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.

Relating glucose clamp profiles to reduction of blood glucose after insulin administration.

A model was established allowing prediction of blood glucose response from glucose clamp results performed in healthy volunteers. Data from published studies performed in healthy volunteers were used to establish, test, and validate a model for the evaluation of glucose reductions from glucose clamp results. Studies included those that measured blood glucose and glucodynamic response over time after administration of 0.05 U/kg of regular human insulin (HR) and insulin lispro (LP) with and without the benefit of a glucose clamp procedure. An inhibitory effect E(max) model was used to describe the relationship; the model differed between the HR and LP responses by the intensity of the counterregulatory response as assessed by glucagon measurements. The relationships were used to predict blood glucose responses from a clamp study assessing NPH insulin and HR administrations. Glucose concentrations measured after administration of NPH insulin and HR without a clamp were compared to the model-predicted results to assess the accuracy of the model predictions. The E(max) model successfully correlated the glucose clamp results with the blood glucose depressions in the presence and absence of a counterregulatory response. However, predictions of glucose depression were only accurately modeled in the absence of a counterregulatory glucagon response. The correlations established with a minimal counterregulatory response underscore the value of glucose clamp procedures in defining the time-activity profiles of insulins when the clamp is established at fasting glucose concentrations.

Clinical pharmacokinetics and pharmacodynamics of insulin lispro mixtures.

Rapid-acting insulin analogues such as insulin lispro and insulin aspart produce a more physiological profile of insulin activity than does conventional regular human insulin because of their unique pharmacokinetics. These insulin analogues are absorbed rapidly from the subcutaneous injection site, resulting in a better matching of the appearance of insulin in the circulation with nutrient absorption from the intestine. In addition, they are shorter-acting than regular human insulin, thus decreasing the risk of late postprandial hypoglycaemia due to inappropriate hyperinsulinaemia. Because self-prepared mixtures of these rapid-acting insulin analogues with longer-acting insulins such as neutral protamine Hagedorn (NPH) insulin have been shown to be clinically useful, and because manufactured fixed-ratio mixtures of regular human insulin and NPH already represent a large proportion of insulin use, manufactured fixed-ratio mixtures of insulin lispro and a sustained-release insulin known as NPL have been developed (insulin lispro mixtures). NPL is a protamine-based insulin lispro formulation with pharmacokinetics and glucodynamics comparable to those of human NPH insulin. NPL was developed for use within insulin lispro mixtures because an exchange between soluble insulin lispro and protamine-bound human insulin within human NPH precludes prolonged storage of mixtures of these insulins. An insulin lispro mixture consisting of 25% insulin lispro and 75% NPL is now commercially available. This preparation is intended primarily as an alternative to human insulin 30/70, which is commonly used within a twice-daily injection regimen. A mixture containing 50% insulin lispro and 50% NPL is also available. The rapid activity of insulin lispro is maintained within insulin lispro mixtures, allowing injection just prior to a meal, a convenience that is not available with commercial mixtures of regular human insulin and human NPH insulin, which should be injected 30 to 45 minutes prior to meals. As with insulin lispro itself, the rapid action of insulin lispro within the insulin lispro mixtures also results in a smaller increase in blood glucose levels after meals than with comparable human insulin mixtures. In addition, data from two studies have shown that when Mix25 is injected prior to the evening meal the incidence of nocturnal hypoglycaemia is decreased in comparison with the same dose of human insulin 30/70. The combined rapid and prolonged insulin activity provided by insulin lispro mixtures has been defined both in healthy subjects without diabetes and in patients with diabetes.