Pam Harrison

June 03, 2014

AMSTERDAM — A novel molecule that directly targets inflammation in diabetic nephropathy is safe, well-tolerated, and has significant effects that last for at least 12 weeks after discontinuation of the drug, a phase 2 trial shows.

In patients with type 2 diabetes and albuminuria, treatment with emapticap pegol (NOX-E36, NOXXON Pharma) for 12 weeks reduced the mean albumin/creatinine ratio and the level of glycated hemoglobin (HbA1c), report Hermann Haller, MD, director of nephrology and hypertension at Hannover Medical School in Germany, and colleagues.

"We used to think that diabetic nephropathy was only fibrosis and deterioration of tissue. Now we believe that it is an inflammatory disease and that the kidney is really full of activated macrophages," Dr. Haller told Medscape Medical News.

"This is the first compound we've had that interferes with the inflammatory process in the kidney. We now have a 'big gun,' which is very focused, does not have a lot of side effects, and is both safe and efficacious in a long-lasting and sustained way," he said. "It's a very novel way of treating diabetic nephropathy."

The effect on HbA1c suggests that the unique molecule has beneficial effects on glycemic control as well, he added.

Dr. Haller presented the results here at the European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) 51st Congress.

A Phase 2a Study

The randomized, double-blind, placebo-controlled multisite, phase 2a study was conducted in 5 European countries and involved 72 patients with type 2 diabetes and albuminuria.

All patients were on stable antidiabetic therapy and renin–angiotensin system (RAS) blockade at study enrollment. Baseline albumin/creatinine ratio was above 100 mg/g, estimated glomerular filtration rate was above 25 mL/min per 1.73 m², and HbA1c ranged from 6.5% to 10.5%.

Patients were randomized to emapticap pegol 0.5 mg/kg administered subcutaneously twice a week for 12 weeks, or placebo. This was followed by a 12-week treatment-free observation period.

At the end of the treatment period, mean albumin/creatinine ratio was 32% lower in the emapticap pegol group than in the placebo group (P = .014). And more patients in the emapticap pegol group achieved a reduction in the albumin/creatinine ratio of at least 50% (31% vs 6%).

In the emapticap pegol group, the maximum effect on the mean albumin/creatinine ratio (a reduction of 39%) was seen 8 weeks after the drug was discontinued.

In addition, at the end on the 12-week treatment period, absolute change in HbA1c from baseline was better in the emapticap pegol group than in the placebo group (–0.32% vs +0.06%; P = .096). This became significant 4 weeks after the last dose (P = .036).

No serious adverse effects were observed with emapticap pegol. This is important because this is a life-long treatment, Dr. Haller told Medscape Medical News.

"It takes 2 months before you see an effect from emapticap," he explained. But after discontinuation, "there is a sustained significant effect on inflammation, which means that something is happening during the treatment period that is still there."

A "Totally Different" Mechanism of Action

"We see this as a disease-modifying response," Dr. Haller said. "I believe that this drug stops monocyte influx into the kidney and reduces inflammation, not only in the kidney, but in other tissues as well. The effect is sustained, which has not been shown before."

Drugs such as irbesartan that block the RAS have also been shown to slow down disease progression in diabetic nephropathy. Although the effect is real, "these drugs act through hemodynamic changes in the glomerulus. The moment you stop them, patients go back to their disease," Dr. Haller explained.

With emapticap pegol, the mechanism of action is "totally different," and has nothing to do with RAS blockade. Emapticap pegol is a Spiegelmer — an artificial oligonucleotide that is the mirror image of natural oligonucleotides — that specifically binds and inhibits the proinflammatory C-C chemokine ligand/monocyte chemoattractant protein-1 (CCL2/MCP-1).

Preclinical work has suggested that neutralization of this chemokine prevents the infiltration of proinflammatory cells into the kidney, which allows existing inflammation to resolve over time.

In the future, it might be possible to combine emapticap pegol with RAS blockade. "If you put both of these things together, we might see a highly significant effect on diabetic nephropathy," Dr. Haller said.

Targeting Chronic Inflammation

Considerable progress has been made in the attenuation of the hemodynamic aspects of diabetic nephropathy over the past 15 years, said Denis Fouque, MD, PhD, professor of nephrology at University Claude Bernard Lyon in France, who is chair of the paper selection committee for ERA-EDTA.

"Hyperfiltration is deleterious to the kidney, so the first research was aimed at reducing hyperfiltration. This was successfully done with ACE inhibitors and 'the sartans'," Dr. Fouque told Medscape Medical News.

However, interstitial inflammation parallels glomerular injury in diabetic nephropathy, and chronic inflammation has only become a target for treatment in the past few years. Bardoxolone, a triterpenoid with anti-inflammatory and antioxidant properties, showed initial promise in patients with diabetic nephropathy, but was withdrawn because of serious adverse effects.

"The first step in fibrosis is inflammation," Dr. Fouque explained. "Emapticap pegol acts on the polynuclear macrophage monocyte pathway that leads to inflammation. By targeting drugs to these cells, you may be able to improve interstitial inflammation and reduce interstitial fibrosis, which would otherwise eventually destroy the kidney."

This study was funded by NOXXON Pharma. Dr. Haller reports receiving honoraria from NOXXON Pharma for consulting on the further medical development of the compound. Dr. Fouque has disclosed no relevant financial relationships.

European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) 51st Congress: Abstract 4079. Presented June 1, 2014.

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