HIF-1 Stabilizer Drugs for the Treatment of Anemia
by Dr K Peony Yu of FibroGen
Erythropoeisis is regulated through hypoxia inducible factor (HIF). By stabilizing HIF, it can enter the nucleus and stimulate transcription of mRNA that will increase endogenous erythropoietin. HIF-PHI can stabilize HIF; one in particular is FG-4592 (produced by FibroGen). GlaxoSmithKline has GSK 1278863 and Akebia has AKB-6548. All three are in phase 2 studies with only FG-4592 in a phase 3 study. The mechanism of physiologic adjustment of erythropoiesis at high altitude is the same as that when FG-4592 is administered. Dr Yu then shows observational data that patients living at high altitudes have lower risk of death, hypercholesterolemia, and cancer; she seems to be suggesting that perhaps the use of FG-4592 would also achieve these benefits, though that’s a really big stretch.
In a phase 2 trial, FG-4592 was given to HD patients versus standard ESA therapy to maintain a hemoglobin of 9–13. In this 6 week study, there was a dose-response to the rise in hemoglobin. Indeed, the hemoglobin levels steadily rose with regular administration of FG-4592 while hemoglobin decreased over time with regular administration of ESA (though she does not show data about iron stores over time). Dr Yu even mentions that there were no serious cardiovascular effects with the use of FG-4592, although the duration of this trial was only 6 weeks. In another study, oral FG-4592 given over 19 weeks led to a more stable hemoglobin level than ESA. Indeed FG-4592 is equally as effective when used in conjunction with oral iron or IV iron, unlike ESA (TH-OR096 at Kidney Week 2012).
Dr Yu indicates that the limits to ESA effectiveness is systemic inflammation, as measured by CRP. With FG-4592, CRP levels don’t affect its ability to raise hemoglobin levels. Moreover, the rise in hemoglobin at 12 weeks with FG-4592 is similar to that with ESA that occurs in 24 weeks (TH-OR096 Kidney Week 2012).
In CKD 3 and 4 patients (JASN 2011 22:196A), whether FG-4592 is administered by a weight-based formula or a standard dose of 50 mg or 100 mg, the rate of rise and terminal hemoglobin levels at 16 weeks were the same. In a subgroup analysis, patients receiving FG-4592 three times a week had a lower blood pressure and lower cholesterol. Both of these effects disappear once FG-4592 is discontinued.
Another concern with ESA use is thrombocytosis –> thrombosis. With FG-4592 use, the rise in hemoglobin did not increase platelet count (but this was a subgroup analysis).
Per Dr Yu, the advantages of FG-4592 include: can be orally given, mimics body’s own erythropoiesis, and lowers blood pressure and cholesterol. To this date, there are no serious adverse effects attributable to this drug. There is also no evidence for an increase in thrombosis as measured by platelet count.
FibroGen and Astellas are working together on a phase 3 study on FG-4592 in anemic CKD patients.