预约演示
更新于：2026-10-24
Evobrutinib
埃沃布鲁替尼
更新于：2026-10-24
概要
基本信息
原研机构 |
在研机构- |
权益机构- |
最高研发阶段终止临床3期 |
首次获批日期- |
最高研发阶段(中国)- |
特殊审评- |
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结构/序列
分子式C25H27N5O2 |
InChIKeyQUIWHXQETADMGN-UHFFFAOYSA-N |
CAS号1415823-73-2 |
关联
24
项与 埃沃布鲁替尼 相关的临床试验NCT07214935
A Single-Dose, Randomized, Double-Blind, Placebo- and Positive-Controlled, 4-Way Crossover Study to Evaluate the Effect of Evobrutinib on the QTc (Corrected QT) Interval in Healthy Adult Participants
The purpose of this study is to assess potential effects of M2951 on cardiac repolarization (i.e. prolongation of QT interval).
开始日期2022-11-08 |
申办/合作机构 |
NCT07215806
A Phase I, Open-Label, Multiple-Dose Study of the Effect of Evobrutinib on the Pharmacokinetics of a Combined Oral Contraceptive in Healthy Female Participants
The purpose of this study was to assess the effect of M2951 on the pharmacokinetics (PK) of a combined oral contraceptive [Ethinyl estradiol/Norethisterone (EE/NET)] in healthy female participants.
* Study Duration: up to 46 days
* Treatment Duration: Days 4 to 17 (14 days treatment with M2951); Days 1 and 15 (2 days treatment with Combined Oral Contraceptive [COC])
* Visit Frequency: Participants were resident in the Clinical Research Unit from Day -1 to Day 18.
* Study Duration: up to 46 days
* Treatment Duration: Days 4 to 17 (14 days treatment with M2951); Days 1 and 15 (2 days treatment with Combined Oral Contraceptive [COC])
* Visit Frequency: Participants were resident in the Clinical Research Unit from Day -1 to Day 18.
开始日期2022-08-24 |
申办/合作机构 |
NCT05245396
A Phase I, Single-site, Open-label, Partially Randomized Study to Evaluate the Relative Bioavailability and Pharmacokinetics of Evobrutinib Following Administration of Different Formulations in Healthy Participants
The purpose of this study is to evaluate the pharmacokinetic (PK), pharmacodynamic (PD), and safety and tolerability of evobrutinib after oral administration of immediate release (IR) and modified release (MR) formulations in healthy participants.
开始日期2022-02-02 |
申办/合作机构 |
100 项与 埃沃布鲁替尼 相关的临床结果
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100 项与 埃沃布鲁替尼 相关的转化医学
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100 项与 埃沃布鲁替尼 相关的专利（医药）
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86
项与 埃沃布鲁替尼 相关的文献（医药）2026-08-01·DRUG METABOLISM AND DISPOSITION
Mechanistically resolved prediction of compound hepatotoxicity using primary human liver spheroids—Application to recent real-world cases
Article
作者: Zhou, Tingting ; Liang, Yingxin ; Shao, Siyuan ; Dressler, Julia ; Xing, Chen ; Sheng, Hongda ; Youhanna, Sonia ; Li, Yufeng ; Ryu, Jinhye ; He, Qiaojun ; Klein, Kathrin ; Nies, Anne T ; Taebnia, Nayere ; Shi, Boxu ; Petersson, Carl ; Hauser, Caroline ; Vorrink, Sabine U ; Kölz, Charlotte ; Kukasch, Miriam ; Burk, Oliver ; Jacob, Dominik ; Lauschke, Volker M
Drug-induced liver injury remains a major cause of clinical trial attrition and postmarketing drug withdrawals, reflecting persistent translational gaps in predictive preclinical models of compound hepatotoxicity. Here, we applied a well-characterized 3-dimensional primary human liver spheroid platform to interrogate diverse mechanisms of hepatotoxicity and benchmark performance against recent real-world clinical cases. After multicenter technology transfer, spheroids maintained stable hepatic functionality, including expression of metabolic enzymes and transporters, albumin secretion, and long-term CYP activity. Importantly, repeated-dose exposure to established hepatotoxins demonstrated robust, concentration-dependent toxicity with excellent interexperimental (R2 = 0.98) and interdonor (R2 = 0.89) reproducibility. To resolve toxicity mechanisms, we implemented Seahorse extracellular flux analysis in liver spheroids, which enabled sensitive detection of early mitochondrial dysfunction, allowing mechanistic discrimination between mitochondrial and nonmitochondrial toxins. Cholestatic liability was identified using bile acid coexposure with accurate classification of chlorpromazine and bosentan and confirmation of bile salt export pump downregulation. Importantly, the model also recapitulated hepatotoxicity signals observed in recent clinical development, including for Bruton's tyrosine kinase inhibitors (tolebrutinib and evobrutinib), oral glucagon-like peptide-1 receptor agonists (danuglipron vs orforglipron), synergistic toxicity on azelaprag-tirzepatide coexposure and enhanced sensitivity to the IL-17A inhibitor LY3509754 on coculture with nonparenchymal liver cells. Collectively, we present new assays for the mechanistic resolution of hepatotoxicity and provide further evidence that 3-dimensional human liver spheroids enable reproducible, mechanistically informative, and clinically aligned assessment of drug-induced liver injury across multiple modalities, which supports their application for preclinical de-risking of drug candidates. SIGNIFICANCE STATEMENT: This study shows that primary human liver spheroids provide a reproducible and mechanistically informative platform for preclinical assessments of drug metabolism and liver toxicity. The model maintains stable CYP expression and metabolic activity, captures the impact of nonparenchymal cells on hepatic clearance, and detects mitochondrial, cholestatic, and interaction-driven toxicity, including recent real-world clinical cases. These findings support 3-dimensional human liver spheroids as translational new approach methodologies for integrating metabolism and toxicity in drug development.
2026-06-01·Neurology-Clinical Practice
Uncoupling Relapse Reduction and Disability Progression
Article
作者: Sormani, Maria Pia ; Ponzano, Marta ; Montobbio, Noemi ; Bovis, Francesca ; Krenn, Alessandra ; Signori, Alessio ; Schiavetti, Irene
OBJECTIVES:
The aim of this study was to evaluate whether the treatment effects of tolebrutinib on confirmed disability worsening (CDW) diverge from its effects on relapse prevention compared with other disease-modifying therapies (DMTs) for relapsing multiple sclerosis (MS).
METHODS:
We extracted published effect estimates for annualized relapse rate (ARR) and CDW confirmed at 24 weeks from all phase 3 trials with teriflunomide as the active comparator: ASCLEPIOS (ofatumumab), OPTIMUM (ponesimod), ULTIMATE (ublituximab), EVOLUTION (evobrutinib), and GEMINI (tolebrutinib). When duplicate trials were available, pooled estimates were derived. Log-transformed estimates were used in a weighted linear regression of CDW vs ARR, with bubble size reflecting statistical precision. Tolebrutinib was excluded from the regression fit but displayed for comparison.
RESULTS:
Across 4 DMTs other than tolebrutinib, a strong linear association was observed between treatment effects on ARR and CDW (R2 = 0.997), indicating that disability benefit was generally proportional to relapse reduction. By contrast, tolebrutinib deviated from this relationship, with a hazard ratio for CDW of 0.71 (95% CI 0.53-0.95) despite a relapse rate ratio of 1.03 (95% CI 0.85-1.25).
DISCUSSION:
Tolebrutinib was the only therapy to show a benefit on CDW without a measurable effect on relapses, highlighting a dissociation between disability worsening and relapse suppression not observed with other DMTs.
2026-01-01·Neurology-Neuroimmunology & Neuroinflammation
Bruton Tyrosine Kinase Inhibition Limits Multiple Sclerosis Disease–Driving Inflammation While Promoting Regulatory B Cells
Article
作者: Weber, Martin S. ; Häusser-Kinzel, Silke ; Saberi, Darius ; Geladaris, Anastasia ; Thode, Jacqueline ; Freier, Marie ; Dybowski, Sarah ; Ringelstein, Marius ; Nessler, Stefan ; Torke, Sebastian
BACKGROUND AND OBJECTIVES:
In multiple sclerosis (MS), a variety of immunosuppressive treatments are available. While effective, these approaches often lead to sustained impairment of essential components of the immune system, posing long-term safety concerns. Consequently, there is a growing interest in alternative therapeutic approaches that selectively limit pathogenic B-cell functions while preserving their physiologic roles. In this study, we investigated the therapeutic potential of inhibiting the enzyme Bruton tyrosine kinase (BTK), a key signaling molecule in both B-cell and myeloid cell activation.
METHODS:
The effects of the BTK inhibitor evobrutinib were evaluated in various experimental in vivo models of CNS demyelination, each representing different aspects of disease pathology as well as a naïve healthy condition. The impact on disease onset and severity was determined, and phenotypical alterations in different cell populations were assessed via flow cytometry. Furthermore, functional changes in both murine and human myeloid cells induced by BTK inhibition under specific Fc receptor-dependent stimulation were analyzed in in vitro settings using flow cytometry.
RESULTS:
In a naïve, healthy environment, evobrutinib promoted the development of regulatory B-cell properties. In various experimental models of CNS demyelination, BTK inhibition limited the differentiation of proinflammatory B cells while supporting their regulatory properties. Beyond modulating B-cell responses, BTK inhibition also attenuated the activation of myeloid cells after Fc receptor-mediated antigen uptake, a process assumed to be of importance in conditions, such as neuromyelitis optica spectrum disorder and myelin oligodendrocyte glycoprotein-antibody associated disease. In addition, BTK inhibition was shown to suppress the secretion of proinflammatory cytokines and reduce antigen presentation, further dampening pathogenic immune responses.
DISCUSSION:
These findings highlight the potential of BTK inhibition as a selective and sustainable immunomodulatory strategy for both B cells and myeloid cells in the context of chronic CNS inflammation. Despite their efficacy, broad-spectrum immunosuppressive therapies often fail to provide targeted immune modulation. By contrast, BTK inhibition promotes regulatory B-cell properties while leaving other B-cell functions intact, providing the basis for its broad use-potentially in combination with established anti-inflammatory agents.
196
项与 埃沃布鲁替尼 相关的新闻（医药）2026-10-23
Remibrutinib achieved significant and clinically meaningful reduction in relapses vs. teriflunomide, to approximately 1 relapse every 13 years, without the need for chronic B-cell depletion¹˒² MRI disease activity significantly reduced with remibrutinib vs. teriflunomide in two trials, including reductions in T2 lesion activity by 65% and 70%, and Gd+ T1 lesions by 66% across both trials¹ Over 92% of remibrutinib patients remained free from disease progression as assessed by 6-month CDP, showing clinically meaningful delay of nearly 30% vs. teriflunomide with nominal significance¹ No liver safety signal observed, including no Hy’s Law cases, consistent with proven, robust safety profile of remibrutinib in chronic spontaneous urticaria and symptomatic dermographism¹˒³-⁵ Basel, October 23, 2026 – Novartis today presented positive results from the pivotal Phase III REMODEL-1 and REMODEL-2 trials in relapsing multiple sclerosis (RMS) showing that remibrutinib, a highly selective and efficacious oral Bruton’s tyrosine kinase (BTK) inhibitor, demonstrated superior relapse control and a clinically meaningful delay in disease progression versus teriflunomide with no liver safety signal.¹˒⁶˒⁷ The study results were presented during a late-breaking session at MSToronto2026, the 10th Joint ACTRIMS-ECTRIMS Meeting, and were published simultaneously in The Lancet.¹˒⁸ “The REMODEL trial results showed that oral remibrutinib delivered a significant reduction in relapse activity while also showing a clinically meaningful effect on confirmed disability progression in people living with relapsing MS,” said Prof. Dr. Heinz Wiendl, Professor of Neurology and Chair of the Department of Neurology and Neurophysiology at the Medical Center, University of Freiburg. “As treatment goals in MS continue to evolve beyond relapse control alone, these efficacy findings, together with the favorable safety profile, suggest remibrutinib has the potential to deliver a meaningful, differentiated treatment option for people living with RMS.” Remibrutinib reduced the annualized relapse rate (ARR) versus teriflunomide (REMODEL-1: 0.073 vs. 0.112; REMODEL-2: 0.080 vs. 0.116), the primary endpoint of both trials, with statistically significant and clinically meaningful 35.2% and 31.2% relative reduction, translating to approximately one relapse every 13 years.¹ Remibrutinib achieved a clinically meaningful delay in disability progression, reducing the risk of 6-month confirmed disability progression (6mCDP) by 29.2%, with nominal significance, and a consistent positive trend of 20.5% reduction in 3-month confirmed disability progression (3mCDP).¹ More than 92% of patients receiving remibrutinib remained free from disease progression over 24 months as assessed by 6mCDP.¹ In addition to the efficacy findings, remibrutinib demonstrated no liver safety signal, including no Hy’s Law cases, which have been reported in other late-stage BTK inhibitor programs.¹˒⁹ Across both trials, patients treated with remibrutinib experienced fewer liver enzyme elevations at every threshold, including ALT >3×ULN in 2.0% of patients versus 7.4% with teriflunomide, with the remibrutinib arm rate in range with that seen in placebo groups in prior RMS trials.¹˒⁷˒⁹-¹³ In pooled analyses, treatment discontinuations due to adverse events (AEs) were nearly 50% fewer with remibrutinib than teriflunomide (3.1% vs. 5.8%).¹ Remibrutinib is a highly selective, covalent, oral BTK inhibitor that blocks the BTK pathway, reducing activation of B cells and innate immune cells to modulate immune regulatory networks and related neuroinflammation.⁶˒⁷ Designed to modulate BTK signaling without chronic B-cell depletion, remibrutinib represents a differentiated approach to immune regulation.²˒¹⁴ In preclinical studies, remibrutinib demonstrated the highest BTK selectivity among tested BTK inhibitors.¹⁵ “Novartis has a two-decade legacy developing therapies in multiple sclerosis and continues to advance innovation for people living with the disease,” said Shreeram Aradhye, President, Development, and Chief Medical Officer, Novartis. “The Phase III REMODEL results reinforce our confidence in remibrutinib and its potential to expand treatment choice for people living with RMS. By combining high efficacy with a favorable safety profile through a selective mechanism, remibrutinib has the potential to support long-term disease management without chronic B-cell depletion and to redefine what may be possible across the MS journey.” Additional efficacy findingsRemibrutinib demonstrated superiority versus teriflunomide on all key secondary endpoints within each trial, including significantly reducing disease activity in the brain, as evidenced by MRI scans.¹ Compared with teriflunomide, remibrutinib significantly reduced annualized T2 lesion activity, a marker of chronic disease burden (REMODEL-1: 0.94 vs. 2.71; REMODEL-2: 0.82 vs. 2.77), and significantly reduced the rate of Gd+ T1 lesions per scan, a marker of active inflammation (REMODEL-1: 0.08 vs. 0.24; REMODEL-2: 0.07 vs. 0.21).¹ Serum neurofilament light chain (NfL) outcomes were significantly improved by 9.0% in REMODEL-1 (11.57 vs. 12.73) and 7.0% in REMODEL-2 (12.05 vs. 13.00) versus teriflunomide.¹ In the preplanned pooled REMODEL-1/2 analysis, patients receiving remibrutinib had approximately three times higher odds of achieving overall disease control versus patients receiving teriflunomide.¹ A nominally significant difference in NEDA-3 was observed, with 55.0% of patients receiving remibrutinib achieving no evidence of disease activity across three domains: relapses, disability progression and MRI activity, versus 32.1% of patients receiving teriflunomide.¹ Additional safety findingsThe safety profile of remibrutinib was consistent with the broader development program.¹˒³-⁵˒¹⁶ Numerically fewer patients receiving remibrutinib experienced AEs (79.5% vs. 81.5%) and serious AEs (6.0% vs. 7.0%) than those receiving teriflunomide.¹ Two deaths occurred in the remibrutinib group and were both assessed by investigators as unrelated to study treatment: one accidental carbon monoxide poisoning, for which suicide was ruled out, and one completed suicide.¹ Novartis plans to seek regulatory approval for remibrutinib in RMS globally. About multiple sclerosisMultiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system characterized by myelin destruction and axonal damage in the brain, optic nerves and spinal cord.¹⁷ MS, which affects nearly 3 million people worldwide, can be characterized into three main types: non-active secondary progressive (SPMS), primary progressive (PPMS), and relapsing MS (RMS).¹⁸˒¹⁹ RMS is the most common form and includes clinically isolated syndrome (CIS), relapsing-remitting (RRMS), and active SPMS.¹⁹ The various forms of MS are distinguished by how the disease presents and progresses, including whether patients experience relapses, worsening disability over time, or a combination of both.²⁰ About remibrutinibDiscovered at Novartis, remibrutinib is being investigated in the Phase III REMODEL trials in relapsing multiple sclerosis (RMS) and Phase III REMASTER trial in secondary progressive MS (SPMS). ²¹-²³ Remibrutinib is also being studied in other immune-mediated conditions, such as hidradenitis suppurativa and food allergy.²⁴˒²⁵ Remibrutinib 25 mg was approved for the treatment of adults with chronic spontaneous urticaria (CSU) under the brand name Rhapsido® by the FDA in September 2025 and by the European Medicines Agency in April 2026. ²⁶˒²⁷ In October 2026, Rhapsido received FDA approval as the first treatment for adults with symptomatic dermographism (SD), the most common form of chronic inducible urticaria.⁵ About the REMODEL trialsREMODEL-1/-2 are identical multicenter, randomized, double-blind, active comparator-controlled Phase III studies evaluating the efficacy and safety of remibrutinib compared to teriflunomide for adult patients with relapsing multiple sclerosis (RMS). Approximately 2,000 patients globally with evidence of recent disease activity and an Expanded Disability Status Scale (EDSS) of 0.0–5.5 were randomized 1:1 to receive remibrutinib 100 mg or teriflunomide. The studies consist of an initial double-blind Core Part with a flexible duration of up to a maximum of 30 months, followed by an open-label extension for up to 5 years. The primary endpoint is annualized relapse rate (ARR). Key secondary endpoints include 3- and 6-month confirmed disability progression, the number of new/enlarging T2 lesions per year, the number of Gd+ T1 lesions per scan, serum neurofilament light chain (sNfL) concentration, and the percentage of participants with no evidence of disease activity (NEDA-3).²¹˒²²˒²⁸ About Novartis in NeuroscienceNeurological diseases are deeply personal, affecting people of any age, from newborns to seniors, often striking in the prime of life. In multiple sclerosis (MS), Novartis has helped shape the treatment landscape for decades through scientific innovation and leadership in advancing care for people living with MS. We remain focused on addressing unmet needs and pursuing new approaches that may improve outcomes for people across the MS journey. Building on this foundation, we are doubling down on our commitment to neurology, expanding our legacy of innovation in MS and spinal muscular atrophy (SMA) to work in neuroimmunology, neurodegeneration, and neuromuscular diseases. Our goal is to protect people’s health across their lifespan, developing more treatment options that lead to better outcomes. Disclaimer This press release contains forward-looking statements within the meaning of the United States Private Securities Litigation Reform Act of 1995. Forward-looking statements can generally be identified by words such as “potential,” “can,” “will,” “plan,” “may,” “could,” “would,” “expect,” “anticipate,” “look forward,” or similar expressions, or by express or implied discussions regarding: potential new products; potential new indications for existing products; potential product launches or potential future revenues from any such products; results of ongoing clinical trials; or potential future, pending or announced transactions; potential future sales or earnings; strategy, plans, expectations or intentions, including discussions regarding our continued investment into new R&D capabilities and manufacturing; or our capital structure. You should not place undue reliance on these statements. Such forward-looking statements are based on the current beliefs and expectations of management regarding future events, and are subject to significant known and unknown risks and uncertainties. Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual results may vary materially from those set forth in the forward-looking statements. There can be no guarantee that the investigational or approved products described in this press release will be submitted or approved for sale or for any additional indications or labeling in any market, or at any particular time. Nor can there be any guarantee that such products will be commercially successful in the future. In particular, our expectations could be affected by, among other things, uncertainties concerning: global healthcare cost containment, including ongoing government, payer and general public pricing and reimbursement pressures and requirements for increased pricing transparency; the success of our key products, commercial priorities and strategy; research and development of new products, including clinical trial results and additional analysis of existing clinical data; our ability to obtain or maintain proprietary intellectual property protection, including the ultimate extent of the impact on Novartis of the loss of patent protection and exclusivity on key products; our ability to realize the strategic benefits, operational efficiencies or opportunities expected from our external business opportunities; the development or adoption of new technologies, including artificial intelligence, and new business models; potential significant breaches of information security or disruptions of our information technology systems; actual or potential legal proceedings, including regulatory actions or delays or government regulation related to the products and pipeline products described in this press release; safety, quality, data integrity, or manufacturing issues; major macroeconomic and geo- and socio-political developments, including the impact of any potential tariffs on our products or the impact of war in certain parts of the world; future global exchange rates; future demand for our products; and other risks and factors referred to in Novartis AG’s most recently filed Form 20-F and in subsequent reports filed with, or furnished to, the US Securities and Exchange Commission. Novartis is providing the information in this press release as of this date and does not undertake any obligation to update any forward-looking statements as a result of new information, future events or otherwise. About NovartisNovartis is an innovative medicines company. Every day, we work to reimagine medicine to improve and extend people’s lives so that patients, healthcare professionals and societies are empowered in the face of serious disease. Our medicines reach more than 300 million people worldwide. Reimagine medicine with us: Visit us at www.novartis.com and connect with us on LinkedIn, Facebook, X/Twitter and Instagram. References Comprehensive disease control defined by Phase 3 REMODEL-1/-2 efficacy results presented at MSToronto2026 and Novartis data on file ¹Wiendl, H et al. Efficacy and safety of remibrutinib vs. teriflunomide in relapsing multiple sclerosis: results of the Phase 3 REMODEL-1/-2 trials. Presentation at: MSToronto 2026 Medical Congress; October 23, 2026; Toronto, Ontario, Canada. ²Nuesslein-Hildesheim B, Ferrero E, Schmid C, et al. Remibrutinib (LOU064) inhibits neuroinflammation driven by B cells and myeloid cells in preclinical models of multiple sclerosis. J Neuroinflammation. 2023;20(1):194. Published 2023 Aug 26. doi:10.1186/s12974-023-02877-9³Metz M, Giménez-Arnau AM, Hide M, et al. Remibrutinib in chronic spontaneous urticaria. N Engl J Med. 2025;392(10):984-994. doi:10.1056/NEJMoa2408792 ⁴Giménez-Arnau AM, Szalewski R, Hide M, et al. Remibrutinib in chronic spontaneous urticaria: 52-week results from two phase 3 studies. J Allergy Clin Immunol. 2026;157(1):143-154. doi:10.1016/j.jaci.2025.09.028 ⁵Novartis. Novartis Rhapsido® (remibrutinib) receives FDA approval as first treatment for symptomatic dermographism (SD), expanding its use beyond chronic spontaneous urticaria (CSU). News release. Novartis. October 7, 2026. Available from: https://www.novartis.com/news/media-releases/novartis-rhapsido-remibrutinib-receives-fda-approval-first-treatment-symptomatic-dermographism-sd-expanding-its-use-beyond-chronic-spontaneous-urticaria-csu Last accessed: October 19, 2026⁶ Angst D, Gessier F, Janser P, et al. Discovery of LOU064 (Remibrutinib), a Potent and Highly Selective Covalent Inhibitor of Bruton's Tyrosine Kinase. J Med Chem. 2020;63(10):5102-5118. doi:10.1021/acs.jmedchem.9b01916 ⁷Kaul M, End P, Cabanski M, et al. Remibrutinib (LOU064): A selective potent oral BTK inhibitor with promising clinical safety and pharmacodynamics in a randomized phase I trial. Clin Transl Sci. 2021;14(5):1756-1768. doi:10.1111/cts.13005 ⁸Wiendl H, Bermel R, Airas L, et al. Remibrutinib versus teriflunomide in relapsing multiple sclerosis (REMODEL-1 and REMODEL-2): two randomised, phase 3 trials. Lancet 2026; published online Oct 23 ⁹Lambe J, Fox RJ. Bruton's Tyrosine Kinase Inhibitors in Multiple Sclerosis. Drugs. 2026 Jul;86(7):989-1012. doi: 10.1007/s40265-026-02324-y. Epub 2026 May 13. PMID: 42126690; PMCID: PMC13290806¹⁰Polman CH, O'Connor PW, Havrdova E, et al. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med. 2006;354(9):899-910. doi:10.1056/NEJMoa044397¹¹Maxwell CR, Turner TJ, Wallstroem E, et al. Tolebrutinib liver safety: A detailed overview. Mult Scler Relat Disord. 2026;113:107404. doi:10.1016/j.msard.2026.107404¹²O'Connor P, Wolinsky JS, Confavreux C, et al. Randomized trial of oral teriflunomide for relapsing multiple sclerosis. N Engl J Med. 2011;365(14):1293-1303. doi:10.1056/NEJMoa1014656¹³Arnold DL, Elliott C, Martin EC, Hyvert Y, Tomic D, Montalban X. Effect of Evobrutinib on Slowly Expanding Lesion Volume in Relapsing Multiple Sclerosis: A Post Hoc Analysis of a Phase 2 Trial. Neurology. 2024;102(5):e208058. doi:10.1212/WNL.0000000000208058¹⁴Jain RW, Rayatpour A, Hagen K, et al. Investigations of remibrutinib in models pertinent to multiple sclerosis. Neurotherapeutics. 2026;23(3):e00923. doi:10.1016/j.neurot.2026.e00923 ¹⁵Pulz R, Angst D, Cenni B. Next generation Bruton's tyrosine kinase inhibitors - characterization of in vitro potency and selectivity. Eur J Pharmacol. 2025;1002:177747. doi:10.1016/j.ejphar.2025.177747¹⁶Novartis. Novartis remibrutinib first therapy to achieve Phase III primary endpoint in chronic inducible urticaria (CIndU). Novartis US. Published February 18, 2026. Available from: https://www.novartis.com/us-en/news/media-releases/novartis-remibrutinib-first-therapy-achieve-phase-iii-primary-endpoint-chronic-inducible-urticaria-cindu Last accessed: October 19, 2026¹⁷Ferreira HB, Neves B, Guerra IM, Moreira A, Melo T, Paiva A, Domingues MR. An overview of lipidomic analysis in different human matrices of multiple sclerosis. Mult Scler Relat Disord. 2020;44:102189. doi:10.1016/j.msard.2020.102189 ¹⁸Portaccio E, Magyari M, Kubala Havrdova E, et al. Multiple sclerosis: emerging epidemiological trends and redefining the clinical course. Lancet Reg. Health Eur. 2024;44:100977 ¹⁹National Multiple Sclerosis Society. Types of MS. Available from: https://www.nationalmssociety.org/What-is-MS/Types-of-MS Last accessed: October 19, 2026²⁰Lublin FD, Reingold SC, Cohen JA, et al. Defining the clinical course of multiple sclerosis: the 2013 revisions. Neurology. 2014;83(3):278-286. doi:10.1212/WNL.0000000000000560 ²¹ClinicalTrials.gov. NCT05147220. Efficacy and safety of remibrutinib compared to teriflunomide in participants with relapsing multiple sclerosis (RMS) (REMODEL-1). Available from: https://clinicaltrials.gov/study/NCT05147220 Last accessed: October 19, 2026 ²²ClinicalTrials.gov. NCT05156281. Efficacy and safety of remibrutinib compared to teriflunomide in participants with relapsing multiple sclerosis (RMS) (REMODEL-2). Available from: https://clinicaltrials.gov/study/NCT05156281 Last accessed: October 19, 2026 ²³ClinicalTrials.gov. NCT07225504. A study to evaluate the efficacy and safety of remibrutinib in secondary progressive multiple sclerosis (REMASTER). Available from: https://clinicaltrials.gov/study/NCT07225504 Last accessed: October 19, 2026 ²⁴ClinicalTrials.gov. NCT03827798. Study of efficacy and safety of investigational treatments in patients with moderate to severe hidradenitis suppurativa. Available from: https://clinicaltrials.gov/ct2/show/NCT03827798. Last accessed: October 19, 2026 ²⁵ClinicalTrials.gov. NCT05432388. Study of efficacy, safety and tolerability of remibrutinib in adult participants with an allergy to peanuts. Available from: https://clinicaltrials.gov/study/NCT05432388 Last accessed: October 19, 2026²⁶Novartis. Novartis receives FDA approval for Rhapsido® (remibrutinib), the only oral, targeted BTKi treatment for chronic spontaneous urticaria (CSU). News release. Novartis. September 30, 2025. Available from: https://www.novartis.com/news/media-releases/novartis-receives-fda-approval-rhapsido-remibrutinib-only-oral-targeted-btki-treatment-chronic-spontaneous-urticaria-csu Last accessed: October 19, 2026 ²⁷Novartis. Novartis Rhapsido® receives European Commission approval as first oral targeted treatment for chronic spontaneous urticaria. News release. Novartis. April 27, 2026. Available from: https://www.novartis.com/news/media-releases/novartis-rhapsido-receives-european-commission-approval-first-oral-targeted-treatment-chronic-spontaneous-urticaria Last accessed: October 19, 2026 ²⁸Wiendl H, Airas L, Chitnis T, et al. Phase 3 REMODEL I/II Trials: Efficacy, Safety, and Tolerability of Remibrutinib in Patients with Relapsing Multiple Sclerosis. Mult Scler Relat Disord. 2023;80:105315. doi:10.1016/j.msard.2023.105315 Novartis Media RelationsE-mail: media.relations@novartis.com Novartis Investor RelationsCentral investor relations line: +41 61 324 7944E-mail: investor.relations@novartis.com
临床结果临床3期上市批准
2026-10-21
多发性硬化：口服 BTK 抑制剂缩小慢性活动病灶 30%，复发率降 55%
对患者来说，这次读出最先落到两个数上：复发型研究里年化复发率降 55%，缓慢扩大病灶体积最多缩
30%[4]。同一批数据里，原发进展型那一支只拿到非劣于
Ocrevus，fenebrutinib
的安全性数据这次会上没给[4][9]。亮的和没说的，得一起读。
一、复发型多发性硬化的三期汇总
两项研究怎么搭的
FENhance 1 与 FENhance 2 是两项设计相同的三期研究，登记号 NCT04586010 与
NCT04586023，入组复发型多发性硬化（RMS）成年患者，各入组 746 例与 751
例[1][2]。两项合计
1,497 例，1:1 随机，口服 fenebrutinib 每日两次，对照口服特立氟胺每日一次，双盲、双模拟，至少用药 96
周[3]。FENhance
2 的主要完成时间为 2025 年 9 月，FENhance 1 为 2026 年 1
月[1][2]。
两项研究的主要终点都设为年化复发率。罗氏此前给出的口径是，等 FENhance 1
读出后，两项研究的数据合并起来一并考虑提交监管机构[3]。
四个终点的读数
汇总数据里，fenebrutinib 组 96 周的年化复发率较活性对照降低
55%（p＜0.001）[4]。分项看，FENhance
1 单独读出时降幅 51%，FENhance 2 是 59%，两项汇总落在
55%[5]。到了近两年这个时点，fenebrutinib
组有四分之三的患者达到 NEDA-3，即无疾病活动证据；这是较对照降低
70%（p＜0.001）的相对口径[4]。对照组自己达成多少，通稿没给。复发是这两项研究的主要终点，读出量级最大，也在预期之内。
再往下读，强度开始分化。年化脑体积丢失减少
23%（p＜0.001）[4]。12
周复合确认残疾进展减少 16%，p 值
0.04，刚过常用阈值的线[4]。说实话，这是四项里统计最弱的一项。残疾进展一向最难推动。我倾向于把
16% 读作信号，不是定论。我拿不准它在监管审评里能撑多重。复发、影像、残疾，本就是三层证据，不宜等量齐观。
对照药到底是谁
读这类汇总数据，先要确认参照系是谁。Genentech
的新闻稿通篇只写活性对照，没有点名[4]。把登记信息摊开，FENhance
1 与 FENhance 2 的对照栏里写的都是
特立氟胺[1][2]。罗氏
2025 年 11 月公布 FENhance 2
达到主要终点时的说法，同样是较特立氟胺显著降低年化复发率[3]。对照药为口服特立氟胺，每日一次[3]。
另一项研究要分开看。FENtrepid（NCT04544449）入组 985 例原发进展型 MS 患者，对照药为 ocrelizumab，主要终点是复合 12
周确认残疾进展的发生时间，治疗至少 120
周[6][3]。名字都以
FEN 开头，容易被当成一组。疾病亚型、对照药、主要终点，三项都不同。55% 出自 RMS
两项研究的汇总，比较对象是特立氟胺组[4]。
二、慢性活动病灶首次被药物撼动
慢性活动病灶是什么
多发性硬化里有一类病灶，不跟着复发走。它由早期急性炎症病灶演变而来，在 MRI
上不强化，却持续脱髓鞘、持续丢失轴突，被称为慢性活动病灶，也叫阴燃病灶[7]。它们有两个影像亚型。缓慢扩大病灶（SEL）在纵向
T1、T2
序列上不强化、随时间慢慢变大。顺磁性边缘病灶（PRL）是敏感性加权序列上病灶边缘的一圈顺磁性信号，对应一圈含铁的活化小胶质细胞与巨噬细胞[8]。
它们被盯上的理由是同一个：这类病灶被认为是长期残疾进展的主要驱动之一，其数量与程度同残疾程度和认知损害及其随时间恶化显著相关[8]。2026
年发表的一项系统综述与荟萃分析汇总 20 项研究、共 4,970 例患者，得出多发性硬化患者中缓慢扩大病灶的合并患病率为
57.1%（95%CI：44.9%～69.3%）[7]。这个数不低。能在活体影像上把它认出来，才谈得上拿它当治疗终点。
这次的两个读数
读数分两条，别混着念。第一条是缓慢扩大病灶的体积：fenebrutinib 在复发型（96 周）和原发进展型（120 周）中，让 SEL 体积最多减少
30%（p＜0.001）[4]。「最多」两个字不能丢，它是区间的上限，不是平均降幅。这次读数横跨两项研究：复发型那一支用的是
FENhance 1 和 2，原发进展型那一支对应的是 FENtrepid——唯一一项疗程 120 周的原发进展型研究，对照 Ocrevus、登记 985
例[6]。
第二条读数容易被念错。62% 挂在 PRL
上，量的是边缘病灶的累积，不是已有病灶的体积。一个看体积，一个看累积。新闻稿里，这两个指标也是分开写的[4]。
为什么前瞻设计是一条分界线
「首次」这个词的口径要抠准。原文说的是三期临床中首次在前瞻设计下证实对慢性活动病灶存在治疗作用，不是说首次发现这种病灶，更不是说头一个能治 MS
的药[4]。前瞻的意思，是影像终点在研究开始前就写进方案，按预定时间点采集、按预定方法分析。此前已有干预研究显示，疾病修正治疗后缓慢扩大病灶的数量与体积会下降[7]。但那类证据规模有限，综述作者自己也写明结论仍需进一步验证[7]。
我倾向于把它看成方法学上的一条分界线，疗效大小还得再等。FENhance 1 和 2 合计 1,497 例复发型患者，1:1
随机、双盲双模拟，对照特立氟胺，疗程至少 96 周；FENtrepid 985 例，对照 Ocrevus，疗程至少 120
周[3][6]。样本量与主要终点事先登记过[6]。我拿不准的是另一步：SEL
体积变小，能不能换算成患者几年后的功能结局。影像终点替临床终点，这一步还没走完。
三、原发进展型：非劣终点与肝酶信号
拿 Ocrevus 当对照
FENtrepid 是一项多中心、随机、双盲、双模拟、平行组三期研究，纳入 985 例原发进展型多发性硬化（PPMS）成人患者，fenebrutinib
每日 2 次或每日 1 次，对照 Ocrevus
与安慰剂[9]。研究
2020 年 10 月启动，主要完成日期落在 2025 年 9
月[6]。主要终点不是复发，而是到首次复合 12
周确认残疾进展的时间[6]。
cCDP12 由三部分拼成：EDSS、定时 25
英尺步行（T25FW）、九孔柱测试（9HPT）[9]。持续
12 周确认恶化，才算一次事件。原发进展型没有复发可以数，残疾进展几乎是唯一能站住的硬终点，所以每个分量都很沉。研究要求治疗至少 120 周，比 RMS
那两项的 96
周更长[3][9]。进展本来就慢，观察窗短了看不出分离。这一步设计得老实。
一条跨过 1 的区间
先看那条区间：HR 0.88，95%CI
0.75～1.03[3][9]。上限
1.03 跨过了 1。优效谈不上，这一步只拿到非劣。
换成风险降低的说法是 12%，曲线最早第 24
周分离，数值获益持续整个观察期[3][9]。还有一组数字来自事后分析：把
EDSS 与 9HPT 单独拼成复合终点，风险降低 22%（HR 0.78；95%CI
0.64～0.95）[9]。事后分析是看完数据才切的终点。能提示方向，不能当确证。能落地的结论只有一句：fenebrutinib
在这项研究里非劣于
Ocrevus[3][9]。
肝酶这道旧伤
先说时点：这组数字不是这次会上公布的，本次通稿没有 fenebrutinib
安全性内容[4]。肝酶升高
13.3%，对照组
2.9%[9]。短暂可逆，停药后痊愈，未见潜在严重肝损伤[9]。其余乍看平缓：感染
67.0% 对 70.9%，恶心 12.0% 对 7.1%，严重不良事件 19.1% 对
18.9%[9]。死亡
1.4% 对
0.2%，研究者判定与药无关[9]。复发型那两项另有一组数字：特立氟胺组
1 例死亡，fenebrutinib 组 8
例，原因与时点各异，罗氏称分析在进行中[5]。
这个信号并不新鲜。德国默克 evobrutinib 在 MS 二期临床里，转氨酶升高比例达
26%[10]。2022
年 6 月，FDA 以药物性肝损伤为由，搁置赛诺菲 tolebrutinib 在 MS
与重症肌无力的三期研究[11][12]。停药后指标可逆[11]。后续是
2026 年 6 月欧洲批准 tolebrutinib
用于过去两年无复发的继发进展型多发性硬化，说明书将药物性肝损伤列为已识别风险、需严格监测[13]。罗氏称肝脏安全性与此前一致[3]。监测会是长期作业。
四、中国多发性硬化的可及性现实
三万患者与约 18% 的疾病修正治疗率
根据国家医保局公开的一份药品申报材料，多发性硬化属于中国第一批罕见病病种，患病率约 2.44/100,000，总患病人数约 3
万人，而接受疾病修正治疗的比例仅约
18%[14]。同一批材料还记录，患者中约
70% 为女性，超过 60%
处于育龄期[14]。三万这个数放在全球
2023 年 290
万人的旁边，几乎可以忽略[15]。但对每一个被它撞上的人来说，它是全部。先记住这个分母。
治疗率低不等于没药。特立氟胺 2018 年国内上市、2019 年纳入医保，此后芬戈莫德 2019 年、西尼莫德 2020 年、奥法妥木单抗与富马酸二甲酯
2021 年、奥扎莫德 2023
年陆续落地[14]。另一份
2025 年的材料给出更近的切口：当年确诊并接受生物制剂治疗的患者约 9,000
人[16]。名字不少，真正用上的还是少数。
原发进展型的空白
更难的是分型。原发进展型在中国患者调研中占多发性硬化的
3%～4%，人数不多，疾病负担却更重[16]。2025
年的一份材料写到它时，用的是「临床无药可用」[16]。
这句话有它的年份，我不打算原样搬到今天。变化发生在同一年：奥瑞利珠单抗 2025 年 3
月在中国大陆首次上市，按申报材料口径，它是当时全球首个也是唯一同时获批原发进展型与复发型的多发性硬化药物[16]。同一份材料也说，当时医保目录内的多发性硬化药物均为复发型适应症[16]。上市只是第一步。从能买到到用得上，中间还隔着支付与落地。
口服、可穿透中枢神经系统的可逆非共价 BTK 抑制剂若成立，意味着什么
fenebrutinib 是口服、可穿透中枢神经系统的、可逆非共价 BTK 抑制剂，与多数共价不可逆的同类不同，它同时作用于 B
细胞和小胶质细胞[4]。这些特性如果都成立，指向的是一种不需要输注、能进入中枢神经系统的口服方案。我倾向于把它看作一个待验证的假设。答案还没到。说白了，现在只能谈条件。
按罗氏 2025 年 11
月的说法，等第二项复发型研究读出后，所有数据会被放在一起考虑是否提交监管[3]。这是企业层面的计划，不针对任何一个国家。至于中国什么时候申报、会不会获批、之后进不进医保，公开信息里没有答案。我拿不准这算不算乐观。若真能落地，口服剂型对长期用药的人意味着什么，是可以想象的。我们只能等。
结论
能带走的是这个：一次读出把「控制复发」和「影响隐匿进展」拆成了两个可以分别检验的命题[4]。前一半读数扎实；后一半目前只有
SEL 体积这层影像证据，能不能换算成几年后的功能结局，我拿不准。往后要盯的还是两件事：原发进展型那一支的区间，和肝酶监测。
关于 NextSeq 亦镁诺
NextSeq 亦镁诺（上海亦镁诺生物科技有限公司）专注组学数据分析与AI建模，携手美国合作伙伴 AmpSeq（实验室位于 Maryland、Boston 及
Connecticut），为科研机构与药企提供从快速测序到生信分析的端到端服务。
在分析端，我们支持定制化生信Pipeline开发，并将AI建模能力拓展至肿瘤新抗原预测、mRNA/siRNA设计等药物开发场景；在CGT领域，具备面向长期安全性评估的NGS检测与解读能力。AmpSeq美国实验室同步提供Nanopore及NGS快速测序和交付服务，以灵活方案覆盖从深度分析到快速交付的多样化需求。
如需了解，欢迎在公众号留言，或访问 nextseq.cn /
ampseq.com。
资料来源
[1] A Study to Evaluate the Efficacy and Safety of Fenebrutinib Compared With Teriflunomide in Relapsing Multiple Sclerosis（FENhance 1, NCT04586010）（2021） ｜ 试验登记：登记编号NCT04586010、适应症为复发型多发性硬化、对照药为特立氟胺、主要终点为年化复发率、目标入组746例、2021年3月17日启动而主要完成日期为2026年1月27日、当前状态为进行中且不再招募 https://clinicaltrials.gov/study/NCT04586010
[2] Study to Evaluate the Efficacy and Safety of Fenebrutinib Compared With Teriflunomide in Relapsing Multiple Sclerosis（FENhance 2, NCT04586023）（2021） ｜ 试验登记：登记编号NCT04586023、适应症为复发型多发性硬化、对照药为特立氟胺、主要终点为年化复发率、目标入组751例、2021年3月24日启动而主要完成日期为2025年9月5日、当前状态为进行中且不再招募 https://clinicaltrials.gov/study/NCT04586023
[3] Roche Media & Investor Release: Fenebrutinib Phase III study FENhance 2（2025） ｜ 企业通稿：2025年11月10日发布、FENhance 2为两项复发型多发性硬化关键研究中首先读出的一项且较特立氟胺显著降低至少96周内的年化复发率、FENtrepid研究以延迟复合确认残疾进展发生衡量在至少120周内非劣于奥瑞利珠单抗、最早第24周即见数值获益并持续整个观察期、FENhance 1与2合计1,497例成人复发型患者按1比1随机接受每日两次口服fenebrutinib或每日一次口服特立氟胺、待第二项研究FENhance 1读出后一并考虑提交监管机构、肝脏安全性与此前研究一致 https://assets.roche.com/f/176343/2e977de54e/01-media-investor-release-fenebrutinib-phase-iii-study-fenhance-2-english.pdf
[4] Genentech Presents New Pivotal Trial Data Across Broad Neuroimmunology Portfolio at MSToronto2026（2026） ｜ 企业通稿：第10届ACTRIMS-ECTRIMS联席会议于2026年10月21至23日在多伦多举行、汇总复发型多发性硬化数据显示年化复发率较活性对照降低55%（p＜0.001，96周）、无疾病活动证据NEDA-3达75%较对照降低70%、年总脑体积丧失减少23%而12周复合确认残疾进展减少16%、缓慢扩大病灶体积最多减少30%（p＜0.001，复发型96周与原发进展型120周）、复发型中顺磁性边缘病灶累积减少62%（p=0.001）、fenebrutinib为口服且可穿透中枢神经系统的可逆非共价BTK抑制剂并同时抑制B细胞与小胶质细胞 https://www.gene.com/media/press-releases/15139/2026-10-21/genentech-presents-new-pivotal-trial-data-across-broad-neuroimmunology-portfolio-at-mstoronto2026
[5] Roche's fenebrutinib confirms its potential as first and only BTK inhibitor for relapsing and primary progressive MS in third positive Phase III study (FENhance 1)（2026） ｜ 企业通稿：2026年3月2日发布、FENhance 1达到主要终点且较特立氟胺在至少96周内降低年化复发率51%、与FENhance 2单独读出的59%一致、两项复发型研究合并相当于约每17年一次复发、全部三项三期研究的完整数据将一并提交监管机构、两项复发型研究中肝脏转氨酶升高与特立氟胺相当、FENhance 1中fenebrutinib组与特立氟胺组各有1例无症状Hy's Law病例且停药后缓解、整个开发项目无其他Hy's Law病例、两项复发型研究中特立氟胺组报告1例死亡而fenebrutinib组报告8例不同原因与不同治疗时点的死亡且进一步分析在进行中、迄今逾2,700例受试者与健康志愿者接受过fenebrutinib治疗、约85%的多发性硬化患者初诊为复发缓解型而约15%为原发进展型 https://www.roche.com/media/releases/med-cor-2026-03-02
[6] A Study to Evaluate the Efficacy and Safety of Fenebrutinib Compared With Ocrelizumab in Adults With Primary Progressive Multiple Sclerosis（FENtrepid, NCT04544449）（2020） ｜ 试验登记：登记编号NCT04544449、适应症为原发进展型多发性硬化、对照药为奥瑞利珠单抗、主要终点为复合12周确认残疾进展发生时间、目标入组985例、2020年10月26日启动而主要完成日期为2025年9月17日、当前状态为进行中且不再招募 https://clinicaltrials.gov/study/NCT04544449
[7] Slowly Expanding Lesions in Multiple Sclerosis: A Systematic Review and Meta-Analysis（NeuroSci）（2026） ｜ 论文原文：2026年3月发表于NeuroSci的系统综述与荟萃分析（DOI 10.3390/neurosci7020034，PMID 41874037）、检索截至2025年5月25日并纳入20项研究共4,970例多发性硬化患者、缓慢扩大病灶被视为慢性活动性脱髓鞘与阴燃性炎症的影像学标志并被公认为残疾恶化与脑萎缩的指标、荟萃分析合并患病率为57.1%（95%CI：44.9%至69.3%）、系统综述显示缓慢扩大病灶与慢性神经炎症及持续脱髓鞘和残疾及微结构损伤与轴突变性相关、干预研究显示疾病修正治疗后病灶数量与体积下降 https://pubmed.ncbi.nlm.nih.gov/41874037/
[8] Primary Progressive Multiple Sclerosis—A Key to Understanding and Managing Disease Progression（International Journal of Molecular Sciences）（2024） ｜ 论文原文：2024年发表于国际分子科学杂志的原发进展型多发性硬化综述（PMCID PMC11354232）、缓慢扩大病灶的影像学特征为T2上持续向心性体积扩大且同时T1加权序列信号减低并在连续2至3次MRI检查中显现、顺磁性边缘病灶的典型表现为环绕至少75%病灶的铁负载小胶质细胞与巨噬细胞层并伴脱髓鞘与轴索断裂而可在相位成像与SWI或多梯度回波序列显示、两者数量与程度与残疾程度和认知损害及其随时间恶化呈显著相关 https://pmc.ncbi.nlm.nih.gov/articles/PMC11354232/
[9] 十多年来首个！罗氏公布BTK抑制剂对比奥瑞利珠单抗III期研究数据（2026） ｜ 行业快讯：2026年2月8日罗氏公布FENtrepid最新数据而该研究于2025年11月达到主要终点、研究为多中心随机双盲双模拟平行组三期且共985例原发进展型多发性硬化成人、主要终点为复合12周首次确认残疾进展发生时间并含扩展残疾状态量表与定时25英尺步行及九孔柱测试、残疾进展风险降低12%（HR=0.88，95%CI：0.75至1.03）而曲线最早第24周分离、事后分析显示EDSS与9HPT复合终点风险降低22%（HR=0.78，95%CI：0.64至0.95）、感染67.0%对70.9%与恶心12.0%对7.1%与出血10.2%对8.1%、肝酶短暂可逆性升高13.3%对2.9%且未观察到潜在严重肝损伤、严重不良事件19.1%对18.9%并因此停药4.3%对3.0%而死亡1.4%对0.2% https://www.pharmcube.com/newsLibrary/detail?id=eaeefe2f5c1ed6ae566d7895355cde7d
[10] 出海遭遇“退货” 诺诚健华头顶的“皇冠”会掉落吗？（2023） ｜ 媒体报道：中国经济网2023年2月17日报道、德国默克BTK抑制剂evobrutinib治疗多发性硬化的二期临床中治疗组转氨酶升高患者比例达26%、赛诺菲tolebrutinib于2022年6月因肝损伤被美国食药监局暂停三期临床试验、截至该文时点全球尚无BTK抑制剂在自身免疫性疾病领域获批且已获批产品的适应症均在血液瘤、诺诚健华奥布替尼在多发性硬化的全球二期入组基本完成 https://finance.ce.cn/stock/gsgdbd/202302/17/t20230217_38399395.shtml
[11] Patient enrollment of phase III tolebrutinib trials paused in the U.S.（2022） ｜ 企业通稿：赛诺菲2022年6月30日公告、美国食品药品监督管理局对tolebrutinib在多发性硬化与重症肌无力的三期研究实施部分临床搁置、美国境内新入组暂停且入组不足60天的受试者暂停研究用药而满60天者继续、触发原因为三期中出现有限数量的药物性肝损伤病例且多数受影响患者合并已知易致药物性肝损伤的基础情况、所有病例停药后实验室指标均可逆、2022年5月已修订方案提高监测频率并排除既存肝功能风险因素、美国以外继续入组而MS项目自2019年入组当时逾2,000例在治且疗程最长3年 https://www.sanofi.com/assets/dotcom/pressreleases/2022/2022-06-30-05-30-00-2471767-en.pdf
[12] FDA Pauses Tolebrutinib Trials in MS, Myasthenia Gravis Over Liver Injuries（2022） ｜ 行业快讯：美国食品药品监督管理局对赛诺菲tolebrutinib的多发性硬化与重症肌无力三期研究实施部分临床搁置、五项研究中GEMINI 1与2针对复发型多发性硬化而PERSEUS针对原发进展型、HERCULES针对非复发继发进展型、URSA针对全身型重症肌无力、GEMINI 1与2登记号分别为NCT04410978与NCT04410991且各目标入组900例、受试者随机接受60毫克tolebrutinib或14毫克特立氟胺而疗程为18至36个月 https://www.neurologylive.com/view/fda-pauses-tolebrutinib-trials-in-ms-myasthenia-gravis-over-liver-injuries
[13] Sanofi's Cenrifki (tolebrutinib) approved in the EU as the first disability-targeting medicine for secondary progressive multiple sclerosis without relapses（2026） ｜ 企业通稿：欧洲委员会2026年6月23日批准赛诺菲Cenrifki（tolebrutinib）用于治疗过去两年无复发的继发进展型多发性硬化、为首个以残疾进展为目标的该适应症药物、依据为HERCULES三期研究并辅以GEMINI 1与2复发型研究支持、HERCULES登记号NCT04411641为主要终点为六个月确认残疾进展且按2比1随机接受每日口服tolebrutinib或匹配安慰剂、说明书层面写明药物性肝损伤为已识别的安全风险而需严格遵守肝脏监测要求并及时处置肝酶升高 https://www.sanofi.com/assets/dotcom/pressreleases/2026/2026-06-23-05-00-00-3315699-en.pdf
[14] 国家医保局药品信息（YPSW202500075）—所治疗疾病基本情况：多发性硬化（2025） ｜ 监管披露文件：多发性硬化为第一批中国罕见病病种、患病率约2.44/100,000而总患病人数约3万人、疾病修正治疗药物治疗比例仅约为18%、患者约70%为女性且其中超60%处于育龄期、特立氟胺2018年国内上市而2019年纳入医保、盐酸芬戈莫德与西尼莫德片分别于2019年和2020年国内上市并于2020年纳入医保、奥法妥木单抗与富马酸二甲酯均于2021年国内上市而在2022年纳入医保、盐酸奥扎莫德胶囊2023年国内上市并纳入医保 https://www.nhsa.gov.cn/attach/Ypsn2025/YPSW202500075/YPSW202500075.pdf
[15] Atlas of MS（第三版）— 全球多发性硬化流行病学（2023） ｜ 机构通稿：多发性硬化国际联盟发布的最全面的全球流行病学研究、全球多发性硬化人数由2013年的230万增至2020年的280万并在2023年达到290万、报告同时指出各国在诊断与疾病修正治疗可及性上的障碍与不平等 https://www.msif.org/about-us/who-we-are-and-what-we-do/advocacy/atlas/
[16] 国家医保局药品信息—奥瑞利珠单抗注射液（YPSW202500367）（2025） ｜ 监管披露文件：多发性硬化为第一批罕见病品种而具有高致残与高复发特点、中国患病率为2.32/10万、预计2025年确诊且接受生物制剂治疗的患者约9,000人、原发进展型多发性硬化按中国患者调研数据实际占多发性硬化的3%至4%且疾病负担更重、目录内疾病修饰药物均为复发型适应症而存在长期安全性与依从性局限、奥瑞利珠单抗为全球首个获批同时覆盖原发进展型与复发型的CD20单抗而中国大陆首次上市时间为2025年3月 https://www.nhsa.gov.cn/attach/Ypsn2025/YPSW202500367/YPSW202500367.pdf
📎 本文全部参考文献已汇总，点击底部「阅读原文」一键查看。
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2026-10-20
·药时代
正文共：1761字
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当一家以创新药著称的德国老牌企业决定借助siRNA平台进入血液学领域时，它会如何选择第一个落脚点？
2026年10月19日，默克宣布以约13亿美元股权价值收购英国siRNA生物技术公司Silence Therapeutics，较过去30个交易日平均股价溢价82%。
这笔交易中，默克买下的不只是一个进入血液学赛道的入场券，更是一套经过临床数据验证、可长期复用的基因沉默技术平台，以及平台上最成熟的核心资产：靶向TMPRSS6基因的siRNA疗法divesiran，开发适应症为真性红细胞增多症（PV）。
作为一种慢性骨髓增殖性肿瘤，PV长期以来缺乏改变疾病进程的理想治疗方案：患者体内红细胞过度生成会大幅提升血液黏稠度，进而升高血栓与心血管事件风险，目前临床仍高度依赖频繁放血来控制红细胞压积，这种有创干预对患者长期生活质量的影响不容小觑。
而divesiran的作用机制恰好切中了这一临床痛点，通过沉默TMPRSS6基因，解除其对铁调素的内源性抑制，提升体内铁调素水平，限制骨髓可利用的铁元素供给，从根源上抑制红细胞过度生成。
支撑默克给出高溢价的核心底气，是今年8月公布的Ⅱ期SANRECO试验数据。在依赖放血治疗的PV患者队列中，divesiran治疗组的临床应答率达到88%，安慰剂组仅为19%；截至第36周，治疗组患者平均仅需0.2次放血，而对照组的放血频次为2.1次。威廉・布莱尔投行将这一结果评价为PV领域的“同类最优”数据，足以支撑默克入局的战略判断。
从赛道空间来看，PV适应症的潜在市场规模可达20亿美元。武田同机制产品Mimrylo已于今年8月率先获批该适应症，机构预测其销售峰值在10亿至20亿美元区间。在已有竞品提前卡位的竞争格局下，默克以13亿美元同时拿下divesiran的后期开发权益和完整技术平台，威廉・布莱尔的分析师明确指出，这一交易估值“颇具性价比”。
这种性价比的判断，放在默克近两年的并购轨迹中会更清晰：2025年默克收购SpringWorks Therapeutics，拿下罕见神经纤维瘤病药物；如今借Silence切入血液学赛道，两条动作线指向完全一致的方向。在传统优势管线之外，搭建高专科、高临床壁垒的罕见病产品矩阵。
默克医药健康业务首席执行官Danny Bar-Zohar在交易声明中直言，这笔交易将帮助默克正式切入血液学领域；集团CEO Kai Beckmann也将其定义为公司向“高专科领域、未满足临床需求方向”持续转型的关键一步，通过精准并购切入具备长期价值的终端市场。
除了已跑出优异Ⅱ期数据的divesiran，这笔交易中最值得关注的长期价值，是Silence沉淀的siRNA技术平台。经过多年技术迭代，siRNA疗法已经从早期的概念验证阶段，进入商业化兑现阶段。
Silence的技术平台并不只服务于divesiran一款产品：其管线矩阵中已布局4款心血管代谢领域候选药物，其中zerlasiran已进入临床中期开发阶段；公司此前也与阿斯利康在心血管、代谢、肾脏及呼吸疾病领域建立了深度合作，尽管阿斯利康近期将合作资产SLN312的权益返还给Silence，但平台本身的技术积累与资产产出能力并未因此受损。
对于还未实现商业化、即将面临Ⅲ期临床执行风险的Silence而言，接受82%溢价的现金要约，能为股东提供确定性的价值兑现；
对于刚刚在多发性硬化候选药evobrutinib上遭遇临床失败、终止开发的默克而言，这套可持续产出候选药物的平台型资产，价值远不止单款产品，它能帮企业对冲单管线失败的高风险，搭建稳定的长期管线产出能力。
当然，这笔交易仍然存在不确定性。divesiran的Ⅲ期注册性试验尚未正式启动，Silence计划在2027年上半年评估每12周一次的给药方案，默克预计交易将在2027年第一季度完成交割。
这意味着默克接手的，是一个即将进入关键注册研究、但后期开发策略仍需与全球监管机构反复沟通的早期后期资产。同时，武田的Mimrylo凭借每周一次皮下注射的给药便利性和先发优势，已经在PV市场建立了处方习惯与支付方准入的基础。
尽管divesiran每12周给药一次的频次在患者依从性上具备理论优势，但这一优势能否真正转化为市场份额，仍存在两个待验证的变量：一方面是Ⅲ期试验能否稳定复现Ⅱ期的优异疗效，另一方面是默克的商业化团队，如何在武田产品提前卡位的PV市场中，快速建立差异化的产品认知与渠道优势。
从长期价值来看，这笔13亿美元交易的成败，最终会沿着两个分层维度被市场检验：
作为默克切入血液学赛道的首块跳板，divesiran需要顺利跨过Ⅲ期临床、商业化破局两道关卡，真正把长给药间隔的依从性优势兑现为匹配投入的市场回报；
默克更核心的战略期待，是这套经过临床验证的siRNA技术平台，能在其全球研发与商业化网络的加持下，持续产出覆盖血液学、心血管代谢领域的差异化候选药物，帮公司跳出过去“靠单笔并购补管线缺口”的被动模式，搭建可自我造血的高专科罕见病产品矩阵。
参考资料：
1.https://www.biospace.com/business/merck-kgaa-makes-noise-in-hematology-with-1-1b-silence-buy
2.默克企业官网
3.其他公开资料
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| 适应症 | 最高研发状态 | 国家/地区 | 公司 | 日期 |
|---|---|---|---|---|
| 横纹肌肉瘤 | 临床3期 | 美国 | 2019-09-10 | |
| 横纹肌肉瘤 | 临床3期 | 德国 | 2019-09-10 | |
| 复发性多发性硬化 | 临床3期 | 美国 | 2019-08-26 | |
| 复发性多发性硬化 | 临床3期 | 德国 | 2019-08-26 | |
| 复发-缓解型多发性硬化 | 临床3期 | 美国 | 2019-08-26 | |
| 复发-缓解型多发性硬化 | 临床3期 | 德国 | 2019-08-26 | |
| 系统性红斑狼疮 | 临床2期 | 美国 | 2017-01-04 | |
| 系统性红斑狼疮 | 临床2期 | 日本 | 2017-01-04 | |
| 系统性红斑狼疮 | 临床2期 | 阿根廷 | 2017-01-04 | |
| 系统性红斑狼疮 | 临床2期 | 保加利亚 | 2017-01-04 |
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临床结果
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| 研究 | 分期 | 人群特征 | 评价人数 | 分组 | 结果 | 评价 | 发布日期 |
|---|
N/A | 1,329 | BTK inhibitors | 蓋淵鏇壓鑰廠製衊淵願(鹹願衊鹹繭鏇願獵遞構) = Both active treatments demonstrated a greater sustained improvement in disability (?15%) compared with placebo (?5%,p=0.0023). 膚願窪繭憲襯鬱鏇觸選 (製遞顧艱網築網繭廠鑰 ) 更多 | 积极 | 2026-04-25 | ||
临床1期 | - | 14 | (Evobrutinib) | 觸衊繭鬱鑰糧餘糧遞繭(構網繭憲壓選夢齋鏇觸) = 憲憲遞獵醖醖壓餘襯構 獵顧鬱醖衊蓋襯艱廠構 (選鑰壓鬱艱艱廠繭製醖, 33.2) 更多 | - | 2026-01-15 | |
(Evobrutinib + Carbamazepine) | 觸衊繭鬱鑰糧餘糧遞繭(構網繭憲壓選夢齋鏇觸) = 獵範鏇鹽壓蓋廠網齋膚 獵顧鬱醖衊蓋襯艱廠構 (選鑰壓鬱艱艱廠繭製醖, 23.1) 更多 | ||||||
临床1期 | - | 40 | (Part 1: Cocktail) | 蓋膚簾範範衊範願築簾(鏇繭襯顧範糧憲醖廠憲) = 壓鏇積窪遞願繭繭構鏇 鹹簾衊構齋壓餘鏇廠廠 (廠鏇願顧鏇壓鏇壓顧鬱, 21.5) 更多 | - | 2025-12-05 | |
(Part 1: Evobrutinib + Cocktail) | 蓋膚簾範範衊範願築簾(鏇繭襯顧範糧憲醖廠憲) = 繭顧衊簾艱襯製襯選蓋 鹹簾衊構齋壓餘鏇廠廠 (廠鏇願顧鏇壓鏇壓顧鬱, 23.7) 更多 | ||||||
临床1期 | - | 20 | 廠鬱窪鹹製製窪積淵襯(廠衊積鏇網廠鬱鏇簾繭) = 鬱選製壓製遞鏇艱獵構 鏇夢淵蓋範顧蓋糧窪膚 (鬱獵範鹽蓋構齋簾製艱, 26.7) 更多 | - | 2025-11-14 | ||
临床1期 | - | 36 | (Evobrutinib 45mg) | 廠鹽壓選鬱積鏇餘願顧(範艱窪襯遞淵積鹽齋願) = 衊鑰願鹽衊築窪醖顧鏇 簾蓋鬱遞齋壓顧積壓衊 (艱顧廠鏇憲觸繭鑰憲繭, 衊鏇壓窪遞衊網遞廠鏇 ~ 鹽範齋糧夢衊築鬱廠襯) 更多 | - | 2025-11-13 | |
(Evobrutinib 225mg) | 廠鹽壓選鬱積鏇餘願顧(範艱窪襯遞淵積鹽齋願) = 餘範鹹餘鹽製顧繭艱遞 簾蓋鬱遞齋壓顧積壓衊 (艱顧廠鏇憲觸繭鑰憲繭, 夢選襯觸鏇鑰顧範鹹憲 ~ 窪廠夢顧醖淵膚範齋製) 更多 | ||||||
临床1期 | 24 | 齋艱醖鑰鬱憲製遞獵膚(壓艱顧壓鏇積築鹽壓構) = 壓醖窪遞醖夢艱襯繭蓋 顧願構網窪夢鹽鏇襯繭 (齋遞選艱糧淵壓醖廠獵, 23.6) 更多 | - | 2025-10-28 | |||
临床3期 | 1,124 | (Teriflunomide) | 鑰襯醖襯製鏇憲獵鏇觸(鏇襯襯積構獵簾範襯鹹) = 簾觸壓築糧範網淵鏇構 選範夢鬱遞繭構範艱壓 (網構製艱構鏇鹽選餘遞, 餘繭蓋遞夢鏇壓壓觸鏇 ~ 夢獵夢網獵鑰積選糧積) 更多 | - | 2025-06-12 | ||
(Evobrutinib) | 鑰襯醖襯製鏇憲獵鏇觸(鏇襯襯積構獵簾範襯鹹) = 遞廠淵構積遞齋築繭醖 選範夢鬱遞繭構範艱壓 (網構製艱構鏇鹽選餘遞, 範窪鏇壓鏇壓製網夢構 ~ 繭淵獵憲鏇構積獵顧壓) 更多 | ||||||
临床3期 | 1,166 | (Teriflunomide) | 選鑰鹹鏇鹽遞簾簾鬱獵(襯顧淵願窪蓋網窪艱衊) = 繭蓋醖築網鏇積顧衊齋 窪製夢醖願夢衊鑰構獵 (鹽網簾壓夢廠鑰鑰餘壓, 顧膚範願蓋選鏇鬱鬱蓋 ~ 獵膚構膚顧蓋鹹膚製壓) 更多 | - | 2025-01-14 | ||
(Evobrutinib) | 選鑰鹹鏇鹽遞簾簾鬱獵(襯顧淵願窪蓋網窪艱衊) = 壓構窪憲範選鑰鑰繭衊 窪製夢醖願夢衊鑰構獵 (鹽網簾壓夢廠鑰鑰餘壓, 觸鹽醖願憲選鹹顧獵簾 ~ 鏇餘顧糧範繭艱窪衊範) 更多 | ||||||
临床3期 | - | (evolutionRMS 1) | 製糧壓鹹廠獵醖糧襯鏇(鹹蓋夢鹽醖觸膚憲膚壓) = 顧鬱觸膚鏇餘壓繭構鏇 鬱製醖糧網遞鏇鹽餘鬱 (襯選範醖淵範糧襯範鏇 ) 未达到 | 不佳 | 2023-12-05 | ||
(evolutionRMS 1) | 製糧壓鹹廠獵醖糧襯鏇(鹹蓋夢鹽醖觸膚憲膚壓) = 鬱鏇範壓鹹壓遞獵選獵 鬱製醖糧網遞鏇鹽餘鬱 (襯選範醖淵範糧襯範鏇 ) 未达到 | ||||||
临床2期 | 267 | 構夢鹹衊選積觸壓鹹範(遞衊餘醖壓夢顧網鬱製) = Treatment-emergent adverse events (TEAEs) were reported by 142/164 PwRMS (86.6%) 艱範窪簾壓遞築構壓淵 (遞餘觸壓觸網鬱廠膚衊 ) 更多 | 积极 | 2023-09-30 | |||
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