14 CLINICAL STUDIES

14.1 Iron Deficiency Anemia in Patients Who Are Intolerant to Oral Iron or Have Had Unsatisfactory Response to Oral Iron

IDA-301 Trial (referred to as IDA Trial 1) (NCT 01114139), IDA-302 Trial (referred to as IDA Trial 2) (NCT 01114204) and IDA-304 Trial (referred to as IDA Trial 3) (NCT 02694978)

The safety and efficacy of Feraheme in patients with iron deficiency anemia, regardless of etiology and a history of unsatisfactory oral iron therapy or in whom oral iron could not be used, were assessed in two randomized, controlled clinical trials (IDA Trial 1 and 2) with Feraheme administered as a rapid intravenous injection (prior method of administration no longer approved). In IDA Trial 1, patients were randomized to treatment with Feraheme or placebo. In IDA Trial 2, patients were randomized to treatment with Feraheme or iron sucrose. Feraheme (510 mg) and placebo were administered as two intravenous single dose injections over 3-8 days, and iron sucrose (200 mg) was administered as 5 intravenous injections or infusions over a period of 14 days.

In IDA Trial 1, the mean age of patients was 45 years (range, 18 to 91); 89% were female; 56% were Caucasian, 25% were Black, 16% were Asian, and 3% were other races.

In IDA Trial 2, the mean age of patients was 48 years (range, 18 to 89); 83% were female; 84% were Caucasian, 11% were Asian, 1% were Black, and 4% were other races.

Table 3 shows changes from baseline to Week 5 in hemoglobin and transferrin saturation in IDA Trial 1 and 2.

Table 3: Changes from Baseline to Week 5 in Hemoglobin (Hgb) and Transferrin Saturation in IDA Trial 1 and 2 (Intent to Treat Population)
* p≤0.001 for main efficacy endpoint
ENDPOINT	IDA Trial 1		IDA Trial 2
ENDPOINT	Feraheme N = 608	Placebo N = 200	Feraheme N = 406	Iron Sucrose N = 199
Baseline Hgb mean (SD), g/dL	8.9 (0.9)	8.8 (0.9)	8.9 (0.9)	8.8 (1.0)
Proportion of patients with Hgb Increase of ≥2.0 g/dL at any time from Baseline to Week 5, %	81.1	5.5	84.0	81.4
Treatment Difference (%, 95% CI)	75.6* (71.2, 80.0)		2.6 (-3.9, 9.1)
Mean change in Hgb from Baseline to Week 5 mean (SD), g/dL	2.6 (1.5)	0.1 (0.9)	2.9 (1.6)	2.7 (1.3)
Proportion of patients with Hgb ≥12 g/dL at any time from Baseline to Week 5, %	50.5	3.0	66.7	48.2
Baseline TSAT mean (SD) , %	7.0 (12.9)	5.4 (4.9)	6.1 (9.9)	5.5 (10.3)
Mean change in TSAT from Baseline to Week 5 mean (SD), %	11.4 (15.1)	0.4 (5.8)	15.7 (16.8)	11.9 (14.4)

In IDA Trial 1, fatigue-related symptoms and impacts were assessed using a patient reported outcome instrument, FACIT-Fatigue (score range from 0 to 52 with higher scores indicating less fatigue). After 5 weeks, Feraheme-treated patients reported greater improvement from baseline in the fatigue score (+11.7 ± 11.73 points) than did patients in the placebo arm (+6.8 ± 9.51 points) with a treatment difference of 4.9 (95% CI: 3.08-6.71) points.

The safety of Feraheme in IDA patients with a history of unsatisfactory oral iron therapy or in whom oral iron could not be used was also assessed in another randomized, multicenter, double-blind safety clinical trial (IDA Trial 3). Patients were randomized in a 1:1 ratio to either two infusions of 510 mg (1.020 g) of Feraheme (n=997) or two infusions of 750 mg (1.500 g) of ferric carboxymaltose (FCM) (n=1000). Both IV irons were infused over a period of at least 15 minutes. Most patients received their second infusion of Feraheme or FCM 7(+1) days after the first infusion. This study included patients with any etiology of IDA including CKD excluding dialysis-dependent CKD.

In IDA Trial 3, the mean age of patients was 55 years (range, 18 to 96); 76% were female; 71% were Caucasian, 24% were Black, 3% were Asian, and 2% were other races.

The study met the primary endpoint to demonstrate non-inferiority to FCM with respect to the percentage of patients who experienced moderate-to-severe hypersensitivity reactions (including anaphylaxis) or moderate-to-severe hypotension (Feraheme: 0.6%; FCM: 0.7%; treatment difference: -0.1%; exact 95% confidence interval: -0.91% to +0.70%).

Table 4 shows the mean increase from baseline to week 5 in hemoglobin (Hgb) per treatment (Feraheme 2 x 510 mg; FCM 2 x 750 mg) and per gram of iron administered (Feraheme 1.020 g; FCM 1.500 g) in IDA Trial 3.

Table 4: Summary of Hemoglobin (Hgb) Changes per Treatment and per Gram of Iron Administered From Baseline to Week 5 (Intent to Treat Population) in IDA Trial 3
aAdjusted for difference in baseline Hgb
ENDPOINT	Feraheme 2 x 510mg N = 997	Ferric Carboxymaltose (FCM) 2 x 750mg N = 1000
Baseline Hgb mean (SD); g/dL	10.42 (1.48)	10.39 (1.46)
Mean change in Hgb from Baseline to Week 5 per Gram of Iron Administered mean (SD); g/dL	1.35 (1.35)	1.10 (1.05)
Treatment Difference Per Gram of Irona (%, 95%CI)	0.26 (0.17, 0.36)
Mean change in Hgb from Baseline to Week 5 mean (SD); g/dL	1.38 (1.35)	1.63 (1.54)
Treatment Differencea (%, 95% CI)	-0.24 (-0.35, -0.13)

In IDA Trial 3, the incidence of severe hypophosphatemia (defined by blood phosphorous of <0.6 mmol/L at week 2) in the patients receiving Feraheme (0.4% of patients) was less than those receiving FCM (38.7% of patients).

14.2 Iron Deficiency Anemia in Patients with Chronic Kidney Disease

Trial 62745-7 (referred to as CKD Trial 1) (NCT 00255437), Trial 62745-6 (referred to as CKD Trial 2) (NCT 00255424), and Trial 62745-5 (referred to as CKD Trial 3) (NCT 00233597).

The safety and efficacy of Feraheme for the episodic treatment of iron deficiency anemia in patients with CKD were assessed in three randomized, open-label, controlled clinical trials (CKD Trial 1, 2 and 3) where Feraheme was administered as a rapid intravenous injection (prior method of administration - no longer approved). These trials also included an uncontrolled, follow-up phase in which patients with persistent iron deficiency anemia could receive two additional 510 mg intravenous injections of Feraheme. The major efficacy results from the controlled phase of each study are shown in Table 5.

In all three trials, patients with CKD and iron deficiency anemia were randomized to treatment with Feraheme or oral iron. Feraheme was administered as two 510 mg undiluted intravenous injections and oral iron (ferrous fumarate) was administered as a total daily dose of 200 mg elemental iron daily for 21 days. The major trial outcomes assessed the change in hemoglobin from baseline to Day 35. CKD Trial 1 and 2 enrolled patients with non-dialysis dependent CKD and CKD Trial 3 enrolled patients who were undergoing hemodialysis.

In CKD Trial 1, the mean age of patients was 66 years (range, 23 to 95); 60% were female; 65% were Caucasian, 32% were Black, and 2% were other races. In the Feraheme and oral iron groups, 42% and 44% of patients, respectively, were receiving erythropoiesis stimulating agents (ESAs) at baseline.

In CKD Trial 2, the mean age of patients was 65 years (range, 31 to 96); 61% were female; 58% were Caucasian, 35% were Black, and 7% were other races. In the Feraheme and oral iron groups, 36% and 43% of patients, respectively, were receiving ESAs at baseline.

In CKD Trial 3, the mean age of patients was 60 years (range, 24 to 87); 43% were female; 34% were Caucasian, 59% were Black, and 7% were other races. All patients were receiving ESAs.

Table 5 shows the Baseline and mean change to Day 35 in hemoglobin (Hgb, g/dL), transferrin saturation (TSAT, %) and ferritin (ng/mL) in each treatment group for Trial 1, 2, and 3.

Table 5: Changes from Baseline to Day 35 in Hemoglobin (Hgb), Transferrin Saturation and Ferritin (Intent to Treat Population) in CKD Trials 1, 2 and 3
* p≤0.001 for main efficacy endpoint
ENDPOINT	CKD Trial 1 Non-Dialysis		CKD Trial 2 Non-Dialysis		CKD Trial 3 Dialysis
ENDPOINT	Feraheme N = 226	Oral Iron N = 77	Feraheme N = 228	Oral Iron N = 76	Feraheme N = 114	Oral Iron N = 116
Baseline Hgb mean (SD), g/dL	9.9 (0.8)	9.9 (0.7)	10.0 (0.7)	10.0 (0.8)	10.6 (0.7)	10.7(0.6)
Hgb change from Baseline at Day 35 mean (SD), g/dL	1.2* (1.3)	0.5(1.0)	0.8* (1.2)	0.2 (1.0)	1.0*(1.1)	0.5 (1.1)
Baseline TSAT mean (SD), %	9.8 (5.4)	10.4 (5.2)	11.3 (6.1)	10.1 (5.5)	15.7(7.2)	15.9 (6.3)
TSAT change from Baseline at Day 35 mean (SD), %	9.2 (9.4)	0.3 (4.7)	9.8 (9.2)	1.3 (6.4)	6.4 (12.6)	0.6 (8.3)
Baseline ferritin mean (SD), ng/mL	123.7 (125.4)	146.2 (136.3)	146.1 (173.6)	143.5 (144.9)	340.5 (159.1)	357.6 (171.7)
Ferritin change from Baseline at Day 35 mean (SD), ng/mL	300.7 (214.9)	0.3 (82.0)	381.7 (278.6)	6.9 (60.1)	233.9 (207.0)	-59.2 (106.2)

Following completion of the controlled phase of each of the Phase 3 trials, patients who were iron deficient and anemic could receive two additional 510 mg intravenous injections of Feraheme for a total cumulative dose of 2.04 g. Overall, 69 patients received two additional 510 mg intravenous injections of Feraheme, and on Day 35 following these additional injections, the majority of these patients (70%) experienced an increase in hemoglobin and iron parameters (TSAT and ferritin). The mean change (±SD) in hemoglobin level from the retreatment baseline for patients with an increase in hemoglobin was 0.86 (± 0.68) g/dL and was 0.5 (± 0.8) g/dL for all patients.

In a randomized, controlled clinical trial of 162 IDA patients with CKD (92 Non-Dialysis and 70 on Dialysis), mean change in hemoglobin from Baseline to Week 5 was 0.71 ±1.03 g/dL for Feraheme-treated patients and 0.61 ±0.97 g/dL for iron sucrose-treated patients.