Investigational therapies for renal disease-induced anemia.
BACKGROUND
The main pillars for the treatment of chronic kidney disease (CKD) associated anemia are peptidic erythropoiesis stimulating agents (ESAs) and iron preparations. Both approaches benefit from long-term efficacy and safety data but are surrounded by clinical and economic concerns, driving the search for novel anti-anemic drugs.


METHODS
By answering pivotal questions, the authors describe the recent developments of next generation ESAs, introduce cutting-edge iron formulations and focus on investigational approaches that interact with pathways involved in erythropoietin (Epo) synthesis and myeloid hematopoiesis. Finally, the challenges encountered with these drug candidates are discussed.


CONCLUSIONS
Current peptidic ESAs are effective and well-tolerated, but are costly, require parenteral application and iron supplementation. ESA resistance may develop calling for increased doses. Therefore, orally available hypoxia-inducible factor (HIF) stabilizing compounds are attractive alternatives, which may be approved in the near future. Prominent compounds are molidustat, daprodustat and roxadustat. HIF stabilizers suppress hepcidin production and improve iron balance as the present ESAs, but also raise safety concerns in association with their pleiotropic actions. Other investigational erythropoietic biologics are growth-differentiation factor-11 (GDF11) ligand traps (sotatercept, luspatercept), which are also well advanced in development. Possibly, they will provide an add-on for established therapies. However, immunogenicity of these compounds still needs to be carefully investigated.
a Clinic and Policlinic IV, Section of Nephrology , LMU Munich , Munich , Germany.
Holger
H
Schmid
b Institute of Physiology , University of Luebeck , Luebeck , Germany.
Wolfgang
W
Jelkmann
D000740:Anemia / Q000188:drug therapy* / Q000209:etiology; D000818:Animals; D001688:Biological Products / Q000009:adverse effects / Q000627:therapeutic use; D015195:Drug Design; D004351:Drug Resistance; D015507:Drugs, Investigational / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D004921:Erythropoietin / Q000096:biosynthesis; D006397:Hematinics / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D010455:Peptides / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D051436:Renal Insufficiency, Chronic / Q000150:complications
D001688:Biological Products; D015507:Drugs, Investigational; D006397:Hematinics; D010455:Peptides; D004921:Erythropoietin
Anemia; CKD; GDF11 ligand traps; HIF stabilizers; epoetin; erythropoiesis-stimulating agents; hepcidin; iron