加拿大Probity医学研究所Kim A Papp团队研究了IL17A/F纳米体索洛奇单抗治疗斑块型银屑病的疗效。2021年4月24日，该研究发表在《柳叶刀》杂志上。

索洛奇单抗（也被称为M1095）是一种新型三价纳米体，由一价骆驼源纳米体组成，特定于人白细胞介素（IL）-17A、IL-17f和人血清白蛋白。纳米体是一类基于单结构域、骆驼源、纯重链抗体的新型专有治疗蛋白。研究组评估了索洛奇单抗在斑块型银屑病患者中四种剂量方案的疗效、安全性和耐受性，并与安慰剂进行了比较。

研究组在保加利亚、加拿大、捷克共和国、德国、匈牙利、波兰和美国的41个诊所和研究机构进行了一项多中心、随机、安慰剂对照、临床2b期试验。招募年龄为18-75岁、患有稳定的中重度斑块型银屑病的参与者，排除先前接受过两种以上生物制剂或任何针对IL-17治疗的候选者。研究人员、参与者和供应商在研究期间互不知情。

将参与者按1:1:1:1:1:1随机分为6组，分别为安慰剂组、索洛奇单抗30 mg组、索洛奇单抗60 mg组、索洛奇单抗120 mg正常负荷组、索洛奇单抗120 mg增加负荷组或苏金单抗300 mg组。所有参与者都经历了4周的筛选期、12周的安慰剂对照诱导期、12周的剂量维持或升级期以及24周的反应评估或剂量保持期。主要结局为与安慰剂组相比，索洛奇单抗组在第12周时研究者整体评估（IGA）清除或几乎清除（得分0或1）的参与者比例。在意向治疗的基础上评估主要结局和安全性结局。

2018年8月15日至2019年3月27日，研究组对383名患者进行了资格评估，其中313名入选，并随机分组，其中安慰剂组52名、索洛奇单抗30 mg组52名、索洛奇单抗60 mg组52名、索洛奇单抗120 mg正常负荷组53名、索洛奇单抗120 mg增加负荷组51名、苏金单抗300 mg组53名。各组参与者的基线特征相似。

在第12周，安慰剂组没有一名患者的IGA得分为0或1（0%），而索洛奇单抗30 mg组中有25名（48.1%），索洛奇单抗60 mg组中有44名（84.6%），索洛奇单抗120 mg正常负荷组中有41名（77.4%），索洛奇单抗120 mg增加负荷组中有45名（88.2%），苏金单抗300 mg组中有41名（77.4%）。

在安慰剂对照诱导期内，313名受试者中有155名（49.5%）出现一种或多种轻中度不良事件；在0-12周期间，所有索洛奇单抗组受试者中最常见的不良事件是鼻咽炎（13.5%）、瘙痒（6.7%）和上呼吸道感染（4.3%）。所有索洛奇单抗组中有一名患者在第12-52周患上了克罗恩病。在52周内，索洛奇单抗的安全性与苏金单抗相似，但可能存在可控的念珠菌感染，索洛奇单抗组的发生率为17.4%，苏金单抗组的发生率为1.9%。

研究结果表明，使用120 mg或以下剂量的索洛奇单抗治疗中重度斑块型银屑病临床益处显著，具有快速起效、持久改善和可接受的安全性。

附：英文原文

Title: IL17A/F nanobody sonelokimab in patients with plaque psoriasis: a multicentre, randomised, placebo-controlled, phase 2b study

Author: Kim A Papp, Mark A Weinberg, Alun Morris, Kristian Reich

Issue&Volume: 2021/04/24

Abstract:

Background

Sonelokimab (also known as M1095) is a novel trivalent nanobody comprised of monovalent camelid-derived (ie, from the Camelidae family of mammals, such as camels, llamas, and alpacas) nanobodies specific to human interleukin (IL)-17A, IL-17F, and human serum albumin. Nanobodies are a novel class of proprietary therapeutic proteins based on single-domain, camelid, heavy-chain-only antibodies. We assessed the efficacy, safety, and tolerability of sonelokimab across four dosage regimens compared with placebo in patients with plaque-type psoriasis. Secukinumab served as an active control.

Methods

This multicentre, randomised, placebo-controlled, phase 2b trial was done at 41 clinics and research sites in Bulgaria, Canada, Czech Republic, Germany, Hungary, Poland, and the USA. Participants (aged 18–75 years) with stable moderate to severe plaque-type psoriasis (defined as an Investigator's Global Assessment [IGA] score of ≥3, a body surface area involvement of ≥10%, and a Psoriasis Area and Severity Index score of ≥12) for more than 6 months before randomisation, who were candidates for systemic biological therapy were included. Participants previously treated with more than two biologics or any therapy targeting IL-17 were excluded. Randomisation was stratified by weight (≤90 kg or >90 kg) and previous use of biologics. Investigators, participants, and vendors remained masked for the duration of the study, with the exception of each site's study drug administrator (who did not complete any other assessments in the study) and a study monitor who only assessed drug preparation, administration, and accountability. The study sponsor remained masked until all week 24 data were clean and locked. Participants were randomly assigned (1:1:1:1:1:1) using a centralised interactive response technology system to one of six parallel treatment groups: placebo group, sonelokimab 30 mg group, sonelokimab 60 mg group, sonelokimab 120 mg normal load group, sonelokimab 120 mg augmented load group, or secukinumab 300 mg group. All participants underwent a 4-week screening period, a 12-week placebo-controlled induction period, a 12-week dose maintenance or escalation period, and a 24-week response assessment or dose-holding period. During the placebo-controlled induction period (weeks 0–12), participants received either placebo (at weeks 0, 1, 2, 3, 4, 6, 8, and 10), sonelokimab 30 mg, 60 mg, or 120 mg normal load (at weeks 0, 2, 4, and 8), sonelokimab 120 mg augmented load (at weeks 0, 2, 4, 6, 8, and 10), or secukinumab 300 mg (at weeks 0, 1, 2, 3, 4, and 8), with placebo given at weeks 1, 3, 6, and 10 in the sonelokimab 30 mg, 60 mg, and 120 mg normal load groups, at weeks 1 and 3 in the sonelokimab 120 mg augmented load group, and at weeks 6 and 10 in the secukinumab 300 mg group. During the dose maintenance or escalation period (weeks 12–24), participants assigned to the placebo group received sonelokimab 120 mg (at weeks 12, 14, 16, and then every 4 weeks); those assigned to sonelokimab 30 mg or 60 mg groups with an IGA score of more than 1 were escalated to 120 mg and then every 4 weeks, and those with an IGA score of 1 or less stayed on the assigned dose at week 12 and then every 4 weeks; those assigned to the sonelokimab 120 mg groups received sonelokimab 120 mg at week 12 and then every 8 weeks (normal load group) or every 4 weeks (augmented load); and those assigned to the secukinumab 300 mg group received secukinumab 300 mg at week 12 and then every 4 weeks. During this period, placebo was given at week 14 in all groups, except in participants who initially received placebo, and at week 16 in the sonelokimab 120 mg normal load group. In the response assessment with dose-holding period (weeks 24–48), participants in the sonelokimab 30 mg or 60 mg groups who had dose escalation to 120 mg remained on the same regimen regardless of the IGA score at week 24. Participants in the secukinumab 300 mg group also remained on the same regimen regardless of IGA score at week 24. Participants in the sonelokimab 30 mg and 60 mg groups without dose escalation, and all participants in the two sonelokimab 120 mg groups (including placebo rollover patients) were eligible to stop the study drug at week 24. Those participants with an IGA score of 0 at week 24 received placebo; these participants resumed the previous dose of sonelokimab every 4 weeks when they had an IGA score of 1 or more (assessed every 4 weeks). Participants in these groups with an IGA score of 1 or more at week 24 continued on the same dosage. All study treatments were administered as subcutaneous injections. The final dose in all groups was given at week 44. The primary outcome was the proportion of participants in the sonelokimab groups with an IGA of clear or almost clear (score 0 or 1) at week 12 compared with the placebo group. The primary outcome and safety outcomes were assessed on an intention-to-treat basis. The study was not powered for formal comparisons between sonelokimab and secukinumab groups. This trial is registered with ClinicalTrials.gov, NCT03384745.

Findings

Between Aug 15, 2018, and March 27, 2019, 383 patients were assessed for eligibility, 313 of whom were enrolled and randomly assigned to the placebo group (n=52), the sonelokimab 30 mg group (n=52), the sonelokimab 60 mg group (n=52), the sonelokimab 120 mg normal load group (n=53), the sonelokimab 120 mg augmented load group (n=51), or the secukinumab 300 mg group (n=53). Baseline characteristics of participants were similar among the groups. At week 12, none (0·0% [95% CI 0·0–6·8]) of the 52 participants in the placebo group had an IGA score of 0 or 1 versus 25 (48·1% [34·0–62·4], p<0·0001) of 52 participants in the sonelokimab 30 mg group, 44 (84·6% [71·9–93·1], p<0·0001) of 52 participants in the sonelokimab 60 mg group, 41 (77·4% [63·8–87·7], p<0·0001) of 53 participants in the sonelokimab 120 mg normal load group, 45 (88·2% [76·1–95·6], p<0·0001) of 51 participants in the sonelokimab 120 mg augmented load group, and 41 (77·4% [63·8–87·7], p<0·0001) of 53 participants in the secukinumab 300 mg group. During the placebo-controlled induction period, 155 (49·5%) of 313 participants had one or more mostly mild to moderate adverse event; the most frequent adverse events in all participants on sonelokimab during weeks 0–12 were nasopharyngitis (28 [13·5%] of 208 participants), pruritus (14 [6·7%] participants), and upper respiratory tract infection (nine [4·3%] participants). One patient from all sonelokimab-containing groups had Crohn's disease that developed during weeks 12–52. Over 52 weeks, sonelokimab safety was similar to secukinumab, with the possible exception of manageable Candida infections (one [1·9%] of 53 participants in the secukinumab group had a Candida infection vs 19 [17·4%] of 257 participants in all sonelokimab-containing groups).

Interpretation

Treatment with sonelokimab doses of 120 mg or less showed significant clinical benefit over placebo, with rapid onset of treatment effect, durable improvements, and an acceptable safety profile.

DOI: 10.1016/S0140-6736(21)00440-2

Source: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)00440-2/fulltext