Biotechnology products and indications I. Proteins
Ronald P. Evens in Biotechnology, 2020
Growth factor (GF) proteins number 21, as listed in Table 8.4. These proteins can be divided into two areas: blood cell GFs, also known as colony-stimulating factors (CSFs), and tissue GFs, all of which are ligands to communicate between cells and stimulate new cell outcomes and functions. The CSFs are secreted by specific cells in organs, for example, erythropoietin by the kidney, and stimulate another cell type to produce an effect; in this example, bone marrow erythroid progenitors are stimulated to accelerate their production of red blood cells and correct anemia. All these GFs are produced by rDNA technology. CSF products for leukocytes are available worldwide, that is, filgrastim, pegfilgrastim, and sargramostim in the United States, and also molgramostim, regramostim, lenograstim, and nartograstim in rest of the world. Biosimilar filgrastim products include biograstim, filgrastim-Hexal, nivestim, ratiograstim, and tevagrastim. They all stimulate white blood cell production and limit infectious complications in myeloid-suppressed cancer patients. Two epoetin molecules (epoetin alfa and epoetin beta) stimulate red blood cell production, with two U.S. products available (Epogen and Procrit), along with Eprex, NeoRecormon, Silapo and Epogin in Europe and Asia. Biosimilar products for epoetin alfa are also available, such as Retacrit. Aranesp in the United States and Nespo in Europe are the hyperglycosylated products of epoetin that have extended half-lives and require less frequent dosing. A pegylated form of epoetin alfa has been developed as well to extend the dosing interval. Becaplermin is a tissue GF for the epidermis and is used to accelerate wound healing in diabetic ulcers. The second recombinant tissue GF is palifermin, impacting keratinocytes, and is used to more rapidly resolve the mucositis in cancer patients receiving chemotherapy, radiation therapy, and bone marrow transplants. Bone growth and bone fusion are accelerated with osteogenic protein-1 and platelet derived GF-BB, both GFs. Recently, neurotrophic keratitis has become treatable with a GF, oxervate. Pegylation has been used to create new GFs with longer half-lives and extended duration of action, for example, filgrastim daily is dosed daily for 5–10 d versus peg-filgrastim (Neulasta) in a single dose. Biosimilar products have also been approved for filgratim around the world; Fulphila, Nivestym, Udencya, and Zarxio.
Roxadustat in the treatment of anaemia in chronic kidney disease
Published in Expert Opinion on Investigational Drugs, 2018
Lucia Del Vecchio, Francesco Locatelli
Roxadustat was also tested in 90 HD patients treated with epoetin alfa who were randomized to 6 treatment cohorts with various starting doses and adjustment rules (1.0–2.0 mg/kg or tiered weight based) over 25 weeks [41]. The study consisted of two parts, the first to define optimal roxadustat starting dose and the second to compare the drugs. A period of 6 weeks of treatment was observed for the first part of the study, with 8 weeks of follow up, while the second part provided 19 weeks of therapy and 4 weeks of follow up. Intravenous iron was prohibited. Compared to the epoetin alfa group, a significant higher percentage of patients in pooled roxadustat 1.5–2.0 mg/kg groups had ΔHb of +0.5 g/dl or greater from baseline (33% and 79%, respectively). The average roxadustat dose requirement for Hb level maintenance was ∼1.7 mg/kg. A positive impact of roxadustat on iron availability was observed. Indeed, in the patients who discontinued iron therapy, a higher decline in serum Hb, transferrin saturation, serum iron, and reticulocyte count was observed during epoetin alfa therapy compared to roxadustat treatment. As for the ND-CKD populations, also in HD patients, roxadustat significantly decreased hepcidin levels; the magnitude of the effect was higher compared to epoetin alfa therapy. Moreover, average weekly roxadustat maintenance dose was not associated with CRP levels. As expected, the patients treated with epoetin alfa had significantly higher mean peak EPO levels (median dose of 90 U/kg/week, EPO of ∼700 mIU/ml) compared to those treated with roxadustat (mean dose of 1.3 mg/kg, EPO of ∼130 mIU/ml).
Investigational hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHI) for the treatment of anemia associated with chronic kidney disease
Published in Expert Opinion on Investigational Drugs, 2018
Lucia Del Vecchio, Francesco Locatelli
Two phase-II studies were also conducted in China [56]. In one study, 91 ND-CKD patients were randomized to either low (1.1–1.75 mg/kg) or high (1.50–2.25 mg/kg) roxadustat doses or to placebo. An Hb increase of ≥1 g/dl from baseline was obtained in 80% and 87.1% of the low- and high-dose cohorts, respectively, but in only 23.3% of the patients receiving placebo. In the dialysis study, 87 subjects were randomized to low (1.1–1.8 mg/kg), medium (1.5–2.3 mg/kg), and high (1.7–2.3 mg/kg) roxadustat doses or to continue epoetin alfa. Interestingly, at randomization, the patients were stratified according to baseline epoetin alfa doses. In the roxadustat cohorts, Hb levels were maintained in a higher percentage of patients compared to epoetin alfa (59.1%, 88.9%, and 100% in the low-, medium-, and high-dose cohorts versus 50% of the epoetin alfa-treated subjects). Similarly, to what observed in the other clinical trials, roxadustat caused a decrease in hepcidin levels, total, LDL and HDL cholesterol, and platelet count.
Epoetin alfa-epbx: a new entrant into a crowded market. a historical review of the role of erythropoietin stimulating agents and the development of the first epoetin biosimilar in the United States
Published in Expert Review of Clinical Pharmacology, 2021
Sid Anand, Jafar Al-Mondhiry, Katrina Fischer, John Glaspy
Fishbane S, Singh B, Kumbhat S, et al. Intravenous Epotein Alfa-epbx versus Epoetin Alfa for Treatment of Anemia in End Stage Kidney Disease. Clin J Am Soc Nephrol.13(8):1204–14, (2018).Glaspy J, Crawford J, Vansteenkiste J, et al. Erythropoiesis-stimulating agents in oncology: a study-level meta-analysis of survival and other safety outcomes. Br J Cancer. 102(2):301–15, (2010).Semenza GL. Hypoxia -inducible factors in physiology and medicine. Cell. 148(3):399–408, (2012).Goldsmith D, Dellanna F, Schiestl M, et al. Epoetin Biosimilars in the Treatment of Renal Anemia: What Have We Learned from a Decade of European Experience? Clinical Drug Investigation, (6):481–490, (2018).Farhat F, Torres A, Park W, et al. The concept of biosimilars: from characterization to evolution – a narrative review. Oncologist. (3):346–352, (2018).Palmer SC, Navaneethan SD, Craig JC et al. Meta-analysis: erythropoiesis-stimulating agents in patients with chronic kidney disease. Ann Intern Med. 6;153(1):23–33 (2010).Mergerlin F, Lopert R, Taymor K, et al. Biosimilars and the European Experience: Implications for the United States. Health Aff (Millwood). 32(10):1803–1810, (2013).
Related Knowledge Centers
- Anemia
- Cell Culture
- Chronic Kidney Disease
- Darbepoetin Alfa
- Molecular Cloning
- Red Blood Cell
- Chemotherapy
- Erythropoietin
- Erythropoiesis
- N-Linked Glycosylation