Safety and tolerability of prescribed usage of Derise® (Darbepoetin Alfa, Hetero) in symptomatic anemia: A Post Marketing Surveillance Study


 Background This post marketing surveillance, observational, prospective, safety study evaluated the safety, tolerability and long term immunogenicity of prescribed usage of Darbepoetin alfa, (DA-α, manufactured by Hetero Biopharma) in Indian patients with chronic kidney disease with anemia.Methods All patients with anemia of chronic kidney disease prescribed Hetero-Darbepoetin were the target patient population. The present study gathered the data from 503 Hetero-Darbepoetin alfa prescribed patients. This study collected information of patient demography, patient's medical history, concomitant medications, action taken with respect to Hetero-Darbepoetin-alfa, AE details (AE term, start date, stop date, severity, action taken, outcome and causality), periodic Hemoglobin (Hb) levels and abnormal laboratory tests results until treatment is discontinued or the patient is lost to follow-up. Immunogenicity data was collected in 121 patients at the end of treatment and after 1 year. Statistical analyses were performed to explore and analyze details of individual case safety reports of adverse events such as incidence, severity, seriousness, outcome, duration, action taken, and causality relationship of individual adverse event (AE) to the prescribed study drug. Results 87 AEs were reported in this study and most of them were mild to moderate in intensity. No deaths or serious adverse events (SAEs) were reported in this study. Anti-drug antibodies were not detected in any subject at the end of treatment phase and after 12 months long term follow up period. Baseline mean Hemoglobin value was 8.34 (SD 1.24) g/dL and last visit mean Hemoglobin value was 10.42 (SD 1.28) g/dL. The mean difference between baseline and last visit was 2.10 [2.00, 2.20], statistically significant (p-value <.0001). Conclusions The safety and tolerability of the usage of DA-α (manufactured by Hetero Biopharma) is similar to that reported in the published literature of the innovator. No patients showed anti-drug antibodies after treatment. Additionally, the patients also showed significant improvement in hemoglobin levels, compared to baseline.Clinical Trial Registry Number: CTRI/2017/04/008338 [Registered on CTRI http://ctri.nic.in/Clinicaltrials/login.php : 12/04/2017]; Trial Registered Retrospectively

Hetero Biopharma Ltd. has developed Darbepoetin Alfa which in this post marketing surveillance study showed that it is safe for the treatment of symptomatic anemia in patients with chronic kidney disease.

Background
The primary cause of renal anemia in chronic kidney disease (CKD) is the de ciency of endogenous erythropoietin mainly produced by kidneys. 1 Progression of renal anemia not only increases the risk of cardiovascular (CV) disease, but also is an independent risk factor for the deterioration of renal function, causing the vicious cycle known as cardio-renal anemia syndrome. 2 Erythropoietin alfa is the standard of care for treatment of anemia related to CKD undergoing dialysis and not on dialysis. Darbepoetin alfa has similar mechanism for erythropoiesis as native & recombinant human erythropoietin (rHuEPO). Darbepoetin alfa proven to achieve signi cant reductions in RBC transfusion requirements and clinically relevant improvements in fatigue and other patient-reported outcomes. Darbepoetin alfa has 3-fold longer elimination half-life and decreased clearance compared to erythropoietin alfa. This ensures a comparatively reduced number of (Darbepoetin alfa) injections in treatment of anemia in CKD patients.
Hetero conducted Phase-III interventional clinical studies with Darbepoetin alfa (DA-α, manufactured by Hetero Biopharma) for obtaining manufacturing authorization in India. This study showed e cacy and safety in improving anemia associated with CKD undergoing dialysis and those not on dialysis( CTRI/2012/07/002835) who were administered DA-α for a period of 12-24 weeks. 3,4 The current study was subsequently conducted as an observational, prospective post-marketing surveillance study as per the local regulatory requirements to collect real world safety and long term immunogenicity data in prescriber setting.

Study Design
This was an observational, multicenter, prospective, non-interventional post-marketing surveillance study performed at nine centers across India between 21 Jun 2016 ( initiation) to 07 Sep 2018 ( termination) to evaluate the safety, tolerability and long term immunogenicity of DA-α (manufactured by Hetero Biopharma) in daily medical practice conditions. A total of 503 patients were included in this study to evaluate the safety, tolerability and long term immunogenicity of DA-α in prescribed settings. Data collection included patient demography, patient's medical history, concomitant medications, action taken with respect to DA-α, AE details, periodic Hb levels and abnormal laboratory tests results. DA-α was dosed either 0.45 mcg/kg once weekly (QW) or 0.75 mcg/kg once every 2 weeks (Q2W) or 1.5 mcg/kg once monthly, as per regulatory approval and as mentioned in the approved prescribing information. If the increase in Hb was less than 1 g/dL in four weeks, the dose was increased by 25%. If the rise in Hb is greater than 2 g/dL in four weeks, the dose was reduced by 25%. If the Hb exceeds 12 g/dL, a dose reduction was considered. If the Hb continued to increase, the dose was reduced by 25%. If after a dose reduction, Hb continued to increase, the dose was temporarily withheld until the Hb begins to decrease, with reinitiated at 25% lower than the previous dose. Safety, tolerability and immunogenicity data was recorded in the approved post-marketing surveillance (PMS) forms.
This study was conducted in accordance with the ethical guidelines outlined in the Declaration of Helsinki, 1964 as revised in 2013, Post Authorization Safety Studies (Post Marketing Surveillance study, (PMS)), as per the guidelines of Schedule Y (amended Drug &Cosmetic Act 2013), and Guidelines for Similar Biologics 2012, India along with subsequent amendments and Indian regulatory laws governing biomedical research in human patients. The study was approved by the Drugs Controller General, India (DCGI), CDSCO and subsequently registered with clinical trial registry (CTRI/2017/04/008338) retrospectively. Institutional ethics committee approvals were obtained from each participating study center before initiating the study.

Participants
In this study, patients of either gender with CKD suffering from renal anemia prescribed and administered DA-α (manufactured by Hetero Biopharma) as per the prescribing information were enrolled. Patients with clinical history/ evidence of allergy/ hypersensitivity to components of Hetero-Darbepoetin alfa, receiving hormonal agents, therapeutic biologic products, or radiotherapy unless receiving concomitant myelosuppressive chemotherapy were not included as per the prescribing information contraindications.

Study Assessments
Adverse events and immunogenicity were assessed during the study. Adverse events were evaluated based on their expectedness, seriousness, incidence, severity, outcome, duration, action taken and causality. Immunogenicity was evaluated by assessing serum for the presence of anti-darbepoetin alfa antibodies at baseline, end of treatment (up to 24 weeks) and long term follow up after 12 months. Immunogenicity samples were stored in the freezer at -65±10°C. Anti-darbepoetin alfa antibodies in human serum were detected by acid dissociation bridging ELISA. Samples with absorbance value (OD) less than the cut point was considered negative for anti-drug antibody. Sample with OD equal to or above the cut point was to be considered positive. As a routine, the Hb levels were monitored during the study.

Statistical analysis
This study was planned to include 500 patients prescribed DA-α for anemia associated with chronic kidney disease during the routine clinical practice in India. Baseline summary statistics, including mean, median and standard deviation for age, weight, and proportion of males/females to be provided by treatment group. The variables measured on continuous scale compared using t-test and the proportion of males/females compared using Fisher's exact test. Adverse events (AEs) were summarized by system organ class (SOC) and by preferred terms using the Medical Dictionary for Regulatory Activities Terminology (MedDRA v21). The AE severities were graded by using Common Terminology Criteria for Adverse Events, CTCAE (v4). The causality was assessed by using WHO-UMC causality assessment system. All statistical analysis was performed using SAS® Version 9.4 (SAS Institute Inc., NC, USA).

Patient characteristics
A total of 503 patients post marketing data was included in this study ( Table 1). Of these, 121 patients were also evaluated for immunogenicity at the end of treatment and after one year for long term immunogenicity.

Immunogenicity Analysis
Out of 503 patients, 121 patients agreed for immunogenicity assessment during the treatment and after long term follow up of 12 months. Out of 121 patients, 111 patients had baseline and end of treatment immunogenicity data and 102 patients had baseline, end of treatment and long term immunogenicity data after 12 months. No anti -darbepoetin alfa antibodies were detected in this population of patients receiving DA-α at the end of treatment and after 12 months of follow up period.

Bene cial Effects
The mean Hb levels improved from 8.34 (SD 1.24) g/dL at baseline to 10.42 (SD 1.28) g/dL at the end of the treatment (Fig:1). The change in mean Hb levels from baseline to end of treatment was statistically signi cant [ 2.10 g/dL (95% CI 2.00, 2.20); p= <.0001].

Discussion
Darbepoetin alfa (DA-α manufactured by Hetero Biopharma) is the long-acting ESA with less frequent dosing intervals compared to epoetins alfa and beta. This study was conducted to evaluate the safety, tolerability and long term immunogenicity of DA-α (manufactured by Hetero Biopharma) in treatment of anemia associated with chronic kidney disease in real world prescriber setting. Overall, 17.3% patients reported AEs in this study which is lesser than the phase III study reported AEs (39.7% in dialysis and 25.8% in pre-dialysis) conducted in CKD patients. 4,4 The AEs reported in various SOCs are lesser than the pre-approval studies by DA-α in CKD patients.
Respiratory, thoracic and mediastinal disorders (1.8% vs 14.3%) and General disorders and administration site conditions (3.8% vs 12.7%) SOCs reported lesser AEs than the pre-approval studies. 16 Similarly the most commonly reported AEs like headache (5% vs 9.5%) and pyrexia (2.6% vs 4.8%) reported less frequently in this study compared to previous studies. The concernregarding development of antibodies against darbepoetin leading to loss of its effectiveness ruled out by negative antibodies at the end of treatment and after 1 year. 5 Patients who were treated with DA-α (manufactured by Hetero Biopharma) could effectively maintain their Hb levels in the target therapeutic ranges during the treatment period and one year follow up. The AEs reported in this study were lesser than the popular DREAM-J surveillance study of long-term use of darbepoetin alfa in nondialysis patients with chronic kidney disease. DREAM-J study reported 44.4% AEs. 6 This post marketing surveillance study results suggests that there is no apparent risk for life threatening or serious adverse events under clinical conditions where DA-α (manufactured by Hetero Biopharma) is prescribed for the management of anemia associated with chronic kidney disease.

Conclusion
Our study results demonstrate that DA-α (manufactured by Hetero Biopharma) is safe and tolerable in treating patients with anemia associated with chronic kidney disease with signi cant improvement in hemoglobin levels. This data provides a trend of its safety pro le and e cacy in real world scenario of prescribed settings and is consistent with the phase-III study and published literature. 7

Declarations
Ethics approval and consent to participate The study was conducted in accordance with the ethical guidelines outlined in the Declaration of Helsinki, 1964 as revised in 2013, Schedule Y along with subsequent amendments and Indian regulatory laws governing biomedical research in human patients. Institutional ethics committee approval was obtained from each participating study center before initiating the study. The study was an observational, non-interventional post marketing surveillance (PMS) study based on prescribed usage of the darbepoetin alpha in patients having diseases as per approved indications. As per the applicable regulatory guidelines, written informed consent is not mandatory to be obtained from the subjects in who are being prescribed the marketed study drug in these studies. However, for the purpose of good documentation practices & upholding the ethics considerations, written informed consent was obtained from each subject before enrolling them into the study. The study was registered with the clinical trial registry (CTRI/2017/04/008338) retrospectively.
Ethics committee name and address CONSORT2010ChecklistP1PMS.pdf