1. INJECTAFER Pharmacokinetics (PK) and Pharmacodynamics (PD) Christy S. John, Ph.D Division of Clinical Pharmacology V Office of Clinical Pharmacology Division of Clinical Pharmacology V Office of Clinical Pharmacology Office of Translational Sciences CDER, FDA

2. OVERVIEW Chemistry and dosing regimen Iron transport and storage Pharmacokinetic profile Pharmacodynamic profile Conclusions

3. INJECTAFER

4. INJECTAFER (Ferric carboxymaltose) Single Dose Vials ( 2mL and 10 mL; 50 mg iron in each mL) Supplied as a dark brown, sterile, aqueous, isotonic solution Injected undiluted or infused following dilution in 250 mL saline

5. Dosing Regimen Proposed Dose: 15mg/kg; Maximum single weekly doses of 1,000 mg Total Dose: Maximum Total Dose of 2,500 mg given over 3 weeks Administered either by rapid intravenous (IV) push injection or by IV infusion. 600 to 1,000 mg doses: IV infusion over ≥ 15 minutes or undiluted IV push injection over 15 minutes < 500 mg doses: undiluted IV push injection at 100 mg per minute

6. Iron Transport and Storage Iron Transport and Storage PK Parameter: –Total Serum Iron Concentration PD Parameters: –Transferrin Saturation: TS is estimated by measures of total iron binding capacity (TIBC) and serum iron –Serum ferritin: an iron-storage protein

7. Dose Escalation PK/PD Study A single-center, randomized, double-blind, placebo-controlled multiple dose study Study included single IV doses of 100, 500, 800 and 1,000 mg via IV infusion or bolus (Injectafer; n = 6, placebo; n = 2) A total of 32 patients were studied

8. Total Serum Iron Concentrations Vs. Time

9. PK Parameters: Total Serum Iron Outcome 100 mg 500 mg 800 mg 1,000 mg Cmax (µg/mL) 37(4)157(19)324(64)333(42) AUC 0-72 (µg-h/mL) 432(75)2365(332)5252(1042)6415(1516) CL(mL/min)4.4(0.9)3.5 (0.5) (0.5)2.59(0.5)2.7(0.6) Average (SD) Normal serum iron concentration range is 4-15 µg/mL (LabCorp)

10. PD for Injectafer: Serum Ferritin Parameters Serum Ferritin 100 mg 500 mg 800 mg 1,000 mg Pre-dose(ng/mL)2(2)5(7)4(3)3(2) Max. Conc. (ng/mL) 49(20)423(400)488(165)652(218) Peak (Hours) 4896120120 Average (Standard Deviation) Normal Ferritin Concentrations: Male: ~ 12 - 300 ng/mL Female: ~ 12 - 150 ng/mL

11. PD for Injectafer: Transferrin Saturation

12. Summary: PK/PD Study Serum Iron Concentrations –increased with increasing Injectafer doses –increase in AUC was higher than expected for dose proportionality Serum Ferritin Concentrations –increased with increasing Injectafer doses –More than twice upper bound for normal serum ferritin with 1000 mg Injectafer dose Transferrin Saturation Increased/assay problems

13. CONCLUSIONS Clinical pharmacology data indicated increased levels of serum iron, serum ferritin and transferrin saturation in blood after Injectafer administration Data support the ability of Injectafer to replenish body iron stores Higher Injectafer doses produce ferritin levels that exceed normal human values