Orismilast in moderate-to-severe psoriasis: Efficacy and safety from a 16-week, randomized, double-blinded, placebo-controlled, dose-finding, and phase 2b trial (IASOS).

BACKGROUND: Orismilast is a novel oral phosphodiesterase-4 (PDE4) B/D inhibitor being investigated as a potential treatment for moderate-to-severe psoriasis. OBJECTIVE: To evaluate efficacy and safety of orismilast modified-release formulation in moderate-to-severe psoriasis. METHODS: This multicenter, randomized (1:1:1:1 to 20, 30, 40 mg orismilast or placebo, twice daily), double-blinded, placebo-controlled, parallel-group, phase 2b, 16-week, dose-ranging study evaluated orismilast in adults with moderate-to-severe plaque psoriasis (NCT05190419). Efficacy end points were analyzed using multiple imputation. RESULTS: Of 202 randomized patients, baseline characteristics were balanced across arms, except greater severe disease proportions for orismilast vs placebo. Orismilast showed significant improvements in the primary end point, percentage change in Psoriasis Area and Severity Index (PASI), from baseline to week 16 (orismilast -52.6% to -63.7% and placebo, -17.3%; all P <.001). Greater proportions receiving orismilast achieved PASI75 (39.5%-49.0%; P <.05) and PASI90 (22.0%-28.3%; P <.05 for 20 and 40 mg) vs placebo (PASI75, 16.5% and PASI90, 8.3%) at week 16. Safety findings were as expected with PDE4 inhibition; dose-dependent tolerability effects observed. LIMITATIONS: Small sample size, disease severity imbalance between groups, limited duration and diversity in study population. CONCLUSION: Orismilast demonstrated greater efficacy vs placebo and a safety profile in line with PDE4 inhibition.

Effects of cladribine tablets on lymphocyte subsets in patients with multiple sclerosis: an extended analysis of surface markers.

BACKGROUND: Cladribine tablets 3.5 mg/kg cumulative over 2 years (CT3.5) had significant clinical/imaging effects in patients with clinically isolated syndrome (CIS; ORACLE-MS) or relapsing-remitting MS (RRMS; CLARITY and CLARITY Extension). This analysis compared the effect of cladribine tablets on the dynamics of immune cell reduction and reconstitution in ORACLE-MS, CLARITY, and CLARITY Extension during the first year of treatment (i.e. the first course of CT1.75) in patients randomized to CT3.5. METHODS: Lymphocyte subtypes were analyzed using multiparameter flow cytometry. Changes in cell counts and relative proportions of lymphocytes were evaluated at weeks 5, 13, 24, and 48. RESULTS: Across studies, consistent and comparable selective kinetics of immune cell populations occurred following the first treatment year with CT. A rapid reduction in CD16+/CD56+ cells (week 5 nadir), a more marked reduction in CD19+ B cells (week 13 nadir), and a less-pronounced effect on CD4+ (week 13 nadir) and CD8+ T cells (week 24 nadir) was shown. There was little effect on neutrophils or monocytes. Lymphocyte recovery began after treatment with CT3.5. Regarding relative proportions of naïve and memory T-cell subtypes in ORACLE-MS, the proportion of naïve-like naturally occurring T-regulatory cells (nTregs) decreased, and the proportion of memory-like nTregs increased, relative to total CD4+ T cells. CONCLUSIONS: CT3.5 has comparable effects on the immune systems of patients with CIS or RRMS. The pronounced reduction and recovery dynamics of CD19+ B cells and relative changes in the proportion of some immune cell subtypes may underlie the clinical effects of CT3.5.

Gender differences in severity, symptomatology and distribution of melancholia in major depression.

BACKGROUND: Studies of gender differences in the clinical presentation of depression have provided divergent results. This study aimed at analyzing gender differences in severity, symptomatology and distribution of melancholia in major depression. SAMPLING AND METHODS: The study comprised 930 in- and out-patients (652 women, 278 men) from 6 randomized controlled trials. All patients fulfilled DSM-III or DSM-III-R criteria for major depression. The 17-item Hamilton Depression Scale (HDS) was applied to all patients. A multi-axial evaluation was completed using the Newcastle 1 Depression Rating Scale from 1965 for melancholia (N1) in a subsample of patients (n = 439). A factor analysis on the HDS was performed. Non-parametric statistical tests were used and only gender differences greater than 20% were considered clinically relevant. RESULTS: The median on the HDS total score was 22 and the median number of symptoms was 13 for both men and women. Presentation of specific symptoms was similar for men and women. The factor analysis revealed no gender differences, and neither did analyses on symptoms of Axes II and IV. According to the N1, 80% of the men and 66% of the women suffered from melancholic depression (p = 0.004). CONCLUSIONS: In a large and broad sample of in- and out-patients with major depression, the severity and symptomatology of depression were similar for men and women. Melancholic depression was significantly more frequent among male than female patients. Inclusion and exclusion criteria in the randomized controlled trials provided a selected group of patients, which limited the generalisability of the results to an exclusive subgroup of patients treated for depression in routine clinical practice.

Are gender differences important for the clinical effects of antidepressants?

OBJECTIVE: Gender differences in antidepressant treatment response, side effects, dropout rates, and plasma concentrations were examined in patients with major and predominantly melancholic depression. METHOD: The study included a subgroup of 292 inpatients (96 men, 196 women) from three Danish double-blind, randomized, controlled trials. All patients completed a 5-week treatment period and fulfilled the DSM-III or DSM-III-R criteria for major depression. Clomipramine (150 mg/day) was the reference treatment, and comparable treatments were citalopram (40 mg/day), paroxetine (30 mg/day), and moclobemide (400 mg/day). Assessments were performed by using the 17-item Hamilton Depression Rating Scale and the Udvalg for Kliniske Undersøgelser Side Effect Rating Scale. In a subgroup of 110 patients, weekly measurements of clomipramine plasma concentrations were obtained. Nonparametric statistical tests and multiple linear and logistic regression models were used for statistical evaluations. RESULTS: Both genders had similar remission rates (Hamilton depression scale score <8) when treated with clomipramine and had significantly higher remission rates with clomipramine than with the comparable treatments. The plasma concentrations of clomipramine were significantly higher for female than for male patients. No gender differences were found in posttreatment Hamilton depression scale scores, nor did the therapeutic effects of treatment depend on gender. Rates of dropout and side effects were similar for men and women. No relationship between plasma concentrations, gender, and therapeutic outcome was found. CONCLUSIONS: In a group of patients with major and predominantly melancholic depression, differentiation according to gender was not important in treatment with common antidepressants. Women appeared to have higher plasma concentrations of tricyclic antidepressants than men. The consequences of this difference for clinical effects are unclear. Gender-specific recommendations for dosing of tricyclic antidepressants may be considered.