Iron Replacement Therapy with Oral Ferric Maltol: Review of the Evidence and Expert Opinion
Abstract
:1. Introduction
2. Iron Replacement Therapy
3. Ferric Maltol
3.1. Preclinical and Pharmacology Studies
3.1.1. Preclinical Evidence
3.1.2. Clinical Pharmacology
3.1.3. Posology
3.2. Clinical Evidence Base
3.2.1. Study Designs
3.2.2. Efficacy Outcomes
3.2.3. Safety Findings
4. Review of the Evidence and Clinical Implications
5. Summary and Future Directions
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Study | Location | Underlying Condition | Anemia and Iron Deficiency Definitions | Patients, N | Design | Comparator | Primary Endpoint |
---|---|---|---|---|---|---|---|
Adult | |||||||
Phase III IBD (AEGIS 1/2) [62,64] | Global | Eligibility criteria: Quiescent or mild or moderate IBD UC: SCCAI score <4 at screening and randomization CD: CDAI score <220 at randomization At baseline: UC: FM n = 29; placebo n = 29 Median (range) SCCAI score: FM 2.0 (0–3); placebo 2.0 (0–3) CD: FM n = 35; placebo n = 35 Median (range) CDAI score: FM 75 (14–199); placebo 108 (10–220) | Hb ≥9.5 to <12.0 g/dL (women) or <13.0 g/dL (men) Ferritin <30 μg/L at screening | 128 (FM n = 64; placebo n = 64) 97 started OL FM after DB FM (n = 50) or DB placebo (n = 47) | Randomized, DB, superiority52-week OL extension | Placebo (DB period only) | Hb change from baseline to week 12 |
Phase IIIB IBD (H2H) [71] | Global | Eligibility criteria: Quiescent or mild or moderate IBD UC: SCCAI score ≤5 during screening CD: CDAI score ≤300 during screening At baseline: UC: FM n = 46, IV FCM n = 46 Mean (SD) SCCAI score: FM 2.2 (1.8); IV FCM 2.3 (1.6) CD: FM n = 79, IV FCM n = 79 Mean (SD) CDAI score: FM 129.6 (60.1); IV FCM 140.5 (75.8) | Hb ≥8.0 to ≤11.0 g/dL (women) or ≤12.0 g/dL (men) Ferritin <30 μg/L or ferritin <100 μg/L + TSAT <20% | 250 (ITT: FM n = 125, IV FCM n = 125; PP: FM n = 78, IV FCM n = 88) | Randomized, OL, non-inferiority | IV FCM | Hb responder rate at week 12 (≥2 g/dL increase or normalization) |
Phase III CKD [72] | USA | Eligibility criteria: CKD stage III or IV (eGFR ≥15 to <60 mL/min/1.73 m2, not on dialysis) At baseline:Mean (SD) eGFR: FM 31.9 (11.5) mL/min/1.73 m2 Placebo 29.7 (10.6) mL/min/1.73 m2 | Hb ≥8.0 to <11.0 g/dL Ferritin <250 μg/L + TSAT <25% or ferritin <500 μg/L + TSAT <15% | 167 (FM n = 111; placebo n = 56) 125 started OL FM after 16 weeks of DB FM (n = 86) or DB placebo (n = 39) | Randomized, DB, superiority36-week OL extension | Placebo | Hb change from baseline to week 16 |
Phase IIIB PH [68]‘ | Germany | Eligibility criteria: any form of PH with mean resting pulmonary artery pressure ≥25 mmHg At baseline: PAH (n = 14) PH due to left heart disease (n = 1) Inoperable chronic thromboembolic PH (n = 7) Mean (SD) pulmonary artery pressure 50 (11) mmHg | Hb ≥7 to <12 g/dL (women) or ≥8 to <13 g/dL (men) Ferritin <100 μg/L or ferritin 100–300 μg/L + TSAT <20% | 22 | Single-arm OL, exploratory | None | Hb change from baseline to week 12 |
Pediatric | |||||||
Phase I [73] | UK | Eligibility criteria: Iron deficiency of any cause At baseline: CD (n = 8) Other gastrointestinal disorders (n = 11) Vitamin D deficiency (n = 7) CKD (n = 4) Other conditions (n = 7) | Ferritin <30 μg/L or ferritin <50 μg/L + TSAT <20% | 37 | Randomized, exploratory | Different FM doses | PK, iron uptake |
Study | Mean Hb and Change from Baseline | Hb Responder Rate 1 | Proportion of Patients Achieving Hb Normalization 2 | Proportion of Patients Achieving ≥2 g/dL Increase in Hb | Mean Ferritin | Mean TSAT |
---|---|---|---|---|---|---|
Phase III IBD (AEGIS 1/2) [62,64] | Baseline FM: 11.0 g/dL Placebo: 11.1 g/dL Week 12 FM: 13.2 g/dL Placebo: 11.2 g/dL Mean (SE) difference in change from baseline to week 12 FM vs. placebo: 2.25 (0.12) g/dL p < 0.0001 Up to week 64 DB FM to OL FM: 13.95 g/dL DB placebo to OL FM: 13.33 g/dL | NR | Week 12 FM: 66% Placebo: 13% Up to week 64 DB FM/placebo to OL FM: 86% | Week 12 FM: 56% Placebo: 0 Up to week 64%NR | Baseline FM: 8.6 μg/L Placebo: 8.2 μg/L Week 12 FM: 26.0 μg/L Placebo: 9.8 μg/L Mean increase at week 12 FM: 17.3 μg/L Placebo: 1.2 μg/L Up to week 64 DB FM/placebo to OL FM: 57.4 μg/L | Baseline FM: 10.6% Placebo: 9.5% Week 12 FM: 28.5% Placebo: 9.8% Mean increase at week 12 FM: 18.0 percentage points Placebo: −0.4 percentage points Up to week 64 DB FM/placebo to OL FM: 29% |
Phase IIIB IBD (H2H) [71] | ITT population Baseline FM: 10.0 g/dL IV FCM: 10.1 g/dL Week 12 FM: 12.5 g/dL IV FCM: 13.2 g/dL LSM difference (95% CI) between groups at week 12 FM–IV FCM: −0.6 (−1.0 to −0.2) g/dL p = 0.002 Up to week 52/EoT FM: 12.8 g/dL IV FCM: 13.0 g/dL | ITT population Week 12 FM: 67% IV FCM: 84% Risk difference (95% CI) FM–IV FCM: −0.17 (−0.28 to −0.06) PP population Week 12 FM: 68% IV FCM: 85% Risk difference (95% CI) FM–IV FCM: −0.17 (−0.30 to 0.05) 3 | ITT population Week 12 FM: 55% IV FCM: 81% Up to week 52/EoT NR | ITT population Week 12 FM: 61% IV FCM: 77% Up to week 52/EoT NR | ITT population Baseline FM: 16.6 μg/L IV FCM: 9.2 μg/L Week 12 FM: 25.7 μg/L IV FCM: 139.2 μg/L LSM difference (95% CI) between groups at week 12 FM–IV FCM: −113.1 (−145.9 to –80.2) μg/L p < 0.001 Up to week 52/EoT FM: 78.9 μg/L IV FCM: 103.4 μg/L | NR |
Phase III CKD [72] | Baseline FM: 10.1 g/dL Placebo: 10.0 g/dL LSM change from baseline to week 16 FM: 0.5 g/dL Placebo: −0.0 g/dL LSM (SE) difference between groups at week 16 FM–placebo: 0.5 (0.2) g/dL p = 0.01 Up to week 52/EoT DB FM to OL FM: 10.9 g/dL DB placebo to OL FM: 10.9 g/dL | NR | Week 16 FM: 27% Placebo: 13% Up to week 52/EoT NR | Week 16 FM: 6% Placebo: 0 Up to week 52/EoT NR | Baseline FM: 97.0 μg/L Placebo: 104.2 μg/L LSM change from baseline to week 16 FM: 25.4 μg/L Placebo: −7.2 μg/L LSM (SE) difference between groups at week 16 FM–placebo: 32.7 (9.4) μg/L p < 0.001 Up to week 52/EoT DB FM to OL FM: 142.5 μg/L DB placebo to OL FM: 146.3 μg/L | Baseline FM: 15.7% Placebo: 15.6% LSM change from baseline to week 16 FM: 3.8 percentage points Placebo: −0.9 percentage points LSM (SE) difference between groups at week 16 FM–placebo: 4.6 (1.1) percentage points p < 0.001 Up to week 52/EoT DB FM to OL FM: 23.5% DB placebo to OL FM: 21.4% |
Phase IIIB PH [68] | Baseline FM: 10.7 g/dL Week 12 FM: 13.6 g/dL Median increase from baseline to week 12: 2.9 g/dL p < 0.001 | NR | NR | NR | Baseline FM: 13.1 μg/L Week 12 FM: 36.6 μg/L p < 0.001 | Baseline FM: 7.5% Week 12 FM: 31.7% p < 0.001 |
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Schmidt, C.; Allen, S.; Kopyt, N.; Pergola, P. Iron Replacement Therapy with Oral Ferric Maltol: Review of the Evidence and Expert Opinion. J. Clin. Med. 2021, 10, 4448. https://doi.org/10.3390/jcm10194448
Schmidt C, Allen S, Kopyt N, Pergola P. Iron Replacement Therapy with Oral Ferric Maltol: Review of the Evidence and Expert Opinion. Journal of Clinical Medicine. 2021; 10(19):4448. https://doi.org/10.3390/jcm10194448
Chicago/Turabian StyleSchmidt, Carsten, Stephen Allen, Nelson Kopyt, and Pablo Pergola. 2021. "Iron Replacement Therapy with Oral Ferric Maltol: Review of the Evidence and Expert Opinion" Journal of Clinical Medicine 10, no. 19: 4448. https://doi.org/10.3390/jcm10194448