FibroGen announces proof-of-principle for FG-4592 Phase 2 study in hemodialysis patients

FibroGen, Inc., today announced proof-of-principle for oral anemia therapy FG-4592, a hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor (PHI), in end-stage renal disease (ESRD) patients receiving hemodialysis. In this first clinical study of a HIF-PHI to include a recombinant human erythropoietin (rhEPO) control arm, FG-4592 was directly compared with rhEPO on numerous parameters in this controlled study. Six weeks of dosing with FG-4592 maintained correction of hemoglobin in the absence of intravenous (IV) iron supplementation and led to marked, dose-dependent decreases in hepcidin (an iron regulatory hormone) compared with levels achieved with rhEPO. An interim analysis of results from this ongoing phase 2 study were reported at the 2011 National Kidney Foundation Spring Clinical Meetings in Las Vegas, Nevada, April 26-30 (Abstract #188).

Patients were required to have stable hemoglobin maintained by stable steady-state doses of IV rhEPO prior to randomization to either 6 weeks of study treatment with FG-4592 (1.0, 1.5, or 2.0 mg/kg three times a week) or to IV rhEPO (dosed according to community standard of care). As per protocol, IV iron supplementation was not allowed beginning 2 weeks prior to randomization and extending throughout the dosing period. The dosing period was followed by an 8-week safety assessment period, during which all patients received IV rhEPO and were allowed to receive IV and oral iron.

Key findings reported from the interim analysis were as follows:

• While rhEPO has been reported to suppress hepcidin levels, a significant decrease in serum hepcidin beyond baseline levels in stably corrected patients previously on maintenance doses of rhEPO was observed with FG-4592 treatment in the two highest dose cohorts
• FG-4592 administered for 6 weeks was well tolerated and resulted in a statistically significant mean increase in hemoglobin from baseline of approximately 1 g/dL in the two highest dose cohorts (p<0.001 for 1.5 and 2.0 mg/kg FG-4592 compared with a 0.8 g/dL decrease in mean hemoglobin in patients who continued rhEPO therapy), over the 6-week dosing period.
• 89% of patients treated with either 1.5 or 2.0 mg/kg FG-4592 maintained correction of hemoglobin levels on day 43 at ≥ (baseline - 0.5g/dL); in comparison, hemoglobin was maintained by only 40% of rhEPO IV patients at day 43
• Mean corpuscular volume (MCV), a measure of red blood cell size, is generally decreased in iron-deficient patients. MCV was significantly increased at week 6 by treatment with FG-4592 compared with baseline following chronic rhEPO therapy
• Serum iron was significantly increased by FG-4592 (combined 1.0, 1.5, and 2.0 mg/kg cohorts) compared with the decrease in serum iron observed in rhEPO-treated patients at week 6
• Cardiovascular and thrombotic events that occur in association with rhEPO are adverse events of special interest to regulatory agencies. No safety signal related to treatment with FG-4592 was discerned by the clinical investigators or the Data Monitoring Committee (DMC) with respect to any such events. This finding is consistent with results in all clinical studies of FG-4592 to date.

"These results represent the first proof-of-principle that FG-4592 can maintain or increase hemoglobin levels in patients with ESRD on hemodialysis using doses that have been shown to be effective in studies of nondialysis patients with chronic kidney disease," said Peony Yu, MD, Vice President of Clinical Development. "These data, which are the first to be generated on a HIF-PHI in the hemodialysis setting where there is a high background rate of adverse events, suggest a favorable safety profile for FG-4592."

"The observation that FG-4592 therapy led to statistically significant reduction in serum hepcidin levels beyond what was observed with rhEPO suggests that HIF-PHIs may be effective at treating anemia in patients who are unable to achieve adequate increases in hemoglobin levels due to the presence of significant inflammation," said Thomas B. Neff, Chief Executive Officer. "The increases observed in MCV raise the possibility that HIF-PHIs may also have a clinically beneficial effect on iron deficiency anemia. We plan to explore the impact of increased MCV in treatment of anemia in newly initiated dialysis ESRD. Potential therapeutic effects of HIF-PHIs outside of chronic kidney disease settings, such as iron deficiency anemia, are worthy of additional investigation."

In another study presented at NKF, the pharmacokinetics (PK) and pharmacodynamics (PD) of FG-4592 in hemodialysis were reported. Results demonstrated that hemodialysis does not have a clinically significant impact on the PK/PD of orally administered FG-4592. This finding is supportive of a flexible dosing schedule of FG-4592 for patient convenience, not limited by hemodialysis schedule. Levels of EPO in plasma were measured in this study. Peak concentrations of circulating plasma endogenous erythropoietin (eEPO) nearly tripled with a doubling of dose of FG-4592, but the C_max values remained significantly less than the peak circulating plasma rhEPO levels (eEPO C_max was less than 10% of rhEPO C_max levels expected for dialysis patients receiving the U.S. mean dose [approximately 8000 U] of synthetic source rhEPO⁹).