MIRCERA^® Clinical Data

Clinical Studies in Adult Patients*¹

The efficacy and safety of MIRCERA^® in adult patients were assessed in 7 open-label, multicenter clinical studies that randomized patients to either MIRCERA^® or a comparator ESA.

Three studies evaluated anemic patients with CKD who were not treated with an ESA at baseline, and four studies evaluated patients who were receiving an ESA for treatment of the anemia of CKD. In all studies, patients were assessed as clinically stable at baseline and without evidence of infection or inflammation as determined by history and laboratory data, including C-reactive protein (CRP) (CRP ≤ 15 mg/L for the ARCTOS study and CRP ≤ 30 mg/L for the remaining studies). A CRP value above the threshold led to the exclusion of no more than 3% of the screened patients.

*Note: At the time of the studies, higher hemoglobin targets were recommended compared to current clinical guidelines and MIRCERA^® Prescribing Information.

Patients Not Currently Treated with an ESA

In the ARCTOS (Administration of C.E.R.A. in CKD patients to treat anemia with a Twice-mOnthly Schedule) study, patients not on dialysis were randomized to MIRCERA^® or darbepoetin alfa for 28 weeks. The starting dose of MIRCERA^® was 0.6 mcg/kg administered subcutaneously once every 2 weeks and the starting dose of darbepoetin alfa was 0.45 mcg/kg administered subcutaneously once a week.²

In the AMICUS (C.E.R.A. adMinistered Intravenously for anemia Correction and sUStained maintenance in dialysis) study, patients on hemodialysis or peritoneal dialysis were randomized to MIRCERA^® or another ESA (epoetin alfa or epoetin beta) for 24 weeks. The starting dose of MIRCERA^® was 0.4 mcg/kg administered intravenously once every 2 weeks and the starting dose of the comparator was administered intravenously 3 times a week, consistent with the product’s recommended dose.³

In these studies, the observed median dose of MIRCERA^® once every 2 weeks over the course of the correction/evaluation period was 0.6 mcg/kg.

The primary endpoints of these studies were:

• ARCTOS: Hemoglobin level response rate during correction and evaluation period and difference in mean change in hemoglobin concentration between baseline and evaluation period.
• AMICUS: Hemoglobin level response rate during correction period.

In both studies, response rate was defined as an increase in hemoglobin level of at least 1 g/dL versus baseline and to a hemoglobin level of at least 11 g/dL without blood transfusion during the correction and evaluation period in the intent-to-treat (ITT) population. Hemoglobin levels were to be maintained within the range of 11 to 13 g/dL.

Phase III Clinical Studies in Patients Not Currently Treated with an ESA^1,2,3

*Primary endpoint: Hemoglobin level response rate (hemoglobin increase of at least 1 g/dL and to a level of at least 11 g/dL without RBC transfusion) in ITT population. Hemoglobin levels were to be maintained within the range of 11 to 13 g/dL.

ND-CKD = non-dialysis chronic kidney disease, RBC = red blood cell, CI = confidence interval

ARCTOS: MIRCERA^® administered subcutaneously once every two weeks has been proven to correct anemia in ESA-naive patients who are not on dialysis.²

Mean Monthly Hemoglobin Concentrations (in the ITT population)

Secondary endpoint: Mean hemoglobin concentration during the correction and evaluation period in ITT population.

QW = once every week, Q2W = once every 2 weeks, SD = standard deviation, Hb = hemoglobin, BL = baseline, ITT population = intent-to-treat population

AMICUS: MIRCERA^® administered intravenously once every two weeks was shown to be safe and effective as three-times-weekly epoetin for correcting anemia in ESA-naive dialysis patients.³

Mean Monthly Hemoglobin Concentrations (in the ITT population)

Secondary endpoint: Mean hemoglobin concentration during the correction period in ITT population.

Q2W = once every 2 weeks, TIW = 3 times weekly, SD = standard deviation, Hb = hemoglobin, BL = baseline, ITT population = intent-to-treat population

In the CORDATUS trial (The Correction of Renal Anaemia in CKD Patients with Subcutaneous Therapy) a randomized controlled study in patients with CKD not on dialysis and not currently treated with an ESA, MIRCERA®, administered once monthly, was compared to darbepoetin alfa administered every week or every two weeks. Both treatment groups achieved statistically significant hemoglobin response rate when compared with predefined response rate target of 60% [MIRCERA®: 94%, CI: (89%, 97%), p<0.0001; darbepoetin alfa: 94%, CI: (88%, 97%), p<0.0001]. MIRCERA® was non-inferior to the darbepoetin alfa for the mean change of the baseline-adjusted Hb based on the protocol-pre-specified non-inferiority margin of -0.75 g/dl [MIRCERA®: 1.62 g/dL; darbepoetin alfa: 1.66 g/dL; difference: -0.036 g/dL with a two-sided 95% CI: (-0.252, 0.180)].⁴

CORDATUS: MIRCERA^® administered once monthly in ESA-naive patients who were not on dialysis was non-inferior to darbepoetin alfa administered every week or every two weeks.⁴ 

MIRCERA^® and Darbepoetin Alfa Response Rates

*Response rate: defined as % of patients achieving response where response defined as increase in Hb ≥1 g/dL compared with baseline and Hb concentration ≥10 g/dL. Lower limit of 95% confidence interval (CI 95%) for Mircera® response rate to be >60%           
 

CI = confidence interval, ESA = erythropoiesis-stimulating agent, Hb = hemoglobin, ITT = intent-to-treat, ND-CKD = non-dialysis chronic kidney disease, QW = once weekly, Q2W = once every 2 weeks, Q4W = once every 4 weeks, SC = subcutaneously 

Patients Currently Treated with an ESA

Four studies assessed the ability of MIRCERA^® to maintain hemoglobin levels among patients currently treated with other ESAs. Patients were randomized to receive MIRCERA^® either once every 2 weeks or once every 4 weeks, or to continue their current ESA dose and schedule.

At the time of the studies, higher hemoglobin targets were recommended compared to current clinical guidelines and the MIRCERA^® Prescribing Information.

The initial MIRCERA^® dose was determined based on the patient’s previous weekly ESA dose. Treatment with MIRCERA^® once every 2 weeks and once every 4 weeks maintained hemoglobin levels within the targeted hemoglobin range (10-13.5 g/dL).¹

In the MAXIMA (Maintenance of hAemoglobin eXcels with IV adMinistration of C.E.R.A.) study, the observed median doses of MIRCERA^® were 57 mcg once every 2 weeks and 175 mcg once every 4 weeks during the assessment period and the rest of the study.⁵

In the PROTOS (Patients Receiving C.E.R.A. Once a month for the mainTenance Of Stable haemoglobin) study, the MIRCERA^® median doses over the evaluation period and the rest of the study were 56 mcg once every 2 weeks and 150 mcg once every 4 weeks. In this study, MIRCERA^® was administered subcutaneously.⁶

The primary endpoint in these trials was a mean change in hemoglobin level between baseline and evaluation period.

Phase III Clinical Studies in Patients Currently Treated with an ESA^1,5,6

Primary endpoint: Mean change in hemoglobin level between baseline and evaluation period.

This analysis is from the per-protocol (primary analysis) population; numbers indicate total patients randomized.

*MIRCERA^® versus comparator mean hemoglobin difference in the evaluation period.

CI = confidence interval, n/a = not applicable

MAXIMA: MIRCERA^® was found to be as safe as conventional epoetin treatment given three times a week, while maintaining hemoglobin levels in dialysis patients when given intravenously once per month.⁵

Mean Monthly Hemoglobin Concentrations (in the ITT population)

QW = once every week, Q2W = once every 2 weeks, Q4W = once every 4 weeks, TIW = 3 times weekly, SD = standard deviation, Hb = hemoglobin,                            
BL = baseline, ITT population = intent-to-treat population

PROTOS: MIRCERA^® administered subcutaneously every two weeks or once monthly successfully maintained stable Hb levels in dialysis patients converted from epoetin administered once to three times a week.⁶

Mean Monthly Hemoglobin Concentrations (in the ITT population)

QW = once every week, Q2W = once every 2 weeks, Q4W = once every 4 weeks, TIW = 3 times weekly, SD = standard deviation, Hb = hemoglobin, BL=baseline, ITT population=intent-to-treat population

In the STRIATA (Stabilizing haemoglobin TaRgets in dialysis following IV C.E.R.A. Treatment of Anaemia) study, the median dose of MIRCERA^® was 0.35 mcg/kg/week during the evaluation period and the rest of the study.⁷

In the RUBRA (TaRgeting sUstained haemogloBin in dialysis with IV and SC C.E.R.A. Administration) study, the MIRCERA^® median dose was 60 mcg once every 2 weeks during the evaluation period.⁸

The primary endpoint in these trials was a mean change in hemoglobin level between baseline and evaluation period.

Phase III Clinical Studies in Patients Currently Treated with an ESA^1,7,8

Primary endpoint: Mean change in hemoglobin between baseline and the evaluation period.

This analysis is from the per-protocol (primary analysis) population; numbers indicate total patients randomized.

*MIRCERA^® versus comparator mean hemoglobin difference in the evaluation period.

CI = confidence interval, n/a = not applicable

STRIATA: MIRCERA^® administered intravenously every two weeks successfully maintained hemoglobin levels in patients on dialysis directly converted from darbepoetin alfa administered once weekly or every two weeks.⁷

Mean Monthly Hemoglobin Concentrations (in the ITT population)

QW = once every week, Q2W = once every 2 weeks, SD = standard deviation, Hb = hemoglobin, BL = baseline, ITT population = intent-to-treat population

RUBRA: MIRCERA^® administered every two weeks effectively maintained stable control of hemoglobin in dialysis patients who were converted from epoetin given once to three times a week.⁸

Mean Monthly Hemoglobin Concentrations (in the ITT population)

QW = once every week, Q2W = once every 2 weeks, TIW = three times weekly, SD = standard deviation, Hb = hemoglobin, BL = baseline,                            
ITT population = intent-to-treat population

Clinical Studies in Pediatric Patients^1,9

DOLPHIN (The Dose Finding Trial of Pediatrics on Hemodialysis in Nephrology) trial, an open-label, multiple dose, multicenter, dose-finding pediatric study was conducted to determine the dose of intravenous MIRCERA^® when converting from treatment with another ESA (epoetin alfa/beta or darbepoetin alfa).⁹

The study was conducted in 64 pediatric patients with CKD who were on hemodialysis and who had stable hemoglobin (Hb) levels while previously receiving another ESA.

MIRCERA^® was administered intravenously once every 4 weeks for 20 weeks. After the first administration of MIRCERA^®, dosage adjustments were permitted to maintain target hemoglobin levels.

Efficacy:

• Was established based on the change in hemoglobin concentration (g/dL) between the baseline and evaluation period. Of the two conversion factors studied, the recommended conversion factor for MIRCERA^® was confirmed based on patients maintaining hemoglobin within target levels.
• Among the 48 patients who received MIRCERA^® dosed using the recommended conversion factor, 9 patients withdrew due to renal transplant, 2 patients withdrew due to administrative reasons, 1 died, and 1 patient refused treatment. One of the 13 patients who withdrew from the study entered the evaluation period (weeks 17-21).
• For the 36 patients who entered the evaluation period and received the dose of MIRCERA^® calculated using the recommended conversion factor, the mean change in hemoglobin concentration from baseline between the baseline and the evaluation period was -0.15 g/dL with 95% CI (-0.49 to 0.2).
• Supportive efficacy results in the group treated with MIRCERA^® using the recommended conversion factor demonstrated that 75% of patients maintained hemoglobin values within ±1 g/dL of baseline and 81% maintained hemoglobin values within 10 to 12 g/dL during the evaluation period. Seventy-seven percent (77%) of patients had a dose adjustment (either a dose decrease, increase or both).

SKIPPER (Ascertain the Optimal Starting Dose of Mircera Given Subcutaneously for Maintenance Treatment of Anemia in Pediatric Patients With Chronic Kidney Disease on Dialysis or Not Yet on Dialysis) trial, a second open-label, single-arm, multicenter study was performed to ascertain the optimal starting dose of MIRCERA^® administered subcutaneously for the maintenance treatment of anemia in pediatric patients with CKD on dialysis, or not on dialysis when switching from stable subcutaneous (SC) treatment with epoetin alfa, epoetin beta or darbepoetin alfa.

The mean age of patients was 10 years (age range: 4 months to 17 years); 30 % were less than 5 years of age, 27.5% were 5 to 11 years of age, and 42.5% were 12 years of age or older.

The starting dose of MIRCERA^® was based on the conversion factors obtained from the intravenous dose-finding study. MIRCERA^® was administered SC once every 4 weeks for 20 weeks.

Efficacy:

• Once again, efficacy was established based on the change in Hb concentration (g/dL) between the baseline and evaluation periods. The study confirmed that the conversion factors are appropriate.
• Among the 40 patients who received MIRCERA^®, 2 patients (5%) discontinued during the evaluation period. The reasons for discontinuation from the evaluation period were kidney transplant and use of prohibited medication. An additional 4 patients discontinued from the extension period due to kidney transplant.
• For the 38 patients who had Hb concentration data available during the evaluation period (Weeks 17-21), the mean change in Hb concentration between the baseline and the evaluation period was 0.48 g/dL with 95% CI (0.15, 0.82).
• Supportive efficacy results demonstrated that 50% of patients maintained Hb values within ± 1 g/dL of baseline and 63% maintained Hb values within 10 to 12 g/dL during the evaluation period. Dose adjustments (either a dose decrease, increase or both) were reported in 85% of patients.

The efficacy and safety of MIRCERA^® have not been established in pediatric patients of any age whose hemoglobin level has not been previously stabilized by treatment with an ESA.

The adverse reaction profile observed in pediatric patients was consistent with the safety profile found in adults.

• All reported adverse reactions regardless of causality (more than 5% incidence) in the pediatric population included headache (22%), nasopharyngitis (22%), hypertension (19%), vomiting (11%), bronchitis (9%), abdominal pain (8%), arteriovenous fistula thrombosis (6%), cough (6%), device related infection (6%), hyperkalemia (6%), pharyngitis (6%), pyrexia (6%), thrombocytopenia (6%), and thrombosis in device (6%).

For more information, please see the full Prescribing Information, including Boxed WARNING, and Medication Guide (English, Español) for MIRCERA^®.