SIGNAL is a multicenter, randomized, double-blind, placebo-controlled phase 2 study (no. NCT02481674) established to evaluate pepinemab, a semaphorin 4D (SEMA4D)-blocking antibody, for treatment of Huntington’s disease (HD). The trial enrolled a total of 265 HD gene expansion carriers with either early manifest (EM, n = 179) or late prodromal (LP, n = 86) HD, randomized (1:1) to receive 18 monthly infusions of pepinemab (n = 91 EM, 41 LP) or placebo (n = 88 EM, 45 LP). Pepinemab was generally well tolerated, with a relatively low frequency of serious treatment-emergent adverse events of 5% with pepinemab compared to 9% with placebo, including both EM and LP participants. Coprimary efficacy outcome measures consisted of assessments within the EM cohort of (1) a two-item HD cognitive assessment family comprising one-touch stockings of Cambridge (OTS) and paced tapping (PTAP) and (2) clinical global impression of change (CGIC). The differences between pepinemab and placebo in mean change (95% confidence interval) from baseline at month 17 for OTS were −1.98 (−4.00, 0.05) (one-sided P = 0.028), and for PTAP 1.43 (−0.37, 3.23) (one-sided P = 0.06). Similarly, because a significant treatment effect was not observed for CGIC, the coprimary endpoint, the study did not meet its prespecified primary outcomes. Nevertheless, a number of other positive outcomes and post hoc subgroup analyses—including additional cognitive measures and volumetric magnetic resonance imaging and fluorodeoxyglucose–positron-emission tomography imaging assessments—provide rationale and direction for the design of a phase 3 study and encourage the continued development of pepinemab in patients diagnosed with EM HD.

SIGNAL 是一项多中心、随机、双盲、安慰剂对照的 2 期研究（编号 NCT02481674），旨在评估 pepinemab（一种信号蛋白 4D（SEMA4D）阻断抗体）用于治疗亨廷顿舞蹈病（HD）的效果。该试验共招募了 265 名具有早期表现（EM，n  = 179）或晚期前驱（LP，n  = 86）HD 的 HD 基因扩增携带者，随机（1：1）接受 18 个月的 pepinemab 输注（n  = 91 EM, 41 LP) 或安慰剂 ( n = 88 EM，45 LP）。Pepinemab 的总体耐受性良好，包括 EM 和 LP 参与者在内，pepinemab 的严重治疗紧急不良事件发生率相对较低，为 5%，而安慰剂为 9%。共同主要疗效结果测量包括 EM 队列中的评估，包括 (1) 两项 HD 认知评估系列，包括剑桥单触式长袜 (OTS) 和节奏敲击 (PTAP) 和 (2) 临床整体变化印象 (CGIC) ). pepinemab 和安慰剂之间在第 17 个月时 OTS 与基线的平均变化（95% 置信区间）的差异为 −1.98（−4.00，0.05）（单侧P  = 0.028），而 PTAP 为 1.43（−0.37，3.23） （单方面P = 0.06）。同样，由于未观察到共同主要终点 CGIC 的显着治疗效果，因此该研究未达到其预先指定的主要结果。尽管如此，许多其他积极的结果和事后亚组分析——包括额外的认知测量和体积磁共振成像和氟脱氧葡萄糖-正电子发射断层扫描成像评估——为 3 期研究的设计提供了基本原理和方向，并鼓励继续发展pepinemab 在诊断为 EM HD 的患者中的应用。