New drug shows promise against anemia of inflammation

Last Updated: 2014-09-12

By Will Boggs MD

NEW YORK (Reuters Health) - Lexaptepid, a new compound that inactivates the iron regulator hepcidin, may be able to reverse inflammation-induced decreases in serum iron level, researchers from the Netherlands report.

"Our study provided proof-of principle in healthy volunteers that it is actually possible to counteract the effects of inflammation-induced increased hepcidin levels on serum iron," said Dr. Lucas T. van Eijk from Radboud University Medical Center in Nijmegen.

"The pathophysiology of the hepcidin-ferroportin axis is amenable to pharmacologic treatments that may be more effective and better tolerated than the high-dose erythropoietin and IV iron treatments currently used in this patient group," he told Reuters Health by email.

Hepcidin prevents export of iron into the circulation and causes iron-restricted erythropoiesis by inducing the internalization and degradation of the iron-exporting channel ferroportin on duodenal enterocytes and iron-storing cells.

In light of findings that lexaptepid prevents ferroportin degradation and prevents and corrects anemia of inflammation in animal models, Dr. van Eijk and colleagues investigated its effectiveness in preventing the serum iron decrease observed during systemic inflammation in a study of 24 healthy, male volunteers.

After lipopolysaccharide (LPS) administration, both placebo and lexaptepid groups showed increases in plasma hepcidin. The increases were much higher in the lexaptepid group, but the researchers suggest that this "may largely be attributed to a reduced elimination of the lexaptepid-hepcidin complex through the kidney."

Both groups also experienced marked increases of serum iron at three and six hours after endotoxin administration, the researchers report in Blood, online August 27.

Serum iron levels were comparable at three hours in the placebo and lexaptepid groups, but then the levels began to decline in placebo-treated subjects concurrent with increases in hepcidin levels. Lexaptepid-treated subjects, however, showed a prolonged increase in serum iron, peaking at six hours.

By 24 to 48 hours after LPS administration, serum iron was lower in the lexaptepid group than in the placebo group. The researchers suspect that the prolonged elevation in serum iron in the lexaptepid group may have stimulated hepcidin production and thereby may have overcome the effect of lexaptepid.

"The initial increase in serum iron is the result of the acute state of inflammation that is induced by LPS, and is not something which is seen in patients suffering from anemia of chronic disease," Dr. van Eijk said. "They are typically in a continuous state of low serum iron and low transferrin saturation. Our expectation is that by targeting hepcidin, their serum iron levels can be brought into the normal range, but will not result in high serum iron values as observed in our trial in healthy subjects, and thus no compensatory response is to be expected."

Lexaptepid did not alter the parameters of inflammation caused by LPS. "This means that we have no reason to believe that the underlying inflammatory condition of patients suffering from anemia of inflammation would be aggravated by treatment with lexaptepid," Dr. van Eijk explained.

"The next step is to evaluate the effect of lexaptepid in patients with anemia of inflammation. A pilot study in cancer patients was completed and showed first activity to increase hemoglobin levels. In addition, lexaptepid is currently being studied in a trial in dialysis patients," he said.

NOXXON Pharma AG sponsored the study and employs five of the 12 authors.

Dr. Elizabeta Nemeth and Dr. Tomas Ganz from David Geffen School of Medicine at the University of California, Los Angeles, recently reviewed the literature on anemia of inflammation.

"Antagonizing hepcidin is a reasonable approach for treating anemia of chronic disease (ACD) (although antagonizing hepcidin will not address other mechanisms underlying ACD, such as the direct effect of cytokines on erythroid precursors), Dr. Nemeth told Reuters Health by email. "Using a hepcidin binder such as lexaptepid is a good idea, although the long-term efficacy remains to be demonstrated."

"This company has two Phase 2 trials using this drug," she said. "They are the most advanced in terms of human testing in the hepcidin space, so hopefully we will see the results soon."

Dr. Ganz cautioned, "Although this approach is reasonable, anemia of chronic disease is usually not severe, so the treatment must be essentially free of side effects and can't be expensive."

SOURCE: http://bit.ly/1uL6HUy

Blood 2014.