Investigational therapies for renal disease-induced anemia

ABSTRACT

Introduction: 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.

Areas covered: 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.

Expert opinion: 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.

KEYWORDS:

• Anemia
• CKD
• epoetin
• erythropoiesis-stimulating agents
• GDF11 ligand traps
• hepcidin
• HIF stabilizers
• iron

Article highlights

• At present, neither novel second-generation ESAs, such as polysialylated or hybrid Fc-fused rhEpo, nor novel Epo mimetic peptides (e.g. CNTO530) provide definite advantages over established ESAs and retraction of peginesatide was a serious step backwards in this field.

• EPO gene therapy or gene silencing technologies are far from a potential transfer to bedside.

• Molidustat, daprodustat and roxadustat are prominent small molecule hypoxia-inducible factor (HIF) stabilizing compounds, which may be approved in the very near future.

• The human hepcidin modulator lexaptepid pegol and the growth-differentiation factor-11 (GDF11) ligand trap sotatercept are also well advanced in clinical development.

• For iron deficient CKD patients soluble ferric pyrophosphate administered via the dialysate or orally available Ferric citrate hydrate are recent approaches.

• Major concerns are related to selectivity and specificity of these investigational therapies and question unforeseeable long-term and off-target effects.

• Finally, the treating clinician has to realize that these drug candidates will not completely replace conventional ESA and iron preparations but rather play a role as an ‘add-on’ therapy in an always individualized and often multi-targeted approach.

This box summarizes key points contained in the article.

Declaration of interests

W Jelkmann has received financial support from pharmaceutical companies producing and/or marketing recombinant ESAs for advisory tasks and lectures. Specifically, over the past three years, W Jelkmann has been a consultant to Amgen, Hospira and Teva Pharmaceutical Industries Ltd. He has also received honoraria for scientific lectures from Amgen, Hexal, and Teva Pharmaceutical Industries Ltd. W Jelkmann has also received sponsorship for congress organization from Amgen, Hospira, Sandoz Biopharmaceuticals and Teva Pharmaceutical Industries Ltd. Finally, he has received an unrestricted grant for Congress organization from Roche. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.