Delving into the Latest Updates on Evobrutinib with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

M-2951, MSC 2364447, MSC-2364447

+ [2]

Target

BTK

Action

inhibitors

Mechanism

BTK inhibitors(Tyrosine-protein kinase BTK inhibitors)

Therapeutic Areas

NeoplasmsImmune System DiseasesNervous System Diseases+ [2]

Active Indication-

Inactive Indication

Multiple sclerosis relapseMultiple Sclerosis, Relapsing-RemittingRhabdomyosarcoma+ [2]

Originator Organization

Merck Serono SA

Active Organization-

Inactive Organization

Merck Healthcare KGaAEMD Serono Research & Development Institute, Inc.Merck KGaA

License Organization-

Drug Highest PhaseDiscontinuedPhase 3

First Approval Date-

Regulation-

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Structure/Sequence

Molecular FormulaC25H27N5O2

InChIKeyQUIWHXQETADMGN-UHFFFAOYSA-N

CAS Registry1415823-73-2

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.

Start Date24 Aug 2022

Sponsor / Collaborator

Merck Healthcare KGaA

NCT05245396

/ CompletedPhase 1

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.

Start Date02 Feb 2022

Sponsor / Collaborator

Merck Healthcare KGaA

[+1]

100 Clinical Results associated with Evobrutinib

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100 Translational Medicine associated with Evobrutinib

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100 Patents (Medical) associated with Evobrutinib

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79

Literatures (Medical) associated with Evobrutinib

01 Sep 2025·EUROPEAN JOURNAL OF PHARMACOLOGY

Next generation Bruton's tyrosine kinase inhibitors – characterization of in vitro potency and selectivity

Article

Author: Angst, Daniela ; Cenni, Bruno ; Pulz, Robert

Bruton's tyrosine kinase (BTK) mediates B cell receptor and Fc receptor signaling and is a key regulator of autoimmunity and allergy. A series of novel BTK inhibitors (BTKi) are currently in development for non-oncologic indications with covalent-irreversible (remibrutinib, evobrutinib, tolebrutinib, orelabrutinib), covalent-reversible (rilzabrutinib), and non-covalent reversible (fenebrutinib) binding modes. This study characterizes their in vitro potency and selectivity profiles under the same conditions to minimize assay differences across the different binding modes. Covalent BTKi showed human in vitro blood BTK binding in a time- and concentration-dependent manner with remibrutinib being the most potent and fastest in onset of action. Cellular BTK pathway inhibition was determined in human blood B cells and basophils, and for covalent BTKi correlated well with BTK binding. In contrast to the covalent-irreversible remibrutinib, the non-covalent reversible fenebrutinib showed rapid loss of cellular BTK inhibition after washout. Kinase selectivity was assessed in a binding screen across the human kinome, followed by quantification of binding affinities for a selection of kinases. BTKi ranked in their selectivity as follows (most selective to least): remibrutinib, fenebrutinib, evobrutinib, orelabrutinib, rilzabrutinib and tolebrutinib. These data suggest that next generation BTKi show important differences in their in vitro target binding and selectivity when compared under the same conditions.

01 Aug 2025·JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY

Comparative effects of biologics and small molecule inhibitors on cutaneous disease activity in lupus erythematosus: A systematic review and network meta-analysis

Article

Author: Gou, David ; Sun, Wayne ; Rayner, Daniel G ; Xi, Cheng En ; Silang, Isabella ; Khosravi-Hafshejani, Touraj ; Dutz, Jan P

Meta-anal. of comparative effects of biologics and small mol. inhibitors on cutaneous disease activity in lupus erythematosus.Our review builds upon the limitations of previous network meta-analyses by including 29 more trials investigating 25 addnl. unique interventions in our analyses on CLASI-A scores.In addition to anifrolumab, deucravacitinib, and litifilimab, we identified superior efficacy of sifalimumab and daxdilimab compared to placebo-all of which target the type 1 interferon pathway. Litifilimab and daxdilimab inhibit BDCA2 and Ig-like transcript 7, resp., which reside on dendritic cells and stimulate the production of type 1 interferons.Meanwhile, sifalimumab directly inhibits interferon-, and anifrolumab and deucravacitinib target the interferon-receptor and tyrosine kinase 2, resp.-two proteins involved in the interferon signaling pathway.These findings support the continued investigation of the type 1 interferon pathway in the management of CLE.

11 Apr 2025·ACS Pharmacology & Translational Science

Comprehensive Characterization of Bruton’s Tyrosine Kinase Inhibitor Specificity, Potency, and Biological Effects: Insights into Covalent and Noncovalent Mechanistic Signatures

Review

Author: Servant, Nicole B. ; King, Alastair J. ; Jahic, Mirza ; Darragh, Antonia C. ; Lipner, Justin H. ; Hanna, Andrew M.

Uncovering a drug's mechanism of action and possible adverse effects are critical components in drug discovery and development. Moreover, it provides evidence for why some drugs prove more effective than others and how to design better drugs altogether. Here, we demonstrate the utility of a high-throughput in vitro screening platform along with a comprehensive panel to aid in the characterization of 15 Bruton's tyrosine kinase (BTK) inhibitors that are either approved by the FDA or presently under clinical evaluation. To compare the potency of these drugs, we measured the binding affinity of each to wild-type BTK as well as a clinically relevant resistance mutant of BTK (BTK C481S). In doing so, we discovered a considerable difference in the selectivity and potency of these BTK inhibitors to the wild-type and mutant proteins. Some of this potentially contributes to the adverse effects experienced by patients undergoing therapy using these drugs. Overall, noncovalent BTK inhibitors showed stronger potency for both the wild-type and mutant BTK when compared with that of covalent inhibitors, with the majority demonstrating a higher specificity and less off-target modulation. Additionally, we compared biological outcomes for four of these inhibitors in human cell-based models. As expected, we found different phenotypic profiles for each inhibitor. However, the two noncovalent inhibitors had fewer off-target biological effects when compared with the two covalent inhibitors. This and similar in-depth preclinical characterization of drug candidates can provide critical insights into the efficacy and mechanism of action of a compound that may affect its safety in a clinical setting.

85

News (Medical) associated with Evobrutinib

09 Dec 2025

·firstwordpharma.com

Liver signals again trigger partial FDA hold on Roche's fenebrutinib MS studies

In what must feel like a case of déjà vu for Roche, the FDA is once again intervening in the late-stage development of fenebrutinib for multiple sclerosis (MS), placing a partial clinical hold on the US arm of the programme following new reports of liver enzyme abnormalities in ongoing Phase III trials.As a result, new patient enrollment in the US for the FENhance I relapsing MS (RMS) study has been paused as regulators investigate the cases and whether they perhaps point to a broader liver-safety signal for the BTK inhibitor class. Enrollment outside the US continues uninterrupted.Asymptomatic and transientIn a statement Tuesday, Roche said the FDA's action follows two recent cases of elevated hepatic transaminases accompanied by increased bilirubin in the blinded Phase III FENhance RMS programme, patterns it described as "suggestive of drug-induced liver injury." Both patients were asymptomatic, and lab values normalised after treatment was discontinued, according to Roche.Fenebrutinib's development programme also includes FENhance II – which like FENhance I, compares the oral non-covalent BTK inhibitor to Sanofi's Aubagio (teriflunomide) in RMS – and FENtrepid, evaluating fenebrutinib against Roche's Ocrevus (ocrelizumab) in primary progressive MS. Both of those studies are fully enrolled, though while US participants treated for more than 70 days will continue therapy, Roche says a "small number" who started within the past 70 days will discontinue.Repeat holdThis isn't the first time fenebrutinib has drawn the regulator's attention. In late 2023, the FDA imposed a similar partial hold on the programme after two comparable liver-safety cases were reported. As with Tuesday's announcement, that earlier action had also paused US enrollment in FENhance I while allowing the fully enrolled FENhance II and FENtrepid trials to proceed, again with the exception for a handful of patients.Roche last month released topline results showing that FENhance II met its primary endpoint of significantly lowering annualised relapse rate compared to Aubagio over at least 96 weeks, succeeding where two competing BTK inhibitors – Sanofi's tolebrutinib and Merck KGaA's evobrutinib – had previously failed. Meanwhile, FENtrepid has shown non-inferiority to Ocrevus in delaying composite confirmed disability progression over at least 120 weeks.In both those trials, Roche noted that fenebrutinib's liver safety remained consistent with previous studies.Speaking to FirstWord following the readouts, neurologist Robert Naismith of Washington University School of Medicine suggested that liver safety will be watched closely. "There are a lot of patients being enrolled in the Phase III programme, which is a good thing, but it is not the same as being out in the real world. We need to see, once this is used more broadly, whether the liver safety holds up," he said (see – KOL Views Q&A: Roche's fenebrutinib raises BTK hopes in MS but displacing anti-CD20s far from certain).For additional analysis, see – KOL Views Q&A: How fenebrutinib could reshape the MS treatment landscape.

Phase 3Clinical ResultPhase 2Clinical Trial Failure

10 Nov 2025

·endpoints.news

Roche reports two Phase 3 wins for its BTK inhibitor in multiple sclerosis

Roche’s BTK inhibitor has cleared two registrational studies in different types of multiple sclerosis, a surprise turn for a drug class that’s seen several trial failures and safety setbacks. The Swiss drugmaker said Monday that fenebrutinib met the primary endpoint of both Phase 3 studies that separately tested it in people with relapsing multiple sclerosis and primary progressive multiple sclerosis (PPMS). The trials together enrolled more than 1,700 patients, according to a company release . CMO Levi Garraway described the wins as “unprecedented” and said they could pave the way for fenebrutinib to become a “best-in-disease medicine.” The relapsing MS success will be seen as a “positive surprise,” Jefferies analysts said in a note to investors. But the analysts said they weren’t sure if a hit in the primary endpoint chosen for the PPMS trial will be enough for a filing with regulators. Roche didn’t share detailed results from either study, but plans to do so at future medical meetings. The company said it will wait for data from a second Phase 3 RMS trial before finalizing regulatory filing plans. Those results are expected in the first half of 2026. In the first RMS trial, called FENhance 2, fenebrutinib significantly cut the annualized relapse rate versus Sanofi’s Aubagio over a treatment period of at least 96 weeks. Aubagio is an inhibitor of the DHODH enzyme that’s commonly used to treat relapsing MS. The other study, called FENtrepid, looked at fenebrutinib in patients with PPMS. The drug was no worse than Roche’s Ocrevus at slowing disability progression over a treatment period of at least 120 weeks. Ocrevus, which was approved for PPMS in 2017, pulled in just over $2 billion in third-quarter sales this year. Fenebrutinib showed a “numerical benefit” over Ocrevus as early as 24 weeks, according to Roche. It hasn’t been smooth sailing for fenebrutinib, or for other BTK inhibitors for MS. In 2023, the FDA placed a partial clinical hold on fenebrutinib because of drug-related liver injuries in the Phase 3 RMS trials, specifically elevated levels of liver enzymes and bilirubin. The FENhance 2 and FENtrepid trials were already fully enrolled at that point, so they weren’t significantly impacted while Roche investigated two cases of elevated liver biomarkers. Those levels returned to normal after the patients stopped taking the drug. Roche said safety results from the latest studies are consistent with previous trials. Other large drugmakers have also faced liver-related holds for their candidates from the same class, including Merck KGaA and Sanofi . Merck KGaA decided to end development of evobrutinib in March 2024, several months after a Phase 3 failure in RMS. In September, the FDA delayed an approval decision for Sanofi’s tolebrutinib in non-relapsing, secondary progressive multiple sclerosis, citing a “major amendment” to the company’s NDA. The agency is now expected to make a decision by Dec. 28.

Phase 3Clinical ResultDrug ApprovalAccelerated Approval

10 Nov 2025

·firstwordpharma.com

Roche touts upbeat fenebrutinib readouts from two pivotal MS studies

Roche on Monday unveiled favourable top-line findings from two pivotal multiple sclerosis (MS) studies evaluating its investigational brain-penetrant oral BTK inhibitor fenebrutinib — which FirstWord at the beginning of the year named as one of the most important clinical readouts to watch for in 2025.Specifically, the Phase III FENhance 2 study in relapsing MS (RMS) met its key efficacy goal, while the late-stage FENtrepid study in primary progressive MS (PPMS) demonstrated non-inferiority of fenebrutinib to Roche’s own Ocrevus (ocrelizumab) — the only approved PPMS therapy.The FENhance 2 study, together with another similarly designed trial, FENhance 1, randomised 1,497 patients with RMS to receive fenebrutinib or Sanofi’s Aubagio (teriflunomide), while FENtrepid pitted fenebrutinib against Ocrevus in 985 patients with PPMS.Results showed that in FENhance 2, fenebrutinib significantly lowered the primary endpoint of annualised relapse rate compared with Aubagio over at least 96 weeks of treatment. Meanwhile, in FENtrepid, fenebrutinib was non-inferior to Ocrevus in delaying composite confirmed disability progression over at least 120 weeks, with numerical benefits emerging at week 24 and sustained throughout the observation period.“These unprecedented results suggest that fenebrutinib could potentially become a best-in-disease medicine as the first high-efficacy, oral treatment for people with RMS or PPMS," said Levi Garraway, chief medical officer at Roche.Full datasets from FENhance 2 and FENtrepid will be presented at upcoming medical meetings. Together with data from the two studies, the company plans to submit regulatory filings once FENhance 1 also reads out in the first half of next year.On the safety front, Roche noted that fenebrutinib’s liver safety remained consistent with its previous studies, though additional safety data requires further evaluation.Morgan Stanley analysts previously gave the FENhance trials a low probability of success due to BTK class safety concerns and competitor setbacks, while assigning FENtrepid a higher likelihood of success that could produce a stronger dataset than Sanofi’s tolebrutinib if positive.Turning the page on liver toxicityThe BTK inhibitor class has long been troubled by liver toxicity problems, leading the FDA to previously place clinical holds not only on the Roche drug, but also on tolebrutinib, Merck KGaA's evobrutinib and InnoCare's orelabrutinib. However, experts have lately renewed optimism in the class, with fenebrutinib particularly snagging its spot earlier this year on FirstWord’s list of drugs set to shape 2025. For deeper insights, see Spotlight On: Roche keeps faith with fenebrutinib.

Clinical ResultPhase 3

100 Deals associated with Evobrutinib

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External Link

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB15170

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Rhabdomyosarcoma	Phase 3	United States	Merck KGaA	10 Sep 2019
Rhabdomyosarcoma	Phase 3	Germany	Merck KGaA	10 Sep 2019
Multiple sclerosis relapse	Phase 3	United States	Merck KGaA	26 Aug 2019
Multiple sclerosis relapse	Phase 3	Germany	Merck KGaA	26 Aug 2019
Multiple Sclerosis, Relapsing-Remitting	Phase 3	United States	Merck KGaA	26 Aug 2019
Multiple Sclerosis, Relapsing-Remitting	Phase 3	Germany	Merck KGaA	26 Aug 2019
Systemic Lupus Erythematosus	Phase 2	United States	Merck KGaA	04 Jan 2017
Systemic Lupus Erythematosus	Phase 2	Japan	Merck KGaA	04 Jan 2017
Systemic Lupus Erythematosus	Phase 2	Argentina	Merck KGaA	04 Jan 2017
Systemic Lupus Erythematosus	Phase 2	Bulgaria	Merck KGaA	04 Jan 2017

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT05064488 (CTgov)	Phase 1	-	40	rosuvastatin+digoxin+metformin (Part 1: Cocktail)	irfkcedsew(kxiormitmi) = wzrwvzjgzn uqskcgqloi (oakayrvxim, 21.5) View more	-	05 Dec 2025
				Evobrutinib (Part 1: Evobrutinib + Cocktail)	irfkcedsew(kxiormitmi) = iwnhjaegpr uqskcgqloi (oakayrvxim, 23.7) View more
NCT07215806 (CTgov)	Phase 1	-	20	Combined oral contraceptive [ethinyl estradiol/ norethisterone (EE/NET)]+Evobruitnib	sjwgrrnbwi(izlrtrxcgp) = jtcpcpylgj koaaabbbem (njrnbhmbtz, 26.7) View more	-	14 Nov 2025
NCT07214935 (CTgov)	Phase 1	-	36	Evobrutinib (Evobrutinib 45mg)	bjosuvlevo(dxhwmjkxvg) = gbbufperww leviyattuz (vbbeiapyso, uibzeitodq - btarextdul) View more	-	13 Nov 2025
				Evobrutinib (Evobrutinib 225mg)	bjosuvlevo(dxhwmjkxvg) = qcshmrkwjc leviyattuz (vbbeiapyso, lszcfqameq - aofngxxcnl) View more
NCT04546789 (CTgov)	Phase 1	Hepatic Insufficiency	24	M2951 (BTK inhibitor)	cvegawqbnq(qpwuyoueyx) = rqpstzielo ufmfefrmrv (jcktyszxue, 23.6) View more	-	28 Oct 2025
NCT04338022 (evolutionRMS 1, CTgov)	Phase 3	Multiple sclerosis relapse	1,124	Teriflunomide (Teriflunomide)	xokchkkdjt(gesgdrlalq) = tqqgwamsek wzecjsarqe (ylhsottnob, hnndvkbghl - idqvvmswfh) View more	-	12 Jun 2025
				Evobrutinib (Evobrutinib)	xokchkkdjt(gesgdrlalq) = tzggybesow wzecjsarqe (ylhsottnob, ejnzligogc - anaculkvxi) View more
NCT04338061 (evolutionRMS 2, CTgov)	Phase 3	Multiple sclerosis relapse	1,166	Teriflunomide (Teriflunomide)	fxbyilnzdu(earlckgdtl) = wdcuukwacn lnvvdnrwtk (middepduks, hjroxguggt - cmlrqccpod) View more	-	14 Jan 2025
				Evobrutinib (Evobrutinib)	fxbyilnzdu(earlckgdtl) = dejbkmlydp lnvvdnrwtk (middepduks, imwspspclm - ozmynausyx) View more
NCT04338061 \| NCT04338022 (evolutionRMS 1, Biospace) Manual	Phase 3	Multiple sclerosis relapse	-	Evobrutinib (evolutionRMS 1)	sckjqvhbvy(ynfdtnjigi) = vvsdluwypv gwpjdubuth (shzwvrpahh ) Not Met	Negative	05 Dec 2023
				teriflunomide (evolutionRMS 1)	sckjqvhbvy(ynfdtnjigi) = xecyxkiedt gwpjdubuth (shzwvrpahh ) Not Met
NCT02975349 (Phase 2 OLE, ECTRIMS2023)	Phase 2	Bruton Type Agammaglobulinemia	267	Evobrutinib 25mg QD	cavavjyxso(cgpnhuuyam) = Treatment-emergent adverse events (TEAEs) were reported by 142/164 PwRMS (86.6%) ubwqhrfkcx (ljjkzgzrai ) View more	Positive	30 Sep 2023
				Evobrutinib 75mg BID
NCT02975349 (Phase II, EAN2023)	Phase 2	Rhabdomyosarcoma	45	Evobrutinib 75mg twice-daily	omsiqzplov(ecmbnravqn) = puahgvgcnd lpfyjaowid (vjhwmairgf )	Positive	28 Jun 2023
ACTRIMS2023 \| AAN2023	Not Applicable	Multiple sclerosis relapse	-	Evobrutinib 75 mg twice-daily	lpkhtojzxt(ytmkcexwzo) = lofgdpmuiu ydxncowsaq (pcpxlwkdag, 4.5)	-	30 May 2023
				mRNA COVID-19 vaccine	lpkhtojzxt(ytmkcexwzo) = gjkzlxbmja ydxncowsaq (pcpxlwkdag, 4.3)