Latest Key Takeaways
ESAs
IV irons
HIF-PH inhibitors
Overall likelihood of approval
- 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. The ESAs are poised to lose further share to the oral and potentially safer HIF-PH inhibitors, with roxadustat on track for initial approval in the important US market in early 2021, having already been approved in Japan and China. It will be important to see, though, more details from its FDA review. The HIF-PH inhibitors also reduce the dose of IV iron needed in dialysis patients and appear to have other advantages as well. However, concerns over the angiogenic effects of HIF stabilizers could impact usage, and with limited data on safety for this class of drug, physicians may be reluctant to switch from ESAs, which have been the traditional form of treatment for the past 20 years.
ESAs
- Despite dose reductions, ESAs are still currently the mainstay of anemia treatment in dialysis, used in at least 80% 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, is still the largest-selling branded product, as it has retained substantial share in the dialysis market. Outside the US, Amgen’s longer-acting Aranesp leads, though a portion of its sales are in oncology indications. 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 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.
HIF-PH inhibitors
- The HIF-PH inhibitors have the advantages of oral administration, potentially improved safety (as they more physiologically impact erythropoietin than ESAs), improved iron utilization, and possibly greater efficacy in certain patients who can be more difficult to treat with ESAs. However, the unknown angiogenic effects could limit use to low-risk patients, pending data from the large Phase III trials. Hence, they have the potential to take some market share from ESAs, as well as grow anemia treatment in non-dialysis CKD. They are likely to also reduce IV iron use in dialysis patients. Roxadustat appears to be at least as effective as ESAs, and the others have some evidence suggesting that as well, especially since efficacy can be a matter of dose titration.
- While there are signs of a potential CV advantage with roxadustat, the picture may not be as clear as one might have hoped for, though that may just be an indication that ESAs are not as dangerous at the lower Hb targets used. In dialysis patients, there was a benefit on MACE+ versus epoetin alfa, the European endpoint, which is encouraging. Part of the benefit, though, was due to heart failure rather than more typical atherosclerotic endpoints, and more data are needed to see if that was related to lower hypertension, as well as whether there were any differences in various thrombotic events. There was a substantial reduction in events in the incident dialysis subgroup, but details have not been released on the chronic dialysis subgroup. Some controversies over the data have been raised, but more details will likely come out at an FDA advisory committee meeting. In non-dialysis patients, it was positive that roxadustat demonstrated non-inferiority to placebo on CV outcomes. Rates of MACE and MACE+ were slightly numerically higher than placebo, with a somewhat larger numerical increase in the individual endpoint of stroke, though these could all be due to chance. It was somewhat curious, though, that the pattern of slightly higher MACE and a more pronounced increase in stroke was similar to what was seen in Aranesp’s large TREAT study, which contributed to concern over ESAs, though the increase in stroke with Aranesp was substantially higher and statistically significant.
- Roxadustat is also being dosed three times a week, which may be more difficult for non-dialysis patients to remember, opening the door to competitors vadadustat and daprodustat, which have daily dosing, though there may be ways around the issue.
- Global Phase III data for vadadustat were somewhat disappointing, as the drug failed to demonstrate non-inferiority in terms of MACE compared to the ESA darbepoetin alfa in non-dialysis patients. In fact, MACE HR with vadadustat was worse than with darbepoetin, which raises a significant safety concern considering that ESAs are known for a poor CV safety profile. Despite achieving non-inferiority in dialysis patients, approval in this patient population could be negatively influenced by the alarming MACE data from non-dialysis patients.
- Phase III results for GlaxoSmithKline’s daprodustat are expected in 2021.
- 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).
Overall likelihood of approval
- The overall likelihood of approval for Phase I assets is 20.9% for anemia in dialysis-dependent CKD and 39.4% for anemia in dialysis-independent CKD, with the average probabilities that a drug advances from Phase III at 87.5% for both indications. It takes on average 9.6-10.6 years for drugs in these indications to move from Phase I to approval, compared to 9.2 years in the overall hematology space.
Table of Contents
OVERVIEW
DISEASE BACKGROUND
TREATMENT
EPIDEMIOLOGY
KEY REGULATORY EVENTS
CLINICAL TRIAL LANDSCAPE
DRUG ASSESSMENT MODEL
FUTURE TRENDS
KEY OPINION LEADER INSIGHTS
UNMET NEEDS
BIBLIOGRAPHY
LIST OF FIGURES
LIST OF TABLES
