Placebo-Controlled Trial of an Oral BTK Inhibitor in Multiple Sclerosis

Montalbán, Xavier; Arnold, Douglas L.; Weber, Martin; Staikov, Ivan; Piasecka-Stryczyńska, Karolina; Willmer, Jonathan; Martin, Emily C.; Dangond, Fernando; Syed, Serajuddaula; Wolinsky, Jerry S.

doi:10.1056/nejmoa1901981

Cited by 253 publications

(229 citation statements)

References 28 publications

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“…Furthermore, following a single dose of CC‐292, five of six healthy subjects had > 98% BTK occupancy ≤ 4 hours after administration, with complete or near‐complete BTK occupancy sustained for 8–24 hours . These data supported the selection of recommended doses in the phase II program of evobrutinib and were successfully applied in a recent clinical study in MS …”

Section: Discussionsupporting

confidence: 52%

“…20 Furthermore, following a single dose of CC-292, five of six healthy subjects had > 98% BTK occupancy ≤ 4 hours after administration, with complete or near-complete BTK occupancy sustained for 8-24 hours. 21 These data supported the selection of recommended doses in the phase II program of evobrutinib and were successfully applied in a recent clinical study in MS. 22 We found no evidence of a significant exposure-effect relationship between evobrutinib concentration and QTcF. Over the range of doses evaluated, mean ΔΔQTcF was < 5 ms and the upper limit of the 90% two-sided CI was well below the 10 ms threshold of regulatory concern specified in the ICH-E14 guidance 13 at all time points, with the exception of the 100 mg dose group, in which mean ΔΔQTcF ranged from 5.6 to 7.2 ms and the upper limit of the CI ranged from 10.4 ms to 11.7 ms at three time points.…”

Section: Discussionmentioning

confidence: 99%

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Safety, Tolerability, Pharmacokinetics, Target Occupancy, and Concentration‐QT Analysis of the Novel BTK Inhibitor Evobrutinib in Healthy Volunteers

Becker

Martin

Mitchell³

et al. 2019

Clinical Translational Sci

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Bruton's tyrosine kinase (BTK) is a key regulator of B cell receptor and Fc receptor signaling, and a rational therapeutic target for autoimmune diseases. This first‐in‐human phase I, double‐blind, placebo‐controlled trial investigated the safety, tolerability, pharmacokinetics (PK), target occupancy, and effects on QT interval of evobrutinib, a highly selective, oral inhibitor of BTK, in healthy subjects. This dose escalation trial consisted of two parts. Part 1 included 48 subjects in 6 ascending dose cohorts (25, 50, 100, 200, 350, and 500 mg) randomized to a single dose of evobrutinib or placebo. Part 2 included 36 subjects in 3 ascending dose cohorts (25, 75, and 200 mg/day) randomized to evobrutinib or placebo once daily for 14 days. Safety and tolerability, as well as PK and target occupancy (total and free BTK in peripheral blood mononuclear cells), were assessed following single and multiple dosing. PK parameters were determined by noncompartmental methods. QT interval was obtained from 12‐lead electrocardiogram recordings and corrected for heart rate by Fridericia's method (QTcF). Treatment‐emergent adverse events (TEAEs) were mostly mild, occurring in 25% of subjects after single dosing, and 48.1% after multiple dosing. There was no apparent dose relationship regarding frequency or type of TEAE among evobrutinib‐treated subjects. Absorption was rapid (time to reach maximum plasma concentration (Tmax) ~ 0.5 hour), half‐life short (~ 2 hours), and PK dose‐proportional, with no accumulation or time dependency on repeat dosing. BTK occupancy was dose‐dependent, reaching maximum occupancy of > 90% within ~ 4 hours after single doses ≥ 200 mg; the effect was long‐lasting (> 50% occupancy at 96 hours with ≥ 100 mg). After multiple dosing, full BTK occupancy was achieved with 25 mg, indicating slow turnover of BTK protein in vivo. Concentration‐QTcF analyses did not show any impact of evobrutinib concentration on corrected QT (QTc). In summary, evobrutinib was well‐tolerated, showed linear and time‐independent PK, induced long‐lasting BTK inhibition, and was associated with no prolongation of QT/QTc interval in healthy subjects. Evobrutinib is, therefore, suitable for investigation in autoimmune diseases.

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Section: Discussionsupporting

confidence: 52%

Section: Discussionmentioning

confidence: 99%

Safety, Tolerability, Pharmacokinetics, Target Occupancy, and Concentration‐QT Analysis of the Novel BTK Inhibitor Evobrutinib in Healthy Volunteers

Becker

Martin

Mitchell³

et al. 2019

Clinical Translational Sci

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“…Preclinical models 16,26,27 and clinical experience 28 with covalent BTK inhibitors suggest that high levels of BTK occupancy are required for therapeutic effect. Efficacy is expected to occur at BTK occupancy of >90%; thus, at steady state, doses ≥1 mg are projected to be efficacious.…”

Section: Discussionmentioning

confidence: 99%

Safety, pharmacokinetics and pharmacodynamics of branebrutinib (BMS‐986195), a covalent, irreversible inhibitor of Bruton's tyrosine kinase: Randomised phase I, placebo‐controlled trial in healthy participants

Catlett

Nowak

Kundu

et al. 2020

Brit J Clinical Pharma

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Aims Branebrutinib (BMS‐986195) is a potent, highly selective, oral, small‐molecule, covalent inhibitor of Bruton's tyrosine kinase (BTK). This study evaluated safety, pharmacokinetics and pharmacodynamics of branebrutinib in healthy participants. Methods This double‐blind, placebo‐controlled, single‐ and multiple‐ascending dose (SAD; MAD) Phase I study (NCT02705989) enrolled participants into 3 parts: SAD, MAD and JMAD (MAD in first‐generation Japanese participants). In each part, participants were randomised 3:1 to receive branebrutinib (SAD: 0.3–30 mg; [J]MAD: 0.3–10 mg) or placebo. Participants in the MAD parts received branebrutinib daily for 14 days and were followed for 14 days postdosing. Safety was assessed by monitoring, laboratory and physical examinations, vital signs, and recording adverse events (AEs). Pharmacodynamics were assessed with a mass spectrometry assay that measured drug‐occupied and free BTK. Results The SAD, MAD and JMAD parts of the study included 40, 32 and 24 participants. Branebrutinib was well tolerated and AEs were mild/moderate, except for 1 serious AE that led to discontinuation. Branebrutinib was rapidly absorbed, with maximum plasma concentration occurring within 1 hour and a half‐life of 1.2—1.7 hours, dropping to undetectable levels within 24 hours. BTK occupancy was rapid, with 100% occupancy reached after a single 10‐mg dose. BTK occupancy decayed predictably over time (mean half‐life in MAD panels: 115–154 hours), such that pharmacodynamic effects were maintained after branebrutinib plasma levels fell below the lower limit of quantification. Conclusion Rapid and high occupancy of BTK and the lack of notable safety findings support further clinical development of branebrutinib.

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“…Of particular note, the Syk inhibitor (fostamatinib) has been approved for autoimmune thrombocytopenia 102 and the Btk inhibitor evobrutinib is in multiple sclerosis phase III trials after successful initial studies. 103 The latter two organ-specific autoimmune diseases may differ from SLE and RA regarding the role of APA B cells.…”

Section: Therapeutic Implicationsmentioning

confidence: 99%

Therapeutic implications of the anergic/postactivated status of B cells in systemic lupus erythematosus

et al. 2020

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Systemic lupus erythematosus (SLE) is characterised by numerous abnormalities in B lineage cells, including increased CD27++ plasmablasts/plasma cells, atypical CD27-IgD- B cells with increased CD95, spleen tyrosine kinase (Syk)++, CXCR5- and CXCR5+ subsets and anergic CD11c+Tbet+ age-associated B cells. Most findings, together with preclinical lupus models, support the concept of B cell hyperactivity in SLE. However, it remains largely unknown whether these specific B cell subsets have pathogenic consequences and whether they provide relevant therapeutic targets. Recent findings indicate a global distortion of B cell functional capability, in which the entire repertoire of naïve and memory B cells in SLE exhibits an anergic or postactivated (APA) functional phenotype. The APA status of SLE B cells has some similarities to the functional derangement of lupus T cells. APA B cells are characterised by reduced global cytokine production, diminished B cell receptor (BCR) signalling with decreased Syk and Bruton’s tyrosine kinase phosphorylation related to repeated in vivo BCR stimulation as well as hyporesponsiveness to toll-like receptor 9 engagement, but intact CD40 signalling. This APA status was related to constitutive co-localisation of CD22 linked to phosphatase SHP-1 and increased overall protein phosphatase activities. Notably, CD40 co-stimulation could revert this APA status and restore BCR signalling, downregulate protein tyrosine phosphatase transcription and promote B cell proliferation and differentiation. The APA status and their potential rescue by bystander help conveyed through CD40 stimulation not only provides insights into possible mechanisms of escape of autoreactive clones from negative selection but also into novel ways to target B cells therapeutically.

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Placebo-Controlled Trial of an Oral BTK Inhibitor in Multiple Sclerosis

Cited by 253 publications

References 28 publications

Safety, Tolerability, Pharmacokinetics, Target Occupancy, and Concentration‐QT Analysis of the Novel BTK Inhibitor Evobrutinib in Healthy Volunteers

Safety, Tolerability, Pharmacokinetics, Target Occupancy, and Concentration‐QT Analysis of the Novel BTK Inhibitor Evobrutinib in Healthy Volunteers

Safety, pharmacokinetics and pharmacodynamics of branebrutinib (BMS‐986195), a covalent, irreversible inhibitor of Bruton's tyrosine kinase: Randomised phase I, placebo‐controlled trial in healthy participants

Therapeutic implications of the anergic/postactivated status of B cells in systemic lupus erythematosus

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