Disease Analysis: Anemia in Chronic Kidney Disease

Disease Overview

Anemia in chronic kidney disease (CKD), defined as a reduction in red blood cells (RBCs) or hemoglobin levels, often results from decreased levels of erythropoietin and increased levels of hepcidin. Erythropoietin is primarily produced in the kidneys and increases the production of RBCs by acting on precursor cells. However, its levels decline as kidney function worsens, leading to reduced production. Early on, levels of erythropoietin are low in relation to the degree of anemia, though they may not be low on an absolute scale. Increased hepcidin levels in CKD are thought to be a result of kidney inflammation.

Latest key takeaways

• 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 an increased risk of CV events when targeting higher Hb levels, which has led to lower Hb targets and more caution when deciding to initiate the drugs. 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, so is still ramping, though quarterly sales suggest it may be reaching a plateau. The ESAs could lose further share to the oral HIF-PH inhibitors, which are more convenient in non-dialysis patients, reduce the dose of IV iron needed, and have non-inferior efficacy. They also may have a role in ESA-resistant patients. However, while approvals have come in Japan and Europe, albeit with strong safety warnings, the most advanced, roxadustat, has been derailed in the US due to concerns over CV safety relative to ESAs. There are issues for vadadustat, as well, at least in non-dialysis patients. Daprodustat has reported similar CV safety to ESAs, but details are pending. With uncertainty over CV safety, and potential concerns about other long-term safety issues, physicians are likely to be hesitant to switch from ESAs without a financial incentive in dialysis patients, where they have been the traditional form of treatment for the past 20 years. If daprodustat safety can be validated in non-dialysis patients, it could be considered a viable alternative to ESAs; however, uptake could be slow due to the inexperience of prescribers in this novel class.

ESAs

• Despite dose reductions, ESAs are still currently the mainstay of anemia treatment in dialysis, used in at least 75% of patients in major markets; however, ESAs are less commonly used in non-dialysis CKD anemia due to the need for injection, safety issues, a broader spectrum of anemia severity, and cost. The first-on-the-market shorter-acting intravenous 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.
• In the US, the first ESA to be approved, Amgen’s short-acting Epogen, has been the top-selling branded product in the nephrology sector. Aranesp has surpassed it in overall sales, but a portion of that is in oncology. Outside the US, Amgen’s longer-acting Aranesp leads, even when taking account the portion of oncology sales. Biosimilars to Aranesp have been approved in Japan, where it was favored over shorter-acting agents. Mircera, which is even longer-acting, has 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, though overall ESA sales have continued to decline.

IV irons

• Iron is the other major anemia treatment, used for patients with iron deficiency from a potential multitude of causes associated with CKD. 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, which now leads the overall IV iron segment in sales, 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. As a result, Venofer still leads in nephrology sales due to its use in the US dialysis market. Outside the US, including in Europe, iron sucrose similars have surpassed Venofer in gross sales, despite efforts to show they do not have the same efficacy and safety, but sales for both are modest. Outcomes studies of Injectafer and Pharmacosmos’s Monoferric in the related co-morbidity of heart failure are expected in late 2021, and, if positive, could expand usage in CKD patients with heart failure. 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, reduced IV iron use, and possibly greater efficacy in certain patients who can be more difficult to treat with ESAs, as well as at least non-inferiority with regard to efficacy compared to ESAs, though that depends on dosing. However, while approved in Japan and Europe, the most advanced candidate, roxadustat, received a complete response letter from the FDA in 2021 over concerns that it increases the risk of MACE and other thromboembolic events more than ESAs. That may depend on dosing, but the agency wanted to see proof of a safer dose prior to approval. European regulators also saw the safety signals, 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 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, especially in the US, could be negatively influenced by the alarming MACE data from non-dialysis patients.
• Phase III results from GlaxoSmithKline’s ASCEND programs for daprodustat were reported in July 2021, confirming 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. Importantly, the CV safety analysis confirmed non-inferiority with ESAs in MACE risk in both dialysis-dependent and non-dialysis patients. Trial design and non-inferiority margins appeared to be according to FDA preference, but detailed results are still pending, including overall thromboembolic events. If daprodustat does appear safer than others in the class, it would of course have an advantage, but if, as it appears, it is no safer than ESAs, that could still be a limitation to expanding usage in less severe non-dialysis patients.
• At the least, the initial HIF-PH inhibitors should receive an extra payment for two years under Medicare’s Transitional Drug Add-On Payment Adjustment (TDAPA).
• The overall likelihood of approval for Phase I assets is 21.2% for anemia in dialysis-dependent CKD and 40% for anemia in dialysis-independent CKD, with the average probability that a drug advances from Phase III at 88.9% for both indications. It takes on average 9.7–10.8 years for drugs in these indications to move from Phase I to approval, compared to 9.8 years in the overall hematology space.