It is an exciting time in the treatment of renal anemia, with several new therapies recently launched or expected to launch over the next few years. Products or classes such as Mircera, erythropoietin-stimulating agent (ESA) biosimilars, Auryxia and a new class of agents called oral hypoxia inducible factor-prolyl hydroxylase (HIF-PH) inhibitors will likely expand the renal anemia treatment options available to physicians today.
Given the difficulty treating and managing renal anemia in patients with chronic kidney disease, these therapies are followed with much enthusiasm by patients and health care providers alike (see Figure 1).
Anemia is a common complication of CKD, typically occurring early in the development of the disease and becoming more severe as CKD progresses. The primary treatment goal in renal anemia is to increase and maintain hemoglobin and other anemia parameters, such as ferritin.
Decision Resources Group has been surveying nephrologists about the emerging agents and collecting dialysis patient chart information through its ChartTrends series of reports. Using both qualitative and quantitative methods, these reports explore such items as the potential of emerging therapies and ultimately provide recent market insights of prescribers.
Mircera (methoxy polyethylene glycol-epoetin beta), a long-acting ESA, received FDA approval in November 2007 and is marketed by Roche in Europe. Despite approval, it had never launched in the U.S. due to a settlement agreement under which Roche agreed to delay the launch until mid-2014. However, in May 2015 Roche entered into an exclusive license agreement for the commercialization of Mircera in the U.S. with Galenica, the parent company of Vifor Pharma. In addition, Galenica has entered into a supply agreement with Fresenius Medical Care North America (FMCNA) under which Galenica will supply Mircera for FMCNA’s use solely within its dialysis facilities. Therefore, it is likely that Mircera will have a full U.S. commercial launch (excluding current pilot programs in Fresenius clinics) in the near future.
For now, we look at Europe for a proxy for Mircera’s market potential and expected performance in the U.S. For example, ChartTrends: Nephrology in Dialysis (EU5) 2015 indicates that the current Mircera dialysis ESA patient share is just over 10% with a significantly higher share seen in France compared with other European countries under study.1 The majority of these patients are dosed intravenously and the vast majority are dosed once per month, which is not surprising given the long-acting characteristic of Mircera.
While it is too soon to know whether Mircera will be this successful in the U.S., early indications of physician perceptions seem positive. After reviewing Mircera’s product profile in TreatmentTrends: Nephrology (US) Q32014, surveyed U.S. nephrologists estimate that over 30% of their CKD non dialysis (CKD-ND) patients and nearly 40% of their dialysis patients are likely candidates for Mircera (assuming availability).2 In addition, nearly half of surveyed nephrologists by Decision Resources Group are highly interested in the product.3
We believe that between the supply agreement with Fresenius and this positive physician perception research, Mircera should capture patient share against the U.S. dialysis ESA patient leader, Amgen’s Epogen.
In addition to this news, both new ESAs like Mircera and existing ESAs like Amgen’s Epogen and Aranesp are facing another competitor: ESA biosimilars.
An abbreviated pathway, known as 351(k), for approval of biosimilars in the U.S. was established in 2010, but FDA guidance on how to meet requirements for this pathway has been slow to emerge. Unlike small molecule generic drugs, biosimilars are required to undergo head-to-head clinical trials with the reference product in order to confirm that there are no clinically meaningful differences between the two products.
Europe has been ahead of the U.S.in terms of biosimilar development, with ESA biosimilars first launching there in 2007. The first application for a U.S. ESA biosimilar was submitted by Hospira (now part of Pfizer) in December 2014. The application is for Retacrit (epoetin zeta), a proposed biosimilar of Janssen’s Procrit/ Amgen’s Epogen (epoetin alfa), which Hospira has been selling in Europe since 2008. In addition, Sandoz (a division of Novartis) has completed a U.S. Phase III trial for HX-575. HX-575 is another proposed biosimilar to Janssen’s Procrit/ Amgen’s Epogen (epoetin alfa).
It is possible that the first U.S. epoetin alfa biosimilar, Retacrit, will receive approval in mid-2016. If so, this will impact the U.S. ESA market, although it may not be as severe as many anticipate. Once more, we look to Europe to understand the future impact of Retacrit use in the U.S. In ChartTrends: Nephrology in Dialysis (EU5) 2015, we found that current ESA dialysis biosimilar patient share is nearly 15% for ESA biosimilars, while brand-name ESAs capture the majority balance. We find that ESA biosimilar dialysis patient share is highest in Germany, where prescribing quotas strongly encourages nephrologists to use biosimilar ESAs, but overall, we believe the uptake of biosimilars is modest given the length of time they have been on the market in Europe.4 Based on other primary market research, we believe that the ESA brands are competing with the ESA biosimilars on price. In addition, there is a preference for long-acting ESAs such as Aranesp (of which there are no biosimilars to date) and a lack of pressure to switch from branded to biosimilars in European markets outside of Germany. These factors may help explain why European ESA biosimilars do not have higher patient share today.
In TreatmentTrends: Nephrology (US) Q2 2015, most U.S. surveyed nephrologists were almost evenly split in their view of epoetin alfa biosimilars: 48% viewed them as somewhat similar to their branded counterparts, with significant/ possibly significant clinical differences, and 43% viewed them as very similar, having only minor, non-clinically significant differences. In addition, surveyed nephrologists are significantly more likely to use a biosimilar ESA than a novel ESA with no market data (see Figure 2).5 However, there are certainly some barriers to U.S. biosimilar ESA uptake including Amgen’s strong position in this market, branded price competition, as well convincing physicians to switch to a new product.
Another agent that may impact the use of ESAs is Keryx Biopharmaceuticals’ Auryxia (ferric citrate), which launched in the U.S. in December 2014. This is the first phosphate binder indicated to treat elevated phosphate levels that has shown a renal anemia treatment benefit in clinical trials. For example, dialysis patients in a Phase III trial on ferric citrate had increased iron levels, increased hemoglobin levels, and reduced use of IV iron (51.6% decrease compared with the active control group [P < 0.0001]) and ESAs (27.1% decrease compared with the active control group [P = 0.0322]) compared with the control group (sevelamer carbonate or calcium acetate).6 If Auryxia proves to impact the use of ESAs in clinical practice, this will likely lead to greater usage within cost-conscious dialysis centers.
Physician perception of Auryxia has been generally positive. ChartTrends: Nephrology in Dialysis (US) 2015 found that physicians reviewing the Auryxia profile would consider starting slightly over half of their patients on this therapy now. Interestingly, these patients are more likely to be on dialysis longer, are on active vitamin D (AVD), are on Sensipar, and have higher serum phosphorus at the most recent measure.7
In July 2015, Keryx Biopharmaceuticals received a European Medicines Agency’s (EMA Committee for Medicinal Products for Human Use (CHMP) positive opinion for Fexeric (ferric citrate coordination complex) for the treatment of hyperphosphatemia in adults with CKD. If approved, this would make Fexeric the only phosphate binder to treat elevated serum phosphorus levels in both nondialysis and dialysis CKD patients in Europe. It is possible that this product could impact the renal use of ESAs in Europe, similar to what is anticipated in the U.S.
Oral HIP-PH inhibitors
FibroGen, AstraZeneca, and Astellas are co-developing the oral HIF-PH inhibitor, roxadustat, for the treatment of anemia in CKD dialysis and CKD-ND patients. FibroGen and AstraZeneca are co-commercializing roxadustat in the U.S. and China, while Astellas has licensed rights in Europe and Japan. Roxadustat is the most advanced HIF-PH inhibitor in development and is being investigated in a series of clinical trials in both CKD-ND and dialysis patients; a series of Phase II studies in the U.S. and Europe have been completed. In fact, FibroGen expects a U.S. regulatory filing in 2018.
Other companies are also developing oral HIF-PH inhibitors including Akebia Therapeutics (vadadustat), GlaxoSmithKline (daprodustat), Bayer (molidustat), and others. Akebia Therapeutics’ vadadustat recently completed Phase IIb trials in CKD-ND patients and expects to enter a Phase III program later this year. However, over 60% of surveyed nephrologists do not yet differentiate between the oral HIF-PH inhibitors in development. Most of these nephrologists believe that these products are similar in general or that it is too soon to differentiate.8
Later clinical results will likely provide a better indication of how much patient share will be switched from patients currently on ESAs, as well as how much share these new emerging therapies can garner from non-ESA treated anemic patients.
In the near future Auryxia will likely have some impact on ESAs. However, the launch ofMircera and ESA biosimilars will likely have a greater impact in the short term and the oral HIF-PH inhibitors in the longer term. Clearly, the renal anemia market landscape will change over the coming years, hopefully leading to improvements in patient outcomes
- Decision Resources Group ChartTrends: Nephrology in Dialysis (EU5), which analyzed 931 dialysis patient charts submitted by 225 European nephrologists.
- Decision Resources Group TreatmentTrends: Nephrology (U.S.) 03 2014, primary research with a sample of 101 U.S. nephrologists.
- Decision Resources Group TreatmentTrends: Nephrology (U.S.) 03 2014, primary research with a sample of 101 U.S. nephrologists. Highly interested indicates an 8, 9, or 10 on 1-10 scale, with 10 being extremely interested.
- Decision Resources Group ChartTrends: Nephrology in Dialysis (EU5) 2015, where 225 EU5 nephrologists submitted information from 931 dialysis patients charts.
- Decision Resources Group TreatmentTrends: Nephrology (U.S.) 02 2015, primary research with a sample of 100 U.S. nephrologists.
- Keryx Biopharmaceuticals, press release, January 28, 2013.
- Decision Resources Group ChartTrends: Nephrology in Dialysis (U.S.) 2015. Physicians surveyed about their interest in starting 310 patients on Auryxia, after a review of a product profile.
- Decision Resources Group TreatmentTrends: Nephrology (U.S.) 02 2015, primary research with a sample of 100 U.S.nephrologists. Only profiles of roxadustat and vadadustat are shown in this study.