Safety and Efficacy of GFB-887, a TRPC5 Channel Inhibitor, in Patients With Focal Segmental Glomerulosclerosis, Treatment-Resistant Minimal Change Disease, or Diabetic Nephropathy: TRACTION-2 Trial Design.

INTRODUCTION: A critical unmet need exists for precision therapies for chronic kidney disease. GFB-887 is a podocyte-targeting, small molecule inhibitor of transient receptor potential canonical-5 (TRPC5) designed specifically to treat patients with glomerular kidney diseases characterized by an overactivation of the TRPC5-Rac1 pathway. In a first-in-human study, GFB-887 was found to be safe and well tolerated, had a pharmacokinetic (PK) profile allowing once-daily dosing, and dose dependently decreased urinary Rac1 in healthy adults. METHODS: TRACTION-2 is a phase 2a, double-blind, placebo-controlled, multiple-ascending dose study of GFB-887 in patients with focal segmental glomerulosclerosis (FSGS), treatment-resistant minimal change disease (TR-MCD), or diabetic nephropathy (DN) (NCT04387448). Adult patients on stable renin-angiotensin system blockade and/or immunosuppression with persistent proteinuria will be randomized and dosed in 3 ascending dose levels to GFB-887 or placebo for 12 weeks. Cohorts may be expanded or biomarker-enriched depending upon results of an adaptive interim analysis. RESULTS: The primary objective is to evaluate the effect of increasing doses of GFB-887 on proteinuria. Safety and tolerability, quality of life, pharmacokinetic/pharmacodynamic profiles, and the potential association of urinary Rac1 with efficacy will also be evaluated. The projected sample size has 80% power to detect a treatment difference in proteinuria of 54% (FSGS/TR-MCD) or 44% (DN) compared to placebo. CONCLUSION: TRACTION-2 will explore whether targeted blockade of the TRPC5-Rac1 pathway with GFB-887 is an efficacious and safe treatment strategy for patients with FSGS, TR-MCD, and DN and the potential value of urinary Rac1 as a predictive biomarker of treatment response.

Retrospective analysis of suicidality in patients treated with the antidepressant desvenlafaxine.

The objective of this analysis was to assess the risk of increased suicidal thoughts and behavior (suicidality) with desvenlafaxine (administered as desvenlafaxine succinate) in patients with major depressive disorder (MDD). Data from 9 double-blind, 8-week studies in outpatients with MDD were analyzed retrospectively. Patients were randomly assigned to desvenlafaxine (n = 1834) or placebo (n = 1116). Adverse events (AEs) related to suicidality were identified by searching the AE database for text strings possibly related to suicidality; false positives were excluded. Narratives for each case were prepared and blinded for review. Events were classified according to the Columbia Classification Algorithm of Suicide Assessment. Odds ratios were calculated; chi tests were used to compare treatment groups. Occurrence of emerging or worsening suicidality, based on the 17-item Hamilton Rating Scale for Depression suicide item, was compared for desvenlafaxine and placebo using chi tests. In all, 17 (0.93%) of 1834 patients receiving desvenlafaxine and 8 (0.72%) of 1116 receiving placebo reported possible suicidality-related AEs. Events were relatively evenly distributed across treatment groups. One patient randomly assigned to desvenlafaxine treatment died of completed suicide during the on-therapy period. There were no significant differences between groups in the risk for any class of suicide-related events, including completed suicide or suicide attempt. Odds of emergence or worsening of suicidality 17-item (Hamilton Rating Scale for Depression suicide item) did not differ significantly between treatment groups. No evidence of a signal for increased suicidality was detected in adult patients treated with desvenlafaxine in short-term MDD trials. As suicidal events were extremely rare, a true increased risk cannot be ruled out.

A pooled analysis of two placebo-controlled trials of desvenlafaxine in major depressive disorder.

The efficacy, safety, and tolerability of desvenlafaxine (administered as desvenlafaxine succinate) were evaluated in two similarly designed, phase 3, randomized, double-blind, placebo-controlled, venlafaxine-extended-release-referenced, flexible-dose studies of outpatients with a primary diagnosis of major depressive disorder. Owing to a high placebo response, the individual studies were underpowered. Therefore, a post-hoc pooled analysis was performed (desvenlafaxine and placebo data were pooled; venlafaxine extended release data were not, owing to different flexible-dose regimens in the two studies). The primary outcome measure was the change from baseline on the 17-item Hamilton Rating Scale for Depression; the Clinical Global Impressions-Improvement item score was a secondary outcome. Analysis of the pooled data (using a mixed-effect model for repeated measures) revealed that after 8 weeks of treatment, desvenlafaxine was significantly better than placebo on 17-item Hamilton Rating Scale for Depression [-14.21 vs. -11.87 for desvenlafaxine and placebo, respectively; magnitude of effect=-2.34 (P<0.001)] and Clinical Global Impressions-Improvement item scores [1.95 vs. 2.32 for desvenlafaxine and placebo, respectively; magnitude of effect=-0.37 (P<0.001)]. Adverse events were comparable to those found with other drugs sharing a similar mechanism of action. These data support the efficacy, safety, and tolerability of desvenlafaxine in the treatment of major depressive disorder.