Novel Drug Boosts EPO Release in Dialysis Patients

Novel Drug Boosts EPO Release in Dialysis Patients
By John Gever, Senior Editor, MedPage Today
Published: November 30, 2010
Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco and
Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner

Massive increases in natural erythropoietin (EPO) production occurred in dialysis patients as well as healthy volunteers given an investigational oral drug that promotes release of the red blood cell growth factor, according to results of a small trial.

The phase I trial, conducted among 12 dialysis patients and six healthy individuals, found that plasma EPO levels increased from 13- to 31-fold following a single dose of FG-2216, an orally active prolyl-hydroxylase inhibitor, reported Wanja M. Bernhardt, MD, of Friedrich Alexander University in Erlangen, Germany, and colleagues.

The drug targets hypoxia-inducible transcription factors (HIF) that help control endogenous EPO release, the researchers explained online in the Journal of the American Society of Nephrology.
Action Points

* Explain that an investigational oral drug that promotes release of the red blood cell growth factor led to massive increases in natural erythropoietin (EPO) production in dialysis patients as well as healthy volunteers.

* Note that the single-dose study, which was characterized as "proof of principle," was unable to demonstrate that the drug's effect on EPO was durable enough to reduce clinical anemia or to document its safety with repeated dosing.

HIFs are activated or deactivated in response to oxygen levels in the blood. Directly mediating their activity are prolyl-hydroxylase enzymes.

Inhibiting the latter leads to greater HIF activity and, as a result, increased EPO expression, Bernhardt and colleagues indicated.

In the phase I clinical trial, the researchers gave a single 20-mg/kg dose of FG-2216 to six dialysis patients with severely dysfunctional kidneys, six dialysis patients whose kidneys had been removed, and six individuals with normal kidney function and no other major illnesses.

Of the 12 participants with kidneys, all but one showed maximal effects on EPO 12 hours after dosing.

The mean maximal increases from baseline in these individuals were 12.8-fold in the healthy volunteers and 30.8-fold in the nephric dialysis patients.

Among the six anephric dialysis patients, plasma EPO concentrations rose by a mean of 14.5-fold from baseline.

In this latter group, though, the pattern of responses varied considerably. Two patients showed peak increases in EPO at 12 hours, whereas it continued to rise dramatically in two other patients through 24 hours post-dose. The remaining two patients showed comparatively little response to the drug.

Clinical and laboratory safety markers tracked for seven days after dosing -- such as liver enzymes, hemoglobin, and ferritin levels -- showed no change from baseline, the researchers indicated.

Effects on clinical anemia were not examined directly, although the researchers found that reticulocyte counts increased significantly in dialysis patients with intact kidneys (mean 39.4 per n/L baseline to 52.7 per n/L after seven days, P<0.05). In anephric patients, reticulocyte counts remained stable.

In addition to suggesting that the experimental drug FG-2216 might prove to be a useful anemia therapy -- the study also sheds light on the poorly understood etiology of anemia and EPO dysfunction in patients with kidney disease, said Bernhardt and colleagues.

They noted that, in previous studies, dialysis patients had shown EPO spikes following acute hypoxia, as well as reduced need for recombinant EPO supplementation in patients at high altitudes.

"Unused production capacity for EPO, presumably as a result of desensitization of the oxygen-sensing mechanism rather than destruction of its cellular production sites, seems to cause the inappropriately low production of the hormone in patients with chronic kidney disease," they wrote.

However, the single-dose study, which Bernhardt and colleagues characterized as "proof of principle," was unable to demonstrate that the drug's effect on EPO was durable enough to reduce clinical anemia or to document its safety with repeated dosing.

FibroGen supported the study and helped develop the protocol.

Two authors were FibroGen employees and one other reported serving as a consultant to the company.

Primary source: Journal of the American Society of Nephrology
Source reference:
Bernhardt W, et al "Inhibition of prolyl hydroxylases increases erythropoietin production in ESRD" J Am Soc Nephrol 2010; DOI: 10.1681/ASN.2010010116.

http://www.medpagetoday.com/Nephrology/Anemia/23646