Safety and efficacy of fenebrutinib in relapsing multiple
sclerosis (FENopta): a multicentre, double-blind, randomised,
placebo-controlled, phase 2 trial and open-label extension
study

J 2025

Safety and efficacy of fenebrutinib in relapsing multiple sclerosis (FENopta): a multicentre, double-blind, randomised, placebo-controlled, phase 2 trial and open-label extension study

BAR-OR, Amit; Michal DUFEK; Hrvoje BUDINCEVIC; Jelena DRULOVIC; Mario HABEK et. al.

Základní údaje

Originální název

Safety and efficacy of fenebrutinib in relapsing multiple sclerosis (FENopta): a multicentre, double-blind, randomised, placebo-controlled, phase 2 trial and open-label extension study

Autoři

BAR-OR, Amit; Michal DUFEK (203 Česká republika, domácí); Hrvoje BUDINCEVIC; Jelena DRULOVIC; Mario HABEK; Le H HUA; Martin S WEBER; Piia THOMAS; Julie NAPIERALSKI; Maresa Caunt MITZNER; John N RATCHFORD; David CLAYTON; Christopher T HARP; Denison KURUVILLA; Qi QI; Ying-Fang CHEN; Xu YAN; Alexandra GOODYEAR a Jiwon OH

Vydání

Lancet Neurology, NEW YORK, Elsevier, 2025, 1474-4422

Další údaje

Jazyk

angličtina

Typ výsledku

Článek v odborném periodiku

Obor

30210 Clinical neurology

Stát vydavatele

Spojené státy

Utajení

není předmětem státního či obchodního tajemství

Odkazy

URL

Impakt faktor

Impact factor: 46.600 v roce 2023

Organizační jednotka

Lékařská fakulta

DOI

http://dx.doi.org/10.1016/S1474-4422(25)00174-7

UT WoS

001536709600001

EID Scopus

2-s2.0-105010741329

Klíčová slova anglicky

relapsing multiple sclerosis; fenebrutinib

Štítky

14110127, rivok

Příznaky

Mezinárodní význam, Recenzováno

Změněno: 6. 8. 2025 10:27, Mgr. Tereza Miškechová

Anotace

V originále

Background The prospect for Bruton's tyrosine kinase (BTK) inhibition to meaningfully affect relapsing multiple sclerosis has recently been questioned due to inconsistent findings in the magnitude and sustainability of the effect of BTK inhibitors on disease activity. We assessed the safety, efficacy, and CSF drug concentrations of fenebrutinib, a highly selective, noncovalent, reversible BTK inhibitor, in patients with relapsing multiple sclerosis. Methods This multicentre, double-blind, randomised, placebo-controlled, phase 2 trial (FENopta) was conducted at 18 community centres and hospitals across six countries in Europe and North America. Patients with relapsing multiple sclerosis aged 18-55 years with an Expanded Disability Status Scale (EDSS) score of 00-55, and recent documented disease activity, were randomly assigned (2:1) to oral fenebrutinib (200 mg twice daily) or placebo for 12 weeks, using permuted blocks and stratified by the presence or absence of T1 gadolinium-enhancing (Gd+) lesions on the brain MRI at screening. The randomisation sequence was generated by an interactive voice or web response system and both patients and investigators were masked to treatment allocation. Participants could enter an optional open-label extension study to receive fenebrutinib for up to 192 weeks. The primary efficacy endpoint was the total number of new T1 Gd+ lesions on brain MRI at weeks 4, 8, and 12; with additional MRI assessments at 48-week intervals during the open-label extension. Efficacy analyses were done on randomised patients with evaluable post-baseline MRIs; safety analyses used the safety-evaluable population. This study is registered with ClinicalTrials.gov, NCT05119569, and EudraCT, 2021-003772-14; recruitment is closed and the trial is ongoing. Findings Between March 1, 2022 and March 29, 2023, 109 patients with relapsing multiple sclerosis were randomly assigned treatment: 73 received fenebrutinib and 36 received placebo. 106 patients had evaluable post-baseline brain MRI scans and were assessed for efficacy in the fenebrutinib group (n=70) and placebo group (n=36). The combined number of new T1 Gd+ lesions at weeks 4, 8, and 12 were 0077 (95% CI 0043-0135) in the fenebrutinib group and 0245 (0144-0418) in the placebo group (69% relative reduction [95% CI 34-85]; p=00022). During the open-label extension, through week 48, the unadjusted annualised relapse rate was 004 and 95 (96%) of 99 patients were relapse-free. During the double-blind treatment phase, the most common adverse events that were more frequent in the fenebrutinib group than in the placebo group were hepatic enzyme elevations (four [6%] vs 0), headache (three [4%] vs one [3%]), and nasopharyngitis (two [3%] vs 0); no serious adverse events or deaths occurred. Interpretation Fenebrutinib was well tolerated and exerted an early, robust, and sustained effect of limiting new focal brain lesions. Further studies are needed to better characterise the safety and efficacy of fenebrutinib on both relapsing multiple sclerosis and non-relapsing progressive multiple sclerosis. Funding F. Hoffmann-La Roche. Copyright (c) 2025 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.

Citovat

BAR-OR, Amit; Michal DUFEK; Hrvoje BUDINCEVIC; Jelena DRULOVIC; Mario HABEK; Le H HUA; Martin S WEBER; Piia THOMAS; Julie NAPIERALSKI; Maresa Caunt MITZNER; John N RATCHFORD; David CLAYTON; Christopher T HARP; Denison KURUVILLA; Qi QI; Ying-Fang CHEN; Xu YAN; Alexandra GOODYEAR a Jiwon OH. Safety and efficacy of fenebrutinib in relapsing multiple sclerosis (FENopta): a multicentre, double-blind, randomised, placebo-controlled, phase 2 trial and open-label extension study. Lancet Neurology. NEW YORK: Elsevier, 2025, roč. 24, č. 8, s. 656-666. ISSN 1474-4422. Dostupné z: https://dx.doi.org/10.1016/S1474-4422(25)00174-7.

@article{2511220,
   author = {BarandOr, Amit and Dufek, Michal and Budincevic, Hrvoje and Drulovic, Jelena and Habek, Mario and Hua, Le H and Weber, Martin S and Thomas, Piia and Napieralski, Julie and Mitzner, Maresa Caunt and Ratchford, John N and Clayton, David and Harp, Christopher T and Kuruvilla, Denison and Qi, Qi and Chen, YingandFang and Yan, Xu and Goodyear, Alexandra and Oh, Jiwon},
   article_location = {NEW YORK},
   article_number = {8},
   doi = {http://dx.doi.org/10.1016/S1474-4422(25)00174-7},
   keywords = {relapsing multiple sclerosis; fenebrutinib},
   language = {eng},
   issn = {1474-4422},
   journal = {Lancet Neurology},
   title = {Safety and efficacy of fenebrutinib in relapsing multiple sclerosis (FENopta): a multicentre, double-blind, randomised, placebo-controlled, phase 2 trial and open-label extension study},
   url = {https://www.sciencedirect.com/science/article/pii/S1474442225001747?via%3Dihub},
   volume = {24},
   year = {2025}
}

TY  - JOUR
ID  - 2511220
AU  - Bar-Or, Amit - Dufek, Michal - Budincevic, Hrvoje - Drulovic, Jelena - Habek, Mario - Hua, Le H - Weber, Martin S - Thomas, Piia - Napieralski, Julie - Mitzner, Maresa Caunt - Ratchford, John N - Clayton, David - Harp, Christopher T - Kuruvilla, Denison - Qi, Qi - Chen, Ying-Fang - Yan, Xu - Goodyear, Alexandra - Oh, Jiwon
PY  - 2025
TI  - Safety and efficacy of fenebrutinib in relapsing multiple sclerosis (FENopta): a multicentre, double-blind, randomised, placebo-controlled, phase 2 trial and open-label extension study
JF  - Lancet Neurology
VL  - 24
IS  - 8
SP  - 656-666
EP  - 656-666
PB  - Elsevier
SN  - 14744422
KW  - relapsing multiple sclerosis
KW  - fenebrutinib
UR  - https://www.sciencedirect.com/science/article/pii/S1474442225001747?via%3Dihub
N2  - Background The prospect for Bruton's tyrosine kinase (BTK) inhibition to meaningfully affect relapsing multiple sclerosis has recently been questioned due to inconsistent findings in the magnitude and sustainability of the effect of BTK inhibitors on disease activity. We assessed the safety, efficacy, and CSF drug concentrations of fenebrutinib, a highly selective, noncovalent, reversible BTK inhibitor, in patients with relapsing multiple sclerosis. Methods This multicentre, double-blind, randomised, placebo-controlled, phase 2 trial (FENopta) was conducted at 18 community centres and hospitals across six countries in Europe and North America. Patients with relapsing multiple sclerosis aged 18-55 years with an Expanded Disability Status Scale (EDSS) score of 00-55, and recent documented disease activity, were randomly assigned (2:1) to oral fenebrutinib (200 mg twice daily) or placebo for 12 weeks, using permuted blocks and stratified by the presence or absence of T1 gadolinium-enhancing (Gd+) lesions on the brain MRI at screening. The randomisation sequence was generated by an interactive voice or web response system and both patients and investigators were masked to treatment allocation. Participants could enter an optional open-label extension study to receive fenebrutinib for up to 192 weeks. The primary efficacy endpoint was the total number of new T1 Gd+ lesions on brain MRI at weeks 4, 8, and 12; with additional MRI assessments at 48-week intervals during the open-label extension. Efficacy analyses were done on randomised patients with evaluable post-baseline MRIs; safety analyses used the safety-evaluable population. This study is registered with ClinicalTrials.gov, NCT05119569, and EudraCT, 2021-003772-14; recruitment is closed and the trial is ongoing. Findings Between March 1, 2022 and March 29, 2023, 109 patients with relapsing multiple sclerosis were randomly assigned treatment: 73 received fenebrutinib and 36 received placebo. 106 patients had evaluable post-baseline brain MRI scans and were assessed for efficacy in the fenebrutinib group (n=70) and placebo group (n=36). The combined number of new T1 Gd+ lesions at weeks 4, 8, and 12 were 0077 (95% CI 0043-0135) in the fenebrutinib group and 0245 (0144-0418) in the placebo group (69% relative reduction [95% CI 34-85]; p=00022). During the open-label extension, through week 48, the unadjusted annualised relapse rate was 004 and 95 (96%) of 99 patients were relapse-free. During the double-blind treatment phase, the most common adverse events that were more frequent in the fenebrutinib group than in the placebo group were hepatic enzyme elevations (four [6%] vs 0), headache (three [4%] vs one [3%]), and nasopharyngitis (two [3%] vs 0); no serious adverse events or deaths occurred. Interpretation Fenebrutinib was well tolerated and exerted an early, robust, and sustained effect of limiting new focal brain lesions. Further studies are needed to better characterise the safety and efficacy of fenebrutinib on both relapsing multiple sclerosis and non-relapsing progressive multiple sclerosis. Funding F. Hoffmann-La Roche. Copyright (c) 2025 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.
ER  -

BAR-OR, Amit; Michal DUFEK; Hrvoje BUDINCEVIC; Jelena DRULOVIC; Mario HABEK; Le H HUA; Martin S WEBER; Piia THOMAS; Julie NAPIERALSKI; Maresa Caunt MITZNER; John N RATCHFORD; David CLAYTON; Christopher T HARP; Denison KURUVILLA; Qi QI; Ying-Fang CHEN; Xu YAN; Alexandra GOODYEAR a Jiwon OH. Safety and efficacy of fenebrutinib in relapsing multiple sclerosis (FENopta): a multicentre, double-blind, randomised, placebo-controlled, phase 2 trial and open-label extension study. \textit{Lancet Neurology}. NEW YORK: Elsevier, 2025, roč.~24, č.~8, s.~656-666. ISSN~1474-4422. Dostupné z: https://dx.doi.org/10.1016/S1474-4422(25)00174-7.

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