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

BACKGROUND: Bruton's tyrosine kinase (BTK) regulates the functions of B cells and myeloid cells that are implicated in the pathogenesis of multiple sclerosis. Evobrutinib is a selective oral BTK inhibitor that has been shown to inhibit B-cell activation both in vitro and in vivo. METHODS: In this double-blind, randomized, phase 2 trial, we assigned patients with relapsing multiple sclerosis to one of five groups: placebo, evobrutinib (at a dose of 25 mg once daily, 75 mg once daily, or 75 mg twice daily), or open-label dimethyl fumarate (DMF) as a reference. The primary end point was the total (cumulative) number of gadolinium-enhancing lesions identified on T1-weighted magnetic resonance imaging at weeks 12, 16, 20, and 24. Key secondary end points included the annualized relapse rate and change from baseline in the score on the Expanded Disability Status Scale (EDSS). RESULTS: A total of 267 patients were randomly assigned to a trial group. The mean (±SD) total number of gadolinium-enhancing lesions during weeks 12 through 24 was 3.85±5.44 in the placebo group, 4.06±8.02 in the evobrutinib 25-mg group, 1.69±4.69 in the evobrutinib 75-mg once-daily group, 1.15±3.70 in the evobrutinib 75-mg twice-daily group, and 4.78±22.05 in the DMF group. The baseline adjusted rate ratios for the total number of lesions over time as compared with placebo were 1.45 in the evobrutinib 25-mg group (P = 0.32), 0.30 in the evobrutinib 75-mg once-daily group (P = 0.005), and 0.44 in the evobrutinib 75-mg twice-daily group (P = 0.06). The unadjusted annualized relapse rate at week 24 was 0.37 in the placebo group, 0.57 in the evobrutinib 25-mg group, 0.13 in the evobrutinib 75-mg once-daily group, 0.08 in the evobrutinib 75-mg twice-daily group, and 0.20 in the DMF group. There was no significant effect of trial group on the change from baseline in the EDSS score. Elevations in liver aminotransferase values were observed with evobrutinib. CONCLUSIONS: Patients with relapsing multiple sclerosis who received 75 mg of evobrutinib once daily had significantly fewer enhancing lesions during weeks 12 through 24 than those who received placebo. There was no significant difference with placebo for either the 25-mg once-daily or 75-mg twice-daily dose of evobrutinib, nor in the annualized relapse rate or disability progression at any dose. Longer and larger trials are required to determine the effect and risks of evobrutinib in patients with multiple sclerosis. (Funded by EMD Serono; ClinicalTrials.gov number, NCT02975349.).

Pharmacokinetics of dapsone gel, 5% for the treatment of acne vulgaris.

BACKGROUND: Oral dapsone has been available for over 60 years and has been used to treat severe acne vulgaris; however, the oral formulation is known to cause dose-dependent haematological reactions and is currently indicated only for diseases such as dermatitis herpetiformis and Hansen's disease. A gel formulation of dapsone was recently developed to treat acne vulgaris. As dapsone is administered topically, it was expected that systemic absorption would be considerably lower than that observed with oral dapsone therapy, thereby avoiding any adverse haematological effects. OBJECTIVE: To report the pharmacokinetic profile of topically applied dapsone gel, 5% in the treatment of acne vulgaris. STUDY PARTICIPANTS AND METHODS: Three prospective, open-label studies enrolled a total of 548 subjects with acne vulgaris: two phase I pharmacokinetic studies (crossover and drug interaction) and one phase III long-term safety study. In the crossover study (n = 18), topical dapsone gel applied twice daily for a total of 14 days to 22.5% of the body surface area was compared with a single dose of oral dapsone 100mg (the typical clinical dose). In the drug-interaction study (n = 24), oral trimethoprim/sulfamethoxazole monotherapy, topical dapsone gel monotherapy and the two in combination were used twice daily for 7, 21 and 7 days, respectively. In the long-term safety study (n = 506), topical dapsone gel was applied twice daily to acne-affected areas for up to 12 months. Blood samples were drawn at various timepoints in each study to assess drug and metabolite concentrations. Systemic concentrations of dapsone, N-acetyl dapsone, dapsone hydroxylamine, trimethoprim and sulfamethoxazole were determined, according to the study design. RESULTS: In the crossover study, the mean area under the plasma concentration-time curve (AUC) from 0 to 24 hours for dapsone was 417.5 ng x h/mL after 2 weeks of dapsone gel therapy (n = 10), compared with an AUC from time zero to infinity of 52,641 ng x h/mL after a single dose of oral dapsone; this represents a 126-fold lower systemic exposure for dapsone gel at typical therapeutic doses. In the drug-interaction study, the AUC from 0 to 12 hours for dapsone was 221.52 ng x h/mL after 3 weeks of dapsone gel monotherapy compared with 320.3 ng x h/mL after 1 week of coadministration with trimethoprim/sulfamethoxazole. In the long-term safety study, the mean plasma dapsone concentrations ranged from 7.5 to 11 ng/mL over 12 months. Overall, total systemic exposures to dapsone and its metabolites were approximately 100-fold less for dapsone gel than for oral dapsone, even in the presence of trimethoprim/sulfamethoxazole. There were no reports of any haematological adverse events. CONCLUSIONS: Topical application of dapsone gel in various settings ranging from 2 weeks to 12 months resulted in systemic exposures to dapsone and its metabolites that were approximately 100-fold less than those after oral dapsone at a therapeutic dose level. The concentrations of dapsone and its metabolites reached steady state and did not increase during prolonged treatment.