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]

NCT05248945

/ CompletedPhase 1

Phase I, Open-Label, Single-Sequence Study of the Effect of Multiple Doses of Carbamazepine on Single-Dose Evobrutinib Pharmacokinetics in Healthy Participants

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

100 Translational Medicine associated with Evobrutinib

100 Patents (Medical) associated with Evobrutinib

Literatures (Medical) associated with Evobrutinib

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.

01 Jan 2025·Multiple Sclerosis Journal-Experimental Translational and Clinical

Positive effect of evobrutinib in CNS remyelination models and lack of synergy with clemastine—A dose response study

Article

Author: Stankoff, B. ; Boschert, U. ; Aigrot, M.S. ; Zalc, B. ; Martin, E. ; Lubetzki, C. ; Frère, N. ; Lepaulmier, R.

Background:

To recover normal functions, remyelination in multiple sclerosis is crucial. Although endogenous remyelination occurs, it is often insufficient, and finding molecules promoting repair of demyelinated lesions is needed.

Objectives:

To compare the remyelination potential of evobrutinib, an inhibitor of Bruton's tyrosine kinase and clemastine, an antagonist of M1 muscarinic acetylcholine receptor.

Methods:

Remyelination was investigated in lysolecithin demyelinated organotypic mouse cerebellar slices and a transgenic Xenopus model of inducible-demyelination.

Results:

Evobrutinib (100 nM) and clemastine (200 nM) potentiated remyelination of mouse cerebellar slices by a factor of 2.9 and 1.76, respectively. In conditionally demyelinated Xenopus , evobrutinib and clemastine increased remyelination by a factor of 1.61 and 1.92, respectively. Evobrutinib targets Bruton's tyrosine kinase expressed by microglia, and we showed that the increase in number of myeloid cells following demyelination is due to an extravasation from nearby vessels of macrophages migrating toward the optic nerve. In contrast, clemastine is expected to antagonize muscarinic receptor 1 expressing cells of the oligodendroglial lineage. We investigated a possible synergistic effect on remyelination by adding simultaneously both molecules. In both experimental models tested no significative improvement on remyelination of co-treatment with evobrutinib plus clemastine was observed.

Discussion:

While evobrutinib increased 1.59 fold the number of microglia/macrophages, in the presence of clemastine the number of innate immune cells was decreased by 0.39 fold, therefore counteracting the beneficial effect of microglia/macrophages on remyelination.

News (Medical) associated with Evobrutinib

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

25 Apr 2025

·www.pharmaceutical-technology.com

Merck KGaA nears $3.5bn deal for SpringWorks

Merck KGaA is in late-stage discussions to acquire SpringWorks. Credit: Anne Czichos via Getty Images. Merck KGaA is edging closer to the SpringWorks deal, which was first rumoured in February, confirming late-stage negotiations at an estimated price of $47 per share – potentially valuing the deal at around $3.5bn. The company confirmed in a 24 April statement that while no final, legally binding agreement has been established, the “parties are in discussion on the basis of a price of around $47 per share.” The news follows months of speculation. Market chatter around a potential acquisition began on 10 February 2025, when Reuters reported that Merck KGaA was exploring a deal. That same day, the German pharma firm acknowledged the discussions, but cautioned that there was no guarantee of a transaction. Following the report, SpringWorks shares jumped 34%, pushing the company’s market capitalisation over $4bn. Merck KGaA’s CEO Belén Garijobut declined to provide updates on the deal during the company’s full-year earnings press call in March, keeping investors in suspense. Shares in SpringWorks were up by almost 9% when the markets opened on 25 April, after the latest development. A successful acquisition would bolster Merck KGaA’s oncology portfolio with SpringWork’s pipeline of targeted therapies. These include Ogsiveo (nirogacestat), which is approved for treating desmoid tumours, as well as the MEK inhibitor Gomekli (mirdametinib), which was approved in February 2025 for treating neurofibromatosis type 1 (NF1), a rare genetic disorder. According to projections from GlobalData’s Pharma Intelligence Center, Gomekli is projected to generate up to $564m in global sales by 2030, while Ogsiveo sales are expected to reach $1.2bn by the same year. GlobalData Strategic Intelligence US Tariffs are shifting - will you react or anticipate? Don’t let policy changes catch you off guard. Stay proactive with real-time data and expert analysis. By GlobalData Learn more about Strategic Intelligence GlobalData is the parent company of Pharmaceutical Technology. Merck KGaA already has a strong oncology pipeline. Its top-selling product in 2024 was Erbitux (cetuximab), which generated €1.16bn ($1.25bn) in revenue. The drug is a monoclonal antibody used to treat certain head and neck cancers, and colorectal cancer. However, not all programs have been as successful. In June 2024, Merck KGaA terminated the Phase III TrilynX clinical trial of xevinapant after the drug failed to significantly improve survival in patients with locally advanced head and neck cancer. Additionally, Merck KGaA has faced setbacks in its neurology pipeline, including the discontinuation of BTK inhibitor evobrutinib in March 2024. The decision followed two Phase II trials in relapsing multiple sclerosis, where the drug did not achieve a statistically significant reduction in annual relapse rates compared to Sanofi’s Aubagio (teriflunomide). The programme had already come under scrutiny in April 2023, when the US Food and Drug Administration (FDA) placed a partial clinical hold on a Phase III study after cases of liver injury were reported. Merck KGaA has continued to prioritise the expansion of its oncology portfolio. Earlier in April 2025, the company signed a $1.4bn multi-year collaboration with Caris Life Sciences to access novel antibody-drug conjugate (ADC) targets. Under the agreement, Caris will identify tumour-associated targets, which Merck KGaA will take into preclinical and clinical development. Merck KGaA also has an internal ADC programme, with its lead candidate M9140 currently in Phase I trials for colorectal cancer.

Drug ApprovalPhase 2AcquisitionPhase 1Phase 3

06 Mar 2025

·www.fiercebiotech.com

Merck KGaA fails midphase lupus trial, says totality of data support further development

The importance of enpatoran to Merck has increased as other prospects have flamed out. \n One of Merck KGaA’s leading immunology assets has flunked a phase 2 lupus trial. Despite the primary endpoint miss, Merck has concluded further development is warranted in light of responses seen in subgroups and a recent win in another form of the disease.Merck tested its oral TLR7/8 inhibitor enpatoran in two forms of lupus. The company reported positive phase 2 data from the cohort of cutaneous lupus erythematosus (CLE) patients late last year. Thursday, Merck revealed the systemic lupus erythematosus (SLE) cohort was less successful. The SLE arm missed its primary endpoint, which assessed responses on a composite scale after 24 weeks of daily dosing.The German drugmaker said it saw “promising responses” in predefined subgroups of patients. Considering the subgroup responses, CLE results and safety profile, Merck judged that the totality of data supports further development.Merck is yet to share the data underpinning its conclusion, with updates to date limited to qualitative assessments of the results. Peter Guenter, CEO of healthcare at Merck, disclosed the CLE success at the company’s Capital Markets Day in October, telling analysts the trial found “very strong and unambiguous proof of concept in cutaneous lupus.” Enpatoran, which Merck is also studying in idiopathic inflammatory myopathies, is one of the two most advanced assets in the company’s neurology and immunology pipeline. Cladribine, the other advanced candidate, is in phase 3 development as a treatment for generalized myasthenia gravis.The importance of enpatoran and cladribine to Merck has increased as other prospects have flamed out. Four years ago, Merck named enpatoran, evobrutinib and xevinapant as three important clinical programs that it expected to help fuel its “next wave of growth.” Evobrutinib failed a phase 3 trial in late 2023 and was quickly axed, while Merck dropped xevinapant in June 2024 after an interim phase 3 analysis.

Phase 3Phase 2Clinical 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

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)	karlobnjsq(rxdowqefyb) = cbpxryoxku glkzcqgysc (jujvfqrooy, rzzzuhtvou - nvpnnthltp) View more	-	14 Jan 2025
				Evobrutinib (Evobrutinib)	karlobnjsq(rxdowqefyb) = kodbpbpepx glkzcqgysc (jujvfqrooy, ivlifqitng - afoaevryxo) View more
NCT04338061 \| NCT04338022 (evolutionRMS 1, Biospace) Manual	Phase 3	Multiple sclerosis relapse	-	Evobrutinib (evolutionRMS 1)	zlhuubdwot(abdrhyvidi) = igtgmhhxfu imnzwroaxi (wrfrzehxes ) Not Met	Negative	05 Dec 2023
				teriflunomide (evolutionRMS 1)	zlhuubdwot(abdrhyvidi) = yvtnyfggtt imnzwroaxi (wrfrzehxes ) Not Met
NCT02975349 (Phase 2 OLE, ECTRIMS2023)	Phase 2	Bruton Type Agammaglobulinemia	267	Evobrutinib 25mg QD	empabdezca(yaheyyukzt) = Treatment-emergent adverse events (TEAEs) were reported by 142/164 PwRMS (86.6%) btrivthdci (iqajvnhgok ) View more	Positive	30 Sep 2023
				Evobrutinib 75mg BID
NCT02975349 (Phase II, EAN2023)	Phase 2	Rhabdomyosarcoma	45	Evobrutinib 75mg twice-daily	qeupizerzv(gcdkorrkjx) = aytxaqwnfk nswtncrboa (uiigcpjvta )	Positive	28 Jun 2023
ACTRIMS2023	Not Applicable	Multiple sclerosis relapse	-	Evobrutinib 75 mg twice-daily	lwbhzhgmbj(umuttdripp) = nvdtpqwyhs naigurkxvy (tstdjsbsik, 4.5)	-	30 May 2023
				mRNA COVID-19 vaccine	lwbhzhgmbj(umuttdripp) = hvfopicwzx naigurkxvy (tstdjsbsik, 4.3)
ACTRIMS2023	Not Applicable	Neuroinflammation	-	Evobrutinib	edfuekrmop(qlmbvtmhtr) = vvmzmgotnq trrfmtqgwy (eyayrlcxof )	Positive	30 May 2023
				Anti-CD20 (clone: SA271G2)	mlnfzkmwct(pjisiazilo) = lsqkmdeljk rsnultcspw (yrfevdlezq ) View more
AAN2023	Not Applicable	Neuroinflammation	-	Evobrutinib	wgvuntzosj(qqxzfhasbg) = dmwocsasym ifjazdgukk (flfuekvabo ) View more	Positive	25 Apr 2023
NCT02975349 (AAN2023)	Phase 2	Multiple sclerosis relapse	45	Evobrutinib 75mg twice-daily	xvgwkqwcej(oeuublrvzd) = ihcejsfxod pfugwhcidp (ifvdcuffhx )	-	25 Apr 2023
				mRNA COVID-19 vaccine	xvgwkqwcej(oeuublrvzd) = mbjeqzgwlk pfugwhcidp (ifvdcuffhx )
NCT03233230 \| NCT02975349 \| NCT02975336 (Pubmed)	Phase 2	Multiple Sclerosis \| Rheumatoid Arthritis \| Systemic Lupus Erythematosus	1,083	Evobrutinib	fzwmbsigyk(vhokjgrxsf) = ajbyvdpenb lkmxftvilv (pawmmoijhd ) View more	-	23 Nov 2022
				Placebo	fzwmbsigyk(vhokjgrxsf) = zcpocyoqvy lkmxftvilv (pawmmoijhd ) View more
NCT02975349 (ECTRIMS2022)	Phase 2	Multiple sclerosis relapse	267	Evobrutinib 75mg QD	mwamvviure(fowhqgdnpo) = sbbtsrrhej lwcvbaexxu (awbjixbfqv )	-	12 Oct 2022
				Evobrutinib 75mg BID	mwamvviure(fowhqgdnpo) = rbmpqgwzto lwcvbaexxu (awbjixbfqv )

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