C-C motif-ligand 2 inhibition with emapticap pegol (NOX-E36) in type 2 diabetic patients with albuminuria

Abstract

Background: Emapticap pegol (NOX-E36) is a Spiegelmer® that specifically binds and inhibits the pro-inflammatory chemokine C-C motif-ligand 2 (CCL2) (also called monocyte-chemotactic protein 1). The objective of this exploratory study was to evaluate the safety and tolerability as well as the renoprotective and anti-diabetic potential of emapticap in type 2 diabetic patients with albuminuria. Methods: A randomized, double-blind, placebo-controlled Phase IIa study was initiated in 75 albuminuric type 2 diabetics. Emapticap at 0.5 mg/kg and placebo were administered subcutaneously twice weekly for 12 weeks to 50 and 25 patients, respectively, followed by a treatment-free phase of 12 weeks. Results: Twice weekly subcutaneous treatment with emapticap over 3 months was generally safe and well tolerated and reduced the urinary albumin/creatinine ratio (ACR) from baseline to Week 12 by 29% (P < 0.05); versus placebo a non-significant ACR reduction of 15% was observed (P = 0.221). The maximum difference, 26% (P = 0.064) between emapticap and placebo, was seen 8 weeks after discontinuation of treatment. At Week 12, the HbA1c changed by −0.31% in the emapticap versus +0.05% in the placebo group (P = 0.146). The maximum difference for HbA1c was observed 4 weeks after the last dose with −0.35% for emapticap versus +0.12% for placebo (P = 0.026). No relevant change in blood pressure or estimated glomerular filtration rate was seen between the treatment groups throughout the study. A post hoc analysis with exclusion of patients with major protocol violations, dual RAS blockade or haematuria increased the ACR difference between the two treatment arms to 32% at Week 12 (P = 0.014) and 39% at Week 20 (P = 0.010). Conclusions: Inhibition of the CCL2/CCL2 receptor axis with emapticap pegol was generally safe and well tolerated. Beneficial effects on ACR and HbA1c were observed in this exploratory study, which were maintained after cessation of treatment. Taken together, emapticap may have disease-modifying effects that warrant further investigation in adequately powered confirmatory studies.

PGC‐1α deficiency causes spontaneous kidney inflammation and increases the severity of nephrotoxic AKI

“…Anti-inflammatory effects of PGC-1α have been observed in the skeletal muscle atrophy program, where PGC-1α overexpression reduced Fn14 expression and TWEAK-induced inflammation [25]. TWEAK/Fn14, IL-6, TNF-α, and CCL2 are known mediators of kidney injury, as demonstrated by preclinical and/or clinical interventional studies [26][27][28][29]. Moreover, TWEAK promotes the expression of these cytokines during AKI [20].…”

Diabetic nephropathy: Time to withhold development and progression - A review

“…Emapticap Pegol binds and neutralizes MCP-1. In a phase IIa study, intravenous Emapticap Pegol administration for 12 weeks significantly reduced UAE in T2DM patients with DN [89]. Another CCR2 antagonist (CCX140-B) was tried in DN T2DM patients.…”

A drug development perspective on targeting tumor‐associated myeloid cells

“…Moreover, Emapticap pegol/ NOX-E36, a CCL-2 L -RNA aptamer that blocks CCL2 binding to CCR2, has recently been tested in a phase IIa study in albuminuric type 2 diabetes. Published data suggest that NOX-E36 was not only safe and well-tolerated but might also have disease-modifying effects [66]. Finally, another study also demonstrated that monocyte chemotaxis-related genes are upregulated in melanoma patients resistant to anti-PD-1 therapy [22].…”