Background

Tolebrutinib is an oral, CNS-penetrant, irreversible inhibitor of Bruton’s tyrosine kinase, an enzyme expressed in B lymphocytes and myeloid cells including microglia, which are major drivers of inflammation in multiple sclerosis. We aimed to determine the dose-response relationship between tolebrutinib and the reduction in new active brain MRI lesions in patients with relapsing multiple sclerosis.

Methods

We did a 16-week, phase 2b, randomised, double-blind, placebo-controlled, crossover, dose-finding trial at 40 centres (academic sites, specialty clinics, and general neurology centres) in ten countries in Europe and North America. Eligible participants were adults aged 18–55 years with diagnosed relapsing multiple sclerosis (either relapsing-remitting or relapsing secondary progressive multiple sclerosis), and one or more of the following criteria: at least one relapse within the previous year, at least two relapses within the previous 2 years, or at least one active gadolinium-enhancing brain lesion in the 6 months before screening. Exclusion criteria included a diagnosis of primary progressive multiple sclerosis or a diagnosis of secondary progressive multiple sclerosis without relapse. We used a two-step randomisation process to randomly assign eligible participants (1:1) to two cohorts, then further randomly assign participants in each cohort (1:1:1:1) to four tolebrutinib dose groups (5, 15, 30, and 60 mg administered once daily as an oral tablet). Cohort 1 received tolebrutinib for 12 weeks, then matched placebo (ie, identical looking tablets) for 4 weeks; cohort 2 received 4 weeks of placebo followed by 12 weeks of tolebrutinib. Participants and investigators were masked for dose and tolebrutinib-placebo administration sequence; investigators, study team members, and study participants did not have access to unmasked data. MRI scans were done at screening and every 4 weeks over 16 weeks. The primary efficacy endpoint was the number of new gadolinium-enhancing lesions detected on the scan done after 12 weeks of tolebrutinib treatment (assessed at week 12 for cohort 1 and week 16 for cohort 2), relative to the scan done 4 weeks previously, and compared with the lesions accumulated during 4 weeks of placebo run-in period in cohort 2. Efficacy data were analysed in a modified intention-to-treat population, using a two-step multiple comparison procedure with modelling analysis. Safety was assessed for all participants who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov (NCT03889639), EudraCT (2018-003927-12), and WHO (U1111-1220-0572), and has been completed.

Findings

Between May 14, 2019, and Jan 2, 2020, we enrolled and randomly assigned 130 participants to tolebrutinib: 33 to 5 mg, 32 to 15 mg, 33 to 30 mg, and 32 to 60 mg. 129 (99%) completed the treatment regimen and 126 were included in the primary analysis. At treatment week 12, there was a dose-dependent reduction in the number of new gadolinium-enhancing lesions (mean [SD] lesions per patient: placebo, 1·03 [2·50]; 5 mg, 1·39 [3·20]; 15 mg, 0·77 [1·48]; 30 mg, 0·76 [3·31]; 60 mg, 0·13 [0·43]; p=0·03). One serious adverse event was reported (one patient in the 60 mg group was admitted to hospital because of a multiple sclerosis relapse). The most common non-serious adverse event during tolebrutinib treatment was headache (in one [3%] of 33 in the 5 mg group; three [9%] of 32 in the 15 mg group; one [3%] of 33 in the 30 mg group; and four [13%] of 32 in the 60 mg group). No safety-related discontinuations or treatment-related deaths occurred.

Interpretation

12 weeks of tolebrutinib treatment led to a dose-dependent reduction in new gadolinium-enhancing lesions, the 60 mg dose being the most efficacious, and the drug was well tolerated. Reduction of acute inflammation, combined with the potential to modulate the immune response within the CNS, provides a scientific rationale to pursue phase 3 clinical trials of tolebrutinib in patients with relapsing and progressive forms of multiple sclerosis.

Funding

Sanofi.

中文翻译：

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托布替尼（一种口服脑渗透性 BTK 抑制剂）治疗复发性多发性硬化症的安全性和有效性：2b 期、随机、双盲、安慰剂对照试验

背景

Tolebrutinib 是一种口服、中枢神经系统渗透性、不可逆的布鲁顿酪氨酸激酶抑制剂，布鲁顿酪氨酸激酶是一种在 B 淋巴细胞和包括小胶质细胞在内的骨髓细胞中表达的酶，小胶质细胞是多发性硬化症炎症的主要驱动因素。我们的目的是确定托布替尼与复发性多发性硬化症患者新的活动性脑 MRI 病变减少之间的剂量反应关系。

方法

我们在欧洲和北美 10 个国家的 40 个中心（学术机构、专科诊所和普通神经病学中心）进行了为期 16 周的 2b 期、随机、双盲、安慰剂对照、交叉、剂量探索试验。符合资格的参与者是年龄在 18-55 岁、被诊断为复发性多发性硬化症（复发缓解型或复发性继发进行性多发性硬化症）的成年人，并且符合以下一个或多个标准：上一年内至少有一次复发，一年内至少有两次复发过去 2 年，或筛选前 6 个月内至少有一个活动性钆增强脑部病变。排除标准包括原发性进行性多发性硬化症的诊断或继发性进行性多发性硬化症无复发的诊断。我们使用两步随机化过程将符合条件的参与者 (1:1) 随机分配到两个队列，然后进一步将每个队列中的参与者 (1:1:1:1) 随机分配到四个托布替尼剂量组（5、15、30 ，以及每日一次 60 mg 口服片剂）。第 1 组接受托布替尼治疗 12 周，然后使用匹配的安慰剂（即外观相同的药片）治疗 4 周；第 2 组接受 4 周的安慰剂治疗，随后接受 12 周的托布替尼治疗。参与者和研究人员不知道剂量和托布替尼-安慰剂给药顺序；研究人员、研究小组成员和研究参与者无法获得未公开的数据。MRI 扫描在筛选时进行，并在 16 周内每 4 周进行一次。主要疗效终点是托布替尼治疗 12 周后扫描中检测到的新钆增强病灶数量（队列 1 在第 12 周评估，队列 2 在第 16 周评估），相对于 4 周前进行的扫描，以及与队列 2 中 4 周安慰剂磨合期累积的病变进行比较。使用两步多重比较程序和模型分析，在改良的意向治疗人群中分析疗效数据。对接受至少一剂研究药物的所有参与者进行安全性评估。该试验已在 ClinicalTrials.gov (NCT03889639)、EudraCT (2018-003927-12) 和 WHO (U1111-1220-0572) 注册，并已完成。

发现

2019年5月14日至2020年1月2日期间，我们招募了130名参与者并随机分配至托布替尼：33至5毫克、32至15毫克、33至30毫克和32至60毫克。129 例 (99%) 完成了治疗方案，126 例被纳入主要分析。在治疗第 12 周，新的钆增强病灶数量呈剂量依赖性减少（每位患者的平均 [SD] 病灶：安慰剂，1·03 [2·50]；5 mg，1·39 [3· 20]；15 mg，0·77 [1·48]；30 mg，0·76 [3·31]；60 mg，0·13 [0·43]；p=0·03）。报告了一项严重不良事件（60 mg 组中的一名患者因多发性硬化症复发而入院）。托布替尼治疗期间最常见的非严重不良事件是头痛（5 mg 组中 33 例中 1 例 [3%]；15 mg 组 32 例中 3 例 [9%]；15 mg 组 33 例中 1 例 [3%]。 30 mg 组；60 mg 组 32 人中有 4 人 [13%]。没有发生与安全相关的停药或与治疗相关的死亡。

解释

12周的托布替尼治疗导致新的钆增强病变呈剂量依赖性减少，60毫克剂量最有效，并且该药物耐受性良好。急性炎症的减少，加上调节中枢神经系统内免疫反应的潜力，为托布替尼在复发和进展型多发性硬化症患者中进行 3 期临床试验提供了科学依据。

资金

赛诺菲。