppression was associated with a positive effect on lean body mass, though effects on muscle mass were modest. The phase 2/3 trial found that the effects of treatment did not meet the primary endpoint pre-specified futility analysis threshold (change from baseline of ≥ 1.5 points on the NSAA total score).
CONCLUSIONS: The futility analysis demonstrated that taldefgrobep alfa did not result in functional change for boys with DMD. The program was subsequently terminated in 2019. Overall, there were no safety concerns, and no patients were withdrawn from treatment as a result of treatment-related adverse events or serious adverse events.
BACKGROUND: NCT02145234, NCT02515669, NCT03039686.
The goal of this program was to develop a treatment to improve muscle function in patients with Duchenne muscular dystrophy (DMD). Muscle weakness in patients with DMD is progressive, leading to the irreversible loss of walking ability and eventually death due to cardiorespiratory failure. One potential way of improving muscle function is to target a protein known as myostatin that acts in healthy muscle to regulate muscle size. Studies in animals have shown that blocking myostatin can increase muscle size. Taldefgrobep alfa is a drug designed to block myostatin and it was shown to induce muscle growth in animals. A study in healthy volunteers found that taldefgrobep alfa was able to increase muscle size in humans and was not associated with safety concerns. Following this, a study was conducted in boys with DMD who were either treated with taldefgrobep alfa or a placebo. This first study in patients found that treatment was able to reduce myostatin levels and had a small effect on muscle size, supporting a larger trial in more patients with DMD. The aim of the larger trial was to test if taldefgrobep alfa had a meaningful effect on muscle function in patients with DMD. Results from this key trial did not meet the targeted improvement in function and a decision was made to end the trial and halt the use of taldefgrobep alfa as a potential treatment for DMD. No patients stopped treatment with taldefgrobep alfa as a result of adverse safety effects and no safety concerns were identified.