Targeting inflammation in diabetic kidney disease: early clinical trials

ABSTRACT

Introduction: The age-standardized death rate from diabetic kidney disease increased by 106% from 1990 to 2013, indicating that novel therapeutic approaches are needed, in addition to the renin-angiotensin system (RAS) blockers currently in use. Clinical trial results of anti-fibrotic therapy have been disappointing. However, promising anti-inflammatory drugs are currently on phase 1 and 2 randomized controlled trials.

Areas covered: The authors review the preclinical, phase 1 and 2 clinical trial information of drugs tested for diabetic kidney disease that directly target inflammation as a main or key mode of action. Agents mainly targeting other pathways, such as endothelin receptor or mineralocorticoid receptor blockers and vitamin D receptor activators are not discussed.

Expert opinion: Agents targeting inflammation have shown promising results in the treatment of diabetic kidney disease when added on top of RAS blockade. The success of pentoxifylline in open label trials supports the concept of targeting inflammation. In early clinical trials, the pentoxifylline derivative CTP-499, the CCR2 inhibitor CCX140-B, the CCL2 inhibitor emapticap pegol and the JAK1/JAK2 inhibitor baricitinib were the most promising drugs for diabetic kidney disease. The termination of trials testing the anti-IL-1β antibody gevokizumab in 2015 will postpone the evaluation of therapies targeting inflammatory cytokines.

KEYWORDS:

• Chemokine
• chronic kidney disease
• CCX140
• diabetes
• diabetic kidney disease
• inflammation
• interleukin-1-beta
• treatment

Article highlights

• Despite renin-angiotensin system (RAS) blockade, treatment of diabetic kidney disease is unsatisfactory

• Several therapeutic add-on approaches on top of RAS blockade are under investigation, with promising results obtained with SGLT2 inhibitors

• In addition, anti-inflammatory drugs are currently on phase 1 and 2 clinical trials

• The success of pentoxifylline in open label trials supports the concept of targeting inflammation.

• In early clinical trials, the pentoxifylline derivative CTP-499, the CCR2/CCL2-targeting drugs CCX140-B and emapticap pegol, and the JAK1/JAK2 inhibitor baricitinib were the most promising anti-inflammatory drugs for diabetic kidney disease.

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Declaration of interest

This work was supported by grants from the Ministry of Science (SAF 2012-38830), FISEC07/90021, 10/0072, PI13/00047, PI15/00298, PIE13/00051, CP14/00133, ISCIII-RETIC REDinREN RD12/0021 Fondos FEDER, the Spanish Society of Nephrology, the Comunidad de Madrid S2010/BMD-2378, FRIAT-IRSIN, CIBERDEM, FP7 Diabetes kidney connect and PRIORITY. It is also supported by ISCIII Joan Rodes JR14/00028 to B Fernandez-Fernandez and Miguel Servet MS12/03262, MS14/00133 to AB Sanz and MD Sanchez-Nino. Finally, there is support from the Programa Intensificación Actividad Investigadora (ISCIII/Agencia Laín-Entralgo/CM) to A Ortiz. A Ortiz has also served as a consultant for Servier. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.