To date there have been very limited options for treating end-stage renal disease (ESRD) patients with the anemia of chronic kidney disease. Although darbepoetin alfa is available, it is not widely used to treat dialysis patients, making Amgen’s Epogen (epoetin alfa) the sole erythropoiesis-stimulating agent (ESA) used in these patients. However, key U.S. patents on epoetin alfa have begun to expire (see Table 1), clearing the way for companies to develop biosimilar epoetins for use in this population. Furthermore, novel, orally administered, low molecular weight drugs are deep in U.S. clinical trials for the treatment of anemia in patients with ESRD, including hypoxia inducible factor (HIF) stabilizers. With the coming of these medications, the anemia treatment paradigm may evolve rapidly in the near future.
While nephrology may be focused on the effects that expiration of U.S. epoetin patents will have on the availability of ESA biosimilars, other disease states will experience biosimilar entrants as well. The passage of the Biologics Price Competition and Innovation (BPCI) Act, as a part of the Affordable Care Act of 2010, provided a regulatory pathway for the development and approval of biosimilars by the U.S. Food and Drug Administration. Biologic products such as epoetin, insulin, and therapeutic monoclonal antibodies are produced in living organisms using advanced biotechnology techniques. The FDA has approved many biologics under section 505 of the 1938 Federal Food, Drug, and Cosmetic Act (FDCA).1,2In 1999, the FDCA created a formal application for biologic products that combined manufacturing regulations with that of product quality; however, requirements were not set forth for possible “generic” biologic products.3The BPCI Act of 2009 changed that by providing the legal means for an abbreviated licensure pathway for biosimilar biological products.2In it, a biosimilar was defined as a biological product that is highly similar to the reference product notwithstanding minor differences in clinically inactive components, and lacking clinically meaningful differences between it and the reference biologic product in terms of the safety, purity, and potency.4Due to the nature of expressing biologic products in cell culture systems, biosimilars cannot be exact replicas of their reference products, only very similar. Recombinant human erythropoietin products with the same 165 amino acid backbones are known to have differences in glycosylation patterns that affect their molecular half life.5This is also an expectation during the production of the reference product epoetin alfa, which is not identical to endogenously produced erythropoietin known to contain between 4 to 14 sialic acid residues.6
It is quite likely that the first U.S. biosimilar biologic product approved via the BPCI Act pathway will be an ESA to treat the anemia of kidney disease. However, five European biosimilar ESAs have been available for prescription since 2007.7To date, two manufacturers have parlayed their European experience into clinical development plans for biosimilar ESAs for the U.S. market (see Table 2), which will likely be available in 2015.
After six years of successful use in Europe, data have accumulated showing biosimilar ESAs to be effective, safe alternative choices to brand name epoetin alfa for anemia treatment in patients with kidney disease.7These new anemia treatment alternatives have increased competition and lowered the price of ESAs across Europe. There should be no confusion between biosimilar biologic products and Omontys (peginesatide)—a PEGylated peptide ESA—which is no longer available for prescription following instances of anaphylactic death.
FDA guidance on biosimilar product development
In February 2012, the FDA released draft guidance documents on the quality and scientific considerations for biosimilar product development.4,8In its quality guidance document, the FDA refers to the BPCI Act in describing the critical requirements for a successful application, stating that it must demonstrate six scientific facts (see Table 3).8To do so, the FDA provides flexibility in study design, given that a clear rationale exists based in scientific experience with the reference product’s efficacy and safety record. In some instances, a non-inferiority study design may be appropriate for comparing safety and efficacy, and would allow for a smaller sample size than an equivalence (two-sided) design.
According to study registrations for clinical investigations in patients with kidney disease, the developers of biosimilar epoetin for the U.S. market have chosen rigorous randomized, double-blind, 52-week-long parallel studies to demonstrate safety and efficacy, in addition to shorter-term, cross-over designs to show traditional pharmacokinetic bioequivalence to the reference product. Consistent with the FDA’s good manufacturing practices, there are requirements to demonstrate biosimilar product quality for chemistry, manufacturing, and controls. Accordingly, determination of comparability between a proposed biosimilar product and its reference biologic product will require stringent characterization through well-conceived clinical studies, as well as preclinical studies characterizing product quality (see Table 3). Patient registries have been required of European biosimilar developers to continue to assess risk following approval.9
It is worth noting that the identical principles for establishing biosimilarity for biologic products are the same as those for demonstrating comparability following a modification in the manufacturing process of an already licensed biologic product.10These regulations have minimized the likelihood of creating an ineffective, unsafe epoetin product whether a biosimilar or its reference product. To this end, it is critical to differentiate between biosimilar products developed in Europe or the U.S. from those developed in countries without rigorous biosimilar regulatory pathways. True biosimilar biologics are developed using strict regulations such as those mapped by the European Medicines Agency (EMA) in the EU, as well as in other nations such as Canada, Australia, and Japan, and now by the FDA in the U.S. Lesser quality biologics are manufactured in Africa, the Middle East, and Latin America where producers must only show bioequivalence data for approval but not necessarily the quality data for comparative physiochemical and functional studies. Although documented cases of pure red-cell aplasia (PRCA) have been observed in patients receiving both FDA and EMA-approved originator epoetins,11lesser quality products administered subcutaneously have been associated with alarmingly high rates of PRCA.12Comparisons have suggested that what is known about the safety of originator epoetin alfa can be extrapolated to the currently available European biosimilar epoetins.7
The successful incorporation of biosimilar epoetins into the standard of care in European nephrology practices and dialysis clinics is indicative of their high quality. The examples in excellence already set for manufacturing quality, clinical study, and risk management strategies 3,10must be the goal of U.S. regulators as the map for biosimilar epoetin development is charted and followed.
Novel developmental ESAs
Another very promising area of ESA development includes a class of novel agents known as HIF stabilizers.13Erythropoietin gene expression is regulated in part by the transcription factor HIF-1a that when bound to the constitutively expressed HIF-1b protein, binds the epo gene’s powerful 3’ enhancer.14HIF-1a gets its name because of its activation by hypoxic conditions, which have been known to enhance red cell production in humans for well over a century.15Under normoxic conditions, HIF-1a is bound by von Hippel-Lindau protein, facilitating HIF-1a ubiquitinization and subsequent proteasomal degradation. However, von Hippel-Lindau protein binding to HIF-1a requires hydroxylation of a HIF-1a proline by prolyl hydroxylase PHD2, an oxygen-dependent enzyme.14
Since its identification and subsequent cloning in the early 1990s, HIF-1a has been the focus of intensive research. In addition to its critical role in erythropoiesis, over the years it has been demonstrated as having important roles in maintaining cellular homeostasis during hypoxic conditions, regulation of angiogenesis, and cell survival. HIF stabilizers have been used experimentally to combat necrosis in healing skin16and to treat ischemic stroke through neuroprotection and prevention of vascular leakage.17
A number of low molecular weight drugs are currently in late clinical development (see Table 2) that enhance native erythropoietin expression by inhibiting oxygen-mediated modification of HIF by prolyl hydroxylase such as metal chelators18and 2-oxoglutarate analogues.13One orally active oxoglutarate analogue HIF stabilizer was shown in a proof of concept study to stimulate erythropoiesis in humans.19This phase 1 study enrolled nephric and anephric hemodialysis patients as well as healthy volunteers, who when treated with a single dose experienced increases in plasma erythropoietin levels of 30.8 times, 14.5 times, and 12.7 times over baseline, respectively. The authors concluded that inappropriate oxygen sensing causes renal anemia, not necessarily a loss of the ability to produce erythropoietin–even in anephric patients who produced erythropoietin presumably through hepatic pathways.
While early efforts using HIF stabilizers revealed some issues,13subsequent testing with other agents has demonstrated safety and efficacy in phase 1 and 2 trials. Phase 2 study reports have shown that when administered orally for 12 weeks, the HIF stabilizer roxadustat increased mean hemoglobin concentrations by 3.1 g/dL from a baseline of 8.8 g/dL in peritoneal dialysis patients.20,21Another prolyl hydroxylase inhibitor, GSK1278863, has been studied in 73 ESA naïve patients with non-dialysis dependent kidney disease. Following four weeks of treatment with GSK1278863, patients experienced dose-dependent increases in hemoglobin concentrations and decreases in circulating hepcidin.22In addition to these agents, AKB-6548, yet another promising HIF stabilizer is well into phase 2 clinical trials (see Table 2). At this point, it is difficult to say which agent may be available first; optimistically, a HIF stabilizer could be available for treating anemic patients with chronic kidney disease during 2016.
There are populations of anemic patients who do not respond optimally to epoetin therapy.23In patients with chronic kidney disease who may be resistant or hyporesponsive to epoetin therapy, anemia treatment with HIF stabilization through prolyl hydroxylase inhibition may provide additional benefits by suppressing hepcidin and increasing the availability of circulating iron.24Moreover, an oral drug to treat anemia would be a preferred formulation for some patients.
The development of biosimilars and the identification of novel HIF stabilizers will in all likelihood change the way that anemia is treated by nephrologists. With a good record of safety arising from the European experience and a stringent U.S. regulatory oversight process, biosimilar epoetin alfa should prove an effective alternative to brand name epoetin alfa. Additionally, the HIF stabilizers in clinical trials hold promise, providing a truly unique modality for anemia treatment through a novel mechanism of action. Additional options to current epoetin therapy will enable nephrologists to select what is best for each patient and may provide efficiencies for treating anemia in patients with kidney disease.
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