From the Department of Neurology (T.O.C.), Johns Hopkins University, Baltimore, MD; Department of Neurology (B.T.D.), Boston Children's Hospital, Harvard Medical School, MA; Department of Neurology (J.W.D., S.D.Y., T.D.), Stanford University, Palo Alto, CA; Department of Physical Therapy (L.L.N.), University of Texas Southwestern Medical Center, Dallas; Scholar Rock, Inc. (D.B., G.S., S.C., M.S., R.I., T.J.X., J.O.N., J.R., A.P., N.K., G.N., Y.C.), Cambridge, MA; Vanadro, LLC (S.B.), Urbandale, IA; Tourmaline Bio, Inc. (R.I.), New York, NY; Pfizer, Inc. (A.P.), New York, NY; Harmony Biosciences (G.N.), Plymouth Meeting, PA; and Stealth BioTherapeutics (Y.C.), Needham, MA.
Neurology. 2024 Mar 12;102(5):e209151. doi: 10.1212/WNL.0000000000209151. Epub 2024 Feb 8.
Currently approved therapies for spinal muscular atrophy (SMA) reverse the degenerative course, leading to better functional outcome, but they do not address the impairment arising from preexisting neurodegeneration. Apitegromab, an investigational, fully human monoclonal antibody, inhibits activation of myostatin (a negative regulator of skeletal muscle growth), thereby preserving muscle mass. The phase 2 TOPAZ trial assessed the safety and efficacy of apitegromab in individuals with later-onset type 2 and type 3 SMA.
In this study, designed to investigate potential meaningful combinations of eligibility and treatment regimen for future studies, participants aged 2-21 years received IV apitegromab infusions every 4 weeks for 12 months in 1 of 3 cohorts. Cohort 1 stratified ambulatory participants aged 5-21 years into 2 arms (apitegromab 20 mg/kg alone or in combination with nusinersen); cohort 2 evaluated apitegromab 20 mg/kg combined with nusinersen in nonambulatory participants aged 5-21 years; and cohort 3 blindly evaluated 2 randomized apitegromab doses (2 and 20 mg/kg) combined with nusinersen in younger participants ≥2 years of age. The primary efficacy measure was mean change from baseline using the Hammersmith Functional Motor Scale version appropriate for each cohort. Data were analyzed using a paired test with 2-sided 5% type 1 error for the mean change from baseline for predefined cohort-specific primary efficacy end points.
Fifty-eight participants (mean age 9.4 years) were enrolled at 16 trial sites in the United States and Europe. Participants had been treated with nusinersen for a mean of 25.9 months before enrollment in any of the 3 trial cohorts. At month 12, the mean change from baseline in Hammersmith scale score was -0.3 points (95% CI -2.1 to 1.4) in cohort 1 (n = 23), 0.6 points (-1.4 to 2.7) in cohort 2 (n = 15), and in cohort 3 (n = 20), the mean scores were 5.3 (-1.5 to 12.2) and 7.1 (1.8 to 12.5) for the 2-mg/kg (n = 8) and 20-mg/kg (n = 9) arms, respectively. The 5 most frequently reported treatment-emergent adverse events were headache (24.1%), pyrexia (22.4%), upper respiratory tract infection (22.4%), cough (22.4%), and nasopharyngitis (20.7%). No deaths or serious adverse reactions were reported.
Apitegromab led to improved motor function in participants with later-onset types 2 and 3 SMA. These results support a randomized, placebo-controlled phase 3 trial of apitegromab in participants with SMA.
This trial is registered with ClinicalTrials.gov (NCT03921528).
This study provides Class III evidence that apitegromab improves motor function in later-onset types 2 and 3 spinal muscular atrophy.
目前批准的脊髓性肌萎缩症（SMA）疗法可逆转退行性病程，从而获得更好的功能结果，但它们不能解决先前存在的神经退行性病变引起的损害。Apitegromab 是一种研究性的、全人源单克隆抗体，可抑制肌肉生长负调节剂肌抑素的激活，从而维持肌肉质量。2 期 TOPAZ 试验评估了 Apitegromab 在 2 型和 3 型晚发性 SMA 患者中的安全性和疗效。
在这项旨在研究未来研究中潜在有意义的合格性和治疗方案组合的研究中，2-21 岁的参与者被分为 3 个队列，每 4 周接受 1 次 IV Apitegromab 输注，持续 12 个月。队列 1 将 5-21 岁的可走动参与者分为 2 个臂（Apitegromab 20mg/kg 单独使用或与 nusinersen 联合使用）；队列 2 评估了 5-21 岁非可走动参与者接受 Apitegromab 20mg/kg 联合 nusinersen 的疗效；队列 3 则盲法评估了 2 种随机 Apitegromab 剂量（2mg/kg 和 20mg/kg）联合 nusinersen 在≥2 岁的年轻参与者中的疗效。主要疗效指标为根据每个队列的情况使用 Hammersmith 功能运动量表适当的基线平均变化。使用双侧 5%的检验对预定的队列特定主要疗效终点的基线平均变化进行了分析。
58 名参与者（平均年龄 9.4 岁）在美国和欧洲的 16 个试验点入组。在任何一个 3 个试验队列中，参与者在入组前均已接受 nusinersen 治疗，平均时间为 25.9 个月。在第 12 个月，Hammersmith 量表评分的基线平均变化在队列 1（n=23）中为-0.3 分（95%CI-2.1 至 1.4），在队列 2（n=15）中为 0.6 分（-1.4 至 2.7），在队列 3（n=20）中，2mg/kg（n=8）和 20mg/kg（n=9）臂的平均评分分别为 5.3（-1.5 至 12.2）和 7.1（1.8 至 12.5）。最常见的 5 种治疗后出现的不良事件为头痛（24.1%）、发热（22.4%）、上呼吸道感染（22.4%）、咳嗽（22.4%）和鼻咽炎（20.7%）。无死亡或严重不良反应报告。
Apitegromab 可改善晚发性 2 型和 3 型 SMA 患者的运动功能。这些结果支持在 SMA 患者中进行 Apitegromab 的随机、安慰剂对照 3 期试验。
该试验在 ClinicalTrials.gov（NCT03921528）上注册。
本研究提供了 III 级证据，表明 Apitegromab 可改善晚发性 2 型和 3 型脊髓性肌萎缩症的运动功能。
