# A New Paradigm for Iron Replacement Therapy

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2024 · $640,377

## Abstract

Project Summary/ Abstract
Anemia impacts ~25% of the world’s population and contributes to adverse outcomes. Several forms of anemia,
including anemia of inflammation (AI) and iron-refractory iron deficiency anemia (IRIDA) are caused in part by
pathologic iron (Fe) restriction. In these conditions, chronic immune activation or genetic mutations upregulate
the Fe regulating hormone hepcidin, which in turn inhibits activity of ferroportin, the only known Fe exporter.
Hepcidin excess thus imposes a severe form of hypoferremia as Fe liberated via hemoglobin recycling in
macrophages, nutritional iron absorbed by enterocytes, and other stored Fe cannot be exported to the plasma
iron-carrier protein transferrin for distribution.
 Fe replacement in patients with hepcidin excess can be challenging. Most intravenous Fe replacement drugs
are Fe-carbohydrate nanoparticles that are accumulated and metabolized in macrophages, requiring ferroportin
for Fe mobilization. Thus, iv replacement can simultaneously have limited efficacy for anemia correction while
potentially contributing to Fe overload in macrophages. Hepcidin-driven Fe restriction also limits the efficacy of
nutritional Fe supplements. There is no clinically available hepcidin-modulating drug. Erythropoiesis stimulating
agents (ESA) may offer a therapeutic benefit for some patients, but are associated with cardiovascular toxicity,
thrombosis, and malignancy in some studies.
 An alternate approach is to deliver Fe directly to transferrin via mechanisms independent of ferroportin. An
intravenous formulation comprising iron pyrophosphate citrate (FPC) that releases Fe directly to transferrin has
FDA approval for use during hemodialysis. However, care must be taken to ensure that serum FPC
concentrations do not exceed serum total Fe binding capacity, as exposure to toxic labile Fe occurs above this
threshold. To safely administer therapeutically meaningful quantities of Fe, FPC is slowly infused over hours.
 There remains an unmet need for drugs to efficiently and safely replenish Fe via ferroportin-independent
pathways. We posit that a highly effective direct-to-transferrin Fe replacement drug can be developed through
the judicious application of coordination chemistry principals. Here, we propose drug design based on a set
prospectively defined molecular properties. Preliminary in vitro and in vivo data in support of our approach is
provided using the complex Fe-BBG (BBG = N,N-(bis)-2-hydroxybenzyl-L-glutamic acid) that we synthesized as
our initial drug prototype. We will iteratively synthesize and screen a library of complexes for efficacy and safety
signals. Promising candidates will be advanced to demonstrate therapeutic efficacy for anemai correction in
rodent models of IRIDA and chronic kidney disease. The output of this work will be one or more de-risked
candidates for development as direct-to-transferrin Fe replacement drugs.

## Key facts

- **NIH application ID:** 10917145
- **Project number:** 5R01HL169470-02
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Eric Michael Gale
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $640,377
- **Award type:** 5
- **Project period:** 2023-09-01 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10917145

## Citation

> US National Institutes of Health, RePORTER application 10917145, A New Paradigm for Iron Replacement Therapy (5R01HL169470-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10917145. Licensed CC0.

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