Merck takes evobrutinib for MS into phase 3, on mixed data
First drug in class to reach this stage for the illness
Merck KGaA is putting its BTK inhibitor evobrutinib to the test in two phase 3 multiple sclerosis (MS) trials, the first drug in the class to reach that stage for the neurodegenerative illness.
The decision comes despite debate about the efficacy of the drug in its main phase 2 trial, which was published in the New England Journal of Medicine during the summer.
The new trials – dubbed EVOLUTION RMS 1 and 2 – will compare twice-daily oral doses of evobrutinib with interferon-beta injections given once a week in patients with relapsing MS, with the primary endpoint being annualised relapse rate after 96 weeks.
If successful, Merck will have a chance to bring forward a new-mechanism therapy for relapsing MS that will compete with blockbuster oral drugs such as Biogen’s Tecfidera (dimethyl fumarate), Novartis’ Gilenya (fingolimod) and Sanofi’s Aubagio (teriflunomide).
It will also have to contend with newer drugs like Roche’s fast-growing injectable Ocrevus (ocrelizumab), Novartis’ Mayzent (siponimod) and potentially Biogen’s Tecfidera follow-up diroximel fumarate (BIIB098).
“Evobrutinib is a potential innovation for people living with MS, as it may offer a novel dual mechanism of action that is thought to impact myeloid cells in addition to B-cells and thus could address MS pathobiology in a fundamentally new way,“ said Merck’s head of R&D Luciano Rossetti.
Merck says evobrutinib met its primary objective in the earlier phase 2 trial, which compared the drug against placebo and revealed a reduction in the total cumulative number of MS lesions at 12, 24 and 48 weeks.
The trial tested three doses of the drug – 25mg and 75mg once daily and 75mg twice-daily – and when Merck first presented the data a year ago it said both 75mg doses had a significant impact on lesions.
However, when the data was published in NEJM, the investigators incorporated adjusted p values for significance that meant that only the middle 75mg once-daily dose had a significant reduction at 12 to 24 weeks.
They concluded “there was no significant difference with placebo for either the 25mg once-daily or 75mg twice-daily dose of evobrutinib, nor in the annualised relapse rate or disability progression at any dose.”
They also flagged a rise in liver enzymes that could bring evobrutinib’s risk:benefit into question if it is also observed in phase 3, and particularly if efficacy turns out to be lower than hoped. Merck says however that the liver enzyme increases reversed after treatment was stopped and had no clinical consequences on patients.
The company is planning to recruit around 1,900 patients into its new trials, with results due in June 2023.
The principal investigator in the EVOLUTION RMS 2 trial – Xavier Montalban of the University of Toronto and St. Michael’s Hospital in Canada and Vall d'Hebron University Hospital in Spain – said there is still a pressing need for drugs with new mechanisms.
“Even with the most effective therapies for RMS, more than 50% of patients experience clinical or subclinical disease activity,” he said.
“Therefore a need still exists for novel oral therapies that address MS pathobiology differently.”
Merck KGaA 正在对其 BTK 抑制剂 evobrutinib 进行两项 3 期多发性硬化症 (MS) 试验，这是同类药物中第一个达到治疗神经退行性疾病阶段的药物。尽管在夏季发表于新英格兰医学杂志的 2 期临床试验中对该药的疗效存在争议，但还是做出了这个决定。新的试验被称为 EVOLUTION RMS 1 和 2，将比较 evobrutinib 每日 2 次口服给药与每周 1 次注射干扰素-β 治疗复发性 MS 患者的疗效，主要终点是 96 周后的年复发率。如果成功，默沙东将有机会提出一种针对复发型 MS 的新机制疗法，与百健的 Tecfidera（富马酸二甲酯）、诺华的 Gilenya（芬戈莫德）和赛诺菲的 Aubagio（特立氟胺）等重磅口服药物展开竞争。它还将不得不与更新的药物竞争，如罗氏的快速增长的可注射 Ocrevus (ocrelizumab)，诺华的 Mayzent (siponimod) 和潜在的 Biogen 的 Tecfidera 后续的富马酸迪罗克米 (BIIB098)。默克研发负责人 Luciano Rossetti 说：“Evobrutinib 对多发性硬化症患者是一个潜在的创新，因为它可能提供一种新的双重作用机制，被认为除了影响 B 细胞外，还影响髓样细胞，因此可以以一种全新的方式解决多发性硬化症的病理生物学问题。”默克公司说，evobrutinib 在早期的 2 期临床试验中达到了它的主要目的，在 12 周、24 周和 48 周时，evobrutinib 与安慰剂进行了比较，结果显示多发性硬化的累积总数减少。该试验测试了三种剂量的药物——25 mg 和 75 mg 每日一次和 75 mg 每日两次——当默克公司一年前首次提交数据时，它说两种 75 mg 剂量对病变有显著影响。然而，当数据发表在 NEJM 上时，研究人员合并了显著性的 p 值，这意味着只有中间的 75 mg 每日一次剂量在 12 到 24 周显著减少。他们得出结论：“evobrutinib 25 mg 每日一次或 75 mg 每日两次与安慰剂相比无显著差异，任何剂量的年复发率或残疾进展也无显著差异。如果在 iii 期试验中也观察到，特别是如果疗效低于预期，他们还认为肝酶升高可能带来 evobrutinib 的风险：获益存在疑问。然而，默克表示，肝酶升高在治疗停止后逆转，对患者无临床后果。该公司计划招募大约 1900 名患者进入新的试验，结果将于 2023 年 6 月公布。EVOLUTION RMS 2 试验的主要研究者 – 多伦多大学的 Xavier Montalban 和 St.加拿大 Michael 医院和西班牙 Vall d’Hebron 大学医院 – 表示，目前仍迫切需要具有新机制的药物。他说：“即使使用最有效的 RMS 疗法，也有超过 50% 的患者经历临床或亚临床疾病活动。”因此，仍然需要针对 MS 病理生物学不同的新型口服治疗。”
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