Inpharma 1527 - 4 Mar 2006

Extended dosing darbepoetin-α effective for anaemia– Samantha Crofskey –

Darbepoetin-α [Aranesp], administered every 3 weeks, is an effective treatment for chemotherapy-inducedanaemia, according to results from a phase III trial presented at the 47th Annual Meeting and Exposition of theAmerican Society of Hematology (ASH) [Atlanta, Georgia, US; December 2005]. Darbepoetin-α reduced theneed for RBC transfusions by almost a half, compared with placebo, in patients with non-myeloid malignancies.Furthermore, significantly more darbepoetin-α than placebo recipients achieved target haemoglobin levels of≥ 11 g/dL. An interim analysis of results from a phase II trial showed that 3-weekly dosing of darbepoetin-α iseffective in raising haemoglobin levels and reducing the requirement for RBC transfusions in anaemic patientswith myelodysplastic syndromes (MDS).

Chemotherapy-induced anaemia is a serious, under darbepoetin-α was 24%, compared with 41% in placebodiagnosed and often under-treated condition; it has recipients [see table 1]. The rates of RBC transfusionsbeen estimated that 50% of patients with a haemoglobin from week 1 to EOTP were 30% and 47%, respectively.level less than the recommended target of 11–12 g/dL do Haemoglobin target levels achievednot receive erythropoietin therapy. Significantly more patients receiving darbepoetin-αThe half-life of darbepoetin-α is approximately than placebo achieved the target haemoglobin level of74 hours, which allows it to be administered at extended ≥ 11 g/dL from week 1 to EOTP (77% and 55% ofdosing intervals of up to once every 3 weeks. patients receiving darbepoetin-α and placebo,Administration of darbepoetin-α at 3-weekly intervals respectively) [see table 2].may enable the synchronisation of treatment with In patients receiving darbepoetin-α, haemoglobinchemotherapy, potentially offering patients and their levels rose steadily through approximately week 9, aftercaregivers added convenience. Previous studies of which they remained relatively stable. The median timedarbepoetin-α, administered every 3 weeks, indicate to achieve the target level was significantly shorter inthat it is an effective treatment for chemotherapy- darbepoetin-α recipients, compared with thoseinduced anaemia. The phase III study presented at the receiving placebo (7 weeks and 16 weeks, respectively).ASH meeting was undertaken to provide further After achieving the target, the mean haemoglobinevidence on the efficacy of 3-weekly dosing. levels in patients receiving darbepoetin-α and placeboThis study was the first randomised, double-blind, were 11.5 g/dL and 11 g/dL, respectively; themulticentre, controlled phase III trial to evaluate the proportions of respective patients who maintained theirefficacy and tolerability of darbepoetin-α, administered haemoglobin level within the recommended range ofevery 3 weeks, for the treatment of chemotherapy- 11–13 g/dL were 67% and 52%.induced anaemia.1

To be eligible for inclusion in the study, patients wereTable 2. Achievement and maintenance of targetrequired to have non-myeloid malignancies, a diagnosishaemoglobin levels, according to therapyof anaemia (haemoglobin levels of < 11 g/dL within

24 hours before randomisation), and have at least Placebo Darbepoetin-(n = 193) α (n = 193)12 weeks of planned chemotherapy. The primary

endpoint of the study was the proportion of patients Achievement of target haemoglobin levels:who received RBC transfusions from week 5 to the end Levels of ≥ 11 g/dL from week 1 55 77of the treatment phase (EOTP). to EOTP (% of patients)

Median time to target levels 16 7Reduced incidence of RBC transfusions(weeks)

A total of 386 anaemic patients received treatment Mean levels after achieving target 11 11.5with darbepoetin-α 300µg (n = 193) or placebo, every (g/dL)three weeks, for 16 weeks. Maintenance of levels after achieving target (% of patients):

At baseline, patients had a mean haemoglobin level of < 11 g/dL 48 2910 g/dL; the most common tumour types were breast 11–13 g/dL 52 67(23% of patients), colon/large intestine (11%), non-small > 13 g/dL <1 4cell lung (10%), ovarian and non-Hodgkin’s lymphoma(both 8%).

Safety profile consistentTable 1. Rates of RBC transfusions, according to The number and type of adverse events weretherapy consistent with that observed in previous studies of

darbepoetin-α in patients with chemotherapy-inducedPlacebo Darbepoetin-αanaemia. Darbepoetin-α was well tolerated; no clinically

Received RBC transfusion (% of patients): important differences in the incidence of adverse events,Week 5 to EOTP 41 24* including serious adverse events, were observedWeek 1 to EOTP 47 30** between treatment groups. Furthermore, incidences of* p < 0.001 cardiovascular and thromboembolic events were** p < 0.005 infrequent in both treatment arms, and were not

associated with increases in haemoglobin levels. Nopatients developed neutralising antibodies toDarbepoetin-α significantly reduced the need for RBCdarbepoetin-α.transfusions by almost a half; from week 5 to EOTP, the

"These results on every-three-week dosing offrequency of RBC transfusions in patients receiving

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Extended dosing darbepoetin-α effective for anaemia – continued[darbepoetin-α] are encouraging", commented Dr Kerry The mean change from baseline in haemoglobin levelsTaylor from Mater Hospital, Brisbane, Queensland, was greater in patients who were treatment-naiveAustralia. "If approved, this extended dosing of (+1.3 g/dL vs +0.5 g/dL in treatment-experienced[darbepoetin-α] may allow physicians to treat anemia on patients). Similarly, the mean change from baseline inthe same schedule as chemotherapy, which is frequently FACT-F scores was higher in the treatment-naive groupadministered every three weeks. This may reduce the than in the treatment-experienced group (+6.2 andnumber of visits patients and their caregivers need to +1.8, respectively).*make to the clinic."

Table 3. Clinical outcomes, according to priorEncouraging results in MDS. . .erythropoietin exposureIn patients with MDS, the majority will develop

clinically significant anaemia during the course of their Darbepoetin-αdisease. Importantly, no recombinant erythropoietins

Treatment- Treatment-have been approved for the treatment of anaemia in naive experiencedMDS patients.

Erythroid-response at week 13 (% of patients):Interim results from an ongoing, open-label, phase IIMajor response 49 24trial evaluating the efficacy and tolerability ofMinor response 21 20darbepoetin-α for the treatment of anaemia inRBC transfusion received (% of patients):209 patients with MDS were presented at the ASHWeeks 1–13 19 29meeting.2

Weeks 5–13 17 26To be eligible for inclusion in the study, patients wereAchievement of target haemoglobin levels:required to have low or intermediate-1 risk MDS, a

haemoglobin level of ≤ 11 g/dL, and French-American- Levels of ≥ 11 g/dL during 67 45weeks 1–13 (% of patients)British classification of refractory anaemia, refractory

Mean haemoglobin levels after 11.8 11.7anaemia with ringed sideroblasts, or refractory anaemiaachieving target (g/dL)with excess blasts. Patients were stratified according to

Mean changes from baseline in 1.3 0.5prior erythropoietin use, and received treatment withhaemoglobin levels at week 13darbepoetin-α 500µg, administered every 3 weeks, for (g/dL)

up to 52 weeks. Maintenance of levels after achieving target (% of patients):The primary endpoint was the proportion of patients

< 11 g/dL 13 19achieving an erythroid response according to11–13 g/dL 80 77International Working Group criteria during the> 13 g/dL 7 413-week test period. Data from 189 patients who have

completed the 13-week test period were presented inFewer treatment-naive than treatment-experiencedthe interim analysis.

patients required a RBC transfusion; the proportions ofAt baseline, the mean haemoglobin levels inpatients receiving an RBC transfusion duringtreatment-naive (n = 130) and treatment-experiencedweeks 1–13 were 19% and 29%, respectively.(59) patients were 9.8 g/dL and 9.9 g/dL, respectively.Corresponding rates of RBC transfusions duringCorresponding values for median endogenousweeks 5–13 were 17% and 26%.erythropoietin levels in these subgroups were

63 mU/mL and 57 mU/mL. Mean Functional Assessment . . . and well toleratedof Cancer Therapy-Fatigue (FACT-F) scores were 29.6 During the 13-week test period, 6% of patientsand 31.4 in treatment-naive and treatment-experienced reported a treatment-related adverse event. One patientpatients, respectively. experienced hypertension, which was considered to be

During the 13-week test period, 49% of treatment- a serious treatment-related adverse event. Nonaive and 24% of treatment-experienced patients thrombotic adverse events have been reported in theachieved a major erythroid response. Corresponding study to date.values for patients achieving a minor erythroid response

* A change of at least 3 points in the FACT-F score is consideredwere 21% and 20% [see table 3].clinically significant.Target haemoglobin levels of ≥ 11 g/dL were achieved1. Taylor K, et al. Randomized, double-blind, placebo-controlled study ofby 67% of treatment-naive and 45% of treatment-

darbepoetin alfa every 3 weeks for the treatment of chemotherapy-inducedexperienced patients. After achieving the target, the anemia. Blood 106: 992 (plus poster) abstr. 3556, No. 11, Part 1, 16 Nov 2005.2. Gabrilove J, et al. A phase 2, single-arm, open-label trial to evaluate themean haemoglobin levels in these respective patients

effectiveness of darbepoetin alfa for the treatment of anemia in patients withwere 11.8 g/dL and 11.7 g/dL; the correspondinglow-risk myelodysplastic syndrome. Blood 106: 714 (plus poster) abstr. 2541,

proportions of patients that maintained their levels No. 11, Part 1, 16 Nov 2005.800999546within the recommended range of 11–13 g/dL were 80%

and 77%.

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