Spebrutinib (CC-292) Affects Markers of B Cell Activation, Chemotaxis, and Osteoclasts in Patients with Rheumatoid Arthritis: Results from a Mechanistic Study

Schäfer, Peter; Kivitz, Alan; Ma, Jianglin; Korish, Shimon; Sutherland, Donna; Li, Li; Azaryan, Ada; Kosek, Jolanta; Adams, Mary; Capone, Lori; Hur, Eun Mi; Hough, Douglas R.; Ringheim, Garth E.

doi:10.1007/s40744-019-00182-7

Cited by 55 publications

(78 citation statements)

References 18 publications

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“…Spebrutinib (CC-292) is the first irreversible covalent oral small molecule that inhibits BTK activity in B and myeloid cells. A phase IIa study with 47 patients over the course of four weeks showed that spebrutinib inhibited cellular responses associated with BTK signaling in primary human immune cells and was well tolerated [ 254 ]. Bristol–Myers Squibb developed a reversible inhibitor, BMS-986142, and an irreversible inhibitor, branebrutinib [ 255 , 256 ] of BTK.…”

Section: Autoimmune Diseasesmentioning

confidence: 99%

Therapeutic Advances in Diabetes, Autoimmune, and Neurological Diseases

Liu

Ting

Al-Azzam³

et al. 2021

IJMS

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Since 2015, 170 small molecules, 60 antibody-based entities, 12 peptides, and 15 gene- or cell-therapies have been approved by FDA for diverse disease indications. Recent advancement in medicine is facilitated by identification of new targets and mechanisms of actions, advancement in discovery and development platforms, and the emergence of novel technologies. Early disease detection, precision intervention, and personalized treatments have revolutionized patient care in the last decade. In this review, we provide a comprehensive overview of current and emerging therapeutic modalities developed in the recent years. We focus on nine diseases in three major therapeutics areas, diabetes, autoimmune, and neurological disorders. The pathogenesis of each disease at physiological and molecular levels is discussed and recently approved drugs as well as drugs in the clinic are presented.

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Section: Autoimmune Diseasesmentioning

confidence: 99%

Therapeutic Advances in Diabetes, Autoimmune, and Neurological Diseases

Liu

Ting

Al-Azzam³

et al. 2021

IJMS

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“…Safety and pharmacokinetics of GS-4059 in healthy volunteers and RA patients were evaluated in phase I placebo-controlled randomized study (NCT02626026), but no results have been posted. Spebrutinib (CC-292), although significantly reducing markers of chemotaxis and osteoclast activity, did not reach the statistically significant ACR 20 criteria (ACR20) response rate at week 4 in RA patients treatment [ 81 ]. HM71224 is a potent small molecule inhibitor BTK.…”

Section: Tsdmards Based On Jaks/mapks/nf-κb/syk-btk-targeted Theramentioning

confidence: 99%

“…AEs resulting from BTK inhibition can be followed in clinical trial of spebrutinib in RA patients [ 81 ]. It was well tolerated and most AEs like nausea, back pain, diarrhea, cough, and migraine were mild in severity.…”

Section: Tsdmards Based On Jaks/mapks/nf-κb/syk-btk-targeted Theramentioning

confidence: 99%

“…It was well tolerated and most AEs like nausea, back pain, diarrhea, cough, and migraine were mild in severity. However, as preclinical toxicology studies in mice showed maturing spermatid degeneration, spebrutinib was taken so far only by female patients, which limits the potential drug usage [ 81 ].…”

Section: Tsdmards Based On Jaks/mapks/nf-κb/syk-btk-targeted Theramentioning

confidence: 99%

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Small Molecule Inhibitors in the Treatment of Rheumatoid Arthritis and Beyond: Latest Updates and Potential Strategy for Fighting COVID-19

Massalska

Maśliński

Ciechomska

2020

Cells

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The development of biological disease-modifying antirheumatic drugs (bDMARDs) and target synthetic DMARDs (tsDMARDs), also known as small molecule inhibitors, represent a breakthrough in rheumatoid arthritis (RA) treatment. The tsDMARDs are a large family of small molecules targeting mostly the several types of kinases, which are essential in downstream signaling of pro-inflammatory molecules. This review highlights current challenges associated with the treatment of RA using small molecule inhibitors targeting intracellular JAKs/MAPKs/NF-κB/SYK-BTK signaling pathways. Indeed, we have provided the latest update on development of small molecule inhibitors, their clinical efficacy and safety as a strategy for RA treatment. On the other hand, we have highlighted the risk and adverse effects of tsDMARDs administration including, among others, infections and thromboembolism. Therefore, performance of blood tests or viral infection screening should be recommended before the tsDMARDs administration. Interestingly, recent events of SARS-CoV-2 outbreak have demonstrated the potential use of small molecule inhibitors not only in RA treatment, but also in fighting COVID-19 via blocking the viral entry, preventing of hyperimmune activation and reducing cytokine storm. Thus, small molecule inhibitors, targeting wide range of pro-inflammatory singling pathways, may find wider implications not only for the management of RA but also in the controlling of COVID-19.

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“…In a mouse xenograft human MM model, a combination of the BTK inhibitor CC-292 (spebrutinib, Celgene Corporation) with the proteasome inhibitor carfilzomib increased vertebral trabecular bone mass compared to carfilzomib alone and reduced tumor burden [ 10 ]. While CC-292 does not inhibit osteoclast differentiation, it inhibits the formation of the osteoclast sealing zone, thus interfering with osteoclast function and activity [ 10 ], and leading to reduced serum levels of the bone resorption biomarker carboxy-terminal collagen cross-linking telopeptide in mice [ 10 ] and humans [ 11 ]. CC-292 reduced tumor load and normalized tumor-associated expansion of T cells and monocytes, and did not affect T cell function in the adoptive transfer TCL1 mouse model of chronic lymphocytic leukemia [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

Prevention of Bone Destruction by Mechanical Loading Is Not Enhanced by the Bruton’s Tyrosine Kinase Inhibitor CC-292 in Myeloma Bone Disease

Ziouti

Rummler

Steyn

et al. 2021

IJMS

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Limiting bone resorption and regenerating bone tissue are treatment goals in myeloma bone disease (MMBD). Physical stimuli such as mechanical loading prevent bone destruction and enhance bone mass in the MOPC315.BM.Luc model of MMBD. It is unknown whether treatment with the Bruton’s tyrosine kinase inhibitor CC-292 (Spebrutinib), which regulates osteoclast differentiation and function, augments the anabolic effect of mechanical loading. CC-292 was administered alone and in combination with axial compressive tibial loading in the MOPC315.BM.Luc model for three weeks. However, neither CC-292 alone nor its use in combination with mechanical loading was more effective in reducing osteolytic bone disease or rescuing bone mass than mechanical stimuli alone, as evidenced by microCT and histomorphometric analysis. Further studies are needed to investigate novel anti-myeloma and anti-resorptive strategies in combination with physical stimuli to improve treatment of MMBD.

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Spebrutinib (CC-292) Affects Markers of B Cell Activation, Chemotaxis, and Osteoclasts in Patients with Rheumatoid Arthritis: Results from a Mechanistic Study

Cited by 55 publications

References 18 publications

Therapeutic Advances in Diabetes, Autoimmune, and Neurological Diseases

Therapeutic Advances in Diabetes, Autoimmune, and Neurological Diseases

Small Molecule Inhibitors in the Treatment of Rheumatoid Arthritis and Beyond: Latest Updates and Potential Strategy for Fighting COVID-19

Prevention of Bone Destruction by Mechanical Loading Is Not Enhanced by the Bruton’s Tyrosine Kinase Inhibitor CC-292 in Myeloma Bone Disease

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