Disease Analysis: Anemia in Chronic Kidney Disease

Disease Overview

The anemia in chronic kidney disease (CKD) market has struggled as usage of high-selling, standard-of-care, injectable erythropoiesis-stimulating agents (ESAs) has declined, especially in the US, due to strict cost controls and an increased risk of CV events when targeting higher Hb levels, which has led to the use of lower Hb targets and more caution when deciding to initiate drug treatment. Biosimilars have also taken their toll, particularly in Europe, where biosimilar short-acting ESAs have taken a majority share of usage. The first biosimilar in the US, Retacrit, was only approved in 2018, but quarterly sales suggest it may be reaching a plateau. The ESAs could lose further share to the oral hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitors, which are more convenient in non-dialysis patients, reduce the dose of IV iron needed, and have non-inferior efficacy.

Latest key takeaways

• Anemia is defined as an absolute reduction in the quantity of hemoglobin (Hb) in the blood. The kidneys produce approximately 90% of the body’s erythropoietin (EPO), a hormone that is key to production of red blood cells, which carry Hb. Consequently, as damage increases in patients with chronic kidney disease (CKD), the ability to produce EPO is reduced, leading to anemia. Iron deficiency is also common among patients with CKD, which can also contribute to impaired levels of Hb. Anemia means that less oxygen is transported to the tissues, which can present in various ways including fatigue, syncope, or dyspnea, and places patients at an increased risk for cardiovascular (CV) events. Key drug treatments include erythropoiesis-stimulating agents (ESAs) that trigger EPO production, and iron supplements to restore normal levels. Patients with advanced CKD can require dialysis, which typically involves the need for long-term venous access, removing intravenous (IV) administration as a barrier to treatment in this population.
• The anemia in CKD market has struggled as usage of high-selling, standard-of-care, injectable ESAs has declined, especially in the US, due to strict cost controls and an increased risk of CV events when targeting higher Hb levels, which has led to the use of lower Hb targets and more caution when deciding to initiate drug treatment. Biosimilars have also taken their toll, particularly in Europe, where biosimilar short-acting ESAs have taken a majority share of usage. The first biosimilar in the US, Retacrit, was only approved in 2018, but quarterly sales suggest it may be reaching a plateau. The ESAs could lose further share to the oral hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitors, which are more convenient in non-dialysis patients, reduce the dose of IV iron needed, and have non-inferior efficacy.
• The overall likelihood of approval for Phase I assets is 19.5% for anemia in dialysis-dependent CKD and 40.5% for anemia in dialysis-independent CKD, with the average probability that a drug advances from Phase III at 90.0% for both indications. It takes on average 9.9–10.9 years for drugs in these indications to move from Phase I to approval, compared to 9.9 years in the overall hematology space.

ESAs

• ESAs are still the mainstay of anemia treatment in dialysis, but are used less commonly in non-dialysis CKD anemia due to the need for injection. Although effective, this class has CV safety issues and is very expensive. The first-to-market shorter-acting IV ESAs are more suited for dialysis than other settings, as they are given with three-times-weekly dosing. Longer-acting products can be given intravenously or, as is more convenient for non-dialysis patients, subcutaneously. In dialysis, the decision on which ESAs to use can vary greatly by country, impacted by cost, contractual arrangements (eg with dialysis providers Fresenius and DaVita in the US, which control a majority of the market), preferences for dosing frequencies, and practical issues at dialysis centers.
• The first ESA to be approved was Amgen’s short-acting Epogen, but longer-acting agents, including Amgen’s Aranesp and Roche/Vifor Pharma’s Mircera, are now in the ascendancy. Sales of Mircera, which is even longer-acting, have continued to grow, especially in the US, where its launch was delayed until 2015, with sales driven by Vifor’s arrangement with Fresenius and expansion to mid-sized and independent dialysis clinics. Biosimilar ESA products are increasingly being used in all of the major markets; however, overall ESA sales have declined owing to cost controls and safety concerns.

IV irons

• IV irons are particularly important in the dialysis segment, as ESAs increase iron requirements for red blood cell production, and IV iron can readily be given in conjunction with dialysis. In non-dialysis patients, oral iron is more convenient, though many patients have gastrointestinal side effects that can impact compliance.
• Non-dextran IV irons are thought to have a lower rate of severe acute adverse events, and Vifor’s Venofer, sold by Daiichi Sankyo in the US, took the lead early on. Venofer has since lost share in the overall IV iron segment to newer options that have allowed higher dosing with fewer administrations, especially Vifor’s own Injectafer, though the growth of these has mainly been in non-dialysis patients and non-CKD indications, where the dosing advantage is more important and outweighs Injectafer’s higher price – it is also not specifically labeled for dialysis patients in the US.
• Notably, outcomes from a study of Pharmacosmos’s Monoferric in the related co-morbidity of heart failure are expected before the end of 2022, and, if positive, could expand usage in CKD patients with heart failure, although Injectafer already has similar positive evidence. Monoferric can be given in a single dose and was approved in the US in 2020 with a non-dialysis indication, though sales in Europe have been moderate and a patent infringement lawsuit seeking to keep it off the market was filed in February 2020, delaying launch until October 2020.

HIF-PH inhibitors

• The HIF-PH inhibitors have the advantages of oral administration and reduced IV iron use, as well as at least non-inferiority with regard to efficacy compared to ESAs, though that depends on dosing. They may also offer an alternative for certain patients who can be more difficult to treat with ESAs.
• While approved in Japan and Europe, roxadustat (FibroGen/AstraZeneca/Astellas) and vadadustat (Akebia/Mitsubishi Tanabe) both received a complete response letter (CRL) from the US FDA (in August 2021 and March 2022, respectively) over safety concerns, with requests for additional clinical trials. Like ESAs, the risk-benefit profile of these agents is driven largely by the risk for major adverse cardiovascular events (MACE). European regulators also saw the safety signals for roxadustat, but due to methodological and study design issues complicating interpretation, relied on data from the pool of patients in ESA comparison studies who were not previously on ESAs (“correction pool”), which did not show an increase in MACE. Nevertheless, all the safety comparisons are in the label, along with the stipulation that dialysis patients should not be switched from ESAs to roxadustat without a good clinical reason, which could lead physicians to hesitate in using the drug.
• Global Phase III data for vadadustat were somewhat disappointing. While it achieved non-inferiority on efficacy in non-dialysis patients, MACE risk was significantly higher for vadadustat than the ESA comparator, though that appeared to be primarily due to patients outside the US where the Hb target was higher. Since the EMA prefers an on-treatment analysis, if that is more favorable for vadadustat in non-dialysis patients it could improve the chances of the drug being approved for the segment there. Despite achieving non-inferiority on MACE in dialysis patients, approval in this patient population could be negatively influenced by the alarming MACE data from non-dialysis patients, as evidenced by the FDA’s CRL. Notably, Otsuka has terminated its licensing agreement with Akebia relating to vadadustat in the US, Europe, and other regions.
• Phase III results from GSK’s ASCEND programs for daprodustat confirmed that the drug had met its primary efficacy endpoints by increasing mean Hb levels in treatment-naïve patients and maintaining Hb levels in ESA-treated patients. In addition, the CV safety analysis confirmed non-inferiority with ESAs in MACE risk in both dialysis-dependent and non-dialysis patients. However, an on-treatment analysis showed that daprodustat was inferior to darbepoetin alfa with respect to CV safety in non-dialysis-dependent patients. GSK filed applications for daprodustat with the EMA and FDA in March 2022 and April 2022, respectively. An FDA Advisory Panel in October 2022 voted in favor of daprodustat in dialysis patients but against use in non-dialysis patients; daprodustat’s PDUFA date is set for 1 February 2023.