Darbepoetin alfa: a review of its use in the treatment of anaemia in patients with cancer receiving chemotherapy

Darbepoetin alfa (Aranesp) is an analogue of recombinant human erythropoietin (rHuEPO) produced using recombinant DNA technology. The high number of sialic acid moieties in darbepoetin alfa results in a prolonged half-life and enhanced in vivo biological activity compared with rHuEPO (as demonstrated in animal studies) and permits a reduction in the frequency of administration.Subcutaneous darbepoetin alfa 2.25 microg/kg once weekly or 500 microg once every 3 weeks (with a provision for dose adjustments) is an effective and well tolerated erythropoietic agent in anaemic patients with cancer receiving chemotherapy. In randomised, controlled clinical trials, the drug increased haemoglobin levels and reduced the need for blood transfusions in patients with various types of nonmyeloid malignancies and also ameliorated anaemia-related fatigue, thereby improving their health-related quality of life (HR-QOL) scores. The once-every-3-weeks dosage regimen provides further convenience by offering the possibility of synchronising its administration with most chemotherapy regimens. Direct comparisons between approved dosages of darbepoetin alfa and other erythropoietic agents have not been conducted. Such comparisons would be very helpful in formulating definitive conclusions about their relative efficacy and cost effectiveness. Darbepoetin alfa provides an effective and well tolerated treatment option for the treatment of anaemia in patients with cancer receiving chemotherapy.     

Darbepoetin alfa.

Darbepoetin alfa is a novel erythropoiesis-stimulating protein developed for the treatment of anaemia associated with chronic kidney disease. In single-dose studies in patients undergoing dialysis, the mean terminal half-life for intravenous darbepoetin alfa was approximately 3-fold longer than for intravenous recombinant human erythropoitin (r-HuEPO, epoetin alfa; 25.3 vs 8.5 hours). The mean terminal half-life after subcutaneous administration of darbepoetin alfa was 48.8 hours. In randomised nonblind trials in patients undergoing dialysis, darbepoetin alfa (0.45 pg/kg) given once weekly for the correction of anaemia increased haemoglobin (Hb) levels to a similar extent as darbepoetin alfa three times weekly or r-HuEPO two or three times weekly. A double-blind, randomised clinical trial reported that switching patients from a three-times weekly regimen of r-HuEPO to once weekly darbepoetin alfa with additional placebo twice weekly (all intravenously) maintained Hb levels between 9.0 and 13.0 g/dl to a similar extent as continued treatment with r-HuEPO three times weekly. In a randomised nonblind study, r-HuEPO-naive patients with chronic renal insufficiency received either subcutaneous darbepoetin alfa once weekly or r-HuEPO twice weekly. 93% of patients receiving darbepoetin alfa and 92% of patients receiving r-HuEPO achieved a Hb increase of > or = 1.0 g/dl from baseline and the mean increase in Hb level over the initial 4 weeks was similar for both treatments. The number and frequency of adverse events, withdrawals and deaths reported in clinical trials did not differ between patients receiving darbepoetin alfa and patients receiving r-HuEPO. There have been no reports of immune responses to darbepoetin alfa in 1534 patients receiving treatment for up to 2 years.     

Darbepoetin alfa: new indication/new dosage. No proven advantage in chemotherapy-induced anaemia

(1) Current treatments for anaemia in patients receiving cancer chemotherapy include blood transfusion and epoetin alfa and beta. These epoetins correct anaemia in 40% to 65% of patients and reduce the number of patients who require transfusions during the second and third months of treatment by 12-35% in absolute terms. (2) Darbepoetin alfa is slightly more glycosylated than epoetin alfa and beta. It is no more effective than these two drugs in chronic renal failure. Darbepoetin alfa is now approved for the treatment of anaemia in patients who are receiving chemotherapy for non myeloid malignancies. (3) Two placebo-controlled dose-finding studies and two placebo-controlled trials involving nearly 1000 patients in total have shown that darbepoetin alfa decreases the number of transfused patients by 17-25% in absolute terms, and that it probably reduces fatigue. However, one-quarter of patients receiving darbepoetin were nonetheless transfused. (4) In the absence of reliable comparisons, there is no firm evidence that darbepoetin alfa is more effective than other epoetins. (5) According to relatively imprecise company reports, darbepoetin alfa increased the risk of thromboembolic events during clinical trials (6% versus 3%), including pulmonary embolism (1.3% versus 0%); the company also states that darbepoetin alfa does not increase the risk of arterial hypertension, a classical effect of epoetin that is mentioned in the summary of product characteristics (SPC). Placebo-controlled trials and dose-finding studies show no impact on the outcome of cancer, but follow-up is limited and a negative effect cannot be ruled out. The company states that no cases of erythroblastopenia have occurred among more than 70 000 treated patients. (6) According to the SPC, darbepoetin alfa can be given once a week. However, the optimal epoetin dosing schedule is unknown. Epoetin therapy takes several weeks to correct anaemia, whereas transfusion is immediately effective. (7) In practice, darbepoetin alfa seems a little easier to administer than epoetin alfa or beta, but the advantages and disadvantages of these drugs as compared with blood transfusion are not entirely clear.     

Darbepoetin alfa. Amgen

Amgen has launched darbepoetin alfa, synthetic recombinant novel erythropoiesis stimulating protein (NESP), for the treatment of anemia associated with renal disease. The drug was approved by the European Commission in June 2001, under the tradename Aranesp, for the treatment of anemia in chronic kidney failure including patients on and not yet on dialysis. The company launched the drug on day one of its approval in the following countries: Germany, Sweden, Denmark, Portugal, the Netherlands, the UK and Austria. Roll out of the drug in Italy, Greece and France will follow as soon as pricing and reimbursement issues are resolved [412240], [412357]. By January 2001, the product was still under review and the company anticipated approval during the first half of 2001 in both the US and Europe [396802]. Launch in the US had originally been scheduled for 2000 [387293], [396802] and Japanese launch is planned for 2004 or 2005 [405915]. In January 2001, Amgen reported that the first pivotal trial of darbepoetin alfa in treating oncology patients with anemia was successful [396526], [396802]. The company anticipated a phase III trial in US patients in 2001 for the oncology indication 13977941. In the fourth quarter of 2000, darbepoetin alfa entered phase I trials in Japan. Japanese development of darbepoetin alfa was being conducted by Kirin Brewery (under the research code KRN-321) [396653]. In January 2001, Genesis Pharma licensed the rights to distribute, market and sell darbepoetin alfa for the treatment of anemia, in Greece and Cyprus [396437]. MegaPharm Ltd signed an agreement with Amgen in February 2001, granting MegaPharm certain exclusive rights to distribute, market and sell darbepoetin alfa in Israel [398897]. In February 2000, Merrill Lynch predicted that darbepoetin alfa sales will be in excess of $1.4 billion at maturity [355817]. In October 2000, darbepoetin alfa annual sales were predicted to hit $3 billion [387293].     

Epoetin alfa for the treatment of cancer- and chemotherapy-related anaemia: product review and update

Anaemia, often associated with chemotherapy, is a common and debilitating disorder in cancer patients. Recombinant human erythropoietin (epoetin alfa) was introduced in the 1990s for the treatment of chemotherapy-related anaemia. Data from randomised, double-blind, placebo-controlled studies and large, non-randomised, community-based studies have demonstrated that either of the FDA-approved dosing schedules of epoetin alfa 150 - 300 U/kg three times weekly or 40,000-60,000 U/week s.c., significantly increases haemoglobin levels, reduces transfusion requirements, and improves quality of life in anaemic cancer patients undergoing chemotherapy or chemoradiation therapy. Guidelines for the effective and safe use of epoetin alfa have been published by major oncology/haematology organisations and are reviewed in this article. Areas of recent and ongoing investigation with epoetin alfa are also covered in this review.     

Darbepoetin alfa: a novel erythropoiesis-stimulating protein

Darbepoetin alfa is a novel erythropoiesis-stimulating protein developed for the treatment of anemia. It is a hyperglycosylated analog of recombinant human erythropoietin with the same mechanism of action as erythropoietin, but with a three-fold longer terminal half-life after intravenous administration than recombinant human erythropoietin and the native hormone both in animal models and in humans. Clinical studies in patients with chronic renal failure either receiving or not receiving dialysis have shown that darbepoetin alfa is equivalent to recombinant human erythropoietin in terms of increases in hemoglobin concentration, percentage of patients achieving target hemoglobin concentration and average time to reach target hemoglobin concentration, although darbepoetin alfa is administered less frequently (once weekly or every other week). Clinical trials in cancer patients either receiving or not receiving chemotherapy have demonstrated that darbepoetin alfa is safe and effective in alleviating anemia at dose intervals of once every 1, 2 or 3 weeks, and results suggest that it may achieve greater and more rapid responses than recombinant human erythropoietin in cancer patients. Furthermore, an improvement in health-related quality of life has been observed in association with anemia correction using darbepoetin alfa therapy in these patients. Darbepoetin alfa has been approved for intravenous and subcutaneous administration by the European Commission and the FDA for the treatment of anemia in patients with chronic renal failure. Additionally, this product was recently approved by the FDA for the treatment of anemia in patients with nonmyeloid malignancies where anemia is due to the effect of concomitantly administered chemotherapy. The recommended starting dose in chronic renal failure patients is 0.45 microg/kg once weekly for both intravenous and subcutaneous administration, with subsequent titration based on the hemoglobin concentration. In cancer patients, the recommended starting dose is 2.25 microg/kg once weekly by subcutaneous injection and subsequent titration. The adverse event profile of darbepoetin alfa is similar to that of recombinant human erythropoietin in both settings. There are no reports of antibody formation associated with darbepoetin alfa in chronic renal failure patients, and three cases of antibody formation, with neutralizing activity in one of the cases, have been reported in cancer patients. However, no cases of antibody-mediated pure red cell aplasia have been reported. The longer half-life of darbepoetin alfa, together with a similar efficacy and safety profile, confers the clinical advantage over recombinant human erythropoietin of allowing a less frequent dosing (once weekly or every other week versus one to three times weekly in renal patients), thus reducing health-care utilization and probably improving patient compliance.     

Darbepoetin alfa: new preparation. Just a me-too: no advantage in anaemia of chronic renal failure

(1) Darbepoetin alfa, an epoetin, is slightly more glycosylated than epoetin alfa and beta. (2) The clinical file on anaemic patients with chronic kidney failure shows no advantage of darbepoetin alfa over other epoetins in terms of efficacy or side effects (subcutaneous injections of darbepoetin alfa are more often painful). (3) The dosing schedules of epoetins have not been compared adequately. Dosing schedules should be adapted for each patient.     

Darbepoetin alfa: an effective treatment with flexible and simplified dosing for anemia in patients with cancer

Anemia is common in patients with cancer or myelodysplastic syndrome. Erythropoietic therapy offers an effective way to manage anemia by increasing hemoglobin levels, decreasing transfusion requirements, and alleviating symptoms. We reviewed data showing the feasibility and effectiveness of treatment with the erythropoiesis-stimulating protein darbepoetin alfa at extended dosing intervals to treat anemia in patients with cancer receiving multicycle chemotherapy. We also explored the darbepoetin alfa's potential for treating anemia in patients with myelodysplastic syndrome. Data from clinical studies and drug therapy evaluations confirm that darbepoetin alfa administered weekly, every 2 weeks, and every 3 weeks corrects and maintains hemoglobin levels in patients with chemotherapy-induced anemia. In addition, the data demonstrate that both weight-based and fixed dosing with darbepoetin alfa are effective, and that early intervention to treat anemia has clinical benefits. Darbepoetin alfa also is an effective treatment for anemia in patients with cancer not receiving chemotherapy, at extended dosing intervals of at least 3 weeks. Extended dosing for anemia treatment can provide benefits for patients, caregivers, and clinicians because it reduces the number of clinic visits needed and permits synchronizing anemia treatment with chemotherapy cycles. Data from recent studies suggest that darbepoetin alfa is effective for treating anemia in patients with myelodysplastic syndrome; this potential use is being investigated further in ongoing studies. Thus, darbepoetin alfa is an attractive therapy option for patients with chemotherapy or cancer-induced anemia. It allows increased flexibility and simplified dosing and may offer some benefit in the treatment of anemia in patients with myelodysplastic syndrome.     

Darbepoetin alfa for anemia in chronic kidney disease

Anemia of chronic kidney disease (CKD) is common, yet it is often under-recognized and undertreated, with serious adverse consequences. It is highly responsive to treatment with erythropoiesis-stimulating agents (ESAs). Darbepoetin alfa is a hyperglycosylated ESA that has a lower affinity to the erythropoietin receptor but a longer half-life than recombinant human erythropoietin, irrespective of administration by a subcutaneous or intravenous route. Owing to its pharmacokinetic characteristics, darbepoetin alfa has been used in extended dosing intervals ranging from once every week to once every 4 weeks in CKD patients on dialysis, as well as in CKD patients not on dialysis. Darbepoetin alfa has been shown to be safe and effective in clinical trials. The safety profile of darbepoetin alfa is similar to that of recombinant human erythropoietin. While target hemoglobin levels in CKD anemia remain debatable, treatment of anemia with ESAs has the proven benefits of reducing transfusions and improving quality of life. Darbepoetin alfa has the potential to simplify the treatment of CKD anemia with many advantages, including infrequent dosing, improved patient convenience and compliance, and decreased healthcare resource utilization.     

Improved Haemoglobin Concentrations with IV Darbepoetin alfa - Case Studies of Haemodialysis Patients

Summary

This paper presents two case histories of patients receiving intravenous (IV) darbepoetin alfa for the treatment of anaemia in chronic renal

failure. The paper sets these cases against the general clinical picture of patients receiving intravenous darbepoetin alfa in our renal unit.     

Darbepoetin alfa for anemia in patients with low or intermediate-1 risk myelodysplastic syndromes and positive predictive factors of response

Abstract

Background:

Current guidelines support the use of erythropoiesis-stimulating agents for the treatment of anemia associated with low-risk myelodysplastic syndromes (MDS).     

Treating anaemia with epoetin alfa is associated with improvements in quality of life in cancer patients receiving chemotherapy

Anaemia is an important factor in the fatigue experienced by many patients receiving chemotherapy. A recent large-scale, randomised, placebo-controlled trial has shown that treatment with epoetin alfa raises haemoglobin levels, reduces fatigue and improves overall quality of life (QoL). In order to examine the relationship between anaemia and QoL more closely, we performed multiple regression analyses, adjusting for possible differences in demographic and clinical characteristics between the treatment groups on the trial data derived from FACT, CLAS and SF-36 QoL assessments. This confirmed that QoL is correlated with haemoglobin levels and that treatment with epoetin alfa is associated with a significant improvement in QoL as measured by validated cancer-specific instruments such as FACT and CLAS. However, the sub-group of patients who suffer disease progression during treatment are not predicted to experience an improvement in QoL, confirming the sensitivity of these scales. Race and tumour type were significantly related to changes in QoL scores, but other factors such as age and gender did not show significant effects on QoL.     

Cost-minimization analysis of once-weekly versus thrice-weekly epoetin alfa for chemotherapy-related anemia

BACKGROUND: For individuals with chemotherapy-related anemia, the clinical effectiveness of epoetin alfa (EPO) dosed once weekly ([QW], 40,000 units per dose) has been demonstrated to be indistinguishable from that observed with thrice-weekly dosing ([TIW], 10,000 units per dose). Whether the advantage of less-frequent administration justifies the higher EPO dosage used in the weekly regimen in terms of overall cost of care is unknown. OBJECTIVE: To conduct a cost-minimization analysis comparing QW and TIW EPO dosing from a societal perspective. METHODS: Direct and indirect medical cost data were calculated for a 16-week period for 2 large, prospective, multicenter, community-based studies. Costs measured included EPO, transfusions, laboratory tests, office visits, and opportunity cost of patient time. RESULTS: The average total costs in 2002 (first half) dollars were nearly equivalent across the 2 groups (QW: 9,204 dollars; 95% confidence interval [CI], 9,057 dollars-9,350 dollars. TIW: 9,265 dollars; 95% CI, 9,083 dollars-9,447 dollars. P=0.60). QW incurred mean drug acquisition costs that were 23% higher (QW: 6,725 dollars; 95% CI, 6,611 dollars-6,838 dollars. TIW: 5,474 dollars; 95% CI, 5,350 dollars-5,598 dollars. P<0.001). However, QW patients can avoid the resource use and time cost associated with 2 additional office visits incurred each week (QW: 592 dollars [583 dollars-600 dollars]; TIW: 1,709 dollars [1,678 dollars-1,740 dollars]; P<0.001). Transfusion and laboratory test costs were slightly higher in the TIW group (QW: 1,888 dollars [1,837 dollars-1,940 dollars]; TIW: 2,082 dollars [2,020 dollars-2,144 dollars]; P<0.001). CONCLUSION: Total anemia treatment costs over a 16-week period with EPO QW were similar to those of TIW dosing. In the absence of cost differences between regimens, the noneconomic advantages of less-frequent dosing intervals should make weekly dosing increasingly attractive to patients, clinicians, and payers.     

Darbepoetin alfa protects the rat heart against infarction: dose-response, phase of action, and mechanisms

Erythropoietin is known to stimulate red cell production and has recently been shown to protect the heart against injury from ischemia/reperfusion. However, it is unknown whether darbepoetin alfa (Dpa), a long-acting analog of erythropoietin, can play a protective role against myocardial infarction. We assessed the potential protective role of Dpa in an in vivo rat model of myocardial ischemia/reperfusion and the underlying mechanisms. We found that a single intravenous Dpa treatment immediately before 30 minutes of regional ischemia reduced myocardial necrosis following 120 minutes of reperfusion in a dose-dependent manner. Optimal protection with Dpa against myocardial infarction was manifest at a dose of 2.5 microg/kg. Dpa conferred cardioprotection when administered after the onset of ischemia and at the start of reperfusion. Dpa (2.5 microg/kg) also reduced infarct size and Troponin I leakage 24 hours after reperfusion. Inhibition of p42/44 MAPK (PD98059), p38 MAPK (SB203580), mitochondrial ATP-dependent potassium (KATP) channels (5-HD), sarcolemmal KATP channels (HMR 1098), but not phosphatidylinositol-3 (PI3) kinase/Akt (Wortmannin and LY 294002) abolished Dpa-induced cardioprotection. Dpa confers immediate and sustained cardioprotection in rats, suggesting a potential therapeutic role of this long-acting erythropoietin analog for the treatment of acute myocardial infarction.     

Economic evaluation of weekly epoetin alfa versus biweekly darbepoetin alfa for chemotherapy-induced anaemia: evidence from a 16-week randomised trial

INTRODUCTION: A 16-week, open-label, multicentre, randomised trial of weekly epoetin alfa 40 000 units versus biweekly darbepoetin alfa 200microg among 358 patients with solid-tumour cancers and chemotherapy-induced anaemia demonstrated superior haematological outcomes with epoetin alfa. We sought to compare resource use, costs and clinical outcomes between treatment groups and report the results using a cost-consequences framework. METHODS: Pre-specified methods were used to assign costs (US dollars, year 2004-5 values) to medical resources and patient time using a societal perspective. Costs for inpatient care, outpatient care and physician services were based on US Medicare reimbursement rates. Indirect costs assigned to patient time spent receiving study medication were based on the mean hourly wage in the US. In the base-case analysis, the average wholesale price was used to assign costs to medications. Clinical outcomes included all haemoglobin levels and transfusions recorded throughout the trial. Sensitivity analyses were performed to evaluate the impact of different costing methods, cost sources, perspectives and methods to assign haemoglobin values following a blood transfusion. RESULTS: Over a mean follow-up duration of 11.8 weeks, the average cost of study medications and their administration was the single largest component of total costs and was similar between groups (epoetin alfa 5979 US dollars and darbepoetin alfa 5935 US dollars, difference 44 US dollars; 95% CI -590, 692). There were no significant differences in the proportions of patients hospitalised (epoetin alfa 24.6%, darbepoetin alfa 22.0%; p = 0.57). Patients randomised to epoetin alfa experienced more inpatient days, on average, than patients randomised to darbepoetin alfa (2.6 vs 1.6, 95% CI for the difference, 0.07, 2.27). However, with regard to transfusions, patients in the epoetin alfa arm required fewer units of blood than patients in the darbepoetin alfa arm (0.46 vs 0.88, 95% CI for the difference -0.77, -0.08). Mean total costs, comprising costs for study medications and their administration, inpatient care, transfusions, unplanned radiation therapy, haematology and laboratory services, chemotherapy and non-chemotherapy drugs and indirect costs were 14,976 US dollars in the epoetin alfa arm compared with 14,101 US dollars in the darbepoetin alfa arm, a difference of 875 US dollars (95% CI for difference -849, 2607), of which 98% of the difference was attributable to higher inpatient costs in the epoetin alfa arm (2374 US dollars vs 1520 US dollars; 95% CI for difference -33, 1955). Assessments of multiple clinical measures demonstrated improved outcomes with epoetin alfa relative to darbepoetin alfa. CONCLUSION: Most clinical outcome measures suggested greater improvement with epoetin alfa relative to darbepoetin alfa, but most costs for both agents appeared similar. Decision makers must evaluate the differences in costs and efficacy measures that are most relevant from their perspectives.