branebrutinib (BMS-986195) / BMS - LARVOL DELTA

A Study of BMS-986166 or Branebrutinib for the Treatment of Participants With Atopic Dermatitis (clinicaltrials.gov) - P2 | N=17 | Completed | Sponsor: Bristol-Myers Squibb | Active, not recruiting ➔ Completed | Trial completion date: Jan 2024 ➔ Aug 2022

Trial completion • Trial completion date • Atopic Dermatitis • Dermatitis • Dermatology • Immunology

A Study to Assess Relative Bioavailability of Branebrutinib, From a Tablet Formulation to the Capsule Formulation, the Effect of Food on the Bioavailability of Branebrutinib From a Tablet Formulation, and the Safety and Drug Levels of Branebrutinib From a Tablet Formulation in Healthy Participants (clinicaltrials.gov) - P1 | N=56 | Completed | Sponsor: Bristol-Myers Squibb | Recruiting ➔ Completed

Trial completion

Study to Assess Safety and Effectiveness of Branebrutinib Treatment in Participants With Active Systemic Lupus Erythematosus or Primary Sjögren's Syndrome, or Branebrutinib Treatment Followed by Open-label Abatacept Treatment in Study Participants With Active Rheumatoid Arthritis (clinicaltrials.gov) - P2 | N=112 | Completed | Sponsor: Bristol-Myers Squibb | Recruiting ➔ Completed | N=185 ➔ 112 | Trial completion date: Jul 2023 ➔ Dec 2022 | Trial primary completion date: Jul 2023 ➔ Dec 2022

Enrollment change • Trial completion • Trial completion date • Trial primary completion date • Immunology • Inflammatory Arthritis • Lupus • Rheumatoid Arthritis • Rheumatology • Sjogren's Syndrome • Systemic Lupus Erythematosus

A Study of BMS-986166 or Branebrutinib for the Treatment of Participants With Atopic Dermatitis (clinicaltrials.gov) - P2 | N=17 | Active, not recruiting | Sponsor: Bristol-Myers Squibb | Recruiting ➔ Active, not recruiting | N=150 ➔ 17 | Trial primary completion date: Nov 2023 ➔ Aug 2022

Enrollment change • Enrollment closed • Trial primary completion date • Atopic Dermatitis • Dermatitis • Dermatology • Immunology

A Study of BMS-986166 or Branebrutinib for the Treatment of Participants With Atopic Dermatitis (clinicaltrials.gov) - P2 | N=150 | Recruiting | Sponsor: Bristol-Myers Squibb | Trial completion date: Feb 2023 ➔ Jan 2024 | Trial primary completion date: Jan 2023 ➔ Nov 2023

Trial completion date • Trial primary completion date • Atopic Dermatitis • Dermatitis • Dermatology • Immunology

Structural journey in the discovery of BTK inhibitors BMS-986142 and branebrutinib, from an early nicotinamide lead to advanced carbazole and dimethylindole cores (ACS-Fall 2022) - "Structure-based design from a nicotinamide core led to the carbazole series of inhibitors that set the stage for the discovery of BMS-986142, a non-covalent, reversible inhibitor of BTK. Further structure- and property-based modifications to the carbazoles afforded the indole-carboxamide scaffold, which was a key step in the discovery of the covalent, irreversible BTK inhibitor, branebrutinib."

Immunology • Inflammatory Arthritis • Lupus • Rheumatoid Arthritis • Rheumatology

ASSESSMENT OF THE DRUG-DRUG INTERACTION POTENTIAL OF BRANEBRUTINIB (BMS-986195), A HIGHLY POTENT AND SELECTIVE IRREVERSIBLE COVALENT INHIBITOR OF BRUTON’S TYROSINE KINASE, IN HEALTHY PARTICIPANTS (EULAR 2022) - "In the first 2-part study, MTX was administered alone or with steady-state (SS) branebrutinib (10 mg QD) in part 1; in part 2, caffeine, montelukast, flurbiprofen, omeprazole, midazolam, digoxin, and pravastatin were taken with or without SS branebrutinib (9 mg QD)...In cycle 1 of the third study, the oral contraceptive (OC) loestrin (1.5 mg norethindrone/30 μg ethinyl estradiol) was taken alone; in cycle 2, SS branebrutinib (9 mg QD) was taken alone or with the OC... In all 3 studies, co-administration of SS branebrutinib was generally well tolerated. The only potentially significant DDIs with substrates of major DMEs or transporters were mild increases in montelukast (CYP2C8) and digoxin (P-gp) exposures."

Clinical • Atopic Dermatitis • Breast Cancer • Dermatitis • Dermatology • Immunology • Inflammation • Inflammatory Arthritis • Lupus • Oncology • Sjogren's Syndrome • Solid Tumor • Systemic Lupus Erythematosus • CYP2C8 • CYP3A4 • SULT1E1

A Study to Assess Relative Bioavailability of Branebrutinib, From a Tablet Formulation to the Capsule Formulation, the Effect of Food on the Bioavailability of Branebrutinib From a Tablet Formulation, and the Safety and Drug Levels of Branebrutinib From a Tablet Formulation in Healthy Participants (clinicaltrials.gov) - P1 | N=56 | Recruiting | Sponsor: Bristol-Myers Squibb | Not yet recruiting ➔ Recruiting

Enrollment open

Study to Assess Safety and Effectiveness of Branebrutinib Treatment in Participants With Active Systemic Lupus Erythematosus or Primary Sjögren’s Syndrome, or Branebrutinib Treatment Followed by Open-label Abatacept Treatment in Study Participants With Active Rheumatoid Arthritis (clinicaltrials.gov) - P2; N=185; Recruiting; Sponsor: Bristol-Myers Squibb

Clinical • New P2 trial • Immunology • Lupus • Rheumatoid Arthritis • Rheumatology • Systemic Lupus Erythematosus

Study to Assess Safety and Effectiveness of Branebrutinib Treatment in Participants With Active Systemic Lupus Erythematosus or Primary Sjögren’s Syndrome, or Branebrutinib Treatment Followed by Open-label Abatacept Treatment in Study Participants With Active Rheumatoid Arthritis (clinicaltrials.gov) - P2 | N=185 | Recruiting | Sponsor: Bristol-Myers Squibb | Trial completion date: Feb 2023 ➔ Jul 2023 | Trial primary completion date: Feb 2023 ➔ Jul 2023

Trial completion date • Trial primary completion date • Immunology • Inflammatory Arthritis • Lupus • Rheumatoid Arthritis • Rheumatology • Sjogren's Syndrome • Systemic Lupus Erythematosus

Study to Assess Safety and Effectiveness of Branebrutinib Treatment in Participants With Active Systemic Lupus Erythematosus or Primary Sjögren’s Syndrome, or Branebrutinib Treatment Followed by Open-label Abatacept Treatment in Study Participants With Active Rheumatoid Arthritis (clinicaltrials.gov) - P2; N=185; Recruiting; Sponsor: Bristol-Myers Squibb; Trial completion date: Jun 2022 ➔ Feb 2023; Trial primary completion date: Jun 2022 ➔ Feb 2023

Clinical • Trial completion date • Trial primary completion date • Immunology • Inflammatory Arthritis • Lupus • Rheumatoid Arthritis • Rheumatology • Sjogren's Syndrome • Systemic Lupus Erythematosus

A Study to Assess Relative Bioavailability of Branebrutinib, From a Tablet Formulation to the Capsule Formulation, the Effect of Food on the Bioavailability of Branebrutinib From a Tablet Formulation, and the Safety and Drug Levels of Branebrutinib From a Tablet Formulation in Healthy Participants (clinicaltrials.gov) - P1 | N=56 | Not yet recruiting | Sponsor: Bristol-Myers Squibb

New P1 trial

Study to Assess the Effect of Branebrutinib on the Drug Levels of Rosuvastatin in Healthy Participants (clinicaltrials.gov) - P1 | N=22 | Completed | Sponsor: Bristol-Myers Squibb | Not yet recruiting ➔ Completed

Trial completion

A Study of BMS-986166 or Branebrutinib for the Treatment of Participants With Atopic Dermatitis (clinicaltrials.gov) - P2; N=150; Recruiting; Sponsor: Bristol-Myers Squibb

Clinical • New P2 trial • Atopic Dermatitis • Dermatitis • Dermatology • Immunology

Branebrutinib (BMS-986195), a Bruton's Tyrosine Kinase Inhibitor, Resensitizes P-Glycoprotein-Overexpressing Multidrug-Resistant Cancer Cells to Chemotherapeutic Agents. (PubMed, Front Cell Dev Biol) - "In addition, we found that branebrutinib is equally cytotoxic to drug-sensitive parental cell lines and the respective P-gp-overexpressing multidrug-resistant variants, suggesting that it is unlikely that the overexpression of P-gp in cancer cells plays a significant role in reduced susceptibility or resistance to branebrutinib. In summary, we discovered an additional pharmacological action of branebrutinib against the activity of P-gp, which should be investigated further in future drug combination studies."

Journal • Oncology • ABCB1

[VIRTUAL] Assessment of the Effects of Syk and BTK Inhibitors on GPVI-mediated Platelet Signaling and Function (ISTH 2021) - "Aims : Determine the effects of 12 TKIs (Bay 61-3606, R406/fostamatinib, entospletinib, TAK-659, ibrutinib, acalabrutinib, ONO-4059/tirabrutinib, AVL-292/spebrutinib, CG-806, BMS-935177, BMS-986195, fenebrutinib) on platelet functional responses...Platelets were stimulated and assessed for P-selectin exposure, PAC-1 binding, ATP secretion, adhesion on collagen and fibrinogen surfaces under static and physiological flow conditions, protein phosphorylation levels, and PI3K/tubulin colocalization to evaluate the effect of each inhibitor on platelet function...Fluorescence imaging of PI3K found co-localization with tubulin when untreated, but is disrupted in platelets treated with the selected TKIs. Conclusions : Clinically relevant TKIs targeting Syk and BTK inhibit platelet functional responses, but may differentially alter PI3K signaling and organization in an inhibitor class specific manner."

Oncology • PLCG2 • SYK

Bleeding by Bruton Tyrosine Kinase-Inhibitors: Dependency on Drug Type and Disease. (PubMed, Cancers (Basel)) - "However, mild bleeding is frequent in patients with B-cell malignancies treated with the irreversible BTKi ibrutinib and the recently approved 2nd generation BTKi acalabrutinib, zanubrutinib and tirabrutinib, and also in volunteers receiving in a phase-1 study the novel irreversible BTKi BI-705564...These include the brain-penetrant irreversible tolebrutinib and evobrutinib (against multiple sclerosis), the irreversible branebrutinib, the reversible BMS-986142 and fenebrutinib (targeting rheumatoid arthritis and lupus erythematodes), and the reversible covalent rilzabrutinib (against pemphigus and immune thrombocytopenia). Remibrutinib, a novel highly selective covalent BTKi, is currently in clinical studies of autoimmune dermatological disorders...By focusing on their pharmacological properties, targeted disease, bleeding side effects and actions on platelets it attempts to clarify the mechanisms underlying bleeding. Specific platelet function tests in blood might help..."

Journal • Review • CNS Disorders • Complement-mediated Rare Disorders • Dermatology • Hematological Disorders • Immunology • Infectious Disease • Inflammatory Arthritis • Lupus • Multiple Sclerosis • Novel Coronavirus Disease • Oncology • Rheumatoid Arthritis • Rheumatology • Thrombocytopenia • Thrombocytopenic Purpura

Assessment of the effects of Syk and BTK inhibitors on GPVI-mediated platelet signaling and function. (PubMed, Am J Physiol Cell Physiol) - "These inhibitors include, four Syk inhibitors, Bay 61-3606, R406 (fostamatinib), entospletinib, TAK-659, four irreversible BTK inhibitors, ibrutinib, acalabrutinib, ONO-4059 (tirabrutinib), AVL-292 (spebrutinib), and four reversible BTK inhibitors, CG-806, BMS-935177, BMS-986195, and fenebrutinib...Similarly, these TKIs reduced the percentage of activated integrin αβ on the platelet surface in response to CRP-XL, as determined by PAC-1 binding...Select TKIs also inhibited platelet aggregate formation on collagen under physiological flow conditions. Together, our results suggest that TKIs targeting Syk or BTK inhibit central platelet functional responses but may differentially affect protein activities and organization in critical systems downstream of Syk and BTK in platelets."

Journal • Oncology • SYK

Achieving a Low Human Dose for Targeted Covalent Drugs: Pharmacokinetic and Pharmacodynamic Considerations on Target Characteristics and Drug Attributes. (PubMed, Biopharm Drug Dispos) - "The model-based approach provided a theoretical framework in achieving a low human dose of targeted covalent drugs, and the resultant strategy was successfully applied in the early stage of a Bruton's tyrosine kinase covalent inhibitor project that discovered low-dose branebrutinib...The model-based approach provided a theoretical framework in achieving a low human dose of targeted covalent drugs, and the resultant strategy was successfully applied in the early stage of a Bruton's tyrosine kinase covalent inhibitor project that discovered low-dose branebrutinib. The PK/PD considerations described are also applicable to the drug design for protein degraders that share the same endpoint as targeted covalent drugs in reducing target levels."

Journal • PK/PD data

Determination of Real Time in Vivo Drug Receptor Occupancy for a Covalent Binding Drug as a Clinical Pharmacodynamic Biomarker by Immunocapture-LC-MS/MS. (PubMed, Anal Chem) - "This strategy has been successfully applied to the measurement of the RO for Bruton's tyrosine kinase (BTK) in the blood lysate of monkeys after dosing with branebrutinib (BMS-986195), a covalent BTK inhibitor being evaluated to treat rheumatoid arthritis...To measure a wide range of % BTK RO, including those of 95%, the required LLOQ at 0.125 nM for QB-BTK and 0.250 nM for drug-bound BTK (DB-BTK) in blood lysate were successfully achieved by using this IC-LC-MS/MS strategy. This proof-of-concept assay demonstrated its suitability with high throughput for real time in vivo BTK RO measurement as a pharmacodynamic (PD) biomarker for clinical drug development."

Biomarker • Journal • PK/PD data • Immunology • Rheumatoid Arthritis • Rheumatology

Discovery of Branebrutinib (BMS-986195): A Strategy for Identifying a Highly Potent and Selective Covalent Inhibitor Providing Rapid In Vivo Inactivation of Bruton's Tyrosine Kinase (BTK). (PubMed, J Med Chem) - "This article will outline the evolution of our strategy to identify a covalent, irreversible inhibitor of BTK that has the intrinsic potency, selectivity, and pharmacokinetic properties necessary to provide a rapid rate of inactivation systemically following a very low dose. With excellent in vivo efficacy and a very desirable tolerability profile, 5a (branebrutinib, BMS-986195) has advanced into clinical studies."

Journal • Preclinical • Immunology • Lupus • Rheumatoid Arthritis • Rheumatology

Study to Assess the Effect of Branebrutinib on the Drug Levels of Rosuvastatin in Healthy Participants (clinicaltrials.gov) - P1; N=22; Not yet recruiting; Sponsor: Bristol-Myers Squibb

Clinical • New P1 trial

Discovery of BMS-986195: A strategy for identifying a highly potent and selective covalent inhibitor providing rapid inactivation of Bruton’s tyrosine kinase (BTK) (ACS-Sp 2018) - "With excellent in vivo efficacy and a very desirable tolerability profile, BMS-986195 has advanced into clinical studies. The structure of BMS-986195 will be disclosed."

Biosimilar • Immunology • Inflammation • Rheumatoid Arthritis

"BTK inhibitor BMS-986195 shows promise in clinic. #ACR17" (@Cortellis)

Biosimilar • Women's Health

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. (PubMed, Br J Clin Pharmacol) - P1; "Rapid and high occupancy of BTK and the lack of notable safety findings support further clinical development of branebrutinib."

Clinical • Journal • PK/PD data