ABBV-105, a selective and irreversible inhibitor of Bruton’s tyrosine kinase, is efficacious in multiple preclinical models of inflammation

Goess, Christian; Harris, Christopher M.; Murdock, Sara; McCarthy, Richard; Sampson, Erik R.; Twomey, Rachel; Mathieu, Suzanne; Mario, Regina; Perham, Matthew; Goedken, Eric R.; Long, Andrew J.

doi:10.1080/14397595.2018.1484269

Cited by 31 publications

(26 citation statements)

References 47 publications

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“…Autoantibodies were reduced in a dose-dependent fashion, but toward the end of the experiment, anti-dsDNA was still ∼10-fold higher than at the beginning of the experiment in animals treated with the highest dose of evobrutinib. A similar effect on autoantibodies was published for ABBV-105 and PF-06250112 (28,70). We did not quantify plasma cells in the bone marrow, and, therefore, we do not know whether they were reduced in a fashion comparable to the spleen.…”

Section: Discussionmentioning

confidence: 76%

“…Several other covalent or noncovalent BTK inhibitors have been tested in the NZB/W lupus model. These include covalent inhibitors HM71224, PF-06250112, ABBV-105, and BTK-BI-1 (28,(70)(71)(72) and the reversible inhibitors G-744 and RN486 (27,73). G-744 and ABBV-105 were tested in an IFN-a-accelerated NZB/W model, whereas the other molecules were tested in spontaneously developing lupus.…”

Section: Discussionmentioning

confidence: 99%

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Efficacy and Pharmacodynamic Modeling of the BTK Inhibitor Evobrutinib in Autoimmune Disease Models

Haselmayer

Camps

Liu-Bujalski

et al. 2019

The Journal of Immunology

116

135

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Section: Discussionmentioning

confidence: 76%

Section: Discussionmentioning

confidence: 99%

Efficacy and Pharmacodynamic Modeling of the BTK Inhibitor Evobrutinib in Autoimmune Disease Models

Haselmayer

Camps

Liu-Bujalski

et al. 2019

The Journal of Immunology

116

135

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“…Similar to ibrutinib, ABBV-105 was able to inhibit paw swelling and bone destruction in rat CIA models and reduced IFNα-accelerated lupus nephritis. Furthermore, antibody responses to thymus-independent and -dependent antigens were reduced [76]. The recently developed BTK inhibitor evobrutinib showed a robust, near-complete reduction of clinical and histological severity in animal models of RA and SLE.…”

Section: Btk Inhibition As a Novel Mechanism In The Treatment Of Cns mentioning

confidence: 99%

Inhibition of Bruton´s tyrosine kinase as a novel therapeutic approach in multiple sclerosis

Torke

Weber

2020

Expert Opinion on Investigational Drugs

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Introduction: B cells have increasingly come under the spotlight as mediators of inflammatory central nervous system (CNS) demyelinating diseases such as multiple sclerosis (MS). B cell depletion via the targeting of the surface molecule CD20 has proven to be highly effective; however, continuous absence of an integral component of the immune system may cause safety concerns over time. Declining humoral competence and potential immune system impairments are key issues, and moreover, unselective removal of B cells reduces immune system control functions which should preferably be maintained in inflammatory CNS disease. Areas covered: This paper illuminates the novel approach of specific interference with B cell signaling by targeting Bruton´s tyrosine kinase (BTK). We discuss the role of BTK within the B cell receptor (BCR) signaling cascade and BTK inhibition as a promising strategy to control inflammatory CNS disease which crucially excludes immune-cell depletion. We searched PubMed or clinicaltrials.gov for the terms 'BTK inhibition' or 'Bruton´s Tyrosine Kinase' or 'anti-CD20ʹ and 'Multiple Sclerosis' Expert opinion: BTK inhibition has shown effectiveness in preclinical models of CNS disease and MS clinical trials. Further studies are necessary to differentiate this approach from B cell depletion and to position it in the armamentarium of therapeutics.

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“…Hence, a need exists for new therapies with novel mechanisms of action. One potential target in RA is Bruton's tyrosine kinase (BTK) (7)(8)(9), a member of the TEC family of nonreceptor tyrosine kinases (10). BTK is highly expressed in hematopoietic cells and plays a critical role in B cell receptor signaling to control B cell function, survival, and proliferation (11).…”

Section: Introductionmentioning

confidence: 99%

Fenebrutinib Versus Placebo or Adalimumab in Rheumatoid Arthritis: A Randomized, Double‐Blind, Phase II Trial

Tuckwell¹,

Katsumoto

Zhao³

et al. 2020

Arthritis & Rheumatology

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Objective To evaluate fenebrutinib, an oral and highly selective noncovalent inhibitor of Bruton's tyrosine kinase (BTK), in patients with active rheumatoid arthritis (RA). Methods Patients with RA and an inadequate response to methotrexate (MTX) (cohort 1; n = 480) were randomized to receive fenebrutinib (50 mg once daily, 150 mg once daily, or 200 mg twice daily), adalimumab (40 mg every other week), or placebo. Patients with RA and an inadequate response to tumor necrosis factor inhibitors (cohort 2; n = 98) received fenebrutinib (200 mg twice daily) or placebo. Both cohorts continued MTX therapy. Results In cohort 1, the percentages of patients in whom American College of Rheumatology 50% improvement criteria (ACR50) was achieved at week 12 were similar in the fenebrutinib 50 mg once daily and placebo groups, and were higher in the fenebrutinib 150 mg once daily group (28%) and 200 mg twice daily group (35%) than in the placebo group (15%) (P = 0.016 and P = 0.0003, respectively). Fenebrutinib 200 mg twice daily and adalimumab (36%) were comparable (P = 0.81). In cohort 2, ACR50 was achieved in more patients receiving fenebrutinib 200 mg twice daily (25%) than placebo (12%) (P = 0.072). The most common adverse events in the fenebrutinib groups included nausea, headache, anemia, and upper respiratory tract infections. Fenebrutinib had significant effects on myeloid and B cell biomarkers (CCL4 and rheumatoid factor). Fenebrutinib and adalimumab caused overlapping as well as distinct changes in B cell and myeloid biomarkers. Conclusion Fenebrutinib demonstrates efficacy comparable to adalimumab in patients with an inadequate response to MTX, and safety consistent with existing immunomodulatory therapies for RA. These data support targeting both B and myeloid cells via this novel mechanism for potential efficacy in the treatment of RA.

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ABBV-105, a selective and irreversible inhibitor of Bruton’s tyrosine kinase, is efficacious in multiple preclinical models of inflammation

Abstract: ABBV-105, a selective BTK inhibitor, demonstrates compelling efficacy in pre-clinical mechanistic models of antibody production and in models of rheumatoid arthritis and lupus.

Cited by 31 publications

References 47 publications

Efficacy and Pharmacodynamic Modeling of the BTK Inhibitor Evobrutinib in Autoimmune Disease Models

Efficacy and Pharmacodynamic Modeling of the BTK Inhibitor Evobrutinib in Autoimmune Disease Models

Inhibition of Bruton´s tyrosine kinase as a novel therapeutic approach in multiple sclerosis

Fenebrutinib Versus Placebo or Adalimumab in Rheumatoid Arthritis: A Randomized, Double‐Blind, Phase II Trial

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