Emerging therapies and new medications for anemia

Article written and reviewed by Dr Luca Moretti

The therapeutic landscape of anemia has changed profoundly in recent years with the advent of new pharmacologic and biotechnologic strategies that are redefining treatment, especially in refractory, rare or transfusion dependent forms. Greater understanding of the molecular mechanisms regulating erythropoiesis, iron metabolism, interactions between the immune system and erythroid cells, and the pathogenesis of inherited anemias has enabled development of targeted medications and innovative therapies, many of which have entered clinical practice while others remain in advanced stages of investigation.

New therapies aim to overcome specific limitations of traditional strategies based on iron, vitamin B12, folic acid, erythropoietin and transfusions through selective intervention on pathogenetic mechanisms; efficacy, safety and ability to modify natural history must be demonstrated separately for each indication. This page examines the principal groups of emerging medications and advanced therapeutic strategies for different forms of anemia, from erythropoiesis modulators and agents targeting iron metabolism to therapies for hemoglobinopathies and approaches based on immunotherapy and molecular medicine.

Innovative agents for stimulating erythropoiesis

New erythropoietic agents and receptor agonists

Recombinant human erythropoietin and its analogs have been central to management of renal anemia and forms secondary to malignancy or myelosuppressive therapy. In recent years, long acting epoetins , including darbepoetin alfa and pegylated epoetin beta, have been developed, allowing less frequent administration, more stable blood levels and potentially better adherence.

Peginesatide is not an available therapy. After commercial withdrawal because of serious hypersensitivity reactions, the European application was withdrawn. Other agonists or peptidomimetics require individual evaluation and do not constitute an established clinical class.

Hypoxia inducible factor prolyl hydroxylase inhibitors (HIF PHIs)

One of the most important pharmacologic innovations of recent years is represented by HIF prolyl hydroxylase inhibitors (HIF PHIs), which stabilize the transcription factor HIF alpha and promote endogenous erythropoietin synthesis by renal and peritubular cells, even in advanced chronic kidney disease. The principal HIF PHIs in clinical use include roxadustat, vadadustat, daprodustat and molidustat.

These agents increase hemoglobin and modify hepcidin and iron metabolism, but efficacy, safety and authorization differ among agents and jurisdictions. The 2026 KDIGO guideline retains ESAs as first line treatment in chronic kidney disease and considers HIF PHIs an alternative in selected patients.
HIF PHIs require careful selection with regard to cardiovascular, thrombotic and oncologic risks. They should not be combined with ESAs and are not a general treatment for anemia of inflammation or refractory anemias.

New strategies targeting iron metabolism

Modulation of hepcidin and ferroportin

Iron metabolism is central to the pathogenesis of anemia of chronic inflammation, myelodysplastic syndromes and thalassemias. Hepcidin is the main negative regulator of systemic iron availability. High levels block ferroportin on intestinal, hepatic and macrophage cells, preventing mobilization of iron for erythropoiesis. Pharmacologic modulation of hepcidin and ferroportin is the focus of numerous studies.

Approaches under development include:

• Hepcidin antagonists or strategies that reduce its activity: experimental approaches intended to increase iron availability in anemia of inflammation;
• Anti TMPRSS6 agents: increase hepcidin and are being studied mainly in disorders with ineffective erythropoiesis and iron overload, not simply in disorders with low hepcidin.
• Ferroportin inhibitors: agents under study mainly in anemias with iron overload and ineffective erythropoiesis, in which reducing iron export may limit pathologic accumulation.

These strategies are particularly promising in anemias associated with chronic disease, thalassemias and sideroblastic anemias, where iron dysregulation limits traditional therapies.

New iron formulations and intelligent delivery agents

Innovation also concerns intravenous iron formulations with high bioavailability and a low risk of severe hypersensitivity reactions, such as ferric carboxymaltose, ferumoxytol and ferric derisomaltose, which allow rapid correction of deficiency in patients intolerant of oral iron, with chronic inflammation or persistent blood loss.

Controlled release systems, nanoformulations and smart vectors capable of selectively delivering iron to hematopoietic marrow while reducing gastrointestinal adverse effects and overload toxicity are being developed. These technologies remain experimental and cannot be considered standard therapy; any clinical usefulness must be demonstrated in appropriate preclinical and clinical studies.

Innovative therapies for inherited anemias and hemoglobinopathies

Erythroid maturation modulators: luspatercept and analogs

A major advance for patients with beta thalassemia, both transfusion dependent and non transfusion dependent, and lower risk myelodysplastic syndromes has been the introduction of luspatercept . Sotatercept is developed for other indications and should not be presented as an emerging medication for anemia. These agents act as ligand traps for members of the TGF beta family, particularly activins, inhibiting signals that impair late erythroid maturation and thereby promoting production of functional red blood cells.

The BELIEVE, BEYOND and MEDALIST studies showed:

• A significant reduction in transfusion requirements in transfusion dependent beta thalassemia and an increase in hemoglobin in non transfusion dependent beta thalassemia, as well as reduced transfusion requirements in the indicated myelodysplastic syndromes;
• A favorable safety profile, with adverse reactions predominantly mild to moderate, including fatigue, joint pain and transient hypertension.

Luspatercept is authorized for defined indications, including anemia associated with beta thalassemia in adults, both transfusion dependent and non transfusion dependent, and anemia associated with lower risk myelodysplastic syndromes; use must follow the regulatory criteria for each indication.

Telomerase inhibition in myelodysplastic syndromes

In lower risk MDS, imetelstat is available as a telomerase inhibitor authorized in the European Union as monotherapy for adults with transfusion dependent anemia due to very low, low or intermediate risk non del(5q) MDS after an unsatisfactory response to or ineligibility for erythropoietin based therapy.

Enzyme modulators and oral therapies: mitapivat and others

In pyruvate kinase deficiency (PKD), an inherited disorder causing chronic hemolysis, the introduction of mitapivat , an allosteric activator of erythrocyte pyruvate kinase, has provided a targeted oral therapy. Mitapivat increases erythrocyte pyruvate kinase activity, improves ATP production and reduces premature red blood cell destruction. In the European Union it is also authorized in adults for treatment of anemia associated with alpha or beta thalassemia, both transfusion dependent and non transfusion dependent.

In pyruvate kinase deficiency, clinical trials have documented increased hemoglobin and reduced transfusion requirements in subsets of patients. In thalassemias, registration studies have shown either reduced transfusions or a sustained increase in hemoglobin depending on transfusion dependence. Safety profile, dose and criteria for continuation differ by indication and must follow product information.

Gene therapies and genome editing

Regenerative medicine and gene therapy technologies are opening unprecedented possibilities in the treatment of hemoglobinopathies, thalassemias and some refractory inherited anemias.
The main approaches include:

• Correction of the genetic defect by insertion of a functional copy of the defective gene, such as lentiviral gene therapy for beta thalassemia and sickle cell disease;
• Genome editing using CRISPR Cas9 or ZFN techniques to reactivate fetal hemoglobin production or correct point mutations;
• Use of genetically corrected autologous hematopoietic stem cells reinfused after myeloablative conditioning.

For some authorized gene therapies, studies have demonstrated transfusion independence in some patients with beta thalassemia or a marked reduction in vaso occlusive crises in sickle cell disease. These outcomes do not automatically mean complete remission and require conditioning, prolonged follow up and risk assessment.

Immunotherapy, biotechnology and new approaches for autoimmune and aplastic anemias

Monoclonal antibodies and anticomplement medications

Autoimmune hemolytic anemias and cold agglutinin anemias have benefited from the introduction of anti CD20 monoclonal antibodies , including rituximab; obinutuzumab remains a nonstandard or investigational option in this setting. These agents selectively reduce the B cell population responsible for production of red blood cell autoantibodies. More recently, sutimlimab, an anti C1s monoclonal antibody, has shown substantial efficacy in selective inhibition of the classical complement pathway, reducing hemolysis in adults with cold agglutinin disease.

In paroxysmal nocturnal hemoglobinuria, available anti C5 agents include eculizumab, ravulizumab and crovalimab, the latter authorized in the European Union for adult and pediatric patients aged at least 12 years and weighing at least 40 kg according to specific clinical criteria. Proximal complement inhibitors are also available: pegcetacoplan targeting C3 and iptacopan targeting factor B as monotherapy options according to indication, whereas danicopan targeting factor D is authorized as add on therapy to ravulizumab or eculizumab in adults with residual hemolytic anemia. Ravulizumab is also used in complement mediated hemolytic uremic syndrome; further use in autoimmune hemolytic anemias and other microangiopathies remains under study.

Thrombopoietin agonists in aplasia and immune cytopenias

In severe aplastic anemia, eltrombopag is incorporated into specific immunosuppressive regimens or may be used in selected settings. Thrombopoietin receptor agonists are also used in platelet cytopenias such as ITP, but they are not a general therapy for anemia or all refractory autoimmune cytopenias. Indications, agents and combinations depend on the diagnosis; romiplostim is not a general standard treatment for aplastic anemia.

The safety profile is generally favorable but requires careful monitoring of thrombotic and hepatotoxic risks, as well as prolonged hematologic follow up to identify any myelodysplastic clones early.

Other emerging medications, combination therapies and future perspectives

Modulators of hemoglobin oxygen affinity

In sickle cell disease and some rare hemoglobinopathies, modification of hemoglobin oxygen affinity represents a new therapeutic target. Voxelotor is no longer a current therapeutic option. Its authorization was suspended and the product withdrawn following safety signals.

Combination therapies and personalized algorithms

Combinations should be limited to regimens supported by evidence and specific indications. Associations such as erythropoietin plus HIF PHI or luspatercept plus intravenous iron are not routine strategies that can be generalized.

Application of precision medicine algorithms integrating genomic, transcriptomic and proteomic information remains largely a research field and, apart from specific validated genomic indications, does not yet allow routine prediction of response for every form of anemia.

Future perspectives and challenges

Perspectives include further development of gene therapies, delivery systems and biomarkers. Many of these technologies remain experimental and cannot be described as certain to enter widespread clinical use soon. Major challenges remain access to the most advanced treatments, the high costs of cellular and gene therapies, the need for multidisciplinary networks and referral centers, long term safety monitoring and early identification of unexpected adverse effects.

Biotechnologic progress is expanding options for specific anemias; the impact on natural history, survival and quality of life must be evaluated separately for each indication and therapy.

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