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Clinical Trial
. 2018 Nov 1;33(11):1950-1959.
doi: 10.1093/ndt/gfx377.

JAK1/JAK2 inhibition by baricitinib in diabetic kidney disease: results from a Phase 2 randomized controlled clinical trial

Katherine R Tuttle  1   2   3 , Frank C Brosius 3rd  4   5 , Sharon G Adler  6 , Matthias Kretzler  4 , Ravindra L Mehta  7 , James A Tumlin  8 , Yoshiya Tanaka  9 , Masakazu Haneda  10 , Jiajun Liu  11 , Maria E Silk  11 , Tracy E Cardillo  11 , Kevin L Duffin  11 , Joseph V Haas  11 , William L Macias  11 , Fabio P Nunes  11 , Jonathan M Janes  11
Affiliations
Clinical Trial

JAK1/JAK2 inhibition by baricitinib in diabetic kidney disease: results from a Phase 2 randomized controlled clinical trial

Katherine R Tuttle et al. Nephrol Dial Transplant. .

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.

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Figures

FIGURE 1
FIGURE 1
Patient disposition through 24 weeks. N = number of participants in each treatment group; n = number of participants in the specified category.
FIGURE 2
FIGURE 2
Efficacy analyses. (A) UACR, first morning urine, (B) ratio of UACR (first morning urine) relative to placebo, (C) UACR, 24-h urine. The primary endpoint was change in first morning UACR at Week 24 compared with baseline. The least squares mean (LSM) treatment difference from placebo is displayed as a ratio ± standard error. *P ≤ 0.05, **P ≤ 0.01 versus placebo.
FIGURE 3
FIGURE 3
Clinical safety indicators. Observed values (mean ± SD) over time for (A) Hematocrit, (B) Hemoglobin, (C) Plasma creatinine, (D) 24-h urine creatinine clearance, (E) eGFR derived by creatinine, and (F) eGFR derived by cystatin C. For hematocrit and hemoglobin, significance for the difference of treatment comparisons was based on the LSMD and analyzed using an ANCOVA model with treatment and baseline value as covariates. For plasma creatinine, creatinine clearance, and eGFR, significance for the difference of treatment comparisons was based on the LSMD and analyzed using MMRM analyses, which included treatment, eGFR group, visit, treatment-by-visit interaction, baseline, and baseline-by-visit interaction. *P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001 versus placebo. QD, once daily; BID, twice daily.
FIGURE 4
FIGURE 4
Biomarker analyses. The fold change from placebo (±standard error) in (A) urinary CXCL10, (B) urinary CCL2, (C, D) plasma sTNFR1 and sTNFR2 and (E) plasma VCAM1. *P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001 versus placebo.
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