Next-generation Bruton's tyrosine kinase inhibitor BIIB091 selectively and potently inhibits B cell and Fc receptor signaling and downstream functions in B cells and myeloid cells.

OBJECTIVES: Bruton's tyrosine kinase (BTK) plays a non-redundant signaling role downstream of the B-cell receptor (BCR) in B cells and the receptors for the Fc region of immunoglobulins (FcR) in myeloid cells. Here, we characterise BIIB091, a novel, potent, selective and reversible small-molecule inhibitor of BTK. METHODS: BIIB091 was evaluated in vitro and in vivo in preclinical models and in phase 1 clinical trial. RESULTS: In vitro, BIIB091 potently inhibited BTK-dependent proximal signaling and distal functional responses in both B cells and myeloid cells with IC50s ranging from 3 to 106 nm, including antigen presentation to T cells, a key mechanism of action thought to be underlying the efficacy of B cell-targeted therapeutics in multiple sclerosis. BIIB091 effectively sequestered tyrosine 551 in the kinase pocket by forming long-lived complexes with BTK with t 1/2 of more than 40 min, thereby preventing its phosphorylation by upstream kinases. As a key differentiating feature of BIIB091, this property explains the very potent whole blood IC50s of 87 and 106 nm observed with stimulated B cells and myeloid cells, respectively. In vivo, BIIB091 blocked B-cell activation, antibody production and germinal center differentiation. In phase 1 healthy volunteer trial, BIIB091 inhibited naïve and unswitched memory B-cell activation, with an in vivo IC50 of 55 nm and without significant impact on lymphoid or myeloid cell survival after 14 days of dosing. CONCLUSION: Pharmacodynamic results obtained in preclinical and early clinical settings support the advancement of BIIB091 in phase 2 clinical trials.

The efficacy and safety of mirabegron compared with solifenacin in overactive bladder patients dissatisfied with previous antimuscarinic treatment due to lack of efficacy: results of a noninferiority, randomized, phase IIIb trial.

OBJECTIVE: To compare the efficacy and safety of mirabegron 50 mg and solifenacin 5 mg in overactive bladder (OAB) patients dissatisfied with previous antimuscarinic treatment due to lack of efficacy. PATIENTS AND METHODS: This randomized, double-blind, phase IIIb, noninferiority study, enrolled male and female patients aged ⩾18 years old, with symptoms of OAB for ⩾3 months, who were dissatisfied with their previous antimuscarinic drug due to lack of efficacy. A total of 1887 patients were randomized to receive mirabegron 50 mg (n = 943) or solifenacin 5 mg (n = 944) daily for 12 weeks. The primary efficacy endpoint was change from baseline to end of treatment in mean number of micturitions/24 h. Noninferiority was confirmed if the lower limit of the two-sided 95% confidence interval (CI) for the treatment difference between solifenacin and mirabegron was > -0.20. Secondary efficacy endpoints, which included change from baseline in mean number of incontinence episodes/24 h, urgency incontinence episodes/24 h, urgency episodes (grade 3 or 4)/24 h and nocturia episodes/24 h, were analyzed using analysis of covariance. RESULTS: For the primary endpoint, adjusted mean treatment difference (95% CI) in mean number of micturitions/24 h was -0.18 (-0.42, 0.06) and therefore noninferiority of mirabegron to solifenacin was not demonstrated. Both treatments demonstrated clinically meaningful reductions in efficacy variables and were well tolerated, with a lower incidence of dry mouth with mirabegron. CONCLUSIONS: Noninferiority of mirabegron compared with solifenacin for reduction in micturition frequency could not be demonstrated in this population of OAB patients who were dissatisfied with previous antimuscarinic therapy due to lack of efficacy. Both mirabegron and solifenacin improved key OAB symptoms with no statistically significant differences observed between the two treatments. Both drugs were well tolerated.

An open-label, positron emission tomography study to assess adenosine A2A brain receptor occupancy of vipadenant (BIIB014) at steady-state levels in healthy male volunteers.

OBJECTIVE: Adenosine A2A receptor antagonists are potential new treatments for Parkinson disease. We used positron emission tomography (PET) of the A2A receptor radiotracer, [C]SCH442416, to assess binding of the novel A2A antagonist, vipadenant (previously known as BIIB014), to human brain A2A receptors and to investigate the relationship among dose, steady-state plasma levels, and receptor occupancy. METHODS: We used PET to compare [C]SCH442416 uptake before and after blockade with daily oral vipadenant (2.5-100 mg/d for 10 or 11 days) in healthy volunteers (n = 15). We estimated receptor occupancy in brain regions of interest, particularly the putamen, by kinetic modeling of PET data. We estimated the dose, minimal plasma concentration at steady state (Cmin), and area under the plasma concentration curve (AUC0-tau) at the steady state required for saturation (> or =90% receptor occupancy) using Bayesian Emax and logistic regression models. RESULTS: The estimated receptor occupancy of vipadenant in the brain regions of interest varied from 74% to 94% at the lowest daily dose (2.5 mg) and reached saturation in all regions at 100 mg. In the putamen, the estimated minimal daily dose, steady-state Cmin, and steady-state AUC0-tau required for receptor saturation were 10.2 mg (interquartile range, 28%), 0.097 microg/mL (27%), and 6 microg h/mL (21%), respectively. CONCLUSIONS: This study provides the first evidence that vipadenant occupies A2A receptors in the human brain. Receptor occupancy was related to both dose and plasma levels of vipadenant. These results, coupled with previous efficacy results in animals, justify continued development of vipadenant as a potential treatment for Parkinson disease.