美国Vaccinex公司Maurice Zauderer小组取得一项新突破。他们发布了早期亨廷顿病中靶向SEMA4D阻断抗体Pepinemab的随机、安慰剂对照2期试验结果。2022年8月8日出版的《自然-医学》杂志发表了这项成果。

SIGNAL是一项多中心、随机、双盲、安慰剂对照的2期临床研究（编号NCT02481674），旨在评估pepinemab（信号素 4D（SEMA4D）的阻断抗体）用于治疗亨廷顿病（HD）。该试验共招募了265名HD基因扩增携带者，具有早期表现(EM, n = 179)或晚期诱导 HD(LP, n = 86)，随机(1:1)接受18个月pepinemab (n = 91 EM，41 LP）或安慰剂（n = 88 EM，45 LP）输注。Pepinemab的耐受性普遍良好，pepinemab治疗引起的严重不良事件发生率相对较低，为5%，而安慰剂组为9%，包括EM和LP参与者。

主要疗效结果测量包括EM队列中的评估：（1）包括单触式stockings of Cambridge（OTS）和paced tapping（PTAP）两项 HD认知评估和（2）临床症状整体改变（CGIC）。在17个月时pepinemab和安慰剂之间的平均变化（95%置信区间）在OTS组为 -1.98（-4.00, 0.05）（单侧P=0.028），对于PTAP为1.43（-0.37, 3.23）（单边P=0.06）。同样，由于没有观察到共同主要终点即CGIC的显著治疗效果，该研究未达到其预先设定的临床终点。然而，许多其他积极成果和事后亚组分析，包括额外的认知测量和体磁共振成像以及氟脱氧葡萄糖-正电子发射断层扫描成像评估，为第3期临床研究的设计提供了思路和方向，并为在EM HD患者中使用pepinemab提供了依据。

附：英文原文

Title: Pepinemab antibody blockade of SEMA4D in early Huntington’s disease: a randomized, placebo-controlled, phase 2 trial

Author: Feigin, Andrew, Evans, Elizabeth E., Fisher, Terrence L., Leonard, John E., Smith, Ernest S., Reader, Alisha, Mishra, Vikas, Manber, Richard, Walters, Kimberly A., Kowarski, Lisa, Oakes, David, Siemers, Eric, Kieburtz, Karl D., Zauderer, Maurice

Issue&Volume: 2022-08-08

Abstract: SIGNAL is a multicenter, randomized, double-blind, placebo-controlled phase2 study (no. NCT02481674) established to evaluate pepinemab, a semaphorin4D (SEMA4D)-blocking antibody, for treatment of Huntington’s disease (HD). The trial enrolled a total of 265HD gene expansion carriers with either early manifest (EM, n=179) or late prodromal (LP, n=86) HD, randomized (1:1) to receive 18monthly infusions of pepinemab (n=91 EM, 41LP) or placebo (n=88 EM, 45LP). 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 month17 for OTS were1.98 (4.00, 0.05) (one-sided P=0.028), and for PTAP1.43 (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 phase3 study and encourage the continued development of pepinemab in patients diagnosed with EM HD.

DOI: 10.1038/s41591-022-01919-8

Source: https://www.nature.com/articles/s41591-022-01919-8