Inpharma 1350 - 10 Aug 2002

Darbepoetin-alfa: improved efficacy against chemotherapy-inducedanaemia?

– Raewyn Poole –

The second-generation erythropoietic agent, darbepoetin-α [‘Aranesp’] may be more effective than the currentstandard therapy, epoetin-α, in the treatment of chemotherapy-induced anaemia in patients with solid tumours,according to results from a phase II study presented at the 38th Annual Meeting of the American Society ofClinical Oncology (ASCO) [Orlando, US; May 2002]. More rapid improvements in haemoglobin levels andquality of life (QOL) were achieved in patients treated with darbepoetin-α, compared with those receivingepoetin-α. Furthermore, the use of loading doses of darbepoetin-α to achieve initial haemoglobin responses,followed by reduced maintenance dosing, was shown to be effective. Reduced frequency of administration wasalso shown to be effective in a separate, placebo-controlled study which demonstrated that darbepoetin-α hadcomparable efficacy when given every 3 or 4 weeks

and 12. ‘Using loading doses of darbepoetin alfa duringLoading doses give rapid reliefthe initial correction of anaemia may relieve fatigue andTreatment with darbepoetin-α using a ‘front loading’improve physical and functional well-being faster thandosing strategy provided more rapid improvements incurrent standard therapy’, said the researchers.haemoglobin levels and QOL domain scores thanFurthermore,‘additional benefit of loading dosestandard epoetin-α therapy in a study involving patientstreatment may include a reduction in caregiver burden’.with chemotherapy-induced anaemia.1;2 In this dose-

finding phase II study, 122 patients with solid tumours Faster responses desirableand haemoglobin levels of ≤ 11 g/dl* were randomised The rapid responses observed in darbepoetin-α,to one of four treatment groups: compared with epoetin-α, recipients is likely to be• darbepoetin-α loading dose of 4.5 µg/kg weekly beneficial in the treatment of anaemia in chemotherapy.

until haemoglobin levels increased to ≥ 12 g/dl, then ‘A therapy requiring a median time of 10 to 12 weeks formaintenance doses of 1.5 µg/kg weekly until week a patient to respond is suboptimal’, given the debilitating12 (n = 32); effects of anaemia in patients receiving chemotherapy,

• darbepoetin-α loading dose of 4.5 µg/kg weekly for said Dr John Glaspy from the University of California Los4 weeks, then maintenance with 2.25 µg/kg weekly Angeles (UCLA), US.until week 12 (n = 30);

Comparable tolerability• darbepoetin-α loading dose of 4.5 µg/kg weekly forDarbepoetin-α and epoetin-α had similar tolerability4 weeks, then maintenance with 3 µg/kg every 2

profiles. The most common adverse events in bothweeks until week 12 (n = 30)groups being gastrointestinal and constitutional• epoetin-α 40 000U once weekly; the dose could besymptoms, which were consistent with those expectedincreased to 60 000 U/week if inadequate responsein patients receiving chemotherapy for cancer. Therewas observed at week 6 (n = 30).was no evidence of the development of antibodies toPatients completed the Functional Assessment ofdarbepoetin-α. ‘The use of "front loading" dosingCancer Therapy (FACT)-Fatigue scale questionnaire atstrategies with darbepoetin alfa appears to be wellweekly intervals, and the FACT-Anemia** questionnairetolerated when compared with current standardat baseline and every month thereafter.therapy’, concluded the researchers.

Higher response ratesLess frequent dosing effectiveCombining results from all three darbepoetin-α

Darbepoetin-α demonstrated efficacy whengroups indicated that it provided higher response ratesadministered at 3- or 4-week intervals in a placebo-and greater increases in haemoglobin levels thancontrolled phase I/II study involving 405 patients withepoetin-α at weeks 4 and 12 [see table 1]. Furthermore,solid tumours.3 Patients with mean haemoglobin levelsachievement of a haemoglobin response† appeared toof < 11 g/dl were randomised to receive darbepoetin-αbe more rapid in darbepoetin-α, compared withdoses of 4.5–15µg/kg (n = 198) or placebo (51) onceepoetin-α, recipients. Interestingly, the dosing scheduleevery 3 weeks, or darbepoetin-α doses of 9–18 µg/kgin which the maintenance dose was administered every(125) or placebo (31) once every 4 weeks.2 weeks had comparable efficacy to those in which

Haematopoetic response‡ rates were as much as 70%darbepoetin-α was administered weekly. The use ofhigher in patients receiving darbepoetin-α, comparedloading doses of darbepoetin-α, followed by reducedwith placebo, and the proportion of patients requiringdosages for maintenance therapy, ‘may decrease thered blood cell transfusions was reduced [see table 3].time to response and increase the proportion ofDarbepoetin-α was well tolerated, with no relationship[patients] responding to therapy relative to currentobserved between the incidence of adverse events andstandard therapy’, said the researchers.dosage. There was no evidence of the development of

Better QOL than epoetin-α antibodies to darbepoetin-α.Greater increases in QOL domain scores for fatigue

Potential for simultaneous treatmentand physical and functional well-being were reported at‘The results suggest that darbepoetin alfa can be safely4, 8 and 12 weeks in darbepoetin-α, compared with

and effectively administered very infrequently comparedepoetin-α, recipients [see table 2]. Of note,with [recombinant human erythropoetin] allowing forimprovements in FACT-Fatigue scores, relative toonce per cycle dosing in patients receivingbaseline, were greater in darbepoetin-α, compared withchemotherapy, concluded the researchers.epoetin-α, recipients at all time points between weeks 2Chemotherapy is often administered at 3-week or

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Darbepoetin-alfa: efficacy in chemotherapy-induced anaemia –continued

4-week intervals, and the researchers suggested thatTable 3. Improvement in haemoglobin levelssimultaneous dosing of anaemia therapy could benefitaccording to therapy and frequency ofpatients by reducing the number of office visits andadministrationinjections required.

3-weekly 4-weeklyadministration administration

Table 1. Improvement in haemoglobin levelsPlacebo Darbepoetin- Placebo Darbepoetin-according to therapy(n = 51) α (n = (n = 31) α (n =

Darbepoetin- Epoetin-α 198) 125)α (n = (n = 30)

Haematopoetic 31 51–71 16 49–7392)response

Haemoglobin response* (% of patients) (% ofpatients)by week 26 20

Transfusion 46 19–30 36 20–354rateby week 61 49during12weeks

Mean change in haemoglobin levels 5–12 (%relative to baseline (g/dl) of

patients)by week + 0.71 + 0.39Mean + 0.1 + 0.6–2.6 + 0.09 +4change in 0.39–1.23by week + 1.34 + 1.03haemoglobin12levels (g/

*Haemoglobin response = increase in haemoglobin levels, relative to dl)baseline, of ≥ 2 g/dl in the absence of a red blood cell transfusion.

* Patients had no signs of iron, folate or vitamin B12 deficiency, andhad not received epoetin-α or > 2 red blood cell transfusions within 8

Table 2. Improvement in quality of life (QOL) and 4 weeks before randomisation, respectively.according to therapy ** The FACT-Anemia assessment consists of fatigue, functional,

physical, emotional and social/family well-being scores.Darbepoetin- Epoetin-α† Haemoglobin response was defined as an increase of ≥ 2 g/dl inαhaemoglobin levels, relative to baseline, in the absence of a red blood

Mean change in FACT*-Fatigue score cell transfusion.relative to baseline:

‡ Haematopoetic response was defined as an increase of ≥ 2 g/dl inweek 4 + 3.8 + 1.7 haemoglobin levels, relative to baseline, or an increase in haemoglobin

levels to ≥ 12 g/dl without a red blood cell transfusion.week 12 + 6 – 1.1Mean change in FACT-Physical well- 1. Glaspy JA, et al. Optimizing the management of anemia in patients with cancer:being score relative to baseline: a randomized, active-controlled study investigating the dosing of darbepoetin

alfa. 38th Annual Meeting of the American Society of Clinical Oncology 21:week 4 + 1.5 + 0.5 362 (plus poster), Part 1, 18 May 2002.

2. Kallich J, et al. Darbepoetin alfa has higher observed improvements in fatigueweek 12 + 3.1 – 1.7and physical well-being than epoetin alfa. 38th Annual Meeting of the AmericanMean change in FACT-Functional well- Society of Clinical Oncology 21: 367 (plus poster), Part 1, 18 May 2002.

being score relative to baseline: 3. Kotasek D, et al. Randomized, double-blind, placebo-controlled, dose-findingstudy of darbepoetin alfa administered once every 3 or 4 weeks in patients withweek 8 + 1.4 – 2solid tumors. 38th Annual Meeting of the American Society of Clinical

week 12 + 0.9 – 1.4 Oncology 21: 356 (plus oral presentation), Part 1, 18 May 2002.800888373

*FACT = Functional Assessment of Cancer Therapy

» Editorial comment: Darbepoetin-α [Amgen; MegaPharm;Kirin-Amgen] is a new erythropoietic agent with a longer serumhalf-life than recombinant human erythropoetin resulting fromintroduced changes in the amino acid sequence that confergreater stability. Darbepoetin-α was approved for use in thetreatment of anaemia in patients receiving chemotherapy fornonmyeloid malignancies in the US in July 2002; the Committeefor Proprietary Medicinal Products (CPMP) recommended inJune 2002 that it be approved for this indication in the EU.Darbepoetin-α has already been approved for use in thetreatment of anaemia in patients with chronic renal failure in theEU and the US.

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