14 CLINICAL STUDIES

14.1 Patients with Inflammatory Bowel Disease (IBD)

The safety and efficacy of ACCRUFER for the treatment of iron deficiency anemia was studied in two randomized, placebo-controlled trials: AEGIS 1 (NCT01252221) and AEGIS 2 (NCT01340872). These trials enrolled 128 patients (age range 18-76 years; 45 males and 83 females) with quiescent IBD (58 patients with Ulcerative Colitis [UC] and 70 patients with Crohns disease [CD]) and baseline Hb concentrations between 9.5 g/dL and 12 /13 g/dL for females / males and ferritin < 30 mcg/L. All patients had discontinued prior oral ferrous product treatment due to lack of efficacy or inability to tolerate oral iron replacement products. Subjects were randomized 1:1 to receive either 30 mg ACCRUFER twice daily or a matched placebo control for 12 weeks.

The major efficacy outcome was the mean difference in Hb concentration from baseline to week 12 between ACCRUFER and placebo. The Least Square [LS] mean difference from baseline was 2.18 g/dL (p<0.0001)(see Table 2).

Table 2. Summary of Hemoglobin Concentration (g/dL) and Change From Baseline to Week 12 AEGIS 1 & 2 - Analysis Using Multiple Imputation - Full Analysis Set Population
Visit (Week) Statistic	ACCRUFER (N = 64)	Placebo (N =64)
Baseline
Mean (SD)	11.0 (1.03)	11.10 (0.85)
Mean change from baseline to Week 12
LS Mean (SE)	2.25 (0.12)	0.06 (0.13)
Treatment Comparison	Difference in Change From Baseline
	LSM Difference (SE) ACCRUFER Placebo)	1-sided lower 97.5%CI	p-value
ACCRUFER versus placebo	2.18 (0.19)	(1.81)	<0.0001
Note: Multiple imputation was based on treatment, gender, disease [UC or CD], and Hb concentration at baseline, Week 4, and 8. For each imputed dataset, the change from baseline to Week 12 was analyzed using an ANCOVA model with treatment as the factor and gender, disease, baseline Hb concentration as covariates.

The LS mean difference in change from baseline Hb to Week 4 and 8 between ACCRUFER and placebo were 1.04 g/dl and 1.73 g/dl, respectively.

The mean ferritin (mcg/L) levels in ACCRUFER subjects at baseline were 8.6 mcg/L [SD 6.77]) and the mean ferritin (mcg/L) levels at Week 12 were 26.0 mcg/L [SD 30.57] with a mean overall improvement of 17.3 mcg/L.

Following completion of the 12-week placebo-controlled phase of the studies, eligible patients transitioned to ACCRUFER 30 mg twice daily open-label treatment for an additional 52 weeks.

During the open-label phase with ACCRUFER, the mean change in Hb concentration from baseline to Week 64 was 3.1 g/dL [SD 1.46 g/dL, n = 35] and the ferritin value demonstrated a mean of 68.9 mcg/L [SD 96.24] at 64 weeks, with a mean overall improvement of 60.4 mcg/L.

14.2 Patients with Chronic Kidney Disease (CKD)

The safety and efficacy of ACCRUFER for the treatment of iron deficiency anemia was studied in AEGIS 3 (NCT02968368), a trial that enrolled 167 patients (mean age 67.4 years, range 30-90 years; 50 males and 117 females) with non-dialysis dependent chronic kidney disease (CKD) and baseline hemoglobin (Hb) concentrations between 8g/dL and 11 g/dL and ferritin < 250 mcg/L with a Transferrin saturation (TSAT) <25% or ferritin < 500 mcg/L with a TSAT <15%. ACCRUFER was administered at a dose of 30 mg twice daily. Subjects were randomized 2:1 to receive either 30 mg ACCRUFER twice daily or a matched placebo control for 16 weeks.

The major efficacy outcome was the mean difference in Hb concentration from baseline to Week 16 between ACCRUFER and placebo. The LS mean difference was 0.52 g/dL (p= 0.0149) (see Table 3).

Table 3. Summary of Hemoglobin Concentration (g/dL) and Change From Baseline to Week 16 Analysis Using Multiple Imputation Intent-to-Treat Population
Visit (Week) Statistic	ACCRUFER (N = 111)	Placebo (N = 56)
Baseline
Mean (SD)	10.06 (0.77)	10.03 (0.82)
Mean change from baseline to Week 16
LS Mean (SE)	0.50 (0.12)	-0.02 (0.16)
Treatment Comparison	Difference in Change From Baseline
	LSM Difference (SE) ACCRUFER – Placebo	95% CI	p-value
ACCRUFER versus placebo	0.52 (0.21)	(0.10, 0.93)	0.0149
Note: Multiple imputation was based on treatment, gender, eGFR at baseline, and Hb concentration at baseline, Week 4 and 8. For each imputed dataset, the change from baseline to Week 16 was analyzed using an ANCOVA model with treatment as the factor and baseline Hb concentration, baseline eGFR as covariates.

The LS mean difference in change from baseline Hb to Week 4 and 8 between ACCRUFER and placebo were 0.13 g/dl and 0.46 g/dl, respectively.

The mean change in ferritin concentration from baseline to Week 16 was 49.3 mcg/L for the ACCRUFER group and 6.3 mcg/L for the placebo group. The mean difference for ACCRUFER versus placebo was 43.0 mcg/L.