Abstract and Introduction
Normocytic normochromic anemia is a common complication in chronic kidney disease and is associated with many adverse clinical consequences. Erythropoiesis-stimulating agents (ESAs) and adjuvant iron therapy represent the primary treatment for anemia in chronic kidney disease. The introduction of ESAs into clinical practice was a success story, mediating an increase in hemoglobin concentrations without the risk for recurrent blood transfusions and improving quality of life substantially. However, recombinant ESAs are still expensive and require a parenteral route of administration. Moreover, concern has arisen following randomized clinical trials showing that higher hemoglobin targets and/or high ESA doses may cause significant harm. This, together with changes in ESA reimbursement policy in some countries, has resulted in a significant reduction in ESA prescribing and the hemoglobin level targeted during therapy. Several attempts are being made to develop new drugs with improved characteristics and/or easier manufacturing processes compared with currently available ESAs, including new treatment approaches that may indirectly improve erythropoiesis. We give an update on the new investigational strategies for increasing erythropoiesis, examining in depth their characteristics and possible advantages in the clinical setting and the caveats to be aware of at the present stage of development.
Normocytic normochromic anemia is one of the hallmarks of progressive chronic kidney disease (CKD). It is mainly due to an absolute or relative decrease in erythropoietin (EPO) production by the failing kidney. However, its pathogenesis is much more complex. Several other factors (iron and vitamin deficiency, infection, inflammation, occult blood loss, oxidative stress, inadequate dialysis, and hyperparathyroidism) often contribute to anemia development and reduce response to treatment.
The introduction of erythropoiesis-stimulating agents (ESAs) has revolutionized the care of anemic patients with CKD and almost completely eradicated the severe anemia of end-stage renal disease (ESRD). Moreover, ESAs decrease the risk for recurrent blood transfusions and iron overload and may improve quality of life. The first-generation ESAs were human recombinant EPOs (epoetin alfa and epoetin beta). Subsequently, 2 second-generation ESAs with a longer duration of action were developed; darbepoetin alfa and methoxy-polyethylene glycol-epoetin beta. Biosimilar epoetins, together with epoetin theta, have also received marketing authorization in many countries.
Today, ESAs and adjuvant iron therapy are the main tools for treating the anemia associated with CKD. Available ESAs are very effective drugs, usually obtaining significant hemoglobin (Hb) level increases. However, recombinant ESAs are still expensive and require cold storage. In addition, they are administered by the parenteral route. Especially with frequent subcutaneous administrations, this may be cumbersome for long-term treatment in non–dialysis-dependent patients with CKD. In hemodialysis (HD) patients, the issue is more complex because intravenous administration increases nurse workload but improves treatment adherence. In addition, in the past several years, clinical trials[4–6] have shown that higher Hb targets and/or application of high ESA doses may increase cardiovascular risk. This, together with changes in ESA reimbursement policy in some countries, has led to reductions in prescribed ESA dose and target Hb levels.[8,9] Hence, an increase in blood transfusion requirements and intravenous iron dosing has occurred. Blood transfusions cannot be considered as an alternative strategy to ESAs because they still have some risks, expose patients to large Hb-level fluctuations, and by definition have limited availability. Moreover, they may enhance the synthesis of alloantigenic antibodies, reducing the likelihood of patients subsequently receiving a kidney transplant. Excessive iron use may cause harm as well.
In the last 2 decades, recombinant forms of EPO have been engineered to have structural modifications that increase half-life and accommodate a wider administration schedule. However, health systems cannot afford to pay more for a secondary advantage, as attested by the limited success of methoxy-polyethylene glycol-epoetin beta in the European market (though this may have been compounded by a several-month shortage of the drug). Moreover, the experience with peginesatide (discussed later) has highlighted that unexpected adverse events may abruptly halt either the development or commercialization of a given molecule after years of investment. The task is becoming increasingly difficult because regulatory authorities rightly require more and more data for safety and hard end points following the concerns surrounding the safety of existing ESAs with regard to cardiovascular events and cancer worsening.
Despite this, the ESA market is huge and still very appealing from an economic standpoint. Attempts are being made to develop new molecules with improved characteristics and/or easier manufacturing processes than those currently available. Their success when entering the ESA market will depend on the balance among price, advantages, and possible risks. There remains the general sentiment that new treatment strategies are needed with a better safety profile than existing ESAs.
In this review, we provide an update on the new treatment approaches for increasing erythropoiesis (Box 1). We report in particular on the new erythropoietic strategies currently in clinical development. Agents that have not yet reached this phase are described in Table 1.[11–25]
Am J Kidney Dis. 2016;67(1):133-142. © 2016 The National Kidney Foundation
The National Kidney Foundation
Published by Elsevier