Background: TMX-049 is a novel xanthine oxidase (XO) inhibitor that reduced both liver and kidney XO activity and decreased albuminuria in a type 2 diabetes (T2D) rat model. This 12-week, placebo-controlled, double-blind study (ClinicalTrials.gov: NCT03449199) was designed to assess effects of TMX-049 40 or 200 mg (T40 or T200) compared to placebo (P) on urinary albumin to creatinine ratio (UACR) in participants with T2D and albuminuria despite treatment with an angiotensin inhibitor.
Methods: Eligible participants had T2D, HbA1c ≤ 11%, UACR 200-3000 mg/g, CKD-EPI eGFR ≥ 30 ml/min/1.73 m2 and serum uric acid (sUA) 4-10 mg/dL and were randomized to P (n=42), T40 (n=44) or T200 (n=44). The primary efficacy analysis utilized change from Baseline to Week 12 (or the last observation) in log-transformed UACR in an analysis of covariance (ANCOVA) model.
Results: Reductions in UACR from Baseline to Week 12 were P: 9%, T40: 14%, T200: 41%; the difference in change was statistically significant vs. P in the T200 group (p=0.031) but not in the T40 group (p=0.795). The reduction with T200 relative to P was 35% (95% CI: 4-56%). Mean changes in sUA were T40: -2.4 mg/dL and T200: -3.2 mg/dL (p<0.001 vs. placebo for both comparisons). A correlation between sUA and UACR change was not apparent in either the T40 or the T200 group. Both TMX-049 doses were generally well tolerated but 2 participants in the T200 group had episodes of gout. The proportion with any AE (P: 45%, T40: 43%, T200: 39%) or any serious AE (P: 10%, T40: 9%, T200: 5%) was similar in the P, T40 and T200 groups. No serious treatment related cutaneous, liver or renal adverse events were reported in either TMX-049 dose groups.
Conclusions: Once daily dosing of T40 or T200 was well tolerated in this 12-week study of participants with T2D and albuminuria. Although both doses reduced sUA, albuminuria reduction was only observed with T200. Reduced DKD progression may be achievable with TMX-049, a dual hepatic and renal XO inhibitor.
G. Bakris: Consultant; Self; Alnylam, Merck & Co., Inc., Relypsa, Inc., Teijin Pharma Limited. Other Relationship; Self; Bayer AG, Novo Nordisk Inc., Vascular Dynamics. H. Mikami: Employee; Self; Teijin Pharma Limited. M. Hirata: Employee; Self; Teijin Pharma Limited. M. Cressman: Employee; Self; Covance, LabCorp.
Teijin America, Inc.