Regulatory Decision Summary for Accrufer

The safety and efficacy of Accrufer for the treatment of iron deficiency anemia (IDA) was studied in three pivotal Phase 3 randomized, double-blind, placebo-controlled, multi-centre trials: ST10-01-301 (AEGIS 1) in subjects with ulcerative colitis (UC) and concomitant IDA where oral ferrous preparations (OFP) have failed or could not be used, ST10-01-302 (AEGIS 2) in subjects with Crohn’s Disease (CD) and concomitant IDA where OFP have failed or could not be used, and ST10-01-303 (AEGIS 3) in subjects with non-dialysis dependent chronic kidney disease (CKD) and concomitant IDA.

AEGIS 1 and AEGIS 2 were identical in protocol and study design. Thus, the two trials were reviewed as one. These trials enrolled 128 subjects (aged 18-76 years; 45 males, 83 females) with quiescent inflammatory bowel disease (IBD) (58 subjects with UC, 70 subjects with CD) and baseline hemoglobin (Hb) concentrations between 9.5 g/dL and 12 or 13 g/dL (for females or males, respectively) and ferritin <30 mcg/L. All subjects had discontinued prior OFP 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 primary efficacy endpoint in AEGIS 1/2 was the mean difference in Hb concentration from baseline to week 12 between Accrufer and placebo. At week 12, the least square (LS) mean change in Hb concentration from baseline was 2.25 g/dL for Accrufer and 0.06 g/dL for placebo. A statistically and clinically significant increase in Hb concentration from baseline was observed between Accrufer and placebo (the LS mean difference from baseline was 2.18 g/dL (p<0.0001)). Additionally, the secondary efficacy endpoints (not multiplicity controlled) were supportive of the primary efficacy outcomes. Notably, more subjects administered Accrufer achieved a clinically relevant increase of 1 g/dL from baseline at week 12 compared to placebo (Accrufer 78.1% of subjects; placebo 10.9% of subjects). A clinically significant difference from baseline of 1 g/dL was observed in the subjects treated with Accrufer as early as at week 4. Furthermore, the mean ferritin levels in subjects treated with Accrufer improved steadily from baseline (8.6 mcg/L) to week 12 (26.0 mcg/L), for a mean overall improvement of 17.3 mcg/L. The treatment effect was demonstrated in both IBD subpopulations.

AEGIS 3 enrolled 167 subjects (aged 30-90 years; 50 males, 117 females) with non-dialysis dependent CKD and baseline Hb concentrations between 8 g/dL and 11 g/dL and ferritin <25 mcg/L with a Transferrin saturation (TSAT) <25% or ferritin <50 mcg/L with a TSAT <15%. Compared to AEGIS 1 and AEGIS 2, the subjects were not required to be OFP failure to be eligible for participation in this study. Subjects were randomized 2:1 to receive either 30 mg Accrufer twice daily or a matched placebo control for 16 weeks.

The primary efficacy endpoint in AEGIS 3 was the mean difference in Hb concentration from baseline to week 16 between Accrufer and placebo. At week 16, the LS mean change in Hb concentration from baseline was 0.50 g/dL for Accrufer and -0.02 g/dL for placebo. A statistically significant increase in Hb concentration from baseline was observed between Accrufer and placebo (the LS mean difference from baseline was 0.52 g/dL (p = 0.0149)). The secondary endpoints (not multiplicity controlled) were supportive of the primary efficacy outcomes. The responder analysis at week 16 showed that more subjects administered Accrufer achieved an increase of 1 g/dL from baseline at week 16 compared to placebo (Accrufer 19.8%; placebo 8.9%). Furthermore, the LS mean change in ferritin concentration from baseline to week 16 in subjects treated with Accrufer was 25.42 mcg/L and -7.23 mcg/L with placebo.

Overall, Accrufer was well tolerated. In AEGIS 1 and AEGIS 2, the majority of subjects experienced treatment emergent adverse events (TEAEs) that were mild or moderate in intensity. No subjects died during study duration. The TEAEs that occurred more frequently in the Accrufer group than placebo were abdominal pain (12.5% vs. 7.8%), diarrhea (9.4% vs. 6.3%), constipation (7.8% vs. 1.6%), flatulence (6.3% vs. 0), rectal haemorrhage (4.7% vs. 1.6%), arthralgia (4.7% vs. 0), and abdominal discomfort (4.7% vs. 0). The most frequently reported severe TEAEs were abdominal pain (7.8% [4.7% considered treatment-related] vs. 1.6%) and diarrhea (4.7% [1.6% considered treatment-related] vs. 1.6%). In AEGIS 3, the majority of TEAEs reported were of mild to moderate intensity. Two subjects died during the 16-week treatment period (1 in Accrufer and 1 in placebo); the events were assessed as being unrelated to the study drug. The TEAEs that occurred more frequently in the Accrufer group than placebo were diarrhea (9.0% vs. 8.9%), constipation (8.1% vs. 3.6%), and feces discolored (7.2% vs. 1.8%).

Overall, Accrufer was shown to be efficacious in the treatment of IDA in adult patients who are unresponsive or intolerant to other oral iron preparations and in study populations with underlying medical conditions that are linked with IDA known to be difficult to treat (i.e., IBD and CKD). Risks are adequately mitigated in the Product Monograph and Risk Management Plan. The anticipated benefits of Accrufer are anticipated to outweigh the risks under the conditions of use recommended in the Product Monograph.

For further details about ACCRUFER, please refer to the Product Monograph, approved by Health Canada and available through the Drug Product Database