JAK1/JAK2 Inhibition by Baricitinib in Diabetic Kidney Disease

Results From a Phase 2 Randomized Controlled Clinical Trial

Katherine R. Tuttle; Frank C. Brosius III; Sharon G. Adler; Matthias Kretzler; Ravindra L. Mehta; James A. Tumlin; Yoshiya Tanaka; Masakazu Haneda; Jiajun Liu; Maria E. Silk; Tracy E. Cardillo; Kevin L. Duffin; Joseph V. Haas; William L. Macias; Fabio P. Nunes; Jonathan M. Janes

Disclosures

Nephrol Dial Transplant. 2018;33(11):1950-1959. 

In This Article

Abstract and Introduction

Abstract

Background: Inflammation signaled by Janus kinases (JAKs) promotes progression of diabetic kidney disease (DKD). Baricitinib is an oral, reversible, selective inhibitor of JAK1 and JAK2. This study tested the efficacy of baricitinib versus placebo on albuminuria in adults with Type 2 diabetes at high risk for progressive DKD.

Methods: In this Phase 2, double-blind, dose-ranging study, participants were randomized 1:1:1:1:1 to receive placebo or baricitinib (0.75 mg daily; 0.75 mg twice daily; 1.5 mg daily; or 4 mg daily), for 24 weeks followed by 4–8 weeks of washout.

Results: Participants (N = 129) were 63±9.1 (mean±standard deviation) years of age, 27.1% (35/129) women and 11.6% (15/129) African-American race. Baseline hemoglobin A1c (HbA1c) was 7.3±1% and estimated glomerular filtration rate was 45.0±12.1 mL/min/1.73 m2 with first morning urine albumin–creatinine ratio (UACR) of 820 (407–1632) (median; interquartile range) mg/g. Baricitinib, 4 mg daily, decreased morning UACR by 41% at Week 24 compared with placebo (ratio to baseline 0.59, 95% confidence interval 0.38–0.93, P = 0.022). UACR was decreased at Weeks 12 and 24 and after 4–8 weeks of washout. Baricitinib 4 mg decreased inflammatory biomarkers over 24 weeks (urine C–X–C motif chemokine 10 and urine C–C motif ligand 2, plasma soluble tumor necrosis factor receptors 1 and 2, intercellular adhesion molecule 1 and serum amyloid A). The only adverse event rate that differed between groups was anemia at 32.0% (8/25) for baricitinib 4 mg daily versus 3.7% (1/27) for placebo.

Conclusions: Baricitinib decreased albuminuria in participants with Type 2 diabetes and DKD. Further research is required to determine if baricitinib reduces DKD progression.

Introduction

Diabetic kidney disease (DKD) is the most common cause of chronic kidney disease worldwide, and current treatments fail to prevent progression to end-stage renal disease (ESRD) in many cases.[1–6] In the year 2014, it was estimated that over 29 million people, or 9.3% of the US population, had diabetes.[7] Approximately 40% of people with Type 2 diabetes develop DKD, and DKD prevalence has increased due to an increase in the total number of people living with diabetes.[8–13] Overall, diabetes accounts for nearly half of all ESRD cases in the USA and most cases of DKD occur in Type 2 diabetes.[8–12,14] Renin–angiotensin system inhibition by angiotensin-converting enzyme (ACE) inhibition or angiotensin II receptor blocking (ARB) agents is the prevailing standard of care, but this treatment approach leaves substantial residual risk for progressive DKD.[15–18] Recent clinical cardiovascular outcome trials of newer antihyperglycemic agents, the sodium–glucose cotransporter 2 (SGLT-2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists, have provided evidence that these agents can reduce albuminuria and loss of kidney function. However, kidney outcomes were secondary and remain to be confirmed among patients with DKD at high risk for progression.[19–24]

DKD is characterized by sustained inflammation that promotes and directs much of the chronic injury process.[25] One of the major pathways that transduce inflammatory signals in DKD is the Janus kinase-Signal Transducer and Activator of Transcription (JAK-STAT) pathway. The JAK-STAT pathway transmits signals from extracellular ligands, including many cytokines and chemokines as well as growth factors and hormones, directly to the nucleus to induce a variety of cellular responses.[26] While many of these responses are best characterized in lymphoid cells, they have also been reported in intrinsic kidney cells such as podocytes,[27] mesangial cells[28] and tubular cells.[27] Gene and protein expression studies of kidney biopsies from people with early- and late-stage DKD have shown increased activation and expression of the JAK-STAT signaling pathway across the spectrum of DKD.[27,29] In particular, increased expression and activity of JAK1 and JAK2 appear to promote DKD development and progression.[30–32] Moreover, studies have suggested interactions between JAK-STAT and angiotensin signaling, including evidence for activating JAK2.[33]

Baricitinib is an oral, small-molecule inhibitor of the JAK family of protein tyrosine kinases that selectively inhibits JAK1 and JAK2, and has demonstrated clinical efficacy in chronic inflammatory conditions such as rheumatoid arthritis.[34–37] Based on the evidence that JAK-STAT activation is central to DKD pathogenesis, this study was conducted to test the efficacy of baricitinib in participants at high risk for DKD progression defined by persistent macroalbuminuria despite ACE inhibitor or ARB therapy. The aim of the study was to evaluate the effect of baricitinib on albuminuria in participants with Type 2 diabetes and DKD.

Comments

3090D553-9492-4563-8681-AD288FA52ACE

processing....