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 KGaAMerck KGaAEMD Serono Research & Development Institute, Inc.

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 is to investigate the effect of multiple doses of carbamazepine on two single doses of evobrutinib pharmacokinetics (PK) in healthy participants. Study details include:
Study Duration: up to 54 days. Treatment Duration: 25 days. Visit Frequency: Participants will be resident in the Clinical Research Unit from Day 1 to Day 20 and return on Day 26 for a Safety Follow-Up visit.

Start Date13 Jan 2022

Sponsor / Collaborator

Merck Healthcare KGaA

NCT05064488

/ CompletedPhase 1

A Phase I, Open-Label, Two-Part Study of the Effect of Multiple-Dose Evobrutinib on Transporter Substrates Digoxin, Metformin, Rosuvastatin, and Sumatriptan Pharmacokinetics in Healthy Participants

This study consists of 2 parts: Part 1 and 2. The purpose of this study is to evaluate the pharmacokinetic, safety and tolerability of multiple doses of evobrutinib on single doses of digoxin, metformin and rosuvastatin in Part-1 and sumatriptan in Part-2 of the study.

Start Date04 Oct 2021

Sponsor / Collaborator

Merck Healthcare KGaA

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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89

Literatures (Medical) associated with Evobrutinib

01 May 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.

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.

14 Mar 2025·JOURNAL OF LEUKOCYTE BIOLOGY

Effect on neutrophil migration and antimicrobial functions by the Bruton's tyrosine kinase inhibitors tolebrutinib, evobrutinib, and fenebrutinib

Article

Author: Pörtner, Noëmie ; De Bondt, Mirre ; Renders, Janne ; Struyf, Sofie ; Baeten, Paulien ; Duran, Gayel ; Petit de Prado, Paloma ; Broux, Bieke ; Hellings, Niels ; Vanbrabant, Lotte ; Berghmans, Nele ; Matthys, Patrick ; de Oliveira, Vívian Louise Soares ; Gouwy, Mieke

Abstract:

Multiple sclerosis (MS) is a neurodegenerative, autoimmune disease that is still incurable. Nowadays, a variety of new drugs are being developed to prevent excessive inflammation and halt neurodegeneration. Among these are the inhibitors of Bruton's tyrosine kinase (BTK). Being indispensable for B cells, this enzyme became an appealing therapeutic target for autoimmune diseases. Recognizing the emerging importance of BTK in myeloid cells, we investigated the impact of upcoming BTK inhibitors on neutrophil functions. Although adaptive immunity in MS has been thoroughly studied, unanswered questions about the pathogenesis can be addressed by studying the effects of candidate MS drugs on innate immune cells such as neutrophils, previously overlooked in MS. In this study, we used 3 BTK inhibitors (evobrutinib, fenebrutinib, and tolebrutinib), and found that they reduce neutrophil activation by the bacterial peptide fMLF and the chemokine interleukin-8/CXCL8. Furthermore, they diminished the production of reactive oxygen species and release of neutrophil extracellular traps. Additionally, the production of CXCL8 and interleukin-1β in response to inflammatory stimuli was decreased. Inhibitory effects of the drugs on neutrophil activation were not related to toxicity. Instead, BTK inhibitors prolonged neutrophil survival in an inflammatory environment. Finally, treatment with BTK inhibitors decreased neutrophil migration toward CXCL8 in a Boyden chamber assay but not in a transendothelial setup. Also, in vivo CXCL1-induced migration was unaffected by BTK inhibitors. Collectively, this study provides novel insights into the impact of BTK inhibitors on neutrophil functions, thereby holding important implications for autoimmune or hematological diseases in which BTK is crucial.

79

News (Medical) associated with Evobrutinib

28 Apr 2025

·pharma.economictimes.indiatimes.com

Germany's Merck KGaA in $3.9 billion deal to buy US biotech firm SpringWorks

Frankfurt: Merck KGaA has struck a deal to buy U.S. biotech company SpringWorks Therapeutics for an equity value of $3.9 billion, as the German company seeks to acquire treatments for rare tumours to boost its cancer drugs business. The family-controlled company said in a statement on Monday the purchase price of $47 per share in cash represents an equity value of about $3.9 billion, equivalent to an enterprise value of $3.4 billion (3.0 billion euros), when SpringWorks' cash holdings are deducted. The deal is one of the largest in years for Merck, but its price tag was 22 per cent lower than the about $60 per share analysts had expected after a Reuters report on February 10 that the companies were in advanced talks. Merck on April 24 lowered price expectations, saying the two companies were in late-stage discussions over a bid of around $47 per SpringWorks share. Merck's shares were down 0.4 per cent in early trade, underperforming the broader German stock market. The deal will be funded with available cash and new debt. It is expected to be accretive to Merck's earnings per share, adjusted for special items, in 2027, said a statement from the German group, based in Darmstadt, near Frankfurt. It added it would still be able to pursue larger transactions. Stamford, Connecticut-based SpringWorks, which listed its shares in New York in 2019, develops drugs to treat cancer and rare types of tumour. It has two products on the market: Ogsiveo with 2024 sales of $172 million to treat desmoid tumours, an aggressive disease affecting soft tissue, as well as Gomekli, which was approved in February to treat NF1-PN, characterised by nerve sheath tumours. "We have the unique opportunity with SpringWorks to establish a leadership position in rare tumours and build a strong foundation for further investments in this area," Peter Guenter, head of healthcare at Merck, said. The transaction will likely close during the second half of 2025, subject to approval of SpringWorks' shareholders and regulatory clearance, Merck added. TRUMP DISRUPTION JP Morgan analyst Anupam Rama previously said the lack of other serious bidders and the challenging macroeconomic environment had probably lowered the valuation. This year had been expected to be stellar for mergers and acqusitions in the sector until the disruption caused by U.S. President Donald Trump's policies, including massive layoffs at the U.S. Food and Drug Administration. That has brought uncertainty to the drug approval process, hampering projected drug sales and affecting valuations. Merck is particularly keen to strengthen its drug development pipeline after high-profile setbacks in late-stage drug trials, including a decision last year to halt development of head and neck cancer drug Xevinapant. A major trial testing multiple sclerosis drug Evobrutinib failed in December 2023. In 2015, the company agreed to buy U.S. lab equipment supplier Sigma-Aldrich for $17 billion, its biggest deal to date. In 2019, Merck acquired U.S. electronics materials manufacturer Versum for around $6.5 billion. (Reporting by Ludwig Burger, Emma-Victoria Farr in Frankfurt and Sabrina Valle in New York; Editing by Kirsten Donovan and Barbara Lewis)

AcquisitionDrug Approval

25 Apr 2025

·pharma.economictimes.indiatimes.com

Germany's Merck says in late-stage discussions to buy SpringWorks for $3.5 billion

Bengaluru: Germany's Merck KGaA said on Thursday it is in late-stage talks to acquire U.S.-based SpringWorks Therapeutics for about $3.5 billion, a deal that could give it access to a recently approved rare disease drug and expand its portfolio of experimental cancer treatments . Merck said that the companies are in discussions on the basis of a price of around $47 per share, which gives a valuation of roughly $3.5 billion, according to Reuters calculations. No final decision has been taken and no legally binding agreement has been entered into, Merck said in a statement. The SpringWorks acquisition would rank as one of the biggest pharma deals for the German healthcare and technology group in recent years, boosting its ongoing efforts to build out its cancer treatment pipeline. In 2015, Merck agreed to buy U.S. lab equipment supplier Sigma-Aldrich for $17 billion. Reuters reported in February that the companies were in advanced talks, which Merck subsequently confirmed. SpringWorks' shares have fallen 17% since then. Shares of SpringWorks settled 9 per cent higher at close, after the Wall Street Journal first reported that Merck is nearing a deal, which could be completed as soon as Monday. The stock was trading closer to $60 in February. SpringWorks, which has a market value of more than $3 billion, did not respond to a Reuters request for comment. The deal could accelerate growth in Merck, particularly as sales of its cancer drug Bavencio slow and multiple sclerosis treatment Mavenclad faces loss of exclusivity, said Barclays analyst Emily Field. The Connecticut-based drugmaker, which went public in 2019, focuses on developing drugs to treat several rare cancers and genetic disorders. Its monotherapy, Ogsiveo , has been approved in the U.S. to treat desmoid tumours - abnormal growth that occurs in connective tissues. In February, the U.S. health regulator approved SpringWorks' genetic disorder drug Gomekli . Merck has recently suffered high-profile setbacks in late-stage drug trials, prompting it to halt development of its head and neck cancer drug xevinapant. A major trial testing multiple sclerosis drug evobrutinib failed in December 2023. (Reporting by Sriparna Roy and Christy Santhosh in Bengaluru, and Sabrina Valle in New York; Editing by Alan Barona)

AcquisitionDrug Approval

25 Apr 2025

·www.biospace.com

SpringWorks Surges on Potential $3.5B Merck KGaA Buyout

iStock, Anton Vierietin The transaction, which sources say could be agreed upon as soon as Monday, would price SpringWorks at $47 per share, totaling approximately $3.5 billion for the acquisition. Germany’s Merck KGaA is in advanced talks with SpringWorks Therapeutics for an acquisition that could be valued at about $3.5 billion, according to several media reports on Thursday. Confirming the news to The Wall Street Journal , Merck KGgA revealed that while no formal, legally binding arrangement has yet been reached, the companies are considering a purchase price of around $47 per share of SpringWorks. If all goes smoothly from here, the parties could reach an agreement as soon as Monday, according to sources familiar with the negotiations. SpringWorks share prices jumped 9% Thursday after the news reports. Rumors of the courtship between Merck KGaA and SpringWorks first broke in February, with anonymous sources telling Reuters at the time that the parties could reach an agreement in weeks’ time. Merck KGaA confirmed the talks, sending SpringWorks’ stocks surging some 30% in reaction, even as the German pharma insisted that “there is no certainty that any transaction will materialize.” But when a deal didn’t materialize, investor interest in SpringWorks waned. Earlier this month, the cancer-focused biotech had dropped roughly 40% from its high in February. Since the first buyout rumors swirled, SpringWorks has become a more valuable prospect for potential buyers, winning FDA approval for Gomekli, its oral drug for neurofibromatosis type 1 with symptomatic plexiform neurofibromas. If the acquisition deal pushes through, Merck KGaA will inherit SpringWorks’ Ogsiveo, indicated for adults with progressing desmoid tumors. Last year, Ogsiveo pulled in $172 million for the company in the U.S alone. SpringWorks is also studying Ogsiveo in other rare cancers, including ovarian granulosa cell tumors and relapsed/refractory multiple myeloma. The SpringWorks deal could help Merck KGaA rebound after a series of clinical setbacks. In April 2023, its BTK blocker evobrutinib was hit with a partial clinical hold from the FDA after the regulator detected cases of liver injury in a Phase III trial. Later that year, in December, Merck KGaA announced that evobrutinib had failed two Phase III studies in relapsing multiple sclerosis, unable to significantly reduce yearly relapse rates versus Sanofi’s Aubagio. Merck KGaA was forced to terminate evobrutinib’s multiple sclerosis run in March 2024. Then, in June 2024, the company also axed a couple of trials of xevinapant after the drug candidate failed to significantly improve survival in patients with locally advanced head and neck cancer. Amid these failures, Merck in April 2024 attempted to buttress its cancer pipeline with a potential $1.4 billion discovery and development deal with Texas biotech Caris Life Sciences, focused on antibody-drug conjugates for oncology targets.

Phase 3AcquisitionDrug ApprovalADCClinical Result

100 Deals associated with Evobrutinib

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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


NCT04338061 (evolutionRMS 2, CTgov)	Phase 3	Multiple sclerosis relapse	1,166	Teriflunomide (Teriflunomide)	muewppccqd(fngbxfwthj) = yrdsbfpzyd eiykgqpozk (mkpknwyghp, jcfekdbtqc - quaeoraajz) View more	-	14 Jan 2025
				Evobrutinib (Evobrutinib)	muewppccqd(fngbxfwthj) = luesbylbwz eiykgqpozk (mkpknwyghp, askpqyffgq - nqtxxtepow) View more
NCT04338061 \| NCT04338022 (evolutionRMS 1, Biospace) Manual	Phase 3	Multiple sclerosis relapse	-	Evobrutinib (evolutionRMS 1)	nafhibdeot(isjqtkktts) = grdsufbuqe aslvljywsh (gxbstmpuwn ) Not Met	Negative	05 Dec 2023
				teriflunomide (evolutionRMS 1)	nafhibdeot(isjqtkktts) = zwssplltat aslvljywsh (gxbstmpuwn ) Not Met
NCT02975349 (Phase 2 OLE, ECTRIMS2023)	Phase 2	Bruton Type Agammaglobulinemia	267	Evobrutinib 25mg QD	iotkbhwfef(usmpylcwed) = Treatment-emergent adverse events (TEAEs) were reported by 142/164 PwRMS (86.6%) mbrzrvrlyk (wliqdwgahj ) View more	Positive	30 Sep 2023
				Evobrutinib 75mg BID
NCT02975349 (Phase II, EAN2023)	Phase 2	Rhabdomyosarcoma	45	Evobrutinib 75mg twice-daily	kxbrisyxfz(wjfuilyutx) = ukyadhgvfg zzfkjdqjbp (obmnxdcket )	Positive	28 Jun 2023
ACTRIMS2023	Not Applicable	Neuroinflammation	-	Evobrutinib	iyjikwjtbl(ptaxypyfln) = ukxuwobvxv nsjbtfydez (qcbiucuxea )	Positive	30 May 2023
				Anti-CD20 (clone: SA271G2)	ptzuepueac(auaubtnndz) = efqkvqaphh xqkleyvxlz (dsnjjkrdlo ) View more
ACTRIMS2023	Not Applicable	Multiple sclerosis relapse	-	Evobrutinib 75 mg twice-daily	rwqpzswtpz(pavsiyjgje) = ajpxwqcvgt itqoronlnk (qqqpcjdkud, 4.5)	-	30 May 2023
				mRNA COVID-19 vaccine	rwqpzswtpz(pavsiyjgje) = csifzhalrs itqoronlnk (qqqpcjdkud, 4.3)
AAN2023	Not Applicable	Neuroinflammation	-	Evobrutinib	jppjdgbbtt(jnwhahuyhk) = ncpadtzbkf epujbinwln (wzrmxbdgmr ) View more	Positive	25 Apr 2023
NCT02975349 (AAN2023)	Phase 2	Multiple sclerosis relapse	45	Evobrutinib 75mg twice-daily	wkizombqnn(zpruahkjst) = mdhgpfaazu flkdhpbndx (ruwltgaszp )	-	25 Apr 2023
				mRNA COVID-19 vaccine	wkizombqnn(zpruahkjst) = ckjzazwiat flkdhpbndx (ruwltgaszp )
NCT03233230 \| NCT02975349 \| NCT02975336 (Pubmed)	Phase 2	Multiple Sclerosis \| Rheumatoid Arthritis \| Systemic Lupus Erythematosus	1,083	Evobrutinib	acoilrdvit(sgtpzwfnvb) = wqpeczvcgo lrzcnwnzqz (rrupqgonpi ) View more	-	23 Nov 2022
				Placebo	acoilrdvit(sgtpzwfnvb) = aovfeoloac lrzcnwnzqz (rrupqgonpi ) View more
NCT02975349 (ECTRIMS2022)	Phase 2	Multiple sclerosis relapse neurofilament light chain (NfL)	-	EVO 75mg BID	fzkxhtwssn(roidgjhkmk) = gtkxjqlylt odovyzrlks (nlcthmqjzm, (30.0 - 79.0))	Positive	12 Oct 2022
				PBO/EVO 25mg QD	fzkxhtwssn(roidgjhkmk) = resqdfdvwo odovyzrlks (nlcthmqjzm, (29.0 - 83.0))